Datasets:
TaylorAI
/
pubmed_other

Dataset card Data Studio Files
xet
Community
file
stringlengths
27
28
text
stringlengths
1
5.17M
PMC007xxxxxx/PMC7387285.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)32300-8 10.1016/j.jaad.2020.07.099 JAAD Online Androgenetic alopecia in COVID-19: Compared to age-matched epidemiologic studies and hospital outcomes with or without the Gabrin sign Wambier Carlos Gustavo MD, PhD a∗ Vaño-Galván Sergio MD, PhD b McCoy John PhD c Pai Suraj MD d Dhurat Rachita MD, PhD d Goren Andy MD c a Department of Dermatology, Alpert Medical School of Brown University, Providence, Rhode Island b Dermatology Department, Ramón y Cajal Hospital, Madrid, Spain c Applied Biology, Inc, Irvine, California d Department of Dermatology, Lokmanya Tilak Municipal Medical College and Hospital Sion, Mumbai, India ∗ Correspondence to: Carlos Gustavo Wambier, MD, PhD, Department of Dermatology, Rhode Island Hospital, 593 Eddy St, APC building, 10th Floor, Providence, RI 02903 29 7 2020 12 2020 29 7 2020 83 6 e453e454 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Graphical abstract ==== Body pmcTo the Editor: We greatly appreciate the various comments to our original article.1 We also would like to thank dermatologists worldwide who have contributed to the knowledge of COVID-19 and androgenetic alopecia (AGA). Attempts to compare data with other epidemiologic studies are interesting, but caution must be used and attention to detail is required. For example, Nanes2 attempted comparisons using the remote Hamilton scale without converting scores to the current Hamilton-Norwood scale (HNS). Nanes also attempted to compare studies that used scores from dermatologist examination with studies that used self-administered surveys as their methodology.2 Refined comparative analyses were available in the Supplementary Materials of our original article (available via Mendeley at https://dx.doi.org/10.17632/jk63cthxbr.2), which included a disclaimer.1 We would like to motivate other groups to evaluate AGA in their populations, specifically comparing outcomes in COVID-19–positive individuals. For example, our Indian colleagues, in a pilot observational prospective study (raw data available via Mendeley at https://dx.doi.org/10.17632/jdkx76y8fz.1), examined outcomes in admitted patients with COVID-19 by AGA severity. In their cohort of 44 men admitted for severe COVID-19, all patients had clinically significant AGA. However, the most severe outcomes (respiratory failure requiring ventilators or fatal outcomes) happened when HNS was greater than 2. One patient was 45 years old and had no previous comorbidities; he required prolonged intensive care unit stay due to ventilator use and had an HNS score of 3v. Thus, in general terms, we prefer to classify patients with severe AGA (HNS score, 3-7) as having the Gabrin sign (Fig 1 ). This definition of the Gabrin sign is currently being used as an inclusion criterion in a randomized controlled clinical trial for early COVID-19 therapy (NCT04446429).Fig 1 The Gabrin sign. Severe AGA with an HNS score of greater than 3 in the context of COVID-19 infection is associated with worse hospital outcomes. The photograph shows a 37-year-old man hospitalized in Brazil for severe COVID-19, without comorbidities; he required a ventilator for 10 days. The bars depict outcomes of a pilot study performed in India in May 2020 among 44 men who had AGA scored with HNS. The Gabrin sign was associated with worse hospital outcomes (use of ventilator and deaths), Fisher's exact test, P = .014. All men had an HNS score of greater than 1. Only men with the Gabrin sign had worse outcomes (red and black bars). Proportions of worse outcomes increased with higher HNS scores (HNS score of 3-7, 62%; HNS score of 3v-7: 67%; and HNS score of 4-7: 75%). AGA, Androgenetic alopecia; HNS, Hamilton-Norwood scale. A comparison of proportions by age range (50-69 y) and severity of HNS with the Norwood study3 shows an increase of relative proportions for an HNS score of 2 to 7 of 7%, HNS score of 3 to 7 of 26%, and HNS score of 4 to 7 of 33%. This gap becomes particularly obvious when comparing the frequencies of HNS scores of 4 to 7 in the age range of 55 to 69 years (Fig 2 ),4 which is the age group that contains the median age of the 122 men hospitalized with COVID-19.1 Severe AGA in young men also confers increased vulnerability. To further exemplify this, we present in this reply letter one of our unpublished patients from Brazil: a previously healthy 37-year-old physician (HNS score of 5) (depicted in Fig 1) with no previous comorbidities; he required hospitalization for 21 days, which included 16 days in the intensive care unit (ventilator for 10 days and hemodialysis for 5 days).Fig 2 Age-matched comparison of AGA of very severe baldness between the Australian 2003 data (general population) versus the Spanish 2020 data (hospitalized men with severe COVID-19). Patients with COVID-19 showed higher frequencies of very severe baldness at all age groups. The gap significantly increases after 55 years. The majority of patients hospitalized because of severe COVID-19 older than 55 years presented with very severe baldness. Very severe baldness accounted for “frontal and vertex” in the data from Severi et al4 and HNS score of 4 to 7 in the data from Wambier et al.1 More details are available via Mendeley at https://dx.doi.org/10.17632/jk63cthxbr.2. AGA, Androgenetic alopecia. Because vaccines are still not available and the epidemic is affecting men disproportionately, particularly bald individuals, more emphasis could be given to investigations directed at antiandrogen therapies, which are routinely prescribed both for hair loss and benign prostatic hyperplasia as the standard of care (such as dutasteride and finasteride). Finally, severe AGA, (HNS score, 3-7)—the Gabrin sign—is an objective phenotype that reflects individual androgen sensitivity throughout decades of life. AGA is associated with individual vulnerability to severe acute respiratory syndrome coronavirus 2 infection through the androgen gateway.5 It is remarkable that severe outcomes such as the requirement for a ventilator and/or fatalities have occurred in men with this phenotype without other known comorbidities at younger age groups, such as 35 to 45 years. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Wambier C.G. Vaño-Galván S. McCoy J. Androgenetic alopecia present in the majority of hospitalized COVID-19 patients—the “Gabrin sign” J Am Acad Dermatol 83 2020 680 682 32446821 2 Nanes B. Androgenetic alopecia in COVID-19: compared to what? J Am Acad Dermatol 2020 10.1016/j.jaad.2020.06.1031 3 Norwood O.T. Male pattern baldness: classification and incidence South Med J 68 11 1975 1359 1365 1188424 4 Severi G. Sinclair R. Hopper J.L. English D.R. Mccredie M.R.E. Androgenetic alopecia in men aged 40–69 years: prevalence and risk factors Br J Dermatol 149 6 2003 1207 1213 14674898 5 Wambier C.G. Goren A. Vaño-Galván S. Androgen sensitivity gateway to COVID-19 disease severity Drug Dev Res 2020 10.1002/ddr.21688
PMC007xxxxxx/PMC7410012.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)32356-2 10.1016/j.jaad.2020.07.119 JAAD Online Technology Pearl Drop dermoscopy for teledermatology Kaliyadan Feroze MD, DNB, MNAMS, FIMSA, SCE-RCP, FRCP a∗ Jayasree Puravoor MD, DNB b Ashique Karalikkattil T. MBBS, DDVL, PGDHS, FRCP c a Faculty of Dermatology, College of Medicine, King Faisal University, Al Ahsa, Saudi Arabia b Medical Trust Hospital, Cochin, Kerala, India c Amanza Health Care, Perinthalmanna, Kerala, India ∗ Correspondence to: Feroze Kaliyadan, Department of Dermatology, College of Medicine, King Faisal University, Al Ahsa, Saudi Arabia, 61982. 6 8 2020 1 2021 6 8 2020 84 1 e25e26 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Key words dermoscopy imaging teledermatology ==== Body pmcTechnology challenge There has been an explosion in the practice of teledermatology recently because of the COVID-19 pandemic. This includes patient-initiated consultations. One of the main limitations of patient-initiated consultations is the difficulty of incorporating dermoscopy. Solution A drop of clear alcohol-based sanitizer is applied over the lesion to be examined, and the patient (or a helper) takes a photograph of the lesion through the fluid. The fluid reduces the reflection from the surface and helps visualization of the subsurface structures (Figs 1 and 2 ). Any smartphone or point-and-shoot camera is good enough for the imaging, making it easy to transfer the image to the dermatologist. The quality and resolution are better when dedicated cameras with macro mode capabilities are used.Fig 1 A, Melanocytic nevus: clinical image. B, Image taken after applying alcohol solution. Fig 2 A, Small cherry angioma: clinical image. B, Image taken after applying alcohol solution. Blum and Giacomel1 have previously described a concept called tape dermoscopy, in which smartphones are used to take dermoscopic images of skin lesions after the immersion fluid is applied, followed by covering of the area with a transparent adhesive tape. The method we describe is simpler and faster, and it avoids the practical difficulties of having to apply adhesive tape over a liquid surface. The main limitations in our method are the minimal magnification (although the inherent zoom of the capture device can be used) and the reflection of the flash interfering with the image quality. The reflection can be reduced by trying out different angles while taking the image. Although the quality of the dermoscopy is obviously not comparable to that of standard dermoscopes, this can be an easy-to-use, simple screening and triage tool in the context of patient-initiated teledermatology. Funding sources: Supported by a 10.13039/501100004686 Deanship of Scientific Research, King Faisal University , Saudi Arabia (grant/award no. 1811015). Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs Reference 1 Blum A. Giacomel J. “Tape dermatoscopy”: constructing a low-cost dermatoscope using a mobile phone, immersion fluid and transparent adhesive tape Dermatol Pract Concept 5 2 2015 87 93
PMC007xxxxxx/PMC7411418.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)32363-X 10.1016/j.jaad.2020.08.009 Research Letter Patient crowdsourcing of dermatologic consults on a Reddit social media community Chu Brian BS a Fathy Ramie AB a Nobles Alicia L. PhD, MS b Lipoff Jules B. MD c∗ a Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania b Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California c Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania ∗ Correspondence to: Jules B. Lipoff, MD, Department of Dermatology, University of Pennsylvania, Penn Medicine University City, 3737 Market St, Suite 1100, Philadelphia, PA 19104 7 8 2020 7 2021 7 8 2020 85 1 226227 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: Despite patient interest in online consultations, before COVID-19, insufficient reimbursement and infrastructure prevented widespread adoption of telemedicine.1 , 2 In turn, patients are turning to social media to seek diagnoses (called crowd-diagnosis).3 The content of these crowdsourced opinions, specifically in dermatology, has not been studied. We sought to observe dermatologic consultation requests and responses on Reddit. Reddit, the sixth-most popular US website with more than 430 million active users,4 hosts a large forum (r/Dermatology) of more than 20,000 subscribers for medically focused dermatologic discussions.∗ Larger forums exist but focus on cosmetics. Unlike other social media, Reddit is favorable for crowd-diagnosis because of anonymity and lack of character limit. We collected all posts (text and images) on r/Dermatology from its inception (August 2011) through 2019 using Pushshift.io. We randomly selected 160 posts per year from 2016 to 2019 (640 total posts) for qualitative content analysis. Authors BC and RF developed a codebook to identify post and comment attributes (Table I ). Each independently reviewed 320 conversations with 50 overlapping for interrater reliability calculation.Table I Qualitative attributes∗ of the random sample of conversations on r/Dermatology and associated frequencies Attributes (all posts) Percentage of all posts (N = 427) Requested a crowd-diagnosis of their dermatologic condition 84 Included an image(s) of their skin 85 Requested advice on treatment or management of an existing condition 21 Requested a second opinion after having interacted with health care 16 Requested dermatologic advice unrelated to diagnosis or treatment 11 Requested advice on whether to seek professional health care of any kind 4 Attributes (posts seeking crowd-diagnosis) Percentage of posts requesting crowd-diagnosis (n = 360) Received comments from other users 69 Received proposed diagnosis(es) from other users 58 Received advice on treatment or management from other users 29 Received advice to seek professional health care of any kind from other users 24 Attributes (posts seeking crowd-diagnosis that received comments) Percentage of posts seeking crowd-diagnosis that received comments (n = 248) Received comments from commenters self-described as dermatologists 3 Received comments from commenters self-described as nondermatologist physicians <1 Received comments from commenters who specifically self-described as not being physicians 12 Received comments from commenters who did not self-describe their status as physicians 84 ∗ Attributes are not mutually exclusive. A total of 34,153 posts were posted during the study period, growing from 387 in 2012 to 3045 in 2016, 5079 in 2017, 7518 in 2018, and 13,152 in 2019. After excluding deleted/promotional posts from the random 640-post sample, 427 posts remained. Excluding deleted accounts, 99% of posts were made by unique users. Most (84%) posts requested crowd-diagnosis of dermatologic conditions, typically attaching clinical images. Of posts requesting crowd-diagnosis, 15% sought second opinions, explicitly mentioning previous health care visits. Fewer posts requested advice on the treatment of existing conditions (21%) or whether to seek in-person health care (4%). Most (69%) posts received comment(s) (median, 3), including proposed diagnoses, treatment advice, and advice on seeking health care. Of diagnosis-seeking posts with comments, 3% received comments from self-described dermatologists and less than 1% received comments from self-described nondermatologist physicians. No academic, governmental, or patient advocacy groups offering advice were observed. Cohen's κ ranged from 0.73 to 1.0 for attributes, indicating high interrater agreement. Example posts illustrate motivations including access, wait times, and discomfort with providers (Table II ).Table II Example posts and motivations for seeking health information on r/Dermatology∗ Example post Plausible motivation of post “Any idea what this spot is? I've been reading random websites for hours and don't know what's going on. I don't have insurance or a doctor either.” Lack of access to health care “The dermatologist prescribed several ointments for my rash, but one of them isn't covered by my insurance. Do I need to use it even though I'm using the other ones?” Lack of insurance coverage for prescribed medications “I have a bad smell from my penis and it's really itchy too, anything I can do for it? I'm too embarrassed to see a doctor.” Discomfort discussing sensitive topics with physician “I really don't want to visit a dermatologist for these bumps. Most of the doctors I've seen have been rude to me because I'm overweight.” Discomfort with physicians' attitudes toward patients “I know I should trust my physicians, but I looked up skin cancer online and I'm really worried.” Seeking a second opinion after having seen a physician “I called a dermatologist to get this examined, but the next opening isn't for months, and it's with an NP not a physician.” Unreasonable wait times ∗ Posts were edited for anonymity and brevity. Posts may reflect more than 1 motivation. Posts on r/Dermatology show that patients seek information on crowd-diagnoses, treatment, and referrals. The rapid growth suggests burgeoning demand for online medical advice, which may include online medical consultations. Although investment in direct-to-consumer teledermatology indicates industry interest, existing platforms mostly target predetermined/uncomplicated conditions rather than the comprehensive care offered by dermatologists in telemedicine and in-person visits.5 Examining how patients engage in online consults may highlight services most sought in teledermatology. Although online communities offer accessibility, significant concerns remain. Many posts sought second opinions, potentially indicating mistrust of providers. Anecdotally, misinformation was present. Inaccurate advice from people without verifiable qualifications may result in acceptance of misguided recommendations by both active and passive viewers. Analysis was limited to 1 community on Reddit, which skews younger and male, primarily from the United States. Future work should explore other online platforms. Patients increasingly turn to social media for health information and crowd-diagnoses. In response, physicians could partner with communities to enhance information exchange (eg, developing rigorous guidelines for requests) to forge sustainable online models of care. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ∗ Since March 23, 2020, the moderators of r/Dermatology have converted the forum into one for verified dermatology providers only. Requests for dermatologic consultations are referred to a new forum, r/DermatologyQuestions. ==== Refs References 1 Uscher-Pines L. Malsberger R. Burgette L. Mulcahy A. Mehrotra A. Effect of teledermatology on access to dermatology care among Medicaid enrollees JAMA Dermatol 152 8 2016 905 912 27144986 2 Rosen A.R. Littman-Quinn R. Kovarik C.L. Lipoff J.B. Landscape of business models in teledermatology Cutis 97 4 2016 302 304 27163914 3 Nobles A.L. Leas E.C. Althouse B.M. Requests for diagnoses of sexually transmitted diseases on a social media platform JAMA 322 17 2019 1712 1713 31688875 4 Alexa Top sites in the United States Available at: https://www.alexa.com/topsites/countries/US 2020 5 Jain T. Lu R.J. Mehrotra A. Prescriptions on demand: the growth of direct-to-consumer telemedicine companies JAMA 322 10 2019 925 926 31348489
PMC007xxxxxx/PMC7413159.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)32358-6 10.1016/j.jaad.2020.08.006 Review Review of adverse cutaneous reactions of pharmacologic interventions for COVID-19: A guide for the dermatologist Martinez-Lopez Antonio PhD, MD ab Cuenca-Barrales Carlos MD b Montero-Vilchez Trinidad MD a Molina-Leyva Alejandro PhD, MD ab∗ Arias-Santiago Salvador PhD, MD abc a Dermatology Unit, Virgen de las Nieves University Hospital, Granada, Spain b TECe19–Clinical and Translational Dermatology Investigation Group, Instituto Biosanitario, Granada, Spain c Dermatology Department, University of Granada, Granada, Spain ∗ Correspondence to: Alejandro Molina-Leyva, PhD, MD, Av De Madrid, 15, 18012 Granada, Spain. 7 8 2020 12 2020 7 8 2020 83 6 17381748 1 8 2020 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. The new coronavirus, severe acute respiratory syndrome coronavirus 2, is associated with a wide variety of cutaneous manifestations. Although new skin manifestations caused by COVID-19 are continuously being described, other cutaneous entities should also be considered in the differential diagnosis, including adverse cutaneous reactions to drugs used in the treatment of COVID-19 infections. The aim of this review is to provide dermatologists with an overview of the cutaneous adverse effects associated with the most frequently prescribed drugs in patients with COVID-19. The skin reactions of antimalarials (chloroquine and hydroxychloroquine), antivirals (lopinavir/ritonavir, ribavirin with or without interferon, oseltamivir, remdesivir, favipiravir, and darunavir), and treatments for complications (imatinib, tocilizumab, anakinra, immunoglobulins, corticosteroids, colchicine and low molecular weight heparins) are analyzed. Information regarding possible skin reactions, their frequency, management, and key points for differential diagnosis are presented. Key words COVID-19 drug treatment drug eruptions drug-related side effects and adverse reactions review Abbreviations used FDA US Food and Drug Administration IL interleukin MERS Middle Eastern respiratory syndrome SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 SJS Stevens-Johnson syndrome ==== Body pmc Capsule Summary • Severe acute respiratory syndrome coronavirus 2 infection has been associated with multiple cutaneous manifestations, such as maculopapular eruption, pseudo-chilblain lesions, urticaria, monomorphic disseminated vesicular lesions, acral vesicular-pustulous lesions, and livedo or necrosis. • Many treatments prescribed for COVID-19 may cause a wide variety of cutaneous adverse effects that should be considered in the differential diagnosis. The new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading rapidly worldwide. To date, there are no proven effective therapies for this virus. Knowledge about SARS-CoV-2 virology is rapidly increasing, and a large number of potential drug targets are being investigated.1 Currently, infection management is mainly supportive, and common drugs prescribed for infection control include antimalarials (chloroquine and hydroxychloroquine), lopinavir/ritonavir, ribavirin, interferon, oseltamivir, remdesivir, favipiravir, and darunavir. Drugs prescribed for complications associated with viral infections include anticytokines (mainly interleukin [IL] 6 blockers and anakinra), imatinib, corticosteroids, colchicine, heparins, immunoglobulins, and hyperimmune plasma.2 Cutaneous manifestations have recently been described in patients with the new coronavirus infection, similar to cutaneous involvement occurring in common viral infections.3, 4, 5 A recently published nationwide consensus study in Spain has widely described these manifestations in a prospective study with 375 cases. In this case collection survey, authors described 5 clinical patterns: acral areas with erythema-edema associated with some vesicles or pustules (pseudo-chilblain lesions), maculopapular eruptions, urticaria, other vesicular lesions (monomorphic disseminated vesicular lesions and acral vesicular-pustulous lesions), and livedo or necrosis.6 The diagnosis of cutaneous manifestations in patients with SARS-CoV-2 infection is challenging for dermatologists.7 , 8 It remains unclear whether these lesions are related to the virus. Skin diseases not related to coronavirus, other seasonal viral infections, and drug reactions should be considered in the differential diagnosis, especially in those patients with nonspecific manifestations such as urticaria or maculopapular eruptions. However, some features may help distinguish COVID-19 cutaneous lesions from drug-related ones. Urticarial lesions and maculopapular eruptions in SARS-CoV-2 infections usually appear at the same time as the systemic symptoms, whereas drug adverse reactions are likely to arise hours to days after the start of the treatment.6 , 9 The aim of this review is to provide dermatologists with an overview of the cutaneous adverse effects associated with the most frequently prescribed drugs in patients with COVID-19, serving as a guide to assist dermatologists and other physicians in differential diagnosis. Antimalarials Hydroxychloroquine and chloroquine are antimalarials that have been widely used in the treatment of some chronic inflammatory diseases. They are currently being investigated in more than 160 clinical trials10 and have been approved for the treatment of COVID-19 by the US Food and Drug Administration (FDA) as an Emergency Use Authorization and by the European Medicines Agency for hospitalized patients in the context of clinical trials or as part of national emergency programs.11 , 12 Although their mechanisms of action against SARS-CoV-2 are not fully understood, both drugs may change the pH at the cell membrane surface and inhibit viral fusion and glycosylation of viral proteins. Moreover, hydroxychloroquine can also inhibit nucleic acid replication and viral assembly.13 , 14 Despite the lack of high-quality scientific articles, several studies have shown improved survival of patients with COVID-19 who were treated with antimalarials. Although 2 studies showed an increased mortality in patients treated with antimalarials, these articles have been retracted because the authors cannot vouch for the veracity of the data.15 , 16 Both treatments are generally well tolerated, with retinopathy being the best known adverse effect. However, cutaneous adverse events might appear in up to 11.5% of patients,17 and some of them can be mistaken for skin manifestations of SARS-CoV-2, especially those with maculopapular rash or exanthematous reactions. This itchy maculopapular eruption tends to appear 2 weeks after the start of the treatment, mainly on the trunk and limbs, and may mean that treatment has to be stopped in some patients.18, 19, 20 Exacerbation of psoriasis is probably the most common cutaneous adverse effect that appears during treatment with antimalarials, with some cases described in patients with autoimmune diseases and also with COVID-19. Lesions of plaque psoriasis, pustular psoriasis, inverse psoriasis, and even erythroderma have been described in patients undergoing treatment with chloroquine and hydroxychloroquine.21, 22, 23, 24 It is important to screen for a personal history of psoriasis in patients with COVID-19 who are candidates for antimalarials to prevent severe flares.25 Cutaneous hyperpigmentation is another well-known skin adverse effect of antimalarial agents that usually appears after long-term treatment, especially under chloroquine treatment. Melanonychia and mucosal pigmentation can also appear because of the high drug binding of both chloroquine and hydroxychloroquine and frequently arise months or years after the beginning of treatment.26, 27, 28 Other cutaneous adverse events have been described29, 30, 31 and are detailed in Table I 32, 33, 34, 35, 36 with their general approach.Table I Adverse cutaneous events related to the most frequently used drugs in COVID-19 Drug Morphology of cutaneous eruption Frequency Key points for differential diagnosis with skin manifestations of COVID-19 How to manage the adverse cutaneous effect Antimalarials Pigmentation disorders 4.9% to 29% Personal history of psoriasis Chronology of drug introduction and onset of symptoms Complete blood count (eosinophilia in DRESS syndrome) Complete metabolic panel to assess renal and liver function may be considered. Biopsy in severe cases with diagnostic doubts∗ Symptomatic (antihistamines ± topical or systemic corticosteroids) in mild to moderate cases Treatment discontinuation in severe cases Maculopapular rash Up to 11.5% Exanthematous reactions DRESS syndrome AGEP Psoriasis exacerbations Erythema multiforme Systemic eczematous contact dermatitis Lopinavir/Ritonavir Maculopapular rash 5% adults/12% children Chronology of drug introduction and onset of symptoms (a few days in the case of rash and SJS, 3-4 wk in the case of leg edema) Biopsy in severe cases with diagnostic doubts∗ Symptomatic (antihistamines ± topical or systemic corticosteroids) in mild to moderate cases Treatment discontinuation in severe cases SJS <1% Leg edema Alopecia areata Skin infections Exfoliative erythroderma Lichenoid eruptions Urticaria Pruritus Xeroderma Oral mucosa lesions Redistribution of body fat, facial wasting, cysts, and ingrown toenails Delayed Ribavirin +/− interferon Eczematous drug reactions 10.3% to 23% Chronology of drug introduction and onset of symptoms Biopsy in severe cases with diagnostic doubts∗ Symptomatic (antihistamines ± topical or systemic corticosteroids) in mild to moderate cases Treatment discontinuation in severe cases Xerosis and pruritus Maculopapular rash 1% to 4% Psoriasis Lichenoid eruptions Alopecia 8.1% to 19% Oseltamivir SJS <1% Special attention in children Chronology of drug introduction and onset of symptoms Biopsy in severe cases with diagnostic doubts∗ Treatment discontinuation TEN Remdesivir Maculopapular rash 1.7% to 7.5% Chronology of drug introduction and onset of symptoms Symptomatic (antihistamines ± topical or systemic corticosteroids) Darunavir Maculopapular rash ∼10% Previous history of reactions with non-nucleoside reverse transcriptase inhibitors Chronology of drug introduction and onset of symptoms (median, 14 d in the case of rash) Biopsy in severe cases with diagnostic doubts∗ Rash is usually self-limiting. Symptomatic (antihistamines ± topical or systemic corticosteroids) in mild to moderate cases Treatment discontinuation in severe cases Thrombocytopenic purpura <1% Vesicular rash <1% Allergic dermatitis <1% SJS <1% TEN <1% Imatinib Maculopapular rash 20% to 67% Complete blood count (eosinophilia) Chronology of drug introduction and onset of symptoms (median, 2.8 mo in the case of rash) Biopsy in severe cases with diagnostic doubts∗ In the case of rash, symptomatic treatment with antihistamines and/or topical corticosteroids Systemic corticosteroids and modification of the imatinib regimen are not usually necessary. In other severe cases, treatment discontinuation should be considered. Edema 48% to 65% Pigmentary disorders 4% to 40% Lichenoid reactions <1% Psoriasiform eruption <1% Pityriasis rosea–like eruption <1% AGEP <1% SJS <1% Urticaria <1% Neutrophilic dermatosis <1% Photosensitivity <1% Porphyria and pseudoporphyria <1% Tocilizumab Maculopapular rash >10%: rash, urticaria, cellulitis <1%: necrotizing fasciitis, cutaneous sarcoidosis, pustular eruptions Chronology of drug introduction and onset of symptoms (rash and urticaria) Bacterial cultures and imaging tests (cellulitis and necrotizing fasciitis) Biopsy in severe cases with diagnostic doubts∗ Symptomatic (antihistamines ± topical or systemic corticosteroids) in mild to moderate cases Treatment discontinuation in severe cases Urticaria Cellulitis Necrotizing fasciitis Cutaneous sarcoidosis Pustular eruptions Anakinra Injection site reaction 13.8% to 14.6% Chronology of drug introduction and onset of the symptoms Vigilance of anakinra dosage Biopsy in severe cases with diagnostic doubts∗ Dosage reduction or treatment discontinuation Desensitization Generalized urticarial rash <1% to 4% Immunoglobulins During the infusion: Urticarial plaques >10% Chronology of drug introduction and onset of symptoms Biopsy in severe cases with diagnostic doubts∗ During the infusion: stop the infusion and administer oral/intravenous diphenhydramine or corticosteroids. Consider premedication with these drugs in patients with previous reactions Delayed: antihistamines and/or topical/systemic corticosteroids Delayed: Maculopapular rash Eczema Erythema multiforme Purpuric erythema <1% Corticosteroids Skin thinning 51% to 73.1% Chronology of drug introduction and onset of symptoms Biopsy in severe cases with diagnostic doubts∗ Treatment discontinuation when possible Acne vulgaris treatment32 in the case of steroid acne Antibiotics/antifungals/antivirals in the case of skin infections Purpura and telangiectasia 7.1% to 23.3% Hypertrichosis 15.8% to 39.1% Hair loss 9.9% to 27.6% Stretch marks 7.1% to 23.3% Risk of skin infections (malassezia folliculitis, cutaneous candidiasis, bacterial cellulitis, or herpes zoster) ∼7% Steroid acne (monomorphic follicular papulopustules that favor the chest and back) 0.3% to 8.7% Colchicine Alopecia <1% (mainly cases of intoxication; other symptoms include diarrhea and gastrointestinal symptoms, rhabdomyolysis, renal and heart failure, bone marrow suppression, and multiorgan failure) Vigilance of colchicine dosage Complete blood count and renal function Biopsy in severe cases with diagnostic doubts∗ (Although not common, the presence of metaphase-arrested keratinocytes on skin biopsy is useful for the diagnosis)113 Dosage reduction or treatment discontinuation Supportive care33,34 Morbilliform rash Bullous dermatitis Erythema nodosum–like lesions TEN-like reactions LMVH Heparin-induced skin necrosis (erythematous plaques, hemorrhagic blisters, necrotic ulcers, and petechiae) <1% Complete blood count (relative decrease in platelet count) Detection of heparin-platelet factor 4 Chronology of drug introduction and onset of symptoms (5-10 d, or less if previously sensitized)35 Biopsy in severe cases with diagnostic doubts∗ (platelet thrombi in the dermal vessels) Rapid discontinuation of LMWH (if not, it can lead to fatal complications such as limb ischemia or myocardial or cerebral infarction)118 and administration of anticoagulants such as danaparoid or argatroban Standard wound care for skin necrosis36 AGEP, Acute generalized exanthematous pustulosis; DRESS, drug reaction with eosinophilia and systemic symptoms; LMWH, low-molecular-weight heparins; SJS, Steven-Johnson syndrome; TEN, toxic epidermal necrolysis. ∗ In certain circumstances/clinical presentations, a skin biopsy may not be able to differentiate drug versus virus-induced eruption. Lopinavir/ritonavir Lopinavir/ritonavir is an oral agent approved for treating HIV infections. This combination may have a role to play in the treatment of other coronavirus infections such as SARS-CoV-1 or Middle East respiratory syndrome (MERS) through 3-chymotrypsin–like protease inhibition.37 , 38 Its use in the treatment of COVID-19 is currently being investigated, after observing promising results in case reports and case series.39 , 40 There are more than 30 registered clinical trials involving lopinavir/ritonavir for the treatment of COVID-19,10 although the results of 1 trial conducted on adult patients hospitalized with severe COVID-19 did not show significant benefits beyond standard care. In this study, the mean time to start treatment was 13 days.41 Cutaneous adverse reactions are among the most common adverse effects in patients treated with lopinavir/ritonavir. According to HIV studies, skin rashes may appear in 5% of adult patients and up to 12% of children. This maculopapular pruritic rash often starts shortly after the start of treatment and is usually well tolerated, although Steven-Johnson syndrome (SJS) associated with serious multiorgan toxicity has been described.42, 43, 44 In patients with HIV treated with this combination, inflammatory, painful leg edema appearing 3 or 4 weeks after starting the treatment has been described, which might be associated with skin rash.45 , 46 Alopecia areata has also been reported as an infrequent and delayed adverse reaction, and treatment needs to be discontinued for improvement to occur.47 , 48 Other cutaneous adverse events49, 50, 51, 52, 53 are detailed in Table I. Ribavirin/interferon Systemic ribavirin, a guanine analogue that inhibits RNA polymerase and has been used in chronic hepatitis C virus infection, is currently being investigated as a treatment for COVID-19 in 3 clinical trials,10 although previous studies in patients with SARS-CoV-1 and MERS showed no significant effectiveness.54 , 55 This drug is usually combined with interferon in both hepatitis C virus and in COVID-19 infections because of the activity of interferon against MERS.56 Drug-induced skin reactions are among the most common adverse effects of both drugs, and their global incidence has been estimated at 13% to 23%.57 , 58 A wide range of cutaneous manifestations have been described59, 60, 61, 62 (Table I). Oseltamivir Oseltamivir is a neuraminidase inhibitor that was successfully used during the 2010 influenza H1N1 outbreak. At the beginning of the SARS-CoV-2 pandemic, oseltamivir was used in many patients, but recent clinical trials did not show significant effectiveness. It is currently being investigated in 6 clinical trials.10 Cutaneous adverse effects are unusual, but the appearance of SJS and toxic epidermal necrolysis should be monitored, especially in children.63 , 64 Remdesivir Remdesivir (GS-5734) is a nucleotide analogue prodrug that inhibits viral RNA polymerases.65 It was developed to treat Ebola disease and other RNA viruses,66 and it has been shown to have potent in vitro activity against SARS-CoV-2 by interfering with NSP12.14 Its effectiveness in the treatment of COVID-19 is currently being tested in 11 ongoing randomized trials.10 It has been approved by the FDA as an Emergency Use Authorization,11 and as of July 3, 2020, the European Commission granted its conditional marketing authorization for the treatment of COVID-19 in adults and adolescents (from 12 years of age and weighing at least 40 kg) with pneumonia requiring supplemental oxygen.12 Although there is little information on remdesivir adverse events, cutaneous manifestations may not be very frequent. A randomized controlled trial assessing investigational therapies for Ebola disease showed cutaneous adverse events in 1.7% (3/175) of patients treated with remdesivir.67 More recently, a cohort of 53 patients receiving a 10-day course of remdesivir were followed up, and 7.55% (4/53) had developed a cutaneous rash.68 Nevertheless, no information is provided about rash morphology, distribution, or timeline in relation to remdesivir that may help clinicians differentiate from cutaneous manifestations of COVID-19.69 A combination of oral antihistamines and topical corticosteroids could be an effective treatment for this adverse event. Favipiravir Favipiravir (T-705) is an antiviral triphosphate that inhibits RNA polymerase, blocking viral replication. It was approved in Japan for treating pandemic influenza virus infections and was also used off label to treat patients infected with the Ebola virus and the Lassa virus.70 It is also currently being considered for the treatment of COVID-19 in 14 clinical trials.10 To our knowledge, no adverse cutaneous events have been reported to date.71, 72, 73 Darunavir Darunavir, a protease inhibitor used against HIV infections, may also have potential efficacy in treating COVID-1974 and is being investigated at this time in 2 clinical trials.10 Maculopapular rash is a common adverse event associated with darunavir75, 76, 77 and should be differentiated from rashes related to COVID-19.69 The median interval between darunavir initiation and rash development is 14 days (range, 1-150 days), and a previous history of rashes linked to non-nucleoside reverse transcriptase inhibitors is a risk factor for darunavir-related rashes.75 Although darunavir-related rashes are often self-limiting and usually mild to moderate in severity,77 , 78 they can occasionally be severe, without improvement after treatment with oral antihistamines or steroids, in which case it is necessary to discontinue darunavir treatment.75 Other cutaneous manifestations are detailed in Table I.77, 78, 79 Imatinib Imatinib, a tyrosine kinase inhibitor, is another drug that may be effective in treating COVID-19 and that is currently being investigated in 4 clinical trials.10 Its activity occurs in the early stages of infection, after internalization and endosomal trafficking, by inhibiting the fusion of the virions at the endosomal membrane.80 More than 20% of patients treated with imatinib may develop a rash, presenting as erythematous and maculopapular lesions.81 The median time to develop a severe rash requiring major interventions was 2.8 months (range, 0.2-8.4 mo). Serial eosinophil blood levels during imatinib treatment showed direct correlation with the development of erythematous and maculopapular skin rash and its severity. Major interventions, including systemic steroids and imatinib dose modification/reduction, are rarely needed (5%), and discontinuation is extremely rare.81 Other cutaneous manifestations are detailed in Table I.82, 83, 84, 85, 86 Anticytokine or immunomodulatory agents Different monoclonal antibodies against cytokines potentially involved in the so-called cytokine storm, a dysfunctional stimulation of the immune system leading to organ damage, have been proposed for the management of COVID-19.87 Tocilizumab, an IL-6 blocker, is the most investigated drug in this field,2 and it is being used at this time in more than 30 clinical trials.10 Its cutaneous manifestations may be divided into true cutaneous adverse effects (urticarial, purpuric, and ulcerating lesions) and those secondary to infection.88 The most common adverse cutaneous reactions to tocilizumab are maculopapular rash, urticaria, and cellulitis.89 , 90 Necrotizing fasciitis, cutaneous sarcoidosis, and pustular eruptions have also been reported.91, 92, 93 Maculopapular rash and urticarial lesions will be the main differential diagnosis for skin manifestations of COVID-19.69 Treatment will require the use of antihistamines and corticosteroids. Although less frequent, the increased risk of skin infections associated with IL-6 blockers should always be considered, because cellulitis and necrotizing fasciitis can be life-threatening conditions that must be adequately and promptly treated. Anakinra, an IL-1 receptor antagonist, is currently under investigation for use in the treatment of COVID-19–associated pulmonary complications with elevated IL-6 levels. To date, up to 17 clinical trials are investigating its use in COVID-19.10 A recent retrospective cohort study has shown significant clinical improvement with high doses in patients with COVID-19 with acute respiratory distress syndrome and hyperinflammation.94 Mild injection site reaction is the most common cutaneous adverse effect during anakinra treatment. However, some investigators have reported the occurrence of severe cutaneous urticarial rash in several patients, which means treatment has to be discontinued. Clinical improvement of the cutaneous rash has been noted after treatment cessation.95, 96, 97 Immunoglobulin therapy Immunoglobulin therapy consists of the use of hyperimmune immunoglobulins or plasma from recovered patients. These antibodies can help clear the free circulating virus and infected cells.98 Its use in the treatment of COVID-19 is currently being investigated in more than 70 clinical trials,10 and the FDA is supporting and coordinating research in this field.99 , 100 Cutaneous adverse reactions in the form of urticarial plaques during the infusion are common, whereas delayed skin reactions in the form of eczema, erythema multiforme, purpuric erythema, or maculopapular rash are infrequent.101, 102, 103 Slowing the infusion rate of immunoglobulin could help reduce infusion reactions.101 In the presence of compatible infusion-related skin lesions, the infusion should be temporarily discontinued, and treatment with oral/intravenous diphenhydramine or corticosteroids may be administered.104 Moreover, patients may infrequently develop systemic sensitivity to immunoglobulin therapy, including anaphylaxis/anaphylactic reactions. In patients with skin reactions to previous infusions, premedication with diphenhydramine and/or corticosteroids should be considered. Delayed skin reactions can be safely treated with antihistamines and/or topical or systemic corticosteroids. COVID-19 infection can produce urticarial rash and purpuric erythema,69 , 105 , 106 which should be distinguished from these reactions. Systemic corticosteroids Data on the use of systemic corticosteroids in COVID-19 infection are controversial, although they have been proposed to control the cytokine storm87 and are also required for shock or exacerbation of chronic obstructive pulmonary disease.2 Their use is currently being investigated in more than 15 clinical trials.10 Recently, the preliminary results of the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial showed that dexamethasone compared to standard care reduced 28-day mortality by a third in patients receiving invasive mechanical ventilation and by a fifth in patients receiving oxygen without invasive mechanical ventilation; the mortality rate did not change in patients not receiving respiratory support.107 The most common adverse cutaneous events, most of them largely delayed, and their general approach are detailed in Table I. With regard to differential diagnosis of cutaneous manifestations of COVID-19, the vascular fragility associated with corticosteroid use, especially in elderly patients, may be similar to the thrombotic complications of COVID-19 infection.108 , 109 Colchicine Colchicine has been proposed for the treatment of COVID-19.110 It is currently being investigated for the treatment of COVID-19 in more than 10 clinical trials.10 Cutaneous adverse events with colchicine are very infrequent, mainly occurring because of intoxication (Table I).111, 112, 113, 114, 115 Low-molecular-weight heparins Low-molecular-weight-heparins are recommended for all in-patients to prevent thrombotic complications,116 and more than 15 clinical trials are investigating their use in COVID-19 at this time.10 Heparin-induced skin necrosis is the most important adverse cutaneous event117 (Table I). Lesions can occur at the injection site or at a distance.118 The diagnosis is usually clinical. Other complementary tests and management are detailed in Table I. Conclusions This new virus is encouraging physicians and scientists to expand their knowledge and describe new findings associated with the disease, including in the field of dermatology. Moreover, the number of investigational drugs is increasing daily. By considering adverse drug reactions in the differential diagnosis, dermatologists can be useful in assisting in the care of these patients. Although the frequency of drug eruption in patients with COVID is currently unknown, drugs may be the causal agent of skin reactions in some patients. There are a wide variety of skin reactions, some of which may be confused with cutaneous manifestations of COVID-19. Diagnosis is usually clinical, and skin biopsy or other complementary tests are generally reserved for severe cases. Management is often symptomatic, but it is sometimes necessary to modify or discontinue the treatment, and some conditions can even be life-threatening. We want to thank Charlotte Bower for improving the English of the manuscript. Funding sources: None Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Liu C. Zhou Q. Li Y. Research and development on therapeutic agents and vaccines for COVID-19 and related human coronavirus diseases ACS Cent Sci 6 3 2020 315 331 32226821 2 Sanders J.M. Monogue M.L. Jodlowski T.Z. Cutrell J.B. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review JAMA April 13, 2020 10.1001/jama.2020.6019 3 Zhang J.J. Dong X. Cao Y.Y. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China Allergy 75 2020 1730 1741 32077115 4 Henry D. Ackerman M. Sancelme E. Finon A. Esteve E. Urticarial eruption in COVID-19 infection J Eur Acad Dermatol Venereol 34 2020 e244 e245 32294273 5 van de Bor M. Fetal toxicology Handb Clin Neurol 162 2019 31 55 31324317 6 Galván Casas C. Català A. Carretero Hernández G. Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases Br J Dermatol 183 2020 71 77 32348545 7 Fernandez-Nieto D. Ortega-Quijano D. Segurado-Miravalles G. Pindado-Ortega C. Prieto-Barrios M. Jimenez-Cauhe J. Comment on: cutaneous manifestations in COVID-19: a first perspective. Safety concerns of clinical images and skin biopsies J Eur Acad Dermatol Venereol 34 2020 e252 e254 32294262 8 van Damme C. Berlingin E. Saussez S. Accaputo O. Acute urticaria with pyrexia as the first manifestations of a COVID-19 infection J Eur Acad Dermatol Venereol 34 2020 e300 e301 32329915 9 Peroni A. Colato C. Schena D. Girolomoni G. Urticarial lesions: if not urticaria, what else? The differential diagnosis of urticaria: part I. Cutaneous diseases J Am Acad Dermatol 62 4 2010 541 555 20227576 10 ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US) Available from: http://clinicaltrials.gov/ 11 US Food and Drug Administration Coronavirus (COVID-19) update: FDA issues emergency use authorization for potential COVID-19 treatment Available from: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment 2020 12 European Medicines Agency COVID-19: what's new [cited 2020 May 20] Available from: https://www.ema.europa.eu/en/human-regulatory/overview/public-health-threats/coronavirus-disease-covid-19/covid-19-whats-new 13 Yao X. Ye F. Zhang M. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Clin Infect Dis 71 2020 732 739 32150618 14 Wang M. Cao R. Zhang L. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro Cell Res 30 3 2020 269 271 32020029 15 Mehra M.R. Ruschitzka F. Patel A.N. Retraction—hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis Lancet 395 2020 1820 32511943 16 Mehra M.R. Desai S.S. Kuy S. Henry T.D. Patel A.N. Retraction: cardiovascular disease, drug therapy, and mortality in Covid-19 N Engl J Med 382 26 2020 2582 17 Mittal L. Zhang L. Feng R. Werth V.P. Antimalarial drug toxicities in patients with cutaneous lupus and dermatomyositis: a retrospective cohort study J Am Acad Dermatol 78 1 2018 100 106.e1 28989103 18 Matsuda T. Ly N.T.M. Kambe N. Early cutaneous eruptions after oral hydroxychloroquine in a lupus erythematosus patient: a case report and review of the published work J Dermatol 45 3 2018 344 348 29239026 19 Schwartz R.A. Janniger C.K. Generalized pustular figurate erythema: a newly delineated severe cutaneous drug reaction linked with hydroxychloroquine Dermatol Ther 33 3 2020 e13380 32253799 20 Takamasu E. Yokogawa N. Shimada K. Sugii S. Simple dose-escalation regimen for hydroxychloroquine-induced hypersensitivity reaction in patients with systemic lupus erythematosus enabled treatment resumption Lupus 28 12 2019 1473 1476 31575325 21 Kutlu Ö. Metin A. A case of exacerbation of psoriasis after oseltamivir and hydroxychloroquine in a patient with COVID-19: will cases of psoriasis increase after COVID-19 pandemic? Dermatol Ther 2020 10.1111/dth.13383 22 Shindo E. Shikano K. Kawazoe M. A case of generalized pustular psoriasis caused by hydroxychloroquine in a patient with systemic lupus erythematosus Lupus 28 8 2019 1017 1020 31166865 23 Ullah A. Zeb H. Khakwani Z. Murphy F.T. Hydroxychloroquine-induced inverse psoriasis BMJ Case Rep 12 2 2019 e224619 24 Wang W.-M. Wang K.Y. Wang T. Jin H.-Z. Fang K. Hydroxychloroquine-induced psoriasis-form erythroderma in a patient with systemic lupus erythematosus Chin ed J 131 15 2018 1887 1888 25 Gravani A. Gaitanis G. Zioga A. Bassukas I.D. Synthetic antimalarial drugs and the triggering of psoriasis—do we need disease-specific guidelines for the management of patients with psoriasis at risk of malaria? Int J Dermatol 53 3 2014 327 330 24320605 26 Schroeder R.L. Gerber J.P. Chloroquine and hydroxychloroquine binding to melanin: some possible consequences for pathologies Toxicol Rep 1 2014 963 968 28962308 27 Bahloul E. Jallouli M. Garbaa S. Hydroxychloroquine-induced hyperpigmentation in systemic diseases: prevalence, clinical features and risk factors: a cross-sectional study of 41 cases Lupus 26 12 2017 1304 1308 28355984 28 Cacoub P. Amoura Z. Costedoat-Chalumeau N. Hydroxychloroquine-induced pigmentation in patients with systemic lupus erythematosus: a case-control study JAMA Dermatol 149 8 2013 935 940 23824340 29 Girijala R.L. Siddiqi I. Kwak Y. Wright D. Patel D.B. Goldberg L.H. Pustular DRESS syndrome secondary to hydroxychloroquine with EBV reactivation J Drugs Dermatol 18 2 2019 207 209 30811149 30 Pearson K.C. Morrell D.S. Runge S.R. Jolly P. Prolonged pustular eruption from hydroxychloroquine: an unusual case of acute generalized exanthematous pustulosis Cutis 97 3 2016 212 216 27023083 31 Pérez-Ezquerra P.R. de Barrio Fernández M. de Castro Martínez F.J. Ruiz Hornillos F.J. Prieto García A. Delayed hypersensitivity to hydroxychloroquine manifested by two different types of cutaneous eruptions in the same patient Allergol Immunopathol (Madr) 34 4 2006 174 175 16964632 32 Zaenglein A.L. Pathy A.L. Schlosser B.J. Guidelines of care for the management of acne vulgaris J Am Acad Dermatol 74 5 2016 945 973 26897386 33 Slobodnick A. Shah B. Pillinger M.H. Krasnokutsky S. Colchicine: old and new Am J Med 128 5 2015 461 470 25554368 34 Stewart S. Yang K.C.K. Atkins K. Dalbeth N. Robinson P.C. Adverse events during oral colchicine use: a systematic review and meta-analysis of randomised controlled trials Arthritis Res Ther 22 1 2020 28 32054504 35 Sator P. Kiprov A. Feldmann R. Breier F. Steiner A. Heparin-induced skin necrosis J Eur Acad Dermatol Venereol 30 1 2016 161 163 25074633 36 Warkentin T.E. Greinacher A. Management of heparin-induced thrombocytopenia Curr Opin Hematol 23 5 2016 462 470 27380556 37 Rabaan A.A. Alahmed S.H. Bazzi A.M. Alhani H.M. A review of candidate therapies for Middle East respiratory syndrome from a molecular perspective J Med Microbiol 66 9 2017 1261 1274 28855003 38 Hui D.S.C. An overview on severe acute respiratory syndrome (SARS) Monaldi Arch Chest Dis 63 3 2005 149 157 16312205 39 Lim J. Jeon S. Shin H.Y. Case of the index patient who caused tertiary transmission of COVID-19 infection in Korea: the application of lopinavir/ritonavir for the treatment of COVID-19 infected pneumonia monitored by quantitative RT-PCR J Korean Med Sci 35 6 2020 e79 32056407 40 Ye X.-T. Luo Y.-L. Xia S.-C. Clinical efficacy of lopinavir/ritonavir in the treatment of Coronavirus disease 2019 Eur Rev Med Pharmacol Sci 24 6 2020 3390 3396 32271456 41 Cao B. Wang Y. Wen D. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19 N Engl J Med 382 19 2020 1787 1799 32187464 42 Calista D. Maculo-papular rash induced by lopinavir/ritonavir Eur J Dermatol 15 2 2005 97 98 15757820 43 Rudin C. Burri M. Shen Y. Long-term safety and effectiveness of ritonavir, nelfinavir, and lopinavir/ritonavir in antiretroviral-experienced HIV-infected children Pediatr Infect Dis J 27 5 2008 431 437 18382386 44 Manfredi R. Sabbatani S. Serious, multi-organ hypersensitivity to lopinavir alone, involving cutaneous-mucous rash, and myeloid, liver, and kidney function AIDS 20 18 2006 2399 2400 17117031 45 Eyer-Silva W.A. Neves-Motta R. Pinto J.F.C. Morais-De-Sá C.A. Inflammatory oedema associated with lopinavir-including HAART regimens in advanced HIV-1 infection: report of 3 cases AIDS 16 4 2002 673 674 11873015 46 Lascaux A.S. Lesprit P. Bertocchi M. Levy Y. Inflammatory oedema of the legs: a new side-effect of lopinavir AIDS 15 6 2001 819 11371707 47 Chrysos G. Mikros S. Kokkoris S. Pastelli A. Kontochristopoulos G. Alopecia induced by lopinavir plus ritonavir therapy in an HIV patient J Drugs Dermatol 6 7 2007 742 743 17763601 48 Bongiovanni M. Chiesa E. Monforte AdA. Bini T. Hair loss in an HIV-1 infected woman receiving lopinavir plus ritonavir therapy as first line HAART Dermatol Online J 9 5 2003 28 49 Türsen Ü. Türsen B. Lotti T. Cutaneous side-effects of the potential covid-19 drugs Dermatol Ther 2020 10.1111/dth.13476 50 Stauber R.E. Fauler G. Rainer F. Anti-HCV treatment with ombitasvir/paritaprevir/ritonavir ± dasabuvir is associated with increased bile acid levels and pruritus Wien Klin Wochenschr 129 21-22 2017 848 851 28980064 51 Scully C. Diz Dios P. Orofacial effects of antiretroviral therapies Oral Dis 7 4 2001 205 210 11575869 52 Achan J. Kakuru A. Ikilezi G. Antiretroviral agents and prevention of malaria in HIV-infected Ugandan children N Engl J Med 367 22 2012 2110 2118 23190222 53 James C.W. McNelis K.C. Cohen D.M. Szabo S. Bincsik A.K. Recurrent ingrown toenails secondary to indinavir/ritonavir combination therapy Ann Pharmacother 35 7-8 2001 881 884 11485139 54 Arabi Y.M. Shalhoub S. Mandourah Y. Ribavirin and interferon therapy for critically ill patients with Middle East respiratory syndrome: a multicenter observational study Clin Infect Dis 70 9 2020 1837 1844 31925415 55 Stockman L.J. Bellamy R. Garner P. SARS: systematic review of treatment effects PLoS Med 3 9 2006 e343 16968120 56 Morra M.E. Van Thanh L. Kamel M.G. Clinical outcomes of current medical approaches for Middle East respiratory syndrome: a systematic review and meta-analysis Rev Med Virol 28 3 2018 e1977 29664167 57 Kerl K. Negro F. Lübbe J. Cutaneous side-effects of treatment of chronic hepatitis C by interferon alfa and ribavirin Br J Dermatol 149 3 2003 656 58 Vázquez-López F. Manjón-Haces J.A. Pérez-Alvarez R. Pérez-Oliva N. Eczema-like lesions and disruption of therapy in patients treated with interferon-alfa and ribavirin for chronic hepatitis C: the value of an interdisciplinary assessment Br J Dermatol 150 5 2004 1046 1047 15149535 59 Patrk I. Morović M. Markulin A. Patrk J. Cutaneous reactions in patients with chronic hepatitis C treated with peginterferon and ribavirin Dermatology 228 1 2014 42 46 24434490 60 Mistry N. Shapero J. Crawford R.I. A review of adverse cutaneous drug reactions resulting from the use of interferon and ribavirin Can J Gastroenterol 23 10 2009 677 683 19826642 61 Patel P. Malik K. Krishnamurthy K. Cutaneous adverse events in chronic hepatitis c patients treated with new direct-acting antivirals: a systematic review and meta-analysis J Cutan Med Surg 20 1 2016 58 66 26162860 62 Cacoub P. Bourlière M. Lübbe J. Dermatological side effects of hepatitis C and its treatment: patient management in the era of direct-acting antivirals J Hepatol 56 2 2012 455 463 21884670 63 Bergstrom K.G. Tamiflu: what dermatologists need to know J Drugs Dermatol 9 1 2010 76 78 20120431 64 Oseltamivir: cutaneous and neurological adverse effects in children Prescrire Int 15 85 2006 182 183 17128526 65 Tchesnokov E.P. Feng J.Y. Porter D.P. Gotte M. Mechanism of inhibition of Ebola virus RNA-dependent RNA polymerase by remdesivir Viruses 11 4 2019 326 30987343 66 World Health Organization WHO R&D blueprint: ad-hoc expert consultation on clinical trials for Ebola therapeutics https://www.who.int/ebola/drc-2018/summaries-of-evidence-experimental-therapeutics.pdf?ua=1 2018 67 Mulangu S. Dodd L.E. Davey R.T. Jr. A randomized, controlled trial of Ebola virus disease therapeutics N Engl J Med 381 24 2019 2293 2303 31774950 68 Grein J. Ohmagari N. Shin D. Compassionate use of remdesivir for patients with severe Covid-19 N Engl J Med 382 24 2020 2327 2336 32275812 69 Recalcati S. Cutaneous manifestations in COVID-19: a first perspective J Eur Acad Dermatol Venereol 34 5 2020 e212 e213 32215952 70 Delang L. Abdelnabi R. Neyts J. Favipiravir as a potential countermeasure against neglected and emerging RNA viruses Antiviral Res 153 2018 85 94 29524445 71 Costanzo M. De Giglio M.A.R. Roviello G.N. SARS CoV-2: recent reports on antiviral therapies based on lopinavir/ritonavir, darunavir/umifenovir, hydroxychloroquine, remdesivir, favipiravir and other drugs for the treatment of the new coronavirus Curr Med Chem 27 2020 4536 4541 32297571 72 PREVAIL II Writing GroupMulti-National PREVAIL II Study TeamDavey R.T. Jr. A randomized, controlled trial of ZMapp for Ebola virus infection N Engl J Med 375 15 2016 1448 1456 27732819 73 Sissoko D. Laouenan C. Folkesson E. Experimental treatment with favipiravir for Ebola virus disease (the JIKI trial): a historically controlled, single-arm proof-of-concept trial in Guinea PLoS Med 13 3 2016 E1001967 26930627 74 Dong L. Hu S. Gao J. Discovering drugs to treat coronavirus disease 2019 (COVID-19) Drug Discov Ther 14 1 2020 58 60 32147628 75 Lin K.Y. Cheng C.Y. Yang C.J. Skin rash related to once-daily boosted darunavir-containing antiretroviral therapy in HIV-infected Taiwanese: incidence and associated factor J Infect Chemother 20 8 2014 465 470 24855915 76 Pernas B. Grandal M. Tabernilla A. Long-term clinical experience with darunavir (2007-2015) in a large cohort of HIV-infected patients in Spain J Med Virol 88 12 2016 2125 2131 27218208 77 Tashima K. Crofoot G. Tomaka F.L. Cobicistat-boosted darunavir in HIV-1-infected adults: week 48 results of a phase IIIb, open-label single-arm trial AIDS Res Ther 11 2014 39 25926858 78 Borras-Blasco J. Navarro-Ruiz A. Borras C. Castera E. Adverse cutaneous reactions associated with the newest antiretroviral drugs in patients with human immunodeficiency virus infection J Antimicrob Chemother 62 5 2008 879 888 18653488 79 Pahk R. Azu M.C. Taira B.R. Sandoval S. Antiretroviral-induced toxic epidermal necrolysis in a patient positive for human immunodeficiency virus Clin Exp Dermatol 34 8 2009 e775 e777 19778313 80 Coleman C.M. Sisk J.M. Mingo R.M. Nelson E.A. White J.M. Frieman M.B. Abelson kinase inhibitors are potent inhibitors of severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus fusion J Virol 90 19 2016 8924 8933 27466418 81 Park S.R. Ryu M.H. Ryoo B.Y. Severe imatinib-associated skin rash in gastrointestinal stromal tumor patients: management and clinical implications Cancer Res Treat 48 1 2016 162 170 26323636 82 Di Tullio F. Mandel V.D. Scotti R. Padalino C. Pellacani G. Imatinib-induced diffuse hyperpigmentation of the oral mucosa, the skin, and the nails in a patient affected by chronic myeloid leukemia: report of a case and review of the literature Int J Dermatol 57 7 2018 784 790 29417559 83 Martinez-Mera C. Capusan T.M. Herrero-Moyano M. Urquia Renke A. Steegmann Olmedillas J.L. de Argila D. Imatinib-induced pseudoporphyria Clin Exp Dermatol 43 4 2018 463 466 29315788 84 Penn E.H. Chung H.J. Keller M. Imatinib mesylate-induced lichenoid drug eruption Cutis 99 3 2017 189 192 28398413 85 Pretel-Irazabal M. Tuneu-Valls A. Ormaechea-Perez N. Adverse skin effects of imatinib, a tyrosine kinase inhibitor Actas Dermosifiliogr 105 7 2014 655 662 23642471 86 Shi C.R. Nambudiri V.E. Imatinib-induced psoriasiform eruption in a patient with chronic myeloid leukemia Am J Hematol 93 3 2018 467 468 28836284 87 Mehta P. McAuley D.F. Brown M. Sanchez E. Tattersall R.S. Manson J.J. COVID-19: consider cytokine storm syndromes and immunosuppression Lancet 395 10229 2020 1033 1034 32192578 88 Czekalska A. Majewski D. Puszczewicz M. Immunodeficiency and autoimmunity during biological disease-modifying antirheumatic drug therapy Reumatologia 57 4 2019 214 220 31548748 89 Kremer J.M. Blanco R. Halland A.M. Clinical efficacy and safety maintained up to 5 years in patients with rheumatoid arthritis treated with tocilizumab in a randomised trial Clin Exp Rheumatol 34 4 2016 625 633 27087059 90 Mysler E. Cardiel M.H. Xavier R.M. López A. Ramos-Esquivel A. Subcutaneous tocilizumab in monotherapy or in combination with nonbiologic disease-modifying antirheumatic drugs in Latin American patients with moderate to severe active rheumatoid arthritis: a multicenter, phase IIIb study J Clin Rheumatol 2020 10.1097/RHU.0000000000001361 91 Del Giorno R. Iodice A. Mangas C. Gabutti L. New-onset cutaneous sarcoidosis under tocilizumab treatment for giant cell arteritis: a quasi-paradoxical adverse drug reaction. Case report and literature review Ther Adv Musculoskelet Dis 11 2019 1759720x19841796 92 Rosa-Goncalves D. Bernardes M. Costa L. Necrotizing fasciitis in a patient receiving tocilizumab for rheumatoid arthritis—case report Reumatol Clin 14 3 2018 168 170 28041910 93 Mori T. Yamamoto T. Tocilizumab-induced pustular drug eruption Int J Rheum Dis 20 11 2017 1776 1777 26218136 94 Cavalli G. De Luca G. Campochiaro C. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study Lancet Rheumatol 2 6 2020 e325 e331 32501454 95 Bettiol A. Silvestri E. Di Scala G. The right place of interleukin-1 inhibitors in the treatment of Behçet's syndrome: a systematic review Rheumatol Int 39 6 2019 971 990 30799530 96 Ortiz-Sanjuán F. Blanco R. Riancho-Zarrabeitia L. Efficacy of anakinra in refractory adult-onset Still's disease: multicenter study of 41 patients and literature review Medicine 94 39 2015 e1554 26426623 97 Orlando I. Vitale A. Rigante D. Lopalco G. Fabiani C. Cantarini L. Long-term efficacy and safety of the interleukin-1 inhibitors anakinra and canakinumab in refractory Behçet disease uveitis and concomitant bladder papillary carcinoma Intern Med J 47 9 2017 1086 1088 28891187 98 Chen L. Xiong J. Bao L. Shi Y. Convalescent plasma as a potential therapy for COVID-19 Lancet Infect Dis 20 4 2020 398 400 32113510 99 US Food and Drug Administration Coronavirus (COVID-19) update: FDA coordinates national effort to develop blood-related therapies for COVID-19. [cited 2020 May 20] Available from: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-coordinates-national-effort-develop-blood-related-therapies-covid-19 100 US Food and Drug Administration Recommendations for investigational COVID-19 convalescent plasma. [cited 2020 May 20] Available from: https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma 101 Miyamoto J. Böckle B.C. Zillikens D. Schmidt E. Schmuth M. Eczematous reaction to intravenous immunoglobulin: an alternative cause of eczema JAMA Dermatol 150 10 2014 1120 1122 24965937 102 Dashti-Khavidaki S. Aghamohammadi A. Farshadi F. Adverse reactions of prophylactic intravenous immunoglobulin; a 13-year experience with 3004 infusions in Iranian patients with primary immunodeficiency diseases J Investig Allergol Clin Immunol 19 2 2009 139 145 103 Brennan V. Salome-Bentley N. Chapel H. Immunology Nurses Study Prospective audit of adverse reactions occurring in 459 primary antibody-deficient patients receiving intravenous immunoglobulin Clin Exp Immunol 133 2 2003 247 251 12869031 104 Cherin P. Marie I. Michallet M. Management of adverse events in the treatment of patients with immunoglobulin therapy: a review of evidence Autoimmun Rev 15 1 2016 71 81 26384525 105 Najarian D.J. Morbilliform exanthem associated with COVID-19 JAAD Case Rep 6 2020 493 494 32313826 106 Mahé A. Birckel E. Krieger S. Merklen C. Bottlaender L. A distinctive skin rash associated with coronavirus disease 2019? J Eur Acad Dermatol Venereol 34 6 2020 e246 e247 107 RECOVERY Collaborative GroupHorby P. Lim W.S. Effect of dexamethasone in hospitalized patients with COVID-19—preliminary report N Engl J Med 2020 10.1056/NEJMoa2021436 108 Jimenez-Cauhe J. Ortega-Quijano D. Prieto-Barrios M. Moreno-Arrones O.M. Fernandez-Nieto D. Reply to “COVID-19 can present with a rash and be mistaken for Dengue”: petechial rash in a patient with COVID-19 infection J Am Acad Dermatol 83 2020 e141 e142 32283233 109 Manalo I.F. Smith M.K. Cheeley J. Jacobs R. A dermatologic manifestation of COVID-19: transient livedo reticularis J Am Acad Dermatol 83 2020 700 32283229 110 Potì F. Pozzoli C. Adami M. Poli E. Costa L.G. Treatments for COVID-19: emerging drugs against the coronavirus Acta Biomed 91 2 2020 118 136 111 Combalia A. Baliu-Piqué C. Fortea A. Ferrando J. Anagen effluvium following acute colchicine poisoning Int J Trichol 8 4 2016 171 172 112 Gürkan A. Oğuz M.M. Boduroğlu Cengiz E. Şenel S. Dermatologic manifestations of colchicine intoxication Pediatr Emerg Care 34 7 2018 e131 e133 29912088 113 Güven A.G. Bahat E. Akman S. Artan R. Erol M. Late diagnosis of severe colchicine intoxication Pediatrics 109 5 2002 971 973 11986465 114 Mason S.E. Smoller B.R. Wilkerson A.E. Colchicine intoxication diagnosed in a skin biopsy: a case report J Cutan Pathol 33 4 2006 309 311 16630182 115 Arroyo M.P. Sanders S. Yee H. Schwartz D. Kamino H. Strober B.E. Toxic epidermal necrolysis-like reaction secondary to colchicine overdose Br J Dermatol 150 3 2004 581 588 15030347 116 Thachil J. Tang N. Gando S. ISTH interim guidance on recognition and management of coagulopathy in COVID-19 J Thromb Haemost 18 5 2020 1023 1026 32338827 117 Adya K.A. Inamadar A.C. Palit A. Anticoagulants in dermatology Indian J Dermatol Venereol Leprol 82 6 2016 626 640 27320765 118 Vu T.T. Gooderham M. Adverse drug reactions and cutaneous manifestations associated with anticoagulation J Cutan Med Surg 21 6 2017 540 550 28639463
PMC007xxxxxx/PMC7414307.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)32409-9 10.1016/j.jaad.2020.08.021 Research Letter All that glisters is not COVID: Low prevalence of seroconversion against SARS-CoV-2 in a pediatric cohort of patients with chilblain-like lesions Denina Marco MD a Pellegrino Francesco MD a Morotti Francesco MD b Coppo Paola MD c Bonsignori Ilaria Maria MD b Garazzino Silvia PhD a Ravanini Paolo MD d Avolio Maria MSc e Cavallo Rossana MD e Bertolotti Luigi PhD f Felici Enrico MD g Acucella Gabriela MD h Montin Davide PhD a Rabbone Ivana PhD b Licciardi Francesco MD a∗ a Department of Pediatrics and Public Health, University of Turin, Turin (TO), Italy b Division of Pediatrics, Department of Health Sciences, University of Piemonte Orientale, Novara (NO), Italy c Unit of Chirurgia Plastica Pediatrica–Dermatologia, Città della salute e della Scienza, Regina Margherita, Children's Hospital, Turin (TO), Italy d Laboratorio di Microbiologia e virologia–AOU Maggiore della Carità di Novara, Novara (NO), Italy e Department of Public Health and Pediatrics, Microbiology and Virology Unit, Città della salute e della Scienza, Molinette Hospital, University of Turin, Turin (TO), Italy f Department of Veterinary Science, University of Turin, Turin (TO), Italy g Pediatric and Pediatric Emergency Unit, Children's Hospital, AO SS Antonio e Biagio e C. Arrigo, Alessandria (AL), Italy h Department of Pediatrics, Ospedale Castelli Verbania (VB) ∗ Correspondence to: Francesco Pellegrino, MD, Piazza Polonia 94, Ospedale Regina Margherita, 10126 Turin (TO), Italy 8 8 2020 12 2020 8 8 2020 83 6 17511753 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: On January 7, 2020, a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was isolated in a patient affected by interstitial pneumonia. As SARS-CoV2 infection has spread worldwide, an increasing number of authors have reported chilblainlike lesions as possible manifestations of SARS-CoV-2 infection.1 , 2 To test this hypothesis, we performed serologic and stool/rectal polymerase chain reaction tests in a cohort of children who developed chilblainlike lesions during the SARS-CoV-2 outbreak in Italy, between March 8 and April 30, 2020. Enrollment criteria are described in the Supplemental material (available via Mendeley at https://doi.org/10.17632/wzh2tyb46y.2). During the enrollment period, 35 cases of chilblainlike lesions were eligible for the study. Twenty-four patients agreed to serologic testing (68.6%). All patients were white, mean age was 13 years (range, 6-17 years), and the female to male ratio was 2:1. Twenty-two patients presented with chilblains on the toes (Fig 1 ) and 2 lesions were located on the heels, 6 patients developed blistering lesions, 83% of lesions lasted more than 14 days, and 8% lasted less than 1 week.Fig 1 Typical chilblainlike lesions in a pediatric patient enrolled in the study. Two patients had known contact with SARS-CoV-2–positive individuals, defined by positive nasal swab result. Seven more patients had close contact with someone who presented symptoms that might be SARS-CoV-2 related such as asthenia, loss of smell (anosmia), cough, and prolonged fever. In 25% of cases, at least 1 parent was a health worker. Further details are available in the Supplemental Results. Chemiluminescence assay (Liaison SARS-CoV-2 IgG, Diasorin) was performed for all patients; 7 patients were tested with In3diagnostic ERADIKIT COVID19, and the other 17 with EDI Novel Coronavirus COVID-19. A total of 3 patients (12.5%) tested positive via both enzyme-linked immunosorbent assay and chemiluminescence. In 1 patient (4.1%), enzyme-linked immunosorbent assay test result was positive, whereas chemiluminescence result was negative. None of the 4 patients with positive results presented with fever, 50% had cough, and 25% presented with transient diarrhea up to 14 days before skin lesion appearance. All 4 patients had contact with a relative who had confirmed SARS-CoV-2 infection (2 patients) or anosmia (2 patients). Fecal polymerase chain reaction was tested in 4 patients (16.6%), and no result was positive; rectal swab was performed in 17 patients (70.8%) and was positive in 1, which also was positive at both serologic tests. Finally, patients with chilblainlike lesions were compared with a cohort of 24 SARS-CoV-2–infected children. Table I shows the comparison between the 2 groups. Chilblain patients were significantly older (13 vs 4 year; P < .001); fever was present in a limited number of cases (16.7% vs 92%; P < .001), and certainty of exposure to SARS-CoV-2 was limited (8% vs 56%; P < .001).Table I Comparison between pediatric cohorts with chilblainlike lesions and severe acute respiratory syndrome coronavirus 2 infection Epidemilogical characteristics and symptoms Chilblains SARS-CoV-2 infection∗ P value No. of patients 24 25 NA Age, y, (range) 13 (10.5–14) 3.8 (0.95–9) <.001 Female patient, no. (%) 15 (62.5) 8 (32) .04 Skin lesions, no. (%) 24 (100) 3 (12) <.001 Fever, no. (%) 4 (16.7) 23 (92) <.001 Cough, no. (%) 10 (41.7) 13 (52) .5 Conjunctivitis, no. (%) 3 (12.5) 0 .1 GI symptoms, no. (%) 5 (20.8) 6 (24) >.99 Certain exposure to SARS-CoV-2, no. (%) 2 (8.3) 14 (56) <.001 The differences between groups were analyzed with Mann-Whitney U test for continuous data and Fisher's exact test for categoric data. All tests were 2 tailed, and the significance was set at P < .05. GI, Gastrointestinal; NA, not available; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. ∗ Twenty-two patients hospitalized and 3 evaluated in the emergency department at the Regina Margherita Children's Hospital. According to our data, the hypothesis of a direct etiologic link between SARS-CoV-2 and chilblain is not confirmed by serologic tests; it is difficult to assess whether in the 4 patients with positive serology SARS-CoV-2 was involved in the pathogenesis of chilblainlike lesions. A limit of our study is the absence of tissue biopsies, so our experimental approach could not rule out the presence of virus in patients' lesions that may induce an interferon-I response.3 As confirmed by other studies,4 the low prevalence (12.5%) of seropositive patients suggests that other pathologic hypotheses should be considered to explain the recent outbreaks of chilblainlike lesions worldwide. Funding sources: None. Conflicts of interest: None disclosed. Reprints not available from the authors. ==== Refs References 1 Piccolo V. Neri I. Filippeschi C. Chilblain-like lesions during COVID-19 epidemic: a preliminary study on 63 patients J Eur Acad Dermatol Venereol 2020 10.1111/jdv.16526 2 de Masson A. Bouaziz J.-D. Sulimovic L. Chilblains are a common cutaneous finding during the COVID-19 pandemic: a retrospective nationwide study from France J Am Acad Dermatol 83 2 2020 667 670 32380219 3 Kolivras A. Dehavay F. Delplace D. Coronavirus (COVID-19) infection-induced chilblains: a case report with histopathologic findings JAAD Case Rep 6 6 2020 489 492 32363225 4 Andina D. Noguera-Morel L. Bascuas-Arribas M. Chilblains in children in the setting of COVID-19 pandemic Pediatr Dermatol 37 3 2020 406 411 32386460
PMC007xxxxxx/PMC7414778.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)32373-2 10.1016/j.jaad.2020.08.016 JAAD Online Telemedicine and the battle for health equity: Translating temporary regulatory orders into sustained policy change Kassamali Bina BA ab Haddadi Nazgol-Sadat MD, MPH c Rashighi Mehdi MD c Cavanaugh-Hussey Margaret MD, MPH ab LaChance Avery MD, MPH ab∗ a Harvard Medical School, Boston, Massachusetts b Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts c Department of Dermatology, University of Massachusetts School of Medicine, Worchester, Massachusetts ∗ Correspondence to: Avery LaChance, MD, MPH, 221 Longwood Ave, Boston, MA 02115 8 8 2020 12 2020 8 8 2020 83 6 e467e468 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: At this moment in the United States, we are battling 2 of the largest public health crises of our time: the coronavirus disease 2019 (COVID-19) pandemic and systemic racism, which has existed for centuries but recently came into sharper public focus. In tandem, these public health crises mean that the COVID-19 pandemic has placed a disproportionate burden of disease incidence, hospitalizations, and deaths on our most vulnerable communities.1 For medical professionals, there has never been a more important time to systematically address health equity in policy and practice. One of the most significant health policy changes during COVID-19 has been the rapid adoption of executive orders, emergency legislation, and regulations to expand access to telehealth services. At the federal level, the Centers for Medicare & Medicaid Services markedly expanded telehealth coverage, including outpatient office visits for new and established patients. All 50 states have broadened telehealth access and decreased regulatory burdens for patients covered by Medicaid plans.2 Most have also released guidelines expanding telehealth access for patients with private plans (Fig 1 ). In response to this and shelter-in-place guidelines, telehealth claims increased by 4347% from March 2019 to March 2020.3 Before the pandemic, ambiguity surrounding Medicaid telehealth policies and coverage was found to be a recurrent barrier to telehealth adoption by safety-net providers.4 Thus, sweeping telehealth coverage gains for patients with Medicaid in particular have been crucial to allow us to continue to care for all patients, especially our most vulnerable, throughout the pandemic.Fig 1 States that have enacted statewide legislative or regulatory policy changes to temporarily expand access or remove barriers to telehealth services during the coronavirus disease 2019 pandemic. AK, Alaska; AL, Alabama; AR, Arkansas; AZ, Arizona; CA, California; CO, Colorado; CT, Connecticut; DC, District of Columbia; DE, Delaware; FL, Florida; GA, Georgia; HI, Hawaii; IA, Iowa; ID, Idaho; IL, Illinois; IN, Indiana; KS, Kansas; KY, Kentucky; LA, Louisiana; MA, Massachusetts; MD, Maryland; ME, Maine; MI, Michigan; MN, Minnesota; MO, Missouri; MS, Mississippi; MT, Montana; NC, North Carolina; ND, North Dakota; NE, Nebraska; NH, New Hampshire; NJ, New Jersey; NM, New Mexico; NV, Nevada; NY, New York; OH, Ohio; OK, Oklahoma; OR, Oregon; PA, Pennsylvania; RI, Rhode Island; SC, South Carolina; SD, South Dakota; TN, Tennessee; TX, Texas; UT, Utah; VA, Virginia; VT, Vermont; WA, Washington; WI, Wisconsin; WV, West Virginia; WY, Wyoming. ∗Private payer coverage already in place or optional. Nearly all of these policy changes, however, will expire at the end of this pandemic. Now is the time for health care providers to advocate for an end to the legislative, regulatory, and technologic barriers to remote care, allowing telehealth access to continue beyond the pandemic. Studies have shown that telehealth can result in significant indirect cost savings, decreased travel time and accompanying work absenteeism, and improved convenience for patients.5 These savings could especially benefit low-income minority patients, many of whom are disproportionately affected by the economic shocks and unemployment caused by the pandemic. Dermatologists have long advocated for expanded telehealth access, but disparities in access to dermatologic care linger in the current reimbursement framework, particularly for the most vulnerable patients. Now more than ever, we should be at the forefront of promoting long-term policy changes that allow for ongoing telehealth coverage. This is particularly important for patients with Medicaid and Medicare, for whom physical disability, transportation limitations, and inflexible work schedules may limit attendance at in-person appointments. As we work to build a more equitable system, we must ensure that our policies do not present telehealth as a luxury service, but rather as a necessary link in the fabric of our health care system: bridging vulnerable populations to care. Additional research must examine how the “digital divide” and various levels of e-health literacy have affected telehealth adoption among marginalized patients during the COVID-19 pandemic. Beyond this research, telehealth equity and health justice will require ongoing advocacy at both state and federal levels to ensure continued access to essential remote care for those who need it most. Funding sources: None. Conflicts of interest: None disclosed. Reprints not available from the authors. ==== Refs References 1 Azar K.M.J. Shen Z. Romanelli R.J. Disparities in outcomes among COVID-19 patients in a large health care system in California Health Aff (Millwood) 39 7 2020 1253 1262 10.1377/hlthaff.2020.00598 32437224 2 Center for Connected Health Policy COVID-19 telehealth coverage policies Available at: https://www.cchpca.org/resources/covid-19-telehealth-coverage-policies Accessed June 1, 2020 3 FH NPIC® database of more than 31 billion privately billed medical and dental claim records from more than 60 contributors nationwide. Copyright 2020, FAIR Health, Inc. All rights reserved. CPT © 2019 American Medical Association (AMA), Available at: https://www.prnewswire.com/news-releases/telehealth-claim-lines-increase-4-347-percent-national-from-march-2019-to-march-2020-301069182.html. Accessed June 1, 2020. 4 Uscher-Pines L. Bouskill K. Sousa J. Shen M. Fischer S. Experiences of Medicaid programs and health centers in implementing telehealth 2019 RAND Corporation Santa Monica, CA 10.7249/rr2564 5 Powell R.E. Henstenburg J.M. Cooper G. Hollander J.E. Rising K.L. Patient perceptions of telehealth primary care video visits Ann Fam Med 15 3 2017 225 229 28483887
PMC007xxxxxx/PMC7417275.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)32414-2 10.1016/j.jaad.2020.08.026 Original Article The risk of respiratory tract infections and interstitial lung disease with interleukin 12/23 and interleukin 23 antagonists in patients with autoimmune diseases: A systematic review and meta-analysis Akiyama Shintaro MD, PhD a Yamada Akihiro MD, PhD ab Micic Dejan MD a Sakuraba Atsushi MD, PhD a∗ a Section of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois b Section of Gastroenterology, Department of Internal Medicine, Toho University Sakura Medical Center, Chiba, Japan ∗ Correspondence to: Atsushi Sakuraba, MD, PhD, Inflammatory Bowel Disease Center, The University of Chicago Medicine, 5841 S Maryland Ave, MC 4076, Chicago, IL 60637. 11 8 2020 3 2021 11 8 2020 84 3 676690 4 8 2020 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Background Respiratory tract infections (RTIs) and interstitial lung disease (ILD) secondary to interleukin (IL) 12/23 or IL-23 antagonists have been reported in autoimmune diseases. Objective To assess the risk of RTIs and noninfectious ILD with these drugs. Methods We conducted a systematic review and meta-analysis of randomized controlled trials. Risk of RTIs and noninfectious ILD was compared to placebo by Mantel-Haenszel risk difference. We divided RTIs into upper RTIs (URTI), viral URTIs, and lower RTIs (LRTIs) including infectious pneumonia. Noninfectious ILD included ILD, eosinophilic pneumonia, and pneumonitis. Results We identified 54 randomized controlled trials including 10,907 patients with 6 IL-12/23 or IL-23 antagonists and 5175 patients with placebo. These drugs significantly increased the risk of RTIs (Mantel-Haenszel risk difference, 0.019; 95% confidence interval, 0.005-0.033; P = .007), which was attributed to URTIs, but not viral URTIs or LRTIs. There was no significant difference in infectious pneumonia and noninfectious ILD between 2 groups. Limitations Because of the rarity of infectious pneumonia and ILD, sensitivity analysis was required. Conclusions The use of IL-12/23 or IL-23 antagonists for autoimmune diseases increased the risk of URTIs, but not viral URTIs, LRTIs, and noninfectious ILD. Key words autoimmune diseases IL12/23 and IL23 antagonists meta-analysis noninfectious interstitial lung disease respiratory tract infections Abbreviations used CD Crohn's disease CI confidence interval FDA US Food and Drug Administration IL interleukin ILD interstitial lung disease LRTI lower respiratory tract infection MedDRA Medical Dictionary for Regulatory Activities MH Mantel-Haenszel OR odds ratio RCT randomized controlled trial RD risk difference RR risk ratio RTI respiratory tract infection URTI upper respiratory tract infection ==== Body pmc Capsule Summary • This meta-analysis showed that IL-12/23 or IL-23 antagonists increased the risk of upper respiratory tract infections (URTIs), but not viral URTIs, lower RTIs, and noninfectious interstitial lung disease in autoimmune diseases. • This result suggests their safe use even during the COVID-19 pandemic, but further observations are required. The clinical benefit of interleukin (IL) 12 and IL-23 inhibition has been shown in psoriasis and Crohn's disease (CD) by briakinumab1 , 2 or ustekinumab.3 , 4 Furthermore, IL-23–specific antagonists, such as tildrakizumab,5 , 6 risankizumab,7 , 8 guselkumab,9 , 10 and brazikumab,11 have completed phase 2 or 3 trials. Currently, IL-12/23 or IL-23 antagonists are the second most commonly prescribed category of biologics for psoriasis and CD, behind anti–tumor necrosis factor agents.12 However, randomized controlled trials (RCTs) of these drugs reported respiratory tract infections (RTIs) as the most common adverse events.13 Furthermore, the surveillance conducted by the US Food and Drug Administration (FDA) reported the development of noninfectious interstitial lung disease (ILD) after ustekinumab.14 Hence, physicians need evidence to decide whether to continue or hold these drugs, particularly during the current COVID-19 pandemic.15, 16, 17 This systematic review and meta-analysis aimed to determine the risk of RTIs and noninfectious ILD with anti–IL-12/23 or anti–IL-23 agents in autoimmune diseases. Methods Search strategy and study selection This meta-analysis was conducted according to an a priori defined protocol based on Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.18 The protocol of this meta-analysis has been submitted to the International Prospective Register of Systematic Reviews (PROSPERO).19 We searched PubMed/MEDLINE, Google Scholar, Scopus, Embase, ClinicalTrials.gov (https://clinicaltrials.gov/), and the Cochrane database from inception to February 1, 2019, to identify studies assessing the efficacy and safety of anti–IL-12/23 and anti–IL-23 therapies in autoimmune diseases. We also searched abstracts from medical conferences and bibliographies of identified articles for additional references. For Google Scholar, only the first 1000 articles were reviewed because this is the maximum number of results provided by the database. When a study registered in ClinicalTrials.gov or presented as an abstract became later available as an article, data were updated accordingly.20 , 21 As for inclusion criteria, we considered RCTs reporting the incidence of adverse events, including RTIs and noninfectious ILD, with anti–IL-12/23 and anti–IL-23 therapies. There were no restrictions regarding age, sex, or duration of the study. We imposed no geographic or language restrictions. Two authors (SA and DM) independently screened each of the potential trials, abstract, and/or full article to determine whether they were eligible for inclusion. Area of disagreement or uncertainty were resolved by consensus among the authors. Studies were identified with the terms “briakinumab,” “ustekinumab,” “tildrakizumab,” “guselkumab,” “risankizumab,” “brazikumab,” “mirikizumab,” “LY2525623,” “anti–interleukin-12/23,” “anti–interleukin-23,” “anti–IL-12/23,” “anti–IL-23,” “anti–interleukin-12,” and “anti–IL-12” (both as medical subject headings and free text terms). RCTs without placebo-controlled groups were excluded. The search strategy is described in Fig 1 .Fig 1 Flow chart of the assessment of the studies identified in the meta-analysis. IL, Interleukin; RCT, randomized controlled trial. Data extraction and quality assessment All data were independently abstracted in duplicate by 2 authors (SA and DM) by using a data extraction form. Data on the study characteristics, such as author name, year of publication, study design, duration, sample size, age of patients, type of medications, and incidence of events were collected. Several published studies included data from multiple RCTs with different regimens or participant characteristics. For instance, the study published by Gordon et al included a comparison between ustekinumab and placebo and another comparison between risankizumab and placebo.7 These comparisons were considered as separate individual RCTs in our meta-analysis to ensure proper comparison and to avoid selection bias. The Jadad score was used to assess the quality of RCTs.22 We also used Cochrane risk-of-bias assessment instrument to evaluate the quality of the RCTs.23 The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was applied to assess the certainty of evidence obtained from this meta-analysis.24 Outcome assessment The primary outcome measure of interest was the risk difference (RD) of the development of RTIs and noninfectious ILD among patients on anti–IL-12/IL-23 or anti–IL-23 agents compared with placebo. Subgroup analyses with each monoclonal antibody and underlying disease were performed. Data were analyzed based on the intention-to-treat principle except where indicated. We determined the number of each adverse event from the articles and the ClinicalTrials.gov database. We sorted RTIs into the following 3 categories: (1) upper RTIs (URTIs), (2) viral URTIs, and (3) lower RTIs (LRTIs). Based on Medical Dictionary for Regulatory Activities (MedDRA) Terminology (https://bioportal.bioontology.org/ontologies/MEDDRA), URTIs included the following diagnoses: nasopharyngitis, laryngitis, pharyngitis, rhinitis, sinusitis, tonsillitis, pharyngotonsillitis, tracheobronchitis, and upper respiratory infection. Viral URTIs included influenza and viral URTI. LRTIs were bronchitis, LRTI, and pneumonia. We included the following diseases in noninfectious ILD: ILD, eosinophilic pneumonia, and pneumonitis. Statistical analysis We undertook a meta-analysis with a random effects model. Mantel-Haenszel (MH) RD was used as our primary method.25 As for rare events, including infectious pneumonia and noninfectious ILD, we performed the sensitivity analysis as described in the “Results” section because of uncertainty regarding the preferred method for rare events. First, we analyzed data by MH odds ratio (OR), Peto OR,26 and MH risk ratio (RR) by excluding double-zero-event studies. Second, data were pooled among each drug, and then meta-analysis was performed by MH RD, MH OR, Peto OR, and MH RR.27 Finally, data were assessed by MH OR, Peto OR, and MH RR by adding 0.5 continuity correction or treatment arm correction to zero-event studies.28 We evaluated the presence of heterogeneity across trials by using the I 2 statistic. An I 2 value of less than 25% indicated low heterogeneity, 25% to 75% indicated moderate heterogeneity, and greater than 75% indicated considerable heterogeneity.29 Heterogeneity was evaluated by using the Cochran Q statistic with a significance level of P < .10.30 Begg and Egger tests were performed to assess publication bias, and funnel plots were constructed to visualize possible asymmetry when 3 or more studies were available.31 , 32 Statistical analyses were performed using Comprehensive Meta-Analysis Software, version 2.0 (Biostat, Englewood, NJ). All statistical tests except for the Q statistic used a 2-sided P value of .05 for significance. Results Study characteristics We identified 21,102 citations through the literature search, excluded 21,030 titles and abstracts after the initial screening, and assessed 72 studies for eligibility. A final number of 43 full-text articles and 2 studies registered only in ClinicalTrials.gov met all eligibility criteria and included 54 RCTs with a total of 10,907 patients with anti–IL-12/IL-23 or anti–IL-23 antibodies and 5175 with placebo (Fig 1). The 54 RCTs included 1 study of brazikumab (59 patients), 8 of briakinumab (1817 patients), 9 of guselkumab (1321 patients), 5 of risankizumab (830), 5 of tildrakizumab (1596 patients), and 26 of ustekinumab (5284 patients). All of the included studies are randomized, double-blind, placebo-controlled studies and have high scores in the Jadad scoring system. The characteristics and outcomes of the included studies are summarized in Table I .33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 The mean ages of patients and percentages of male patients were 43.8 years and 66.6% for guselkumab, 42.8 years and 65.4% for risankizumab, 37.6 years and 62.4% for tildrakizumab, 43.3 years and 49.5% for briakinumab, and 43.3 years and 54.0% for ustekinumab. The percentages of studies that permitted use of concomitant drugs (eg, corticosteroids, budesonide, thiopurines, methotrexate, calcineurin inhibitors, or aminosalicylates) during the trials were 40.0% for risankizumab, 38.5% for ustekinumab, 37.5% for briakinumab, 0% for guselkumab, and 0% for tildrakizumab. As for brazikumab, 1 study for CD was included in this analysis and permitted concomitant drugs (Table I).Table I Characteristics of randomized controlled trials of IL-12/23 or IL-23 antagonists∗ Drugs Target Disease References Age, y Sex, % male Study duration, wk Concomitant therapies during trials Regimen, mg (unless noted otherwise) Jadad score Patients, N RTIs, n Infectious pneumonia, n Noninfectious ILD, n IL-12/23 Placebo IL-12/23 Placebo IL-12/23 Placebo IL-12/23 Placebo Brazikumab IL-23 CD Sands et al (2017)11 37 38 12 Yes 700 IV at wk 0, 4 5 59 60 9 11 0 0 0 0 Guselkumab IL-23 Psoriasis Ohtsuki et al (2018)33 50 68 16 No 50, 100 SC at wk 0, 4, 12 5 128 64 22 7 0 0 0 0 †NCT0290533120 46 68 16 No 100 SC at wk 0, 4, 12 4 62 16 13 1 0 0 0 0 Nemoto et al (2018)34 NA 60 24 No 10, 30, 100, 300 SC (s) 5 20 4 2 0 0 0 0 0 Blauvelt et al (2017)35 44 73 16 No 100 SC at wk 0, 4, 12 5 329 174 55 26 0 0 0 0 Reich et al (2017)10 44 70 16 No 100 SC at wk 0, 4, 12 5 494 248 51 26 0 0 0 0 Gordon et al (2015)9 44 72 16 No 5, 50, 200 SC at wk 0, 4, q12 wk; 15, 100 SC q8 wk 5 207 42 25 3 0 0 0 0 PPP Sofen et al (2014)36 43 63 24 No 10, 30, 100, 300 SC (s) 4 20 4 5 0 0 0 0 0 Healthy volunteer Terui et al (2018)37 52 29 24 No 200 SC at wk 0, 4 5 25 24 8 9 0 0 0 0 Zhuang et al (2016)38 27 96 16 No 0.03, 0.1, 0.3, 1, 3, 10 mg/kg IV; 3 mg/kg SC (s) 5 36 11 5 1 0 0 0 0 Risankizumab IL-23 Psoriasis Gordon et al (2018)7 48 71 16 No 150 SC at wk 0, 4 5 304 102 37 8 0 0 0 0 Gordon et al (2018)7 47 68 16 No 150 SC at wk 0, 4 5 294 98 21 4 0 0 0 0 Krueger et al (2015)39 42 81 24 No 0.01, 0.05, 0.25, 1, 3, 5 mg/kg IV; 0.25, 1 mg/kg SC (s) 5 31 8 11 2 0 0 0 0 Ankylosing spondylitis Baeten et al (2018)64 38 70 16 Yes 18 SC (s); 90, 180 SC at wk 0, 8, 16 5 119 40 31 5 0 0 0 0 CD Feagan et al (2017)8 39 37 12 Yes 200, 600 IV at wk 0, 4, 8 5 82 39 10 5 1 1 0 0 Tildrakizumab IL-23 Psoriasis Reich et al (2017)5 46 67 12 No 100, 200 SC at wk 0, 4 5 617 154 69 17 0 0 0 0 Reich et al (2017)5 46 71 12 No 100, 200 SC at wk 0, 4 5 621 156 76 12 0 0 0 0 Papp et al (2015)6 43 74 16 No 5, 25, 100, 200 SC at wk 0, 4, 16 5 308 45 63 11 0 0 0 0 Healthy volunteer Khalilieh et al (2018)40 26 38 28 No 0.1, 0.5, 3, 10 mg/kg IV (s) 5 22 7 0 0 0 0 0 0 Khalilieh et al (2018)40 27 62 20 No 50, 200 SC (s) 5 28 9 0 0 0 0 0 0 Briakinumab IL-12 IL-23 Psoriasis Gordon et al (2012)1 46 69 12 No 200 SC wk 0, 4; 100 SC wk 8 5 981 484 114 40 2 0 0 0 Gottlieb et al (2011)41 43 67 12 No 200 SC wk 0, 4; 100 SC wk 8 5 138 68 19 8 0 0 0 0 Strober et al (2011)42 45 64 12 No 200 SC wk 0, 4; 100 SC wk 8 5 139 72 20 6 0 0 0 0 Kimball et al (2008)43 46 75 12 No 200 SC (s); 100 SC q2wks for 12 wk; 200 SC q1wk for 4 wk; 200 SC q2wks or q1wk for 12 wk 5 150 30 38 3 0 0 0 0 CD Panaccione et al (2015)2 36 51 12 Yes 200, 400, 700 IV at wk 0, 4, 8 5 200 46 0 0 0 0 0 0 Mannon et al (2004)44 43 25 28 Yes 1, 3 mg/kg SC at wk 0; q1wk from wk 4 to 10 5 32 8 2 0 0 0 0 0 Mannon et al (2004)44 40 20 25 Yes 1, 3 mg/kg SC q1wk for 7 wk 5 31 8 2 0 0 0 0 0 MS Vollmer et al (2011)45 47 25 24 No 200 SC q2wk; 200 SC q1wk 5 146 69 51 29 0 0 0 0 Ustekinumab IL-12 IL-23 Psoriasis Gordon et al (2018)7 48 71 16 No 45 SC (wt ≤ 100 kg); 90 SC (wt > 100 kg) at wk 0, 4 5 100 102 12 8 0 0 0 0 Gordon et al (2018)7 47 68 16 No 45 SC (wt ≤ 100 kg), 90 SC (wt > 100 kg) at wk 0, 4 5 99 98 9 4 0 0 0 0 Landells et al (2015)46 15 49 12 No 0.75 mg/kg SC (wt ≤ 60 kg); 45 SC (60 < wt ≤ 100 kg); 90 SC (wt > 100 kg); 0.375 mg/kg SC (wt ≤ 60 kg); 22.5 SC (60 < wt ≤ 100 kg); 45 SC (>100 kg) at wk 0, 4 5 73 37 16 13 0 0 0 0 Lebwohl et al (2015)47 45 69 12 No 45 SC (wt ≤ 100 kg); 90 SC (wt > 100 kg) at wk 0, 4 5 300 309 38 37 0 0 0 0 Lebwohl et al (2015)47 45 68 12 No 45 SC (wt ≤ 100 kg), 90 SC (wt > 100 kg) at wk 0, 4 5 313 313 32 39 0 0 0 0 Zhu et al (2013)48 40 77 12 No 45 SC at wk 0, 4 5 160 161 28 21 0 0 0 0 Igarashi et al (2012)61 46 80 12 No 45, 90 SC at wk 0, 4 5 126 32 21 4 0 0 1 0 Tsai et al (2011)49 40 85 12 No 45 SC at wk 0, 4 5 61 60 12 10 0 0 0 0 Papp et al (2008)3 45 69 12 No 45, 90 SC at wk 0, 4 5 820 410 119 59 1 1 0 0 Leonardi et al (2008)50 45 69 12 No 45, 90 SC at wk 0, 4 5 510 255 109 52 0 1 0 0 Krueger et al (2007)51 46 59 20 No 45, 90 SC at wk 0, q4wk 5 252 67 95 24 1 0 0 0 PsA Ritchlin et al (2014)62 49 47 16 Yes 45, 90 SC at wk 0, 4, 16 5 207 104 31 15 0 0 0 1 Mclnnes et al (2013)52 48 52 16 Yes 45, 90 SC at wk 0, 4, 16 5 409 205 33 18 0 0 0 0 Gottlieb et al (2009)53 50 59 12 Yes 90 SC q1wk for 4 wk 5 76 70 20 12 0 0 0 0 CD Feagan et al (2016)54 37 40 8 Yes 130 mg, 6 mg/kg IV (s) 5 495 245 23 13 0 0 0 0 Feagan et al (2016)54 39 50 8 Yes 130 mg, 6 mg/kg IV (s) 5 419 208 24 10 0 0 0 0 Sandborn et al (2012)4 39 41 8 Yes 1, 3, 6 mg/kg IV (s) 5 394 132 41 8 0 0 0 0 Sandborn et al (2008)55 40 55 8 Yes 90 SC at wk 0, 1, 2, 3; 4.5 mg/kg IV at wk 0 5 52 52 6 3 0 0 0 0 Atopic dermatitis Khattri et al (2017)56 37 63 16 No 45 SC (wt ≤ 100 kg), 90 SC (wt > 100 kg) at wk 0, 4, 16 5 16 16 2 1 0 0 0 0 Saeki et al (2017)51 39 71 24 No 45, 90 SC at wk 0, 4 5 52 27 15 7 0 0 0 0 GVHD †NCT0171340021 53 63 52 Yes 45 SC (wt ≤ 100 kg), 90 SC (wt > 100 kg) at day -1 and day 20 after transplantation 5 15 15 1 3 0 0 0 0 SLE van Vollenhoven et al (2018)58 40 3 24 Yes 260 (wt 35-55 kg), 390 (55 < wt ≤ 85), 520 (wt > 85 kg) IV wk 0; 90 SC q8wk 5 60 42 21 12 1 0 0 0 Sarcoidosis Judson et al (2014)63 50 51 44 Yes 180 SC wk 0; 90 SC wk 8, 16, 24 5 60 58 40 35 3 0 1 0 MS Segal et al (2008)59 37 36 37 No 27, 90, 180 SC wk 0, 1, 2, 3, 7, 11, 15, 1990 SC q8wks 5 200 49 73 17 0 0 0 0 PPPP Bissonnette et al (2014)60 55 10 16 No 45 SC (wt < 100 kg), 90 SC (wt ≥ 100 kg) at wk 0, 4, 16 5 10 10 0 0 0 0 0 0 PPP Bissonnette et al (2014)60 50 0 16 No 45 SC (wt < 100 kg); 90 SC (wt ≥ 100 kg) at wk 0, 4, 16 5 5 8 0 1 0 1 0 0 CD, Crohn's disease; GVHD, graft-versus-host disease; IL, interleukin; ILD, interstitial lung disease; IV, intravenous; MS, multiple sclerosis; NA, not available; PPP, palmoplantar pustulosis; PPPP, palmoplantar pustular psoriasis; PsA, psoriatic arthritis; q, every; RTI, respiratory tract infection; (s), single dose; SC, subcutaneous; SLE, systemic lupus erythematosus; wt, weight. ∗ Regarding age and sex, data from overall patients in each trials or patients treated IL-12/23 or IL-23 antagonists were used. † This study was registered in ClinicalTrails.gov but later became available as an article. RTIs Meta-analysis with a random effects model showed that the overall risk of RTIs with anti–IL-12/IL-23 or anti–IL-23 agents was significantly higher than that of placebo (MH RD, 0.019; 95% confidence interval [CI], 0.005-0.033; P = .007) (Fig 2 ). The number needed to harm of RTIs was 58.8. Subgroup analysis showed a significantly increased risk of RTIs with briakinumab (MH RD, 0.021; 95% CI, 0.001-0.041; P = .036) and risankizumab (MH RD, 0.040; 95% CI, 0.005-0.076; P = .026). Heterogeneity was absent (I 2 = 0%) in overall and subgroup analyses except for briakinumab (I 2 = 31%). Funnel plot showed no asymmetry, therefore suggesting there were no small-study effects or publication biases, which was supported by Begg and Egger tests (Supplemental Fig 1; available via Mendeley at https://doi.org/10.17632/j7dfkr2s8v.1). We also assessed the differential risk of RTIs by underlying disease and showed a significantly increased risk of RTIs in psoriasis (MH RD, 0.023; 95% CI, 0.010-0.036; P < .001) and ankylosing spondylitis (MH RD, 0.136; 95% CI, 0.006-0.265; P = .040) (Supplemental Fig 2; available via Mendeley at https://doi.org/10.17632/j7dfkr2s8v.1).Fig 2 Meta-analysis of the Mantel-Haenszel (MH) risk difference of respiratory tract infections with IL-12/23 and IL-23 antagonists. CI, Confidence interval; IL, interleukin. We divided RTIs into URTIs, viral URTIs, and LRTIs and investigated each risk with IL-12/23 or IL-23 inhibitors. The overall risk of URTIs was significantly higher in the treatment group compared to placebo (MH RD, 0.017; 95% CI, 0.005-0.029; P = .006) (Supplemental Fig 3, A; available via Mendeley at https://doi.org/10.17632/j7dfkr2s8v.1). Subgroup analysis showed an elevated risk of URTIs with risankizumab (MH RD, 0.028; 95% CI, 0.004-0.053; P = .024). No publication bias was detected by Begg and Egger tests (Supplemental Fig 3, B). Anti–IL-12/IL-23 or anti–IL-23 agents did not increase the overall risks of viral URTIs (MH RD, 0.001; 95% CI, -0.002 to 0.003; P = .60) and LRTIs (MH RD, 0; 95% CI, -0.002 to 0.002; P = .71) (Supplemental Figs 4, A and 5, A; available via Mendeley at https://doi.org/10.17632/j7dfkr2s8v.1). Heterogeneity was absent (I 2 = 0%) in these analyses. Publication bias was indicated in the analysis of viral URTIs (Begg: P < .001; Egger: P = .019) (Supplemental Fig 4, B) and LRTIs (Begg: P < .001; Egger: P = .55) (Supplemental Fig 5, B), but the funnel plots did not appear asymmetric on visual inspection. Infectious pneumonia and noninfectious ILD The total numbers of infectious pneumonia were 9 and 4 cases in the treatment group and placebo, respectively. Mycobacterium tuberculosis and viral pneumonia were not reported. The overall risk of infectious pneumonia was not significantly increased in the treatment group compared to placebo (MH RD, 0; 95% CI, -0.002 to 0.002; P = .87) (Fig 3 ). Heterogeneity was absent (I 2 = 0%). The funnel plot was not asymmetric, indicating no publication bias, which was supported by Egger test (P = .93) but not Begg test (P < .001) (Supplemental Fig 6; available via Mendeley at https://doi.org/10.17632/j7dfkr2s8v.1).Fig 3 Meta-analysis of Mantel-Haenszel (MH) risk difference of infectious pneumonia with IL-12/23 and IL-23 antagonists. CI, Confidence interval; IL, interleukin. In terms of noninfectious ILD, 2 and 1 cases were identified in the treatment and placebo groups, respectively. All 3 cases were reported in trials of ustekinumab and occurred within 16 weeks after initiation of the trial.61, 62, 63 The overall risk of ILD was not significantly increased in the treatment group (MH RD, 0; 95% CI, -0.002 to 0.002; P = .99) (Fig 4 ). Heterogeneity was absent (I 2 = 0%). Begg (P < .001) test was suggestive of publication bias, however the funnel plot was not asymmetric (Supplemental Fig 7; available via Mendeley at https://doi.org/10.17632/j7dfkr2s8v.1).Fig 4 Meta-analysis of the Mantel-Haenszel (MH) risk difference of noninfectious interstitial lung disease with IL-12/23 and IL-23 antagonists. CI, Confidence interval; IL, interleukin. The sensitivity analysis showed consistent results (Supplemental Tables 1-6; available via Mendeley at https://doi.org/10.17632/rdxgpw9yxk.2), except the analysis with 0.5 constant correction of zero-event studies showed a lower risk of infectious pneumonia (Supplemental Table 7; available via Mendeley at https://doi.org/10.17632/rdxgpw9yxk.2) and ILD in the treatment group (Supplemental Table 8; available via Mendeley at https://doi.org/10.17632/rdxgpw9yxk.2). Grading the quality of evidence Based on the GRADE criteria, the overall quality of evidence for this analysis was moderate because infectious pneumonia and ILD were rare events (Supplemental Tables 9 and 10; available via Mendeley at https://doi.org/10.17632/rdxgpw9yxk.2). Discussion Our meta-analysis showed that IL-12/23 or IL-23 inhibitors increased the risk of RTIs, especially URTIs, but not viral URTIs and LRTIs, and noninfectious ILD in autoimmune diseases. We found that risankizumab and briakinumab particularly enhanced the risk of RTIs and hypothesized that concomitant therapies during the trials might differentiate the risk of RTIs. In terms of anti–IL-23 agents, risankizumab showed a higher rate of RCTs that permitted concomitant therapies (40.0%) compared with guselkumab (0%) and tildrakizumab (0%). Among RCTs of risankizumab, the only study reporting an increased risk of RTIs was performed in patients with ankylosing spondylitis, who were permitted to use conventional disease-modifying antirheumatic drugs or low-dose systemic steroids.64 This suggests that combination therapy of anti–IL-23 agents with immunosuppressants might work synergistically to surface the risk of RTIs. As for anti–IL-12/IL-23 agents, each of briakinumab and ustekinumab has a similar percentage of RCTs that permitted concomitant drugs (37.5% for briakinumab and 38.5% for ustekinumab). Other potential risk factors such as age and sex were not different among the drugs. Given that briakinumab has been withdrawn from the application with the FDA because of severe adverse events,1 the difference in risk of RTIs among the 2 drugs would be explained by different properties of these drugs. Our study might support that anti–IL-12/23 and anti–IL-23 therapies can be safely used for autoimmune diseases even during the current COVID-19 pandemic. However, given that influenza vaccination is generally recommended for patients with autoimmune diseases receiving immunosuppressive therapies,65 viral URTIs caused by influenza virus could be prevented in both the treatment and placebo groups, and our finding regarding the risk of viral URTIs might be affected. In addition, studies included in this analysis were conducted before the pandemic and the risk of severe acute respiratory syndrome coronavirus 2 in patients with anti–IL-12/23 or anti–IL-23 therapies could not be assessed. Further studies, particularly during the current pandemic, are necessary to provide enough evidence to ensure the safety of these drugs. Additional investigations are also needed to understand the differential risk of RTIs in psoriasis and ankylosing spondylitis and the mechanism of ILD by IL-12/23 inhibition because patients who are indicated for these drugs, namely psoriasis, rheumatoid arthritis, and inflammatory bowel disease, all carry an increased risk of lung disease.66, 67, 68 IL-12 and IL-23 have fundamental functions in host defense. IL-12 promotes the differentiation of naive T cells into interferon gamma–producing T helper type (Th) 1 cells, which contribute to viral clearance69 and prevent infections of Mycobacterium and Salmonella species.70 Meanwhile, IL-23 maintains IL-17–producing Th17 cells, and the deficiency of IL-17 immunity results in infections of Candida species.71 , 72 Our results showed that IL-12/23 or IL-23 antagonists did not increase the risk of LRTIs and infectious pneumonia, including Mycobacteria tuberculosis or any virus. As for viral RTIs, previous studies showed that IL-17–knockout mice had lower levels of lung inflammation by influenza virus compared with the wild type.73 A study of the Middle East respiratory syndrome coronavirus showed that a patient with a poor outcome had an increased level of IL-17 expression in the lung.69 These data suggest that IL-12/23 or IL-23 inhibitors might theoretically be preventive for severe acute respiratory syndrome coronavirus 2–induced pneumonia rather than detrimental in autoimmune diseases during the COVID-19 pandemic. Limitations First, this study did not assess the long-term effect of IL-12/23 or IL-23 antagonists on RTIs and ILD. However, 92.6% (50/54) of the included studies reported RTIs during placebo-controlled phases. The FDA reported whether the onset of ILD was acute or subacute,14 so our data would most likely include the incidence of these events. Second, regarding infectious pneumonia and ILD, many studies had zero events in both arms (87% [47/54] and 94% [51/54], respectively). Thus, we undertook comprehensive analyses that either included or excluded double-zero-event studies. The analysis with 0.5 constant correction showed a lower risk of these events in the treatment group. We also used treatment arm correction because this method performed better than 0.5 constant correction to examine rare events.74 Third, our study may not reflect the risk in patients at high risk for RTIs because of the possible exclusion of patients with recent RTIs or chronic lung disease in clinical trials. Fourth, we categorized RTIs into URTIs, viral URTIs, and LRTIs based on MedDRA, which is widely used in clinical trials, but not so much in clinical research. Furthermore, the included studies were conducted before the pandemic. Hence, it does not provide evidence of whether there is an increase in RTIs or ILD during the pandemic in patients receiving IL-12/23 or IL-23 antagonists, nor whether these agents can be continued after a diagnosis of COVID-19. A meta-analysis of real-world studies of COVID-19 in patients with autoimmune diseases is needed. Conclusion This meta-analysis showed that IL-12/23 or IL-23 antagonists had an increased risk of URTIs, but not viral URTIs, LRTIs including infectious pneumonia, and noninfectious ILD. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Gordon K.B. Langley R.G. Gottlieb A.B. A phase III, randomized, controlled trial of the fully human IL-12/23 mAb briakinumab in moderate-to-severe psoriasis J Invest Dermatol 132 2012 304 314 22011907 2 Panaccione R. Sandborn W.J. Gordon G.L. Briakinumab for treatment of Crohn's disease: results of a randomized trial Inflamm Bowel Dis 21 2015 1329 1340 25989338 3 Papp K.A. Langley R.G. Lebwohl M. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2) Lancet 371 2008 1675 1684 18486740 4 Sandborn W.J. Gasink C. Gao L.L. Ustekinumab induction and maintenance therapy in refractory Crohn's disease N Engl J Med 367 2012 1519 1528 23075178 5 Reich K. Papp K.A. Blauvelt A. Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials Lancet 390 2017 276 288 28596043 6 Papp K. Thaci D. Reich K. Tildrakizumab (MK-3222), an anti–interleukin-23p19 monoclonal antibody, improves psoriasis in a phase IIb randomized placebo-controlled trial Br J Dermatol 173 2015 930 939 26042589 7 Gordon K.B. Strober B. Lebwohl M. Efficacy and safety of risankizumab in moderate-to-severe plaque psoriasis (UltIMMa-1 and UltIMMa-2): results from two double-blind, randomised, placebo-controlled and ustekinumab-controlled phase 3 trials Lancet 392 2018 650 661 30097359 8 Feagan B.G. Sandborn W.J. D'Haens G. Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn's disease: a randomised, double-blind, placebo-controlled phase 2 study Lancet 389 2017 1699 1709 28411872 9 Gordon K.B. Duffin K.C. Bissonnette R. A phase 2 trial of guselkumab versus adalimumab for plaque psoriasis N Engl J Med 373 2015 136 144 26154787 10 Reich K. Armstrong A.W. Foley P. Efficacy and safety of guselkumab, an anti–interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: results from the phase III, double-blind, placebo- and active comparator-controlled VOYAGE 2 trial J Am Acad Dermatol 76 2017 418 431 28057361 11 Sands B.E. Chen J. Feagan B.G. Efficacy and safety of MEDI2070, an antibody against interleukin 23, in patients with moderate to severe Crohn's disease: a phase 2a study Gastroenterology 153 2017 77 86 28390867 12 Frontanilla D. Vasiliou C. Sawalhi-Leckenby N. Kurniawan A. Crohn's disease: disease coverage. Datamonitor Healthcare Available at: https://pharmastore.informa.com/wp-content/uploads/2018/08/crohnsdisease_5415.pdf 2018 Accessed April 2020 13 Lopez-Ferrer A. Laiz A. Puig L. The safety of ustekinumab for the treatment of psoriatic arthritis Expert Opin Drug Saf 16 2017 733 742 28441904 14 Brinker A. Cheng C. Chan V. Association of noninfectious pneumonia with ustekinumab use JAMA Dermatol 155 2019 221 224 30540343 15 Zumla A. Niederman M.S. Editorial: the explosive epidemic outbreak of novel coronavirus disease 2019 (COVID-19) and the persistent threat of respiratory tract infectious diseases to global health security Curr Opin Pulm Med 26 2020 193 196 32132379 16 Lebwohl M. Rivera-Oyola R. Murrell D.F. Should biologics for psoriasis be interrupted in the era of COVID-19? J Am Acad Dermatol 82 2020 1217 1218 32199889 17 Monteleone G. Ardizzone S. Are patients with inflammatory bowel disease at increased risk for Covid-19 infection? J Crohns Colitis 14 2020 1334 1336 32215548 18 Moher D. Liberati A. Tetzlaff J. Altman D.G. Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement J Clin Epidemiol 62 2009 1006 1012 19631508 19 Booth A. PROSPERO's progress and activities 2012/13 Syst Rev 2 2013 111 24330739 20 Ferris L.K. Ott E. Jiang J. Efficacy and safety of guselkumab, administered with a novel patient-controlled injector (One-Press), for moderate-to-severe psoriasis: results from the phase 3 ORION study J Dermatolog Treat 31 2020 152 159 30887876 21 Pidala J. Beato F. Kim J. In vivo IL-12/IL-23p40 neutralization blocks Th1/Th17 response after allogeneic hematopoietic cell transplantation Haematologica 103 2018 531 539 29242294 22 Jadad A.R. Moore R.A. Carroll D. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17 1996 1 12 8721797 23 Higgins J.P. Altman D.G. Gotzsche P.C. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials BMJ 343 2011 d5928 22008217 24 Guyatt G.H. Oxman A.D. Vist G. GRADE guidelines: 4. rating the quality of evidence—study limitations (risk of bias) J Clin Epidemiol 64 2011 407 415 21247734 25 Friedrich J.O. Adhikari N.K. Beyene J. Inclusion of zero total event trials in meta-analyses maintains analytic consistency and incorporates all available data BMC Med Res Methodol 7 2007 5 17244367 26 Brockhaus A.C. Bender R. Skipka G. The Peto odds ratio viewed as a new effect measure Stat Med 33 2014 4861 4874 25244540 27 Friedenreich C.M. Methods for pooled analyses of epidemiologic studies Epidemiology 4 1993 295 302 8347739 28 Bongartz T. Sutton A.J. Sweeting M.J. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials JAMA 295 2006 2275 2285 16705109 29 Higgins J.P. Thompson S.G. Deeks J.J. Altman D.G. Measuring inconsistency in meta-analyses BMJ 327 2003 557 560 12958120 30 Higgins J. Green S. Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0 2011 The Cochrane Collaboration 31 Begg C.B. Mazumdar M. Operating characteristics of a rank correlation test for publication bias Biometrics 50 1994 1088 1101 7786990 32 Egger M. Davey Smith G. Schneider M. Minder C. Bias in meta-analysis detected by a simple, graphical test BMJ 315 1997 629 634 9310563 33 Ohtsuki M. Kubo H. Morishima H. Guselkumab, an anti-interleukin-23 monoclonal antibody, for the treatment of moderate to severe plaque-type psoriasis in Japanese patients: efficacy and safety results from a phase 3, randomized, double-blind, placebo-controlled study J Dermatol 45 2018 1053 1062 29905383 34 Nemoto O. Hirose K. Shibata S. Li K. Kubo H. Safety and efficacy of guselkumab in Japanese patients with moderate-to-severe plaque psoriasis: a randomized, placebo-controlled, ascending-dose study Br J Dermatol 178 2018 689 696 29222947 35 Blauvelt A. Papp K.A. Griffiths C.E. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: results from the phase III, double-blinded, placebo- and active comparator-controlled VOYAGE 1 trial J Am Acad Dermatol 76 2017 405 417 28057360 36 Sofen H. Smith S. Matheson R.T. Guselkumab (an IL-23-specific mAb) demonstrates clinical and molecular response in patients with moderate-to-severe psoriasis J Allergy Clin Immunol 133 2014 1032 1040 24679469 37 Terui T. Kobayashi S. Okubo Y. Efficacy and safety of guselkumab, an anti-interleukin 23 monoclonal antibody, for palmoplantar pustulosis: a randomized clinical trial JAMA Dermatol 154 2018 309 316 29417135 38 Zhuang Y. Calderon C. Marciniak S.J. Jr. First-in-human study to assess guselkumab (anti-IL-23 mAb) pharmacokinetics/safety in healthy subjects and patients with moderate-to-severe psoriasis Eur J Clin Pharmacol 72 2016 1303 1310 27515978 39 Krueger J.G. Ferris L.K. Menter A. Anti-IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose, randomized, double-blind, placebo-controlled trial J Allergy Clin Immunol 136 2015 116 124 25769911 40 Khalilieh S. Hodsman P. Xu C. Pharmacokinetics of tildrakizumab (MK-3222), an anti-IL-23 monoclonal antibody, after intravenous or subcutaneous administration in healthy subjects Basic Clin Pharmacol Toxicol 123 2018 294 300 29510001 41 Gottlieb A.B. Leonardi C. Kerdel F. Efficacy and safety of briakinumab vs. etanercept and placebo in patients with moderate to severe chronic plaque psoriasis Br J Dermatol 165 2011 652 660 21574983 42 Strober B.E. Crowley J.J. Yamauchi P.S. Olds M. Williams D.A. Efficacy and safety results from a phase III, randomized controlled trial comparing the safety and efficacy of briakinumab with etanercept and placebo in patients with moderate to severe chronic plaque psoriasis Br J Dermatol 165 2011 661 668 21574984 43 Kimball A.B. Gordon K.B. Langley R.G. Safety and efficacy of ABT-874, a fully human interleukin 12/23 monoclonal antibody, in the treatment of moderate to severe chronic plaque psoriasis: results of a randomized, placebo-controlled, phase 2 trial Arch Dermatol 144 2008 200 207 18283176 44 Mannon P.J. Fuss I.J. Mayer L. Anti-interleukin-12 antibody for active Crohn's disease N Engl J Med 351 2004 2069 2079 15537905 45 Vollmer T.L. Wynn D.R. Alam M.S. Valdes J. A phase 2, 24-week, randomized, placebo-controlled, double-blind study examining the efficacy and safety of an anti-interleukin-12 and -23 monoclonal antibody in patients with relapsing-remitting or secondary progressive multiple sclerosis Mult Scler 17 2011 181 191 21135022 46 Landells I. Marano C. Hsu M.C. Ustekinumab in adolescent patients age 12 to 17 years with moderate-to-severe plaque psoriasis: results of the randomized phase 3 CADMUS study J Am Acad Dermatol 73 2015 594 603 26259989 47 Lebwohl M. Strober B. Menter A. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis N Engl J Med 373 2015 1318 1328 26422722 48 Zhu X. Zheng M. Song M. Efficacy and safety of ustekinumab in Chinese patients with moderate to severe plaque-type psoriasis: results from a phase 3 clinical trial (LOTUS) J Drugs Dermatol 12 2013 166 174 23377389 49 Tsai T.F. Ho J.C. Song M. Efficacy and safety of ustekinumab for the treatment of moderate-to-severe psoriasis: a phase III, randomized, placebo-controlled trial in Taiwanese and Korean patients (PEARL) J Dermatol Sci 63 2011 154 163 21741220 50 Leonardi C.L. Kimball A.B. Papp K.A. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1) Lancet 371 2008 1665 1674 18486739 51 Krueger G.G. Langley R.G. Leonardi C. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis N Engl J Med 356 2007 580 592 17287478 52 McInnes I.B. Kavanaugh A. Gottlieb A.B. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial Lancet 382 2013 780 789 23769296 53 Gottlieb A. Menter A. Mendelsohn A. Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomised, double-blind, placebo-controlled, crossover trial Lancet 373 2009 633 640 19217154 54 Feagan B.G. Sandborn W.J. Gasink C. Ustekinumab as induction and maintenance therapy for Crohn's disease N Engl J Med 375 2016 1946 1960 27959607 55 Sandborn W.J. Feagan B.G. Fedorak R.N. A randomized trial of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease Gastroenterology 135 2008 1130 1141 18706417 56 Khattri S. Brunner P.M. Garcet S. Efficacy and safety of ustekinumab treatment in adults with moderate-to-severe atopic dermatitis Exp Dermatol 26 2017 28 35 27304428 57 Saeki H. Kabashima K. Tokura Y. Efficacy and safety of ustekinumab in Japanese patients with severe atopic dermatitis: a randomized, double-blind, placebo-controlled, phase II study Br J Dermatol 177 2017 419 427 28338223 58 van Vollenhoven R.F. Hahn B.H. Tsokos G.C. Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study Lancet 392 2018 1330 1339 30249507 59 Segal B.M. Constantinescu C.S. Raychaudhuri A. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study Lancet Neurol 7 2008 796 804 18703004 60 Bissonnette R. Nigen S. Langley R.G. Increased expression of IL-17A and limited involvement of IL-23 in patients with palmo-plantar (PP) pustular psoriasis or PP pustulosis; results from a randomised controlled trial J Eur Acad Dermatol Venereol 28 2014 1298 1305 24112799 61 Igarashi A. Kato T. Kato M. Efficacy and safety of ustekinumab in Japanese patients with moderate-to-severe plaque-type psoriasis: long-term results from a phase 2/3 clinical trial J Dermatol 39 2012 242 252 21955098 62 Ritchlin C. Rahman P. Kavanaugh A. Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial Ann Rheum Dis 73 2014 990 999 24482301 63 Judson M.A. Baughman R.P. Costabel U. Safety and efficacy of ustekinumab or golimumab in patients with chronic sarcoidosis Eur Respir J 44 2014 1296 1307 25034562 64 Baeten D. Ostergaard M. Wei J.C. Risankizumab, an IL-23 inhibitor, for ankylosing spondylitis: results of a randomised, double-blind, placebo-controlled, proof-of-concept, dose-finding phase 2 study Ann Rheum Dis 77 2018 1295 1302 29945918 65 Lopez A. Mariette X. Bachelez H. Vaccination recommendations for the adult immunosuppressed patient: a systematic review and comprehensive field synopsis J Autoimmun 80 2017 10 27 28381345 66 Kawamoto H. Hara H. Minagawa S. Interstitial pneumonia in psoriasis Mayo Clin Proc Innov Qual Outcomes 2 2018 370 377 30560239 67 Mathai S.C. Danoff S.K. Management of interstitial lung disease associated with connective tissue disease BMJ 352 2016 h6819 26912511 68 Black H. Mendoza M. Murin S. Thoracic manifestations of inflammatory bowel disease Chest 131 2007 524 532 17296657 69 Faure E. Poissy J. Goffard A. Distinct immune response in two MERS-CoV-infected patients: can we go from bench to bedside? PLoS One 9 2014 e88716 24551142 70 Casanova J.L. Abel L. Quintana-Murci L. Immunology taught by human genetics Cold Spring Harb Symp Quant Biol 78 2013 157 172 24092470 71 Yen D. Cheung J. Scheerens H. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6 J Clin Invest 116 2006 1310 1316 16670770 72 Teng M.W. Bowman E.P. McElwee J.J. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases Nat Med 21 2015 719 729 26121196 73 Crowe C.R. Chen K. Pociask D.A. Critical role of IL-17RA in immunopathology of influenza infection J Immunol 183 2009 5301 5310 19783685 74 Sweeting M.J. Sutton A.J. Lambert P.C. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data Stat Med 23 2004 1351 1375 15116347
PMC007xxxxxx/PMC7434450.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)32446-4 10.1016/j.jaad.2020.08.054 JAAD Online Expansion of asynchronous teledermatology during the COVID-19 pandemic Su Mack Y. PhD Das Shinjita MD ∗ Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston ∗ Correspondence to: Shinjita Das, MD, Department of Dermatology, Massachusetts General Hospital, 50 Staniford St, Room 292, Boston, MA 02114 18 8 2020 12 2020 18 8 2020 83 6 e471e472 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: Teledermatology has emerged as a crucial method of delivering care during the coronavirus disease 2019 pandemic. As in-person visits plummeted during the coordinated effort to limit the spread of coronavirus disease 2019,1 teledermatology visits rapidly increased.2 Although significant emphasis has been placed on synchronous telemedicine, such as video or telephone visits, we examine here the expansion of asynchronous telemedicine as a complementary strategy to provide dermatology care during the pandemic. Asynchronous teledermatology in the form of direct-care eVisits (a direct-care asynchronous questionnaire-based encounter via web portal) or provider-to-provider eConsults (provider-to-provider asynchronous consultation via order set in Epic) has demonstrated potential to increase access to dermatology care, with similar patient outcomes.3 , 4 By using store-and-forward technology, asynchronous teledermatology eliminates the need for provider-patient coavailability and provides a safe and convenient method to deliver dermatology care. In response to the pandemic, all in-person dermatology visits except for urgent concerns were suspended at our institution between March 17, 2020, and May 25, 2020. Beyond converting to virtual visits, we accelerated the development and implementation of a pilot direct-care eVisit program. We selected established patients receiving medium- or long-term medications (eg, acne with isotretinoin or psoriasis with biologics) for eVisits. Each eVisit encounter involves patient completion of an online structured questionnaire and submission of photographs, followed by asynchronous dermatologist review and response. Our previously established dermatology eConsult program continued throughout this period. To assess the use of various modalities of dermatology care delivery during the pandemic, we tabulated all in-person visits, virtual visits, eVisits, and eConsults conducted across 12 dermatology clinics affiliated with Massachusetts General Hospital in April 2020. We compared these visit volumes across the same clinics in April 2019. Similar to the experiences of other dermatology departments,2 in-person visits at our institution in April 2020 (n = 67) represented less than 1% of the volume in April 2019 (n = 7919) (Table I ). Meanwhile, 1564 virtual visits were conducted in April 2020 compared with 0 in April 2019. Asynchronous teledermatology visits also increased, driven primarily by eVisits. In April 2020, 197 eVisits were conducted compared with only 3 in April 2019, when the program was in a prepilot phase with only 1 dermatologist testing eVisits. Despite significant nationwide reductions in ambulatory visits,5 provider-to-provider dermatology eConsults increased by more than 20% from April 2019 to April 2020. The growth of eVisits and eConsults resulted in asynchronous teledermatology, accounting for 1 in 5 of all dermatology visits conducted at our institution in April 2020 (Fig 1 ).Table I Volume of dermatology visits in April 2019 and April 2020 April 2019 April 2020 April 2019 (% of all visits) April 2020 (% of all visits) In person 7919 67 98 3 Virtual visit 0 1564 0 77 eVisit 3 197 0 10 eConsult 163 196 2 10 Total 8085 2024 100 100 Virtual visit = synchronous telemedicine via telephone and/or video. eVisit = direct-care asynchronous questionnaire-based encounter via web portal. eConsult = provider-to-provider asynchronous consultation via order set in Epic. Fig 1 Proportion of dermatology visits by type in April 2019 and April 2020. Asynchronous visits are composed of eVisits and eConsults. Teledermatology was our lifeline for maintaining patient care while clinics were closed. Even as clinics reopen, we encourage dermatologists to consider maintaining teledermatology as part of their practice to improve patient access and staff productivity and remain at the forefront of the changing healthcare delivery landscape. More specifically, our experience shows that asynchronous teledermatology has the potential to facilitate routine dermatology care and thus open in-office availability for more urgent issues. Currently, limited reimbursement and efficacy data for asynchronous teledermatology have prohibited its widespread adoption. To address this, we advocate more investigation of asynchronous teledermatology, including patient and provider satisfaction and patient outcomes. Funding sources: None. Conflicts of interest: None disclosed. ==== Refs References 1 Kwatra S.G. Sweren R.J. Grossberg A.L. Dermatology practices as vectors for COVID-19 transmission: a call for immediate cessation of nonemergent dermatology visits J Am Acad Dermatol 82 5 2020 e179 e180 32213307 2 Perkins S. Cohen J.M. Nelson C.A. Bunick C.G. Teledermatology in the era of COVID-19: experience of an academic department of dermatology J Am Acad Dermatol 83 1 2020 e43 e44 32305442 3 Whited J.D. Warshaw E.M. Kapur K. Clinical course outcomes for store and forward teledermatology versus conventional consultation: a randomized trial J Telemed Telecare 19 4 2013 197 204 23666440 4 Pathipati A.S. Ko J.M. Implementation and evaluation of Stanford Health Care Direct-Care teledermatology program SAGE Open Med 4 2016 2050312116659089 5 Mehrotra A. Chernew M. Linetsky D. Hatch H. Cutler D. The impact of the COVID-19 pandemic on outpatient visits: a rebound emerges 2020 To the Point (blog), Commonwealth Fund https://www.commonwealthfund.org/publications/2020/apr/impact-covid-19-outpatient-visits. Accessed July 17, 2020
PMC007xxxxxx/PMC7434615.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)32450-6 10.1016/j.jaad.2020.08.057 Research Letter Skin is a potential host of SARS-CoV-2: A clinical, single-cell transcriptome-profiling and histologic study Sun Yangbai PhD a∗ Zhou Renpeng PhD b Zhang Hao MD c Rong Liu MD de Zhou Wang PhD fg∗ Liang Yimin PhD b∗ Li Qingfeng MD b∗ a Department of Musculoskeletal Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China b Department of Plastic and Reconstructive Surgery, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China c Department of Bone Tumor Surgery, Changzheng Hospital of Second Military Medical University, Shanghai, China d Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China e Department of Intensive Care Unit, Wuhan Leishenshan Hospital, Wuhan, China f Peking-Tsinghua Center for Life Sciences, Tsinghua University, Beijing, China g Qiu-Jiang Bioinformatics Institute, Shanghai, China ∗ Correspondence to: Yangbai Sun, PhD; Wang Zhou, PhD; Yimin Liang, PhD; or Qingfeng Li, MD, Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, 639 Zhi Zao Ju Road, Shanghai 200011, People’s Republic of China. 19 8 2020 12 2020 19 8 2020 83 6 17551757 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide. The lung is the main target organ of SARS-CoV-2; however, extrapulmonary virus distribution1 has been observed. Skin manifestations, including skin rashes, morbilliform exanthema and chilblains,2, 3, 4 have recently been reported as possible presentations in patients with COVID-19. However, the number of such cases has been relatively small, and whether SARS-CoV-2 might infect injured skin and cause COVID-19 is still unknown. We therefore examined whether the skin is a potential host of SARS-CoV-2 by analyzing clinical, histologic, and single-cell transcriptome data. This retrospective analysis included 3128 patients with laboratory-confirmed COVID-19. Data were collected from the Shanghai Public Health Clinical Center and Wuhan Leishenshan Hospital. Skin rashes were present in 52 patients (1.66%). Among them, obvious skin lesions were present in 17 patients (0.54%) before the other symptoms of COVID-19 and in 35 (1.12%) in the early stages of the COVID-19 infection (Fig 1 , A and Supplemental Table I, available via Mendeley at https://data.mendeley.com/datasets/scvph5w5jr/1). The skin rashes were urticarial in 52 patients (52%), followed by papules (15%), erythema and papules (14%), scratch (10%), rhagades (6%), and chilblains (4%).Fig 1 A, Presentation of skin rashes associated with patients with SARS-CoV-2. Left, Localized erythema and papule rash involving the hands. Center, Urticarial rash involving the back. Right, Papular rash on the breast. B, Uniform Manifold Approximation and Projection (UMAP) plot shows the expression levels of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine proteases (TMPRSSs) family genes in skin cells. Coexpression was found in cells in the skin granulosum. C, ACE2 expression in human skin tissue and immunofluorescent staining of viral nucleocapsid protein (NP) in skin tissue from a healthy patient (lower, normal) and a patient with COVID-19 (upper, infected). Scale bar = 50 μm. DAPI, 4′, 6-diamidino-2-phenylindole. Among the 52 patients with skin rashes, 21 patients were treated with oral corticosteroid (prednisone, 10 mg thrice daily), and the average time for skin rash recovery was 4.2 ± 2.3 days. This was significantly shorter than 8.3 ± 5.1 days in patients who were not treated with corticosteroid (Supplemental Table II). Although the use of corticosteroids in treatment of patients with COVID-19 remains controversial,5 our data suggested that skin lesions are associated with COVID-19 and that corticosteroid therapy is effective. To further investigate the association of SARS-CoV-2 and skin rashes present in patients with COVID-19, we performed single-cell RNA sequencing with keratinocytes from normal human skin. The data showed that angiotensin-converting enzyme 2, the viral host cellular receptor, was highly and specifically expressed in the granulosum of the skin, whereas transmembrane serine proteases were relatively scattered in all keratinocytes and melanocytes, and in duct, Schwann, and neurocyte cells. The coexpression of angiotensin-converting enzyme 2 and transmembrane serine proteases was particularly found in the granulosum (Fig 1, B). Nucleocapsid protein was expressed in cytoplasm of epidermis from patients with COVID-19 but was not detected in normal skin tissue (Fig 1, C). These data suggested that the skin is a potential host of SARS-CoV-2. Although this hypothesis needs further study, it is intriguing to conjecture that SARS-CoV-2 may directly infect the keratinocytes in the injured skin (Fig 2 ).Fig 2 The potential risk of SARS-CoV-2 transmission via wounded skin causing COVID-19. ACE2, Angiotensin-converting enzyme 2; TMPRSS, transmembrane serine proteases. In summary we noted in 52 patients with COVID-19, that skin manifestation can be present before the onset of fever or can coexist with fever and that angiotensin-converting enzyme 2 and transmembrane serine proteases were coexpressed in stratum granulosum keratinocytes. These findings highlight the potential risk of SARS-CoV-2 transmission via wounded skin in those with skin manifestations of the disease. Hence, recognition of skin lesions associated with COVID-19 by dermatologists and other health care professionals is essential. Drs Sun, Zhou, and Zhang contributed equally to this work. Funding sources: This work was supported by grants from 10.13039/501100001809 National Natural Science Foundation of China (81701937) and Shanghai Sailing Program (20YF1422800). Conflicts of interest: None disclosed. IRB approval status: The work was performed in accordance with the ethical guidelines of the Instititutional Review Board of the Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University. Reprints not available from the authors. ==== Refs References 1 Xia J. Tong J. Liu M. Shen Y. Guo D. Evaluation of coronavirus in tears and conjunctival secretions of patients with SARS-CoV-2 infection J Med Virol 92 6 2020 589 594 32100876 2 Kolivras A. Dehavay F. Delplace D. Coronavirus (COVID-19) infection-induced chilblains: a case report with histopathologic findings JAAD Case Rep 6 6 2020 489 492 32363225 3 Joob B. Wiwanitkit V. COVID-19 can present with a rash and be mistaken for dengue J Am Acad Dermatol 82 5 2020 e177 32213305 4 Najarian D.J. Morbilliform exanthem associated with COVID-19 JAAD Case Rep 6 6 2020 493 494 32313826 5 Ye Z. Wang Y. Colunga-Lozano L.E. Efficacy and safety of corticosteroids in COVID-19 based on evidence for COVID-19, other coronavirus infections, influenza, community-acquired pneumonia and acute respiratory distress syndrome: a systematic review and meta-analysis CMAJ 192 27 2020 E756 E767 32409522
PMC007xxxxxx/PMC7448764.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)32485-3 10.1016/j.jaad.2020.08.088 JAAD Online Reply to: “Comment on ‘Androgenetic alopecia present in the majority of patients hospitalized with COVID-19’” Wambier Carlos G. MD, PhD ∗ Department of Dermatology, The Warren Alpert Medical School of Brown University, Providence, Rhode Island ∗ Correspondence to: Carlos Gustavo Wambier, MD, PhD, Department of Dermatology, Rhode Island Hospital, 593 Eddy Street, APC Building, 10th Floor, Providence, RI 02903 26 8 2020 1 2021 26 8 2020 84 1 e53e54 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: It is a great pleasure to clarify questions about what is currently known about androgenetic alopecia (AGA) and coronavirus disease 2019 (COVID-19). I thank Bukovac and Makše for their interest in AGA during the pandemic.1 Researchers are encouraged to continue the efforts to understanding of the impact of AGA, regional variations, and the use of androgen-modulating medications in COVID-19. In the descriptive research letter,2 the rates of AGA and age distribution in both sexes were reported among individuals admitted to the hospital due to severe COVID-19 only. It was not a comparative study, nor a study of “correlation with severity of COVID-19.” The awareness of the high incidence of AGA triggered important contributions: increased risk for testing positive among men with full AGA.3 Gabrin sign (Hamilton-Norwood scale [HNS] of 3-7) was associated with worse outcomes among men.4 A comprehensive comparison with previous studies was provided in the Supplemental Materials, (available via Mendeley at https://data.mendeley.com/datasets/jk63cthxbr/2), which included the following disclaimer: “Solid conclusions cannot be made by comparing studies performed at different decades with different populations. The comparison is meant for a general idea of what we know and we don't know. The hypothesis is still to be tested with age and ethnicity-matched controlled studies in patients with COVID-19…” (p. 1). Supplemental Table 3 from that article is provided here for convenience as Table I . Graphs about age-matched comparisons were published in another recent reply letter.4 Table I Comparison by age range of the proportions of 122 men with androgenetic alopecia in the Madrid COVID-19 study versus the Severi et al∗ study <55 y 55-59 y 60-64 y 65-69 y HNS† of 2-7, % Severi et al 62 66 80 85 Madrid COVID-19 70 79 89 90 HNS† of 4-7, % Severi et al 19 20 27 33 Madrid COVID-19 30 50 53 70 ∗ Severi G, Sinclair R, Hopper JL, et al. Androgenetic alopecia in men aged 40-69 years: prevalence and risk factors. Br J Dermatol. 2003;149(6):1207-1213. doi:10.1111/j.1365-2133.2003.05565.x † HNS of >1: Diagnosis of androgenetic alopecia, in Severi et al study reflected frontal only + vertex only + frontal and vertex. HNS of >3: Very severe cases of androgenetic alopecia (or HNS of 4-7) in the Madrid COVID-19 data compared to “frontal and vertex” of Severi et al. HNS of 4a (very severe frontal only) was not computed in the Severi et al numbers, and HNS of 3v (severe frontal with mild vertex involvement) was computed the in Severi et al numbers of the lower part of the table. The Madrid COVID-19 data did not classify 3 and 4 into subcategories, and the Severi et al data did not show the exact HNS scores. Bukovac and Makše attempted interesting comparisons; however, they failed to report that the Supplemental Materials already provided many age-matched comparisons and details of limitations. For example, a gross comparison with an HNS of 4 to 7 was reported, despite the limitations stated in Table I. Further refinement could not be made. Bukovac and Makše speculated with age ranges or AGA classification data not present in the comparative data. The wide-ranged “31% to 53%” made reference to the numeric estimation previously made by researchers reporting a preliminary observation of 41 men admitted for COVID-19, published in the Journal of Cosmetic Dermatology,5 for “clinically significant AGA” (HNS of 3-7) on men with COVID-19 aged 23 to 79 years compared to a similar population. The estimation was not for HNS of 2 to 7, as Bukovac and Makše assumed. The comparison with HNS of 2 to 7 was present in the Supplemental Materials; specifically, and in detail, see Table I. Attempts to convert 2 different scales is intrinsically limited. For example: how could vertex only be converted to an HNS of 3v or HNS of 5? HNS has 3v and 5 depicted with frontal involvement (not vertex only). It is advisable to use the raw data with different data sets that used the HNS. For example, in a study from India, 100% of the patients hospitalized because of COVID-19 had an HNS of 2 to 7 (raw data available via Mendeley at https://doi.org/10.17632/jdkx76y8fz.1),4 which was higher than in the 3 Madrid hospitals. The initial COVID-19 studies reported did not control for sex in the risk stratification. Now, male patients are known to be at increased risk. COVID-19 data can be refined by controlling for use of specific antiandrogens (such as spironolactone, finasteride, and dutasteride) and the presence of the Gabrin sign. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the author. ==== Refs References 1 Bukovac D. Makše U. Comment on “Androgenetic alopecia present in the majority of patients hospitalized.” J Am Acad Dermatol 84 1 2021 e51 e52 32860917 2 Wambier C.G. Vaño-Galván S. McCoy J. Androgenetic alopecia present in the majority of patients hospitalized with COVID-19: the “Gabrin sign.” J Am Acad Dermatol 83 2 2020 680 682 32446821 3 Lee J. Yousaf A. Fang W. Kolodney M. Male balding is a major risk factor for severe COVID-19 J Am Acad Dermatol 2020 10.1016/j.jaad.2020.07.062 4 Wambier C.G. Vaño-Galván S. McCoy J. Pai S. Dhurat R. Goren A. Androgenetic alopecia in COVID-19: compared to age-matched epidemiologic studies and hospital outcomes with or without the Gabrin sign J Am Acad Dermatol 2020 10.1016/j.jaad.2020.07.099 5 Goren A. Vaño-Galván S. Wambier C.G. A preliminary observation: male pattern hair loss among hospitalized COVID-19 patients in Spain—a potential clue to the role of androgens in COVID-19 severity J Cosmet Dermatol 19 7 2020 1545 1547 32301221
PMC007xxxxxx/PMC7455514.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)32499-3 10.1016/j.jaad.2020.08.102 Research Letter Trends in bibliometric indexes of the main dermatology journals (2009 to 2019) Miot Hélio Amante MD, PhD a Ianhez Mayra MD, PhD b Ramos Paulo Müller MD, PhD a∗ a Departmento de Dermatologia e Radioterapia, Universidade Estadual Paulista “Júlio de Mesquita Filho,” Botucatu, Brazil b Departamento de Doenças Infecciosas e Dermatologia, Universidade Federal de Goiás, Goiânia, Brazil ∗ Correspondence to: Paulo Müller Ramos, MD, PhD, Av; Prof. Mário Rubens Guimarães Montenegro, sn, UNESP—São Paulo State University—Campus Botucatu, 18618–687, Botucatu-SP, Brazil 29 8 2020 9 2021 29 8 2020 85 3 782783 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: The 2-year impact factor (IF) from Journal Citation Reports (JCR) is the most commonly used bibliometric index for assessing the influence of a scientific journal. It reproduces the citations of articles within JCR publications over the previous 2 years.1 In 2019, the Journal of the American Academy of Dermatology (JAAD) had 4296 citations from 519 citable articles published in 2018 and 2019, resulting in a 2019 IF calculated as 4296/519 = 8.277. The time trend of a specific journal's IF can reflect effective editorial policies.2 However, self-citations, open access, industry sponsorship, type of article (eg, reviews), amount of citable articles, and social interest (eg, COVID-19) have been proven to influence the IF.2 , 3 Several indexes have been proposed to assess different aspects of scientific influence. For example, the Immediacy Index reflects the citations of articles in the same year they were published, indicating that the contemporaneity of the journal matters. Because up to 20% of a journal's IF can be inflated through self-citations, the 2-year IF without self-citations reflects the actual external influence of the articles. The Eigenfactor Score is a 5-year index weighted by the influence of the citing journals in the entire JCR network, which results in a robust bibliometric index to evaluate the impact of a journal, because self-citations are excluded, despite being inflated by the amount of citable articles of the journal.4 , 5 Here, we report a 10-year analysis on 3 bibliometric indexes of the main dermatology journals: IF, Eigenfactor Score, and Immediacy Index. The median IF of dermatology journals increased by 27.1% (from 1.667 to 2.118), whereas the dermatology journals accounted for in JCR increased by 23.6% (from 55 to 68) between 2010 and 2019. The 5 highest-rated dermatology journals in 2019 accounted for 38.1% of all dermatology citations (107,634 of 282,798). A greater IF increase in the last decade was observed in journals that publish preferably clinical articles (Fig 1 ): JAAD (94%), JAMA Dermatology (83%), and the British Journal of Dermatology (61%).Fig 1 Trends in the 2-year Journal Citation Reports impact factor for the 5 highest-rated dermatology journals. JAAD, Journal of the American Academy of Dermatology—2019: 4296 citations; JAMAderm, JAMA Dermatology—2019: 1834 citations; JID, Journal of Investigative Dermatology—2019: 3486 citations; BJD, British Journal of Dermatology—2019: 3836 citations; JEADV, Journal of the European Academy of Dermatology and Venereology—2019: 2,944 citations. The trend of the Eigenfactor Score for these journals (Fig 2 ) disclosed a noteworthy performance of Journal of the European Academy of Dermatology and Venereology (91%), in contrast to the Journal of Investigative Dermatology (−33%), while the other journals had a slight variation of this index.Fig 2 Trends in the 2-year Journal Citation Reports Eigenfactor Score for the 5 highest-rated dermatology journals. JAAD, Journal of the American Academy of Dermatology—2019: 283 citable articles; JAMAderm, JAMA Dermatology—2019: 109 citable articles; JID, Journal of Investigative Dermatology—2019: 218 citable articles; BJD, British Journal of Dermatology—2019: 237 citable articles; JEADV, Journal of the European Academy of Dermatology and Venereology—2019: 308 citable articles. Finally, the Immediacy Index has confirmed the increase in the rising influence of the dermatology clinical journals: JAAD (388%), British Journal of Dermatology (383%), JAMA Dermatology (235%), and Journal of the European Academy of Dermatology and Venereology (126%). Supplemental Fig 1 (available via Mendeley at https://data.mendeley.com/datasets/t33tkw2cpw/1) presents the trend on Immediacy Index, and Supplemental Table I presents the 2019 most important bibliometric index from the 20 highest-rated dermatology journals. Clinical journals account for most of the citations and overall impact in dermatologic science. The performance of dermatology journals regarding their bibliometric indexes is important in competing for research funding or scholarships.5 Finally, bibliometric indexes are based on the performance of all articles from a specific journal. A high-impact journal is not a guarantee of value for an article published in it, nor are only weak articles published in low-impact journals. Furthermore, it is time to move forward in understanding other bibliometric indexes for a more complete evaluation of journals' scientific influence.4 Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Yuen J. Comparison of Impact Factor, Eigenfactor Metrics, and SCImago Journal Rank Indicator and h-index for neurosurgical and spinal surgical journals World Neurosurg 119 2018 e328 e337 30055360 2 Nestor M.S. Fischer D. Arnold D. Berman B. Del Rosso J.Q. Rethinking the Journal Impact Factor and publishing in the digital age J Clin Aesthet Dermatol 13 1 2020 12 17 3 Mansour A.M. Mollayess G.E. Habib R. Arabi A. Medawar W.A. Bibliometric trends in ophthalmology 1997-2009 Indian J Ophthalmol 63 1 2015 54 58 25686064 4 Time to remodel the journal impact factor Nature 535 7613 2016 466 27466089 5 Rodríguez-Lago L. Molina-Leyva A. Pereiro-Ferreirós M. García-Doval I. Influence of article type on the impact factor of dermatology journals Actas Dermosifiliogr 109 5 2018 432 438 29496199
PMC007xxxxxx/PMC7471802.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)32544-5 10.1016/j.jaad.2020.09.001 Original Article National Psoriasis Foundation COVID-19 Task Force Guidance for Management of Psoriatic Disease During the Pandemic: Version 1 Gelfand Joel M. MD, MSCE ab∗ Armstrong April W. MD, MPH c Bell Stacie PhD d Anesi George L. MD, MSCE, MBE be Blauvelt Andrew MD, MBA f Calabrese Cassandra DO g Dommasch Erica D. MD, MPH h Feldman Steve R. MD, PhD i Gladman Dafna MD, FRCPC jk Kircik Leon MD lm Lebwohl Mark MD l Lo Re Vincent III MD, MSCE bn Martin George MD o Merola Joseph F. MD, MMSc p Scher Jose U. MD q Schwartzman Sergio MD r Treat James R. MD s Van Voorhees Abby S. MD t Ellebrecht Christoph T. MD a Fenner Justine MD l Ocon Anthony MD, PhD u Syed Maha N. MBBS a Weinstein Erica J. MD n Smith Jessica BS d Gondo George MA d Heydon Sue MA d Koons Samantha BS d Ritchlin Christopher T. MD MPH u a Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania b Department of Biostatistics, Epidemiology and Informatics and the Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania c Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, California d National Psoriasis Foundation, Portland, Oregon e Division of Pulmonary, Allergy, and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania f Oregon Medical Research Center, Portland, Oregon g Department of Rheumatology and Immunology, Cleveland Clinic, Cleveland, Ohio h Department of Dermatology, Harvard Medical School, Boston, Massachusetts i Department of Dermatology, Wake Forest School of Medicine, Winston-Salem, North Carolina j Krembil Research Institute, Toronto Western Hospital, Toronto, Ontario, Canada k Psoriatic Arthritis Program, University Health Network, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada l Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York m Department of Dermatology, Indiana University Medical Center, Indianapolis, Indiana n Division of Infectious Diseases, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania o Dermatology Associates, Maui, Hawaii p Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts q Division of Rheumatology, Department of Medicine, New York University Grossman School of Medicine and New York University Langone Orthopedic Hospital, New York, New York r Department of Rheumatology, Hospital for Special Surgery, New York, New York s Department of Pediatric Dermatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania t Department of Dermatology, Eastern Virginia Medical School, Norfolk, Virginia u Division of Allergy, Immunology, and Rheumatology, University of Rochester Medical Center, Rochester, New York ∗ Correspondence to: Joel M. Gelfand, MD, MSCE, Department of Dermatology, Perelman Center for Advanced Medicine, 3400 Civic Center Blvd, Philadelphia, PA, 19104. 4 9 2020 12 2020 4 9 2020 83 6 17041716 2 9 2020 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Objective To provide guidance about management of psoriatic disease during the coronavirus disease 2019 (COVID-19) pandemic. Study design A task force (TF) of 18 physician voting members with expertise in dermatology, rheumatology, epidemiology, infectious diseases, and critical care was convened. The TF was supplemented by nonvoting members, which included fellows and National Psoriasis Foundation (NPF) staff. Clinical questions relevant to the psoriatic disease community were informed by questions received by the NPF. A Delphi process was conducted. Results The TF approved 22 guidance statements. The average of the votes was within the category of agreement for all statements. All guidance statements proposed were recommended, 9 with high consensus and 13 with moderate consensus. Limitations The evidence behind many guidance statements is limited in quality. Conclusion These statements provide guidance for the management of patients with psoriatic disease on topics ranging from how the disease and its treatments impact COVID-19 risk and outcome, how medical care can be optimized during the pandemic, what patients should do to lower their risk of getting infected with severe acute respiratory syndrome coronavirus 2 and what they should do if they develop COVID-19. The guidance is intended to be a living document that will be updated by the TF as data emerge. Key words biologics COVID-19 psoriasis psoriatic arthritis SARS-CoV-2 Abbreviations used CDC Centers for Disease Control and Prevention COVID-19 coronavirus disease 2019 NPF National Psoriasis Foundation SARS COV-2 severe acute respiratory coronavirus 2 TF task force TNF tumor necrosis factor ==== Body pmc Capsule Summary • The National Psoriasis Foundation Coronavirus Disease-19 Task Force produced 22 guidance statements to promote optimal management of psoriatic disease during the pandemic. • Shared decision making is recommended as is adherence to evidence-based recommendations when available. The guidance statements will be updated when necessary in accordance with rapidly evolving science of coronavirus disease 2019. Severe acute respiratory coronavirus 2 (SARS-CoV-2), a single-stranded RNA virus that binds to the angiotensin-converting enzyme 2 receptor and causes the illness called coronavirus disease 2019 (COVID-19), has precipitated devastating personal, economic, and societal repercussions worldwide.1, 2, 3, 4 SARS-CoV-2 usually causes a mild, self-limited illness, but approximately 15% of affected individuals have a more severe, sometimes life-threatening course, with the risk of poor outcomes increasing with age and comorbidities.5, 6, 7 Diffuse alveolar damage and acute respiratory distress syndrome are the most common presentations in severe COVID-19. Additionally, thromboembolic events, along with direct and indirect viral-induced injury, may target the skin, gastrointestinal tract, kidney, heart, and brain, with devastating consequences.8, 9, 10 The type 1 interferon response, which is required to clear the virus, is often insufficient in the early phase of SARS-CoV-2 infection, but a delayed persistent elevation may develop as the illness progresses.11 Profound dysregulation of innate and acquired immunity can occur with more severe COVID-19, including significant lymphopenia as a direct result of viral-induced apoptosis and necrosis of lymphocytes in the spleen and lymph nodes.12 The persistent interferon response can result in systemic hyperinflammation, also known as cytokine storm.13 , 14 Several of the cytokines elevated in severe COVID-19 patients (tumor necrosis factor [TNF], interleukin 6, and interleukin 17) are also elevated in patients with psoriatic disease.15, 16, 17 The current model of COVID-19 is that immune suppression in early infection may be harmful by allowing uncontrolled SARS-CoV-2 replication and dissemination but may be helpful in severe illness by limiting organ damage from a dysregulated hyperimmune response.18 Many treatments used for psoriatic disease directly or indirectly impact immune pathways involved in COVID-19.19, 20, 21, 22 Patients and providers are concerned about the safety of immunomodulating agents in the setting of the COVID-19 pandemic. These concerns are particularly relevant given that many of the comorbidities associated with psoriasis and psoriatic arthritis, including obesity, diabetes, and cardiovascular disease, are risk factors for the development of severe COVID-19.23 , 24 To address the questions posed by patients and providers, the National Psoriasis Foundation (NPF) commissioned a COVID-19 task force (TF) to develop scientifically based guidance that promotes optimal management of psoriatic disease during the pandemic. Methods See the Online Supplement for detailed methods, available via Mendeley Data, V2, at https://doi.org/10.17632/x4mxnjmc76. Establishment of the TF The COVID-19 TF includes 18 physicians with a variety of expertise relevant to decision making in the pandemic from different geographic areas within the United States and Canada, many of whom have frontline experience managing a surge of COVID-19 patients (Supplemental E-Table I, available via Mendeley Data, V1, at https://doi.org/10.17632/2cbs7r7z72.1). The TF was supplemented by nonvoting members, which included 4 trainees in dermatology, rheumatology, and infectious diseases, 1 postdoctoral fellow in epidemiology, as well as senior staff from the NPF. Evidence synthesis The TF co-chairs completed weekly literature searches for COVID-19 in relation to psoriatic disease. TF members also recommended papers of broad importance to COVID-19 related to its basic biology, epidemiology, and treatment. Additional sources of data were obtained from the Centers for Disease Control and Prevention (CDC), World Health Organization, the United States Food and Drug Administration, and the National Institutes of Health. Development of clinical questions The TF met every 2 weeks to discuss the developments in the literature and clinical experience. Clinical questions relevant to the psoriatic disease community were iterated and informed by questions received by the NPF from the broader patient and clinical community. The questions were subdivided into 5 categories, and work groups with balanced expertise were formed. Each TF work group convened to draft responses to the clinical questions based on the available evidence. These responses were reviewed and drafted into guidance statements. Modified Delphi process The guidance statements were presented to the 18 TF members using a modified Delphi process, including 2 rounds of voting with discussion in between. The Delphi approach was based on the RAND appropriateness method, which has been extensively validated.25, 26, 27, 28, 29, 30, 31 TF members were asked to report their level of agreement anonymously with each guidance statement on a scale of 1 to 9. A rating of 1 corresponded to “complete disagreement,” 5 corresponded to “uncertain or neutral,” and 9 corresponded to “complete agreement.” The members were able to provide anonymous written comments. Median vote ratings of 1 to 3, 4 to 6, and 7 to 9 were defined a priori as disagreement, uncertainty/neutral, and agreement, respectively. Panel consensus was determined to be “low” when ≥5 votes fell into the 1 to 3 rating range with ≥5 votes concurrently falling into the 7 to 9 rating range. Consensus was interpreted as “high” if all 18 votes fell within a single tertile, with all other combinations considered as “moderate” levels of consensus. The results were analyzed by the NPF along with an independent analysis of the data by a nonvoting member of the TF, which yielded identical results. Results The NPF COVD-19 TF Delphi was completed over a 2-week period (Supplemental E-Table II, available via Mendeley Data, V1, at https://doi.org/10.17632/2cbs7r7z72). Five categories of questions were explored (Supplemental E-Table III, available via Mendeley Data, V1, at https://doi.org/10.17632/2cbs7r7z72) with 100% complete voting on 22 guidance statements (Table I 32 and Supplemental E-Table IV, available via Mendeley Data, V2, at https://doi.org/10.17632/n78m9f3cpr). The median was within the category of agreement for all statements, with the number of votes outside the range of agreement being only 1 or 2 for statements where agreement was not unanimous. All guidance statements were recommended, 9 with high consensus, and the remainder with moderate consensus.Table I National Psoriasis Foundation COVID-19 Task Force Guidance for Management of Psoriatic Disease During the Pandemic: Version 1 Guidance # Guidance statement Level of consensus 1.1 It is not known with certainty whether having psoriatic disease meaningfully alters the risks of contracting SARS-CoV-2 (the virus that causes COVID-19 illness) or having a worse course of COVID-19 illness. Existing data, with some exceptions, generally suggest that patients with psoriasis and/or psoriatic arthritis have similar rates of SARS-CoV-2 infection and COVID-19 outcomes as the general population. Moderate 1.2 The likelihood of poor outcomes from COVID-19 is driven by risk factors such as older age and comorbidities, such as chronic heart, lung, or kidney disease, and metabolic disorders such as diabetes and obesity. Patients with psoriatic disease are more prone to these comorbidities, particularly in those with more severe disease. High 2.1 It is not known with certainty whether treatments for psoriasis and/or psoriatic arthritis meaningfully alter the risks of contracting SARS-CoV-2 (the virus that causes COVID-19 illness) or having a worse course of COVID-19 illness. Existing data generally suggest that treatments for psoriasis and/or psoriatic arthritis do not meaningfully alter the risk of acquiring SARS-CoV-2 infection or having worse COVID-19 outcomes. Moderate 2.2 It is recommended that patients who are not infected with SARS-CoV-2 continue their biologic or oral therapies for psoriasis and/or psoriatic arthritis in most cases. Shared decision making between clinician and patient is recommended to guide discussions about use of systemic therapies during the pandemic (see Guidance 2.5 for the definition of shared decision making). High 2.3 Chronic systemic corticosteroids should be avoided if possible for the management of psoriatic arthritis. If patients require chronic systemic corticosteroids for management of psoriatic arthritis, the dose should be tapered to the lowest dose necessary to achieve the desired therapeutic effect. Chronic systemic corticosteroid use for the treatment of psoriatic disease at the time of acute infection with SARS-CoV-2 may be associated with worse outcomes from COVID-19 illness. It is important to note, however, that corticosteroids may improve outcomes for COVID-19 when initiated in hospitalized patients requiring oxygen treatment. High 2.4 Individuals newly diagnosed with psoriasis and/or psoriatic arthritis or who are currently not receiving treatment should be aware that untreated psoriatic disease is associated with serious impact on physical and emotional health and, in the case of psoriatic arthritis, can lead to permanent joint damage and disability. Shared decision making between clinician and patient is recommended to guide discussions about use of systemic therapies during the pandemic (see Guidance 2.5 for shared decision making). High 2.5 Providers recommend shared decision making with patients. Shared decision making between clinician and patient should be guided by several factors, including the potential benefits of treatment, the activity of skin and/or joint disease, and response to previous therapies, as well as the patient's underlying risk for poor COVID-19 outcomes and ability to maintain measures to prevent infection with SARS-CoV-2, such as hand hygiene, wearing of masks, and physical distancing, as required by pandemic conditions. A review of known benefits of treatment accompanied by acknowledgment of the uncertainty related to the COVID-19 pandemic and a discussion of a patient's individual circumstances and preferences should guide decision making. Moderate 3.1 Telemedicine should be offered to manage patients wherever possible when local restrictions or pandemic conditions limit the ability for in-person visits. The following patients can be managed with telemedicine: Patients who are clinically stable and previously started on psoriatic disease treatment. Patients requiring a follow-up visit and refills for medication. New patients without timely access to in-person visits. Patients diagnosed with COVID-19 who are experiencing a significant flare. If telemedicine visits become inadequate to monitor patients' disease progress or manage new or evolving symptoms or signs of skin and joint disease, clinicians and patients should consider in-person visits. Moderate 3.2 The following patients should be considered for in-person care if pandemic conditions allow (ie, the clinical practice is open to see patients in person): Patients at risk for melanoma and nonmelanoma skin cancer should be seen in person at a frequency consistent with standard of care for a full skin examination. New patients establishing care. Patients experiencing unstable psoriatic disease/flares. Patients requiring a thorough skin/or joint examination and a full physical examination for rheumatology patients. Moderate 3.3 Providers recommend the recent guidelines published by Lim et al33 on how to optimize safety of office phototherapy for the patients and staff in the setting of the pandemic. See Table II for details. High 4.1 Patients should be advised to follow measures that prevent infection with SARS-CoV-2. These preventative measures include to practice good hand hygiene, to maintain physical distancing from nonhousehold members, and to wear a face covering of the nose and mouth when indoors (except in their own home), and when outdoors but unable to maintain physical distancing. Face coverings should not be used in children under 2 years old due to risk of suffocation. See Supplemental E-Table VI for details. High 4.2 Patients with psoriatic disease should follow measures to prevent infection with SARS-CoV-2 in the work place. If the work place environment does not allow for maintenance of prevention measures, a shared decision-making process between the patient and his/her clinician is recommended to determine whether specific accommodations are medically necessary, especially for individuals who, due to age or underlying health conditions, are at especially high risk for poor COVID-19 outcomes. Moderate 4.3 Youth with psoriatic disease should follow measures to prevent infection with SARS-CoV-2 while at school. These measures include maintaining 6 feet of physical distancing, consistently wearing masks if over the age of 2 years, and washing hands frequently. If the school environment is unable to ensure these prevention measures or families believe their child may not be able to adhere to these practices, we encourage discussion with the patient, caregivers, and his/her clinician to collectively develop a learning plan in the best interest and safety of the child. High 4.4. Patients with psoriatic disease should receive the seasonal inactivated (eg, killed) influenza vaccine when it becomes available. While this vaccine will not protect against SARS-CoV-2, influenza vaccine lowers the risk of infection from seasonal influenza, which is of special importance to individual and public health during the COVID-19 pandemic. Patients taking systemic medications for psoriasis or psoriatic arthritis should discuss the timing of the influenza vaccination with respect to their systemic psoriatic medications with their health care provider in order to optimize the response to the influenza vaccine. High 5.1 Patients with psoriatic disease who become infected with SARS-CoV-2 should monitor their symptoms and discuss the management of their treatments with their health care providers. Moderate 5.2 Patients with psoriatic disease who become infected with SARS-CoV-2 should be prescribed and adhere to evidence-based COVID-19 therapies. Evidence-based therapies should be used, currently including supportive care for patients with mild disease, as well as dexamethasone (systemic corticosteroids) and remdesivir treatment, if available, for hospitalized patients requiring supplemental oxygen. The care of the hospitalized patient should include consultation with rheumatologists, dermatologists, and/or infectious disease specialists as medically necessary. Moderate 5.3 Systemic corticosteroids for the management of COVID-19 in patients with psoriatic disease are not contraindicated and should not be withheld due to the concern of potentially flaring psoriasis upon withdrawal of corticosteroids when evidence demonstrates the effectiveness for treating COVID-19 illness. Moderate 5.4 Hydroxychloroquine or chloroquine are not recommended for the prevention or treatment of COVID-19 in patients with psoriatic disease outside of a clinical trial. Cases of psoriasis flare have been reported in patients on antimalarial medications, but the clinical significance is not well understood. High 5.5 Resumption of psoriasis and/or psoriatic arthritis treatments held during SARS-CoV-2 infection should be decided on a case-by-case basis. Most patients can restart psoriasis and/or psoriatic arthritis treatments after complete resolution of COVID-19 symptoms. In those who have had a severe hospital course, shared decision making made on a case-by-case basis is recommended. Moderate 5.6 Patients with psoriatic disease should be aware that infection with SARS-CoV-2 may result in a flare of psoriasis based on case reports. The clinical significance of the risk of COVID-19 flaring psoriasis is not known. Moderate 5.7 Patients with psoriatic disease who become infected with SARS-CoV-2 should follow CDC guidance on home isolation and discuss with their health care providers when they can end home isolation. We recommend waiting a minimum of 10 days after COVID-19 symptom onset, along with fever resolution for 24 hours, without antipyretics, and improvement in other symptoms before ending home isolation and returning to work, as patients are unlikely to be infectious after this point. In patients with severe cases of COVID-19 or when patients with psoriasis are on medications with immunosuppressive effects, we recommend a case-by-case approach to determining the length of home isolation. Moderate 5.8 Patients with close contact to someone with SARS-CoV-2 infection should quarantine themselves for 14 days after the last contact and discuss the management of their psoriatic disease treatment with their medical provider(s). Moderate CDC, Centers for Disease Control and Prevention; COVID-19, coronavirus disease 2019; SARS-Cov-2, severe acute respiratory syndrome coronavirus 2. Category 1: What are the effects of psoriatic disease itself on SARS-CoV-2 infection and COVID-19 illness? Patients with psoriatic disease appear to have similar rates of infection with SARS-CoV-2 and COVID-19 outcomes33, 34, 35, 36, 37 as the general population (Guidance 1.1). However, uncertainty remains regarding this question. First, a few reports suggest that patients with psoriasis may be more prone to infection with COVID-19 or have worse outcomes.38, 39, 40 For example, a United Kingdom study with more than 17 million patients found a small but statistically increased risk of death from COVID-19 (fully adjusted hazards ratio, 1.19; 95% confidence interval, 1.11-1.27) in individuals with psoriasis, rheumatoid arthritis, or lupus.39 It is unknown from this study the degree to which the observed finding is driven by psoriasis, its severity, or treatment. Additionally, patients with psoriatic disease may be prone to thrombotic complications that can also occur in COVID-19.41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 There was unanimous agreement that severity of COVID-19 is driven by risk factors such as older age and comorbidities (Guidance 1.2).33 , 36 , 37 , 39 , 56, 57, 58, 59 Psoriatic disease—particularly severe psoriasis—is associated with many of the comorbidities that drive COVID-19 mortality.45 , 49 , 60 Category 2: What are the effects of psoriasis or psoriatic arthritis treatment on SARS-CoV-2 infection and COVID-19 illness? The existing literature suggests that treatments for psoriasis or psoriatic arthritis, or both, do not meaningfully alter the risk of acquiring SARS-CoV-2 infection or having worse COVID-19 outcomes (Guidance 2.1).34 , 36 , 37 , 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85 Cyclosporine, the most broadly immunosuppressive of psoriasis treatments, was not found to alter the risk of COVID-19 in 130 patients in Italy with psoriasis or atopic dermatitis (2 became infected with SARS-CoV-2 and recovered without hospitalization).70 This study lacked a comparison group and was too small to reach definitive conclusions. One study suggested that patients with psoriasis on biologics were more likely to be hospitalized for COVID-19 but did not adjust for risk factors known to drive poor COVID-19 outcomes.86 The rheumatology literature also suggests that treatments used for psoriatic disease, such as TNF inhibitors and methotrexate, do not negatively impact COVID-19,87, 88, 89, 90 with 1 large registry (600 case reports from 40 countries) finding that TNF inhibitors are associated with a reduced adjusted odds of COVID-19 hospitalization compared with patients with rheumatic conditions not treated with TNF inhibitors.90 Similarly, adverse effects of TNF inhibitors on COVID-19 were not observed in large registries of patients with inflammatory bowel disease.91 , 92 Small case series have reported poor COVID-19 outcomes in patients on Janus kinase inhibitors for psoriatic arthritis93 and secukinumab for ankylosing spondylitis89; however, these isolated reports could be due to selection bias, chance, or underlying comorbidity. By contrast, an analysis of approximately 1400 patients from the rheumatology, gastroenterology, and dermatology literature concluded that biologic or targeted synthetic disease-modifying antirheumatic drug therapy has not been associated with more severe COVID-19 outcomes.33 Given these data, patients who are not infected with SARS-CoV-2 should continue their biologic or oral therapies for psoriasis or psoriatic arthritis in most cases (Guidance 2.2). Nevertheless, the existing literature is largely based on small case series or large registries of spontaneous reports, and therefore, shared decision-making between clinician and patient is recommended (Guidance 2.2, 2.4, and 2.5). By contrast, studies in the rheumatology and gastroenterology literature have observed that long-term use of oral corticosteroids is associated with worse COVID-19 outcomes (ie, hospitalization or a composite outcome of any or all of intensive care unit admission, ventilator use, or death).33 , 90 , 91 Chronic systemic corticosteroids should be avoided, if possible, for the management of psoriatic arthritis (Guidance 2.3).19 Category 3: How should medical care be delivered to patients with psoriatic disease to lower their risk of infection with SARS-CoV-2 while still ensuring quality of care? The pandemic has disrupted the ability of patients and providers ability to meet in person due to personal protective equipment shortages, measures implemented to lower risk of SARS-CoV-2 transmission, and patients’ personal and economic hardships.94, 95, 96, 97 Patients express concern about being exposed to SARS-CoV-2 in the clinical setting either directly or indirectly (ie, on public transportation). Telemedicine can achieve similar outcomes for psoriasis patients compared with in-person care with a dermatologist98, 99, 100; however, limited information is available on the management of psoriatic arthritis with telemedicine.32 , 101 Telemedicine should be considered when pandemic conditions limit in-person visits (Guidance 3.1).102 However, there are limitations of telemedicine, and therefore, some patients should be evaluated in person (Guidance 3.2). Office-based phototherapy remains an important option for patients with psoriasis (Guidance 3.3, Table II ).103 , 104 Table II Methods to reduce risk of SARS-CoV-2 transmission during delivery of office-based phototherapy∗ Patient protocol Staff protocol • Screened for signs and symptoms of COVID-19 before entering the unit, understanding that treatment will be denied to symptomatic patients. • Attend the phototherapy appointment alone. Minors can be accompanied by a guardian, given all safety protocols are observed • Apply hand sanitizer upon entering and leaving the unit • Patient provided with goggles must sanitize them thoroughly, according to the manufacturer's instruction • Wear a mask, unless phototherapy treatment of the face is required • Practice physical distancing • Schedule patients approximately 30 minutes apart per booth • Practice physical distancing, particularly in waiting area, with seats 6 feet apart. • Wear a mask, eye protection, and apply hand sanitizer before and after each patient encounter. • Avoid turning on the fan of the phototherapy unit if possible; if need be, treatment can be fractionated to avoid excessive heat build-up in the unit • Disinfect high-touch surfaces in the changing area after each patient • Disinfect high-touch area of the phototherapy equipment in between patients • Provide patients with disposable bags to store personal items • Provide goggles to patients if need be; ensuring they are sanitized thoroughly and stored in an individual bag COVID-19, Coronavirus disease 2019; SARS-Cov-2, severe acute respiratory syndrome coronavirus 2. ∗ Adapted from Lim et al.103 Category 4: What should patients with psoriatic disease do to protect themselves from becoming infected with SARS-CoV-2? Patients should be advised to follow measures that prevent infection with SARS-CoV-2 (Guidance 4.1; E-Table VI, available via Mendeley Data, V2, at https://doi.org/10.17632/w5m8jf94m8).105 These prevention measures should be followed at work (Guidance 4.2) and school (Guidance 4.3). In cases where measures to prevent transmission of SARS-CoV-2 at work or school cannot be maintained, shared decision making is recommended to determine whether specific accommodations are medically necessary (Guidance 4.2 and 4.3). Psoriasis, even when involving the face or hands, is not a contraindication to face coverings and hand washing, respectively, and a variety of approaches can be applied to mitigate skin irritation (E-Table VII, available via Mendeley Data, V2, at https://doi.org/10.17632/w5m8jf94m8).106, 107, 108 Patients with psoriatic disease should receive the seasonal inactivated (eg, killed) influenza vaccine, which is of special importance to individual and public health during the COVID-19 pandemic (Guidance 4.4). Providers may consider temporary discontinuation of methotrexate for 2 weeks after the influenza immunization to improve the immunogenicity of the seasonal influenza vaccine.109 Category 5: What should patients with psoriatic disease do if they become infected with SARS-CoV-2? Patients with psoriatic disease who become infected with SARS-CoV-2 should monitor their symptoms (Supplemental E-Table VIII), discuss management of their psoriatic disease treatments with their health care providers, and should be prescribed and adhere to evidence-based COVID-19 treatments, if available (Guidance 5.1 and 5.2).85 , 110, 111, 112 The mortality benefit of initiation of corticosteroids in patients with severe COVID-19 outweighs the risks of potentially precipitating a psoriasis flare, and therefore, acute systemic corticosteroids are not contraindicated for the management of COVID-19 in patients with psoriatic disease (Guidance 5.3).112, 113 On the basis of limited available data, and to be consistent with prescribing information, it may be prudent to hold treatments that target the immune system in the setting of suspected or confirmed SARS-CoV-2 infection, but the final decision needs to be determined on a case-by-case basis. Consistent with guidance from the Food and Drug Administration and the American College of Physicians, the use of hydroxychloroquine or chloroquine is not recommended to prevent or treat COVID-19 in patients with psoriatic disease outside of a clinical trial (guidance 5.4).114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126 Patients with psoriatic disease should be aware that infection with SARS-CoV-2 may result in a flare of psoriasis, which may occur due to discontinuation of psoriasis treatments, treatment of COVID-19 with antimalarial drugs, or due to triggering of inflammation as part of COVID-19 illness (Guidance 5.6).125 , 127, 128, 129 Patients with psoriatic disease who become infected with SARS-CoV-2 should follow CDC guidance130, 131, 132, 133 on home isolation and discuss with their health care providers when they can end home quarantine (Guidance 5.7; Supplemental E-Table IX).130 , 134 , 135 In the event someone with psoriatic disease has close contact (Supplemental E-Table X) with an individual with suspected or confirmed SARS-CoV-2 infection, they should quarantine for 14 days after the last contact, according to CDC guidelines (Guidance 5.8).136 The decision regarding continuing or holding psoriasis treatments during a period of quarantine should be individualized on a case-by-case basis between patient and provider. Resumption of psoriasis or psoriatic arthritis treatments held during SARS-CoV-2 infection should be decided on a case-by-case basis (Guidance 5.5). The persistence of 1 or more symptoms of COVID-19, such as fatigue or joint pain, beyond the acute phase of the illness can occur137 and may complicate the decision to restart psoriasis or psoriatic arthritis medications. Therefore, shared decision making is recommended (Guidance 2.5). Discussion The NPF COVID-19 TF guidance statements serve to promote optimal management of psoriatic disease during the pandemic. There are several strengths to the approach taken. First, the TF assembled is a geographically diverse team that has expertise in adult and pediatric dermatology, rheumatology, critical care, infectious diseases, epidemiology, and basic and translational immunology, with experience managing surges in COVID-19. The TF also includes trainees in dermatology, rheumatology, and infectious disease, who are on the frontlines managing patients with COVID-19, as well as senior staff from the NPF who are in touch daily with patients and providers worldwide whose questions are brought to the TF. Second, we have established a robust process for staying up-to-date with the latest literature relevant to COVID-19 and the management of psoriatic disease resulting in the dissemination and evaluation of hundreds of peer reviewed publications by the TF. Third, a validated Delphi approach enabled transparency and reproducibility of our process for evaluating consensus statements.25, 26, 27, 28, 29, 30, 31 Several limitations are acknowledged. First, the TF did not formally grade the strength of our recommendations.138 With the exception of guidance statements 4.4, 5.2, and 5.4, which are based on large-scale randomized controlled trials, the evidence behind many of the guidance statements was often limited in quality. For example, studies evaluating the safety of treatments for psoriasis and psoriatic arthritis in the setting of COVID-19 involve small case series or large collections of case reports and thus should be considered preliminary. Large-scale, longer-term, population-based studies with appropriate comparator groups, adjustment for relevant confounding variables, and complete ascertainment of clinically important COVID-19 outcomes are urgently needed. Second, the guidance is not intended to be proscriptive or comprehensive. The ultimate judgment regarding how these recommendations should be followed is best left with the treating clinician and the patient in light of the circumstances presented by the individual patient and the variability and biologic behavior of the disease and therapeutics. Third, the TF does not have global representation of experts or direct inclusion of patients. The guidance statements are intended to be part of a “living” document that will be updated and amended when necessary by the rapidly evolving science of COVID-19. Readers are encouraged to visit https://www.psoriasis.org/covid-19-resource-center regularly for the latest guidance from the TF in order to promote optimal care and outcomes for patients with psoriatic disease during the pandemic. The authors thank Monika Goyal, MD, MSCE, for her expert input on guidance statement 4.3. Funding sources: None. Conflicts of interest: Dr Anesi has pending fees from UpToDate for authoring COVID-19 clinical reference material, and research time is supported by the 10.13039/100000133 Agency for Healthcare Research and Quality K12HS026372. Dr Armstrong has served as a research investigator and/or scientific advisor to LEO Pharma, AbbVie, UCB, Janssen, Eli Lilly and Company, Novartis, Ortho Dermatologics, Sun, Dermavant, BMS, Sanofi, Regeneron, Dermira, and Modmed. Dr Blauvelt has served as a scientific adviser and/or clinical study investigator for AbbVie, Almirall, Arena, Athenex, Boehringer Ingelheim, Bristol-Myers Squibb, Dermavant, Eli Lilly and Company, Forte, Galderma, Incyte, Janssen, LEO Pharma, Novartis, Pfizer, Rapt, Regeneron, Sanofi Genzyme, Sun Pharma, and UCB Pharma, and as a paid speaker for AbbVie. Authors Bell, Gondo, Heydon, Koons, and Smith are employees of the National Psoriasis Foundation. Dr Calabrese is a speaker for Sanofi-Regeneron and a consultant for AbbVie. Dr Feldman received research, speaking, and/or consulting support from 10.13039/501100009754 Galderma , GSK/Stiefel, Almirall, Alvotech, LEO Pharma, BMS, Boehringer Ingelheim, 10.13039/100016259 Mylan , 10.13039/100006436 Celgene , 10.13039/100004319 Pfizer , Ortho Dermatology, 10.13039/100006483 AbbVie , 10.13039/100004358 Samsung , Janssen, 10.13039/100004312 Lilly , Menlo, 10.13039/100004334 Merck , 10.13039/100004336 Novartis , 10.13039/100009857 Regeneron , 10.13039/100004339 Sanofi , Novan, Qurient, National Biological Corporation, Caremark, Advance Medical, 10.13039/501100013671 Sun Pharma , Suncare Research, Informa, UpToDate, and the 10.13039/100003185 National Psoriasis Foundation . Dr Feldman also consults for others through Guidepoint Global, Gerson Lehrman, and other consulting organizations, is the founder and majority owner of www.DrScore.com, and is also a founder and part owner of Causa Research, a company dedicated to enhancing patients' adherence to treatment. Dr Gelfand served as a consultant for Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Janssen Biologics, Novartis Corp, Regeneron, UCB (Data Safety and Monitoring Board), Sanofi, and Pfizer, receiving honoraria; in addition, he receives research grants (to the Trustees of the University of Pennsylvania) from 10.13039/100006483 AbbVie , Janssen, 10.13039/100004336 Novartis , 10.13039/100004339 Sanofi , 10.13039/100006436 Celgene , Ortho Dermatologics, and 10.13039/100004319 Pfizer , has received payment for CME work related to psoriasis that was supported indirectly by 10.13039/100004312 Eli Lilly and Company and Ortho Dermatologics, is a co-patent holder of resiquimod for treatment of cutaneous T-cell lymphoma, and is a deputy editor for the Journal of Investigative Dermatology, receiving honoraria from the Society for Investigative Dermatology. Dr Gladman is a consultant for AbbVie, Amgen, BMS, Galapagos, Gilead, Eli Lilly and Company, Janssen, Novartis, Pfizer, and UCB, and receives grants from 10.13039/100006483 AbbVie , 10.13039/100002429 Amgen , Eli Lilly, Janssen, 10.13039/100004336 Novartis , 10.13039/100004319 Pfizer , and 10.13039/100011110 UCB . Dr Kircik has served as an investigator, consultant, or speaker for AbbVie, Almirall, Amgen, Arcutis, Bausch Health Canada, Bristol-Myers Squibb, Boehringer Ingelheim, Cellceutix, Celgene, Coherus, Dermavant, Dermira, Eli Lilly and Company, LEO Pharma, MC2, Maruho, Novartis, Ortho Dermatologics, Pfizer, Dr. Reddy's Laboratories, Sun Pharma, UCB, Taro, and Xenoport. Dr Lebwohl is an employee of Mount Sinai and receives research funds from 10.13039/100006483 AbbVie , 10.13039/100002429 Amgen , Arcutis, Boehringer Ingelheim, Dermavant, 10.13039/100004312 Eli Lilly and Company , Incyte, 10.13039/100005205 Janssen Research & Development , LLC, LEO Pharma, Ortho Dermatologics, 10.13039/100004319 Pfizer , and 10.13039/100011110 UCB , and is a consultant for Aditum Bio, Allergan, Almirall, Arcutis Inc, Avotres Therapeutics, BirchBioMed Inc, BMD Skincare, Boehringer-Ingelheim, Bristol-Myers Squibb, Cara Therapeutics, Castle Biosciences, Corrona, Dermavant Sciences, Evelo, Facilitate International Dermatologic Education, Foundation for Research and Education in Dermatology, Inozyme Pharma, Kyowa Kirin, LEO Pharma, Meiji Seika Pharma, Menlo, Mitsubishi, Neuroderm, Pfizer, Promius/Dr. Reddy's Laboratories, Serono, Theravance, and Verrica. Dr Martin is a consultant for Almirall, Athenex, Bristol-Meyers Squibb, Celgene, Eli Lilly and Company, LEO Pharma, Ortho Dermatologic, Pfizer, and UCB, and is a scientific advisor for Almirall, Athenex, Bristol-Meyers Squibb, Celgene, Eli Lilly and Company, Janssen, LEO Pharma, Ortho Dermatologic, Pfizer, and UCB. Dr Merola is a consultant and/or investigator for Bristol-Myers Squibb, AbbVie, Dermavant, Eli Lilly and Company, Novartis, Janssen, UCB, Sun Pharma, Pfizer, and EMD Sorono. Dr Ritchlin reports personal fees from AbbVie, Amgen, Janssen, Novartis, UCB, and Boerhinger Ingelheim, and grants from 10.13039/100002429 Amgen , 10.13039/100011110 UCB , and 10.13039/100006483 AbbVie outside the submitted work. Dr Schwartzman is a speaker for AbbVie, Genentech, Janssen, Eli Lilly and Company, Novartis, Pfizer, and UCB, owns stock in Amgen, Boston Scientific, Gilead, Medtronic, and Pfizer, is a consultant for AbbVie, Myriad, Janssen, Gilead, Eli Lilly and Company, Novartis, and UCB, is a scientific advisory board member for Myriad, and is a board member of the National Psoriasis Foundation. Dr Scher is a consultant for UCB, Janssen, AbbVie, Pfizer, Novastis, and Sanofi. Dr Syed is supported by a grant from 10.13039/100004319 Pfizer . Dr Van Voorhees has been an investigator for Celgene, Eli Lilly and Company, and AbbVie, and has been an advisor/consultant for AbbVie, Allergan, AstraZeneca, Celgene, Dermira, Merck, Novartis, Pfizer, UCB, and Valeant. Drs Weinstein, Ellebrecht, Ocon, Fenner, Treat, Dommasch, and Lo Re have no conflicts of interest to disclose. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Zhu N. Zhang D. Wang W. A novel coronavirus from patients with pneumonia in China, 2019 N Engl J Med 382 2020 727 733 31978945 2 Diamond B. The renin-angiotensin system: an integrated view of lung disease and coagulopathy in COVID-19 and therapeutic implications J Exp Med 2020 217 3 Hirano T. Murakami M. COVID-19: a new virus, but a familiar receptor and cytokine release syndrome Immunity 52 2020 731 733 32325025 4 Matheson N.J. Lehner P.J. How does SARS-CoV-2 cause COVID-19? Science 369 2020 510 511 32732413 5 Guan W.J. Ni Z.Y. Hu Y. Clinical characteristics of coronavirus disease 2019 in China N Engl J Med 382 2020 1708 1720 32109013 6 Cummings M.J. Baldwin M.R. Abrams D. Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study Lancet 395 2020 1763 1770 32442528 7 Li J. Huang D.Q. Zou B. Epidemiology of COVID-19: a systematic review and meta-analysis of clinical characteristics, risk factors and outcomes J Med Virol 2020 10.1002/jmv.26424 8 Gupta A. Madhavan M.V. Sehgal K. Extrapulmonary manifestations of COVID-19 Nat Med 26 2020 1017 1032 32651579 9 Teuwen L.A. Geldhof V. Pasut A. Carmeliet P. COVID-19: the vasculature unleashed Nat Rev Immunol 20 2020 389 391 32439870 10 Al-Samkari H. Karp Leaf R.S. Dzik W.H. COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection Blood 136 2020 489 500 32492712 11 Hadjadj J. Yatim N. Barnabei L. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients Science 369 2020 718 724 32661059 12 Vabret N. Britton G.J. Gruber C. Immunology of COVID-19: current state of the science Immunity 52 2020 910 941 32505227 13 Henderson L.A. Canna S.W. Schulert G.S. On the alert for cytokine storm: immunopathology in COVID-19 Arthritis Rheumatol 72 2020 1059 1063 32293098 14 Vaninov N. In the eye of the COVID-19 cytokine storm Nat Rev Immunol 20 2020 277 15 Ritchlin C.T. Krueger J.G. New therapies for psoriasis and psoriatic arthritis Curr Opin Rheumatol 28 2016 204 210 27022911 16 Armstrong A.W. Read C. Pathophysiology, clinical presentation, and treatment of psoriasis: a review JAMA 323 2020 1945 1960 32427307 17 Ritchlin C.T. Colbert R.A. Gladman D.D. Psoriatic arthritis N Engl J Med 376 2017 957 970 28273019 18 Catanzaro M. Fagiani F. Racchi M. Corsini E. Govoni S. Lanni C. Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2 Signal Transduct Target Ther 5 2020 84 32467561 19 Coates L.C. Kavanaugh A. Mease P.J. Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2015 treatment recommendations for psoriatic arthritis Arthritis Rheumatol 68 2016 1060 1071 26749174 20 Menter A. Gelfand J.M. Connor C. Joint American Academy of Dermatology-National Psoriasis Foundation guidelines of care for the management of psoriasis with systemic nonbiologic therapies J Am Acad Dermatol 82 2020 1445 1486 32119894 21 Menter A. Strober B.E. Kaplan D.H. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics J Am Acad Dermatol 80 2019 1029 1072 30772098 22 Singh J.A. Guyatt G. Ogdie A. Special article: 2018 American College of Rheumatology/National Psoriasis Foundation guideline for the treatment of psoriatic arthritis Arthritis Rheumatol 71 2019 5 32 30499246 23 Ogdie A. Schwartzman S. Husni M.E. Recognizing and managing comorbidities in psoriatic arthritis Curr Opin Rheumatol 27 2015 118 126 25603040 24 Takeshita J. Grewal S. Langan S.M. Psoriasis and comorbid diseases: epidemiology J Am Acad Dermatol 76 2017 377 390 28212759 25 Mikuls T.R. Johnson S.R. Fraenkel L. American College of Rheumatology Guidance for the Management of Rheumatic Disease in Adult Patients During the COVID-19 Pandemic: version 1 Arthritis Rheumatol 72 2020 1241 1251 32349183 26 Fitch K. Bernstein S.J. Aguilar M.D. Burnand B. LaCalle J.R. The RAND/UCLA Appropriateness Method User's Manual 2001 Rand Corp 27 Brook R. US Agency for Health Care Policy and Research, Office of the Forum for Quality and Effectiveness in Health Care Clinical Practice Guideline Development: Methodology Perspectives. The RAND/UCLA appropriateness method 1994 US Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research Rockville, MD 59 70 28 Shekelle P.G. Kahan J.P. Bernstein S.J. Leape L.L. Kamberg C.J. Park R.E. The reproducibility of a method to identify the overuse and underuse of medical procedures N Engl J Med 338 1998 1888 1895 9637810 29 Shekelle P.G. Chassin M.R. Park R.E. Assessing the predictive validity of the RAND/UCLA appropriateness method criteria for performing carotid endarterectomy Int J Technol Assess Health Care 14 1998 707 727 9885461 30 Hemingway H. Chen R. Junghans C. Appropriateness criteria for coronary angiography in angina: reliability and validity Ann Intern Med 149 2008 221 231 18711152 31 Kravitz R.L. Laouri M. Kahan J.P. Validity of criteria used for detecting underuse of coronary revascularization JAMA 274 1995 632 638 7637144 32 Costa L. Tasso M. Scotti N. Telerheumatology in COVID-19 era: a study from a psoriatic arthritis cohort Ann Rheum Dis 2020 10.1136/annrheumdis-2020-217806 33 Gianfrancesco M. Yazdany J. Robinson P.C. Epidemiology and outcomes of novel coronavirus 2019 in patients with immune-mediated inflammatory diseases Curr Opin Rheumatol 32 2020 434 440 32675715 34 Vispi M. Corradin T. Peccianti C. Psoriasis, biological drugs and coronavirus disease 2019: real life experience of two Italian provinces Dermatol Rep 12 2020 8642 35 Zen M. Fuzzi E. Astorri D. SARS-CoV-2 infection in patients with autoimmune rheumatic diseases in northeast Italy: a cross-sectional study on 916 patients J Autoimmun 112 2020 102502 32527675 36 Haberman R. Axelrad J. Chen A. Covid-19 in immune-mediated inflammatory diseases-case series from New York N Engl J Med 383 2020 85 88 32348641 37 Allocca M. Guidelli G.M. Borroni R.G. Clinical course of COVID-19 in 41 patients with immune-mediated inflammatory diseases: experience from Humanitas Center, Milan Pharmacol Res 160 2020 105061 32629021 38 Kutlu O. Metin A. Dermatological diseases presented before COVID-19: are patients with psoriasis and superficial fungal infections more vulnerable to the COVID-19? Dermatol Ther 2020 e13509 32367558 39 Williamson E.J. Walker A.J. Bhaskaran K. Factors associated with COVID-19-related death using OpenSAFELY Nature 584 7821 2020 430 436 32640463 40 Shahidi-Dadras M. Tabary M. Robati R.M. Araghi F. Dadkhahfar S. Psoriasis and risk of the COVID-19: is there a role for angiotensin converting enzyme (ACE)? J Dermatolog Treat 2020 1 2 41 Gelfand J.M. Dommasch E.D. Shin D.B. The risk of stroke in patients with psoriasis J Invest Dermatol 129 2009 2411 2418 19458634 42 Gelfand J.M. Neimann A.L. Shin D.B. Wang X. Margolis D.J. Troxel A.B. Risk of myocardial infarction in patients with psoriasis JAMA 296 2006 1735 1741 17032986 43 Langan S.M. Seminara N.M. Shin D.B. Prevalence of metabolic syndrome in patients with psoriasis: a population-based study in the United Kingdom J Invest Dermatol 132 2012 556 562 22113483 44 Mehta N.N. Azfar R.S. Shin D.B. Neimann A.L. Troxel A.B. Gelfand J.M. Patients with severe psoriasis are at increased risk of cardiovascular mortality: cohort study using the General Practice Research Database Eur Heart J 31 2010 1000 1006 20037179 45 Noe M.H. Shin D.B. Wan M.T. Gelfand J.M. Objective measures of psoriasis severity predict mortality: a prospective population-based cohort study J Invest Dermatol 138 2018 228 230 28843488 46 Ogdie A. Kay McGill N. Shin D.B. Risk of venous thromboembolism in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: a general population-based cohort study Eur Heart J 39 39 2018 3608 3614 28444172 47 Ogdie A. Yu Y. Haynes K. Risk of major cardiovascular events in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: a population-based cohort study Ann Rheum Dis 74 2015 326 332 25351522 48 Wan J. Wang S. Haynes K. Denburg M.R. Shin D.B. Gelfand J.M. Risk of moderate to advanced kidney disease in patients with psoriasis: population based cohort study BMJ 347 2013 f5961 24129480 49 Wan M.T. Shin D.B. Hubbard R.A. Noe M.H. Mehta N.N. Gelfand J.M. Psoriasis and the risk of diabetes: a prospective population-based cohort study J Am Acad Dermatol 78 2018 315 322.e1 29128465 50 Bilaloglu S. Aphinyanaphongs Y. Jones S. Iturrate E. Hochman J. Berger J.S. Thrombosis in hospitalized patients with COVID-19 in a New York City health system JAMA 324 8 2020 799 801 32702090 51 Kang Y. Chen T. Mui D. Cardiovascular manifestations and treatment considerations in COVID-19 Heart 106 2020 1132 1141 32354800 52 Teague H.L. Varghese N.J. Tsoi L.C. Neutrophil subsets, platelets, and vascular disease in psoriasis JACC Basic Transl Sci 4 2019 1 14 30847414 53 Garbaraviciene J. Diehl S. Varwig D. Platelet P-selectin reflects a state of cutaneous inflammation: possible application to monitor treatment efficacy in psoriasis Exp Dermatol 19 2010 736 741 20482619 54 Saleh H.M.A. Attia E.A.S. Onsy A.M. Saad A.A. Abd Ellah M.M.M. Platelet activation: a link between psoriasis per se and subclinical atherosclerosis—a case–control study Br J Dermatol 169 2013 68 75 23448140 55 Takeshita J. Mohler E.R. Krishnamoorthy P. Endothelial cell-, platelet-, and monocyte/macrophage-derived microparticles are elevated in psoriasis beyond cardiometabolic risk factors J Am Heart Assoc 3 2014 e000507 24584739 56 Shahid Z. Kalayanamitra R. McClafferty B. COVID-19 and older adults: what we know J Am Geriatr Soc 68 2020 926 929 32255507 57 Chen N. Zhou M. Dong X. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Lancet 395 2020 507 513 32007143 58 Wang D. Hu B. Hu C. Clinical Characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China JAMA 323 11 2020 1061 1069 32031570 59 Centers for Disease Control and Prevention Am I at Higher Risk for Severe Illness from COVID-19? Available at: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-at-increased-risk.html 60 Yeung H. Takeshita J. Mehta N.N. Psoriasis severity and the prevalence of major medical comorbidity: a population-based study JAMA Dermatol 149 2013 1173 1179 23925466 61 Pirro F. Caldarola G. Chiricozzi A. The impact of COVID-19 pandemic in a cohort of Italian psoriatic patients treated with biological therapies J Dermatolog Treat 2020 1 5 62 Georgakopoulos J.R. Mufti A. Vender R. Yeung J. Treatment discontinuation and rate of disease transmission in psoriasis patients receiving biologic therapy during the COVID-19 pandemic: a Canadian multicenter retrospective study J Am Acad Dermatol 2020 10.1016/j.jaad.2020.07.021 63 Rodríguez-Villa Lario A. Vega-Díez D. González-Cañete M. Patient's perspective: psychological burden of the COVID-19 pandemic in 146 psoriatic patients treated with biological drugs and small molecules in real clinical practice J Dermatolog Treat 2020 1 3 64 Syed M.N. Shin D.B. Wan M.T. Winthrop K.L. Gelfand J.M. The risk of respiratory tract infections in psoriasis patients treated with IL-23-pathway inhibiting biologics: a meta-estimate of pivotal trials relevant to decision-making during the COVID-19 pandemic J Am Acad Dermatol 2020 10.1016/j.jaad.2020.06.1014 65 Wan M.T. Shin D.B. Winthrop K.L. Gelfand J.M. The risk of respiratory tract infections and symptoms in psoriasis patients treated with interleukin 17 pathway–inhibiting biologics: a meta-estimate of pivotal trials relevant to decision making during the COVID-19 pandemic J Am Acad Dermatol 83 2020 677 679 32416207 66 Fougerousse A.C. Perrussel M. Bécherel P.A. Systemic or biologic treatment in psoriasis patients does not increase the risk of a severe form of COVID-19 J Eur Acad Dermatol Venereol 2020 10.1111/jdv.16761 67 Wang C.J. Truong A.K. COVID-19 infection on IL-23 inhibition Dermatol Ther 2020 e13893 32584451 68 Ebrahimi A. Sayad B. Rahimi Z. COVID-19 and psoriasis: biologic treatment and challenges J Dermatolog Treat 2020 1 5 69 Queiro Silva R. Armesto S. González Vela C. Naharro Fernández C. González-Gay M.A. COVID-19 patients with psoriasis and psoriatic arthritis on biologic immunosuppressant therapy vs apremilast in North Spain Dermatol Ther 2020 e13961 32618402 70 Di Lernia V. Goldust M. Feliciani C. Covid-19 infection in psoriasis patients treated with cyclosporin Dermatol Ther 2020 e13739 32478942 71 Olisova O.Y. Anpilogova E.M. Svistunova D.A. Apremilast as a potential treatment option for COVID-19: no symptoms of infection in a psoriatic patient Dermatol Ther 2020 e13668 32449265 72 Magnano M. Balestri R. Bardazzi F. Mazzatenta C. Girardelli C.R. Rech G. Psoriasis, COVID-19, and acute respiratory distress syndrome: focusing on the risk of concomitant biological treatment Dermatol Ther 2020 e13706 32475056 73 Valenti M. Facheris P. Pavia G. Non-complicated evolution of COVID-19 infection in a patient with psoriasis and psoriatic arthritis during treatment with adalimumab Dermatol Ther 2020 e13708 32474988 74 Strippoli D. Barbagallo T. Prestinari F. Russo G. Fantini F. Biologic agents in psoriasis: our experience during coronavirus infection Int J Dermatol 59 2020 e266 e267 32516447 75 Burlando M. Carmisciano L. Cozzani E. Parodi A. A survey of psoriasis patients on biologics during COVID-19: a single centre experience J Dermatolog Treat 2020 1 76 Di Lernia V. Bombonato C. Motolese A. COVID-19 in an elderly patient treated with secukinumab Dermatol Ther 2020 e13580 32406078 77 Benhadou F. Del Marmol V. Improvement of SARS-CoV-2 symptoms following guselkumab injection in a psoriatic patient J Eur Acad Dermatol Venereol 34 2020 e363 e364 32379925 78 Conti A. Lasagni C. Bigi L. Pellacani G. Evolution of COVID-9 infection in four psoriatic patients treated with biological drugs J Eur Acad Dermatol Venereol 34 2020 e360 e361 32379913 79 Carugno A. Gambini D.M. Raponi F. COVID-19 and biologics for psoriasis: a high-epidemic area experience-Bergamo, Lombardy, Italy J Am Acad Dermatol 83 2020 292 294 32387660 80 Gisondi P. Facheris P. Dapavo P. The impact of the COVID-19 pandemic on patients with chronic plaque psoriasis being treated with biological therapy: the Northern Italy experience Br J Dermatol 183 2020 373 374 32343839 81 Gisondi P. Zaza G. Del Giglio M. Rossi M. Iacono V. Girolomoni G. Risk of hospitalization and death from COVID-19 infection in patients with chronic plaque psoriasis receiving a biologic treatment and renal transplant recipients in maintenance immunosuppressive treatment J Am Acad Dermatol 83 2020 285 287 32330632 82 Brownstone N.D. Thibodeaux Q.G. Reddy V.D. Novel coronavirus disease (COVID-19) and biologic therapy for psoriasis: successful recovery in two patients after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Dermatol Ther (Heidelb) 10 2020 881 885 32468230 83 Facheris P. Valenti M. Pavia G. Complicated coronavirus disease 2019 (COVID-19) in a psoriatic patient treated with ixekizumab Int J Dermatol 59 2020 e267 e268 32557532 84 Messina F. Piaserico S. SARS-CoV-2 infection in a psoriatic patient treated with IL-23 inhibitor J Eur Acad Dermatol Venereol 34 2020 e254 e255 32294258 85 Lima X.T. Cueva M.A. Lopes E.M. Alora M.B. Severe COVID-19 outcomes in patients with psoriasis J Eur Acad Dermatol Venereol 2020 10.1111/jdv.16867 86 Damiani G. Pacifico A. Bragazzi N.L. Malagoli P. Biologics increase the risk of SARS-CoV-2 infection and hospitalization, but not ICU admission and death: real-life data from a large cohort during red-zone declaration Dermatol Ther 2020 e13475 32356577 87 Jovani V. Calabuig I. Peral-Garrido M.L. Incidence of severe COVID-19 in a Spanish cohort of 1037 patients with rheumatic diseases treated with biologics and JAK-inhibitors Ann Rheum Dis 2020 10.1136/annrheumdis-2020-218152 88 Rosenbaum J.T. Hamilton H. Choi D. Weisman M.H. Reveille J.D. Winthrop K.L. Biologics, spondylitis and COVID-19 Ann Rheum Dis 2020 10.1136/annrheumdis-2020-217941 89 Sharmeen S. Elghawy A. Zarlasht F. Yao Q. COVID-19 in rheumatic disease patients on immunosuppressive agents Semin Arthritis Rheum 50 2020 680 686 32512263 90 Gianfrancesco M. Hyrich K.L. Al-Adely S. Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry Ann Rheum Dis 79 2020 859 32471903 91 Brenner E.J. Ungaro R.C. Gearry R.B. Corticosteroids, but not TNF antagonists, are associated with adverse COVID-19 outcomes in patients with inflammatory bowel diseases: results from an international registry Gastroenterology 159 2 2020 481 491.e3 32425234 92 Khan N. Patel D. Xie D. Lewis J. Trivedi C. Yang Y.X. Impact of anti-TNF and thiopurines medications on the development of COVID-19 in patients with inflammatory bowel disease: a nationwide VA cohort study Gastroenterology 2020 10.1053/j.gastro.2020.05.065 93 Haberman R.H. Castillo R. Chen A. COVID-19 in patients with inflammatory arthritis: a prospective study on the effects of comorbidities and DMARDs on clinical outcomes Arthritis Rheumatol 2020 10.1002/art.41456 94 Gisondi P. Piaserico S. Conti A. Naldi L. Dermatologists and SARS-CoV-2: the impact of the pandemic on daily practice J Eur Acad Dermatol Venereol 34 2020 1196 1201 32320091 95 Gupta R. Ibraheim M.K. Doan H.Q. Teledermatology in the wake of COVID-19: advantages and challenges to continued care in a time of disarray J Am Acad Dermatol 83 2020 168 169 32334056 96 Ranney M.L. Griffeth V. Jha A.K. Critical supply shortages-the need for ventilators and personal protective equipment during the Covid-19 pandemic N Engl J Med 382 2020 e41 32212516 97 Cross C. Social Distancing: Keep On Keeping Your Distance 2020 Available at: https://yeswecare.co.za/2020/07/22/social-distancing-keep-on-keeping-your-distance/ 98 Armstrong A.W. Chambers C.J. Maverakis E. Effectiveness of online vs in-person care for adults with psoriasis: a randomized clinical trial JAMA Netw Open 1 2018 e183062 30646223 99 Armstrong A.W. Ford A.R. Chambers C.J. Online care versus in-person care for improving quality of life in psoriasis: a randomized controlled equivalency trial J Invest Dermatol 139 2019 1037 1044 30481495 100 Brunasso A.M.G. Massone C. Teledermatologic monitoring for chronic cutaneous autoimmune diseases with smartworking during COVID-19 emergency in a tertiary center in Italy Dermatol Ther 2020 e13495 101 Wood P.R. Caplan L. Outcomes, Satisfaction, and costs of a rheumatology telemedicine program: a longitudinal evaluation J Clin Rheumatol 25 2019 41 44 30461466 102 American Academy of Dermatology Teledermatology Toolkit. Dermatologists can use telemedicine during COVID-19 outbreak Available at: https://www.aad.org/member/practice/telederm/toolkit 103 Lim H.W. Feldman S.R. Van Voorhees A.S. Gelfand J.M. Recommendations for phototherapy during the COVID-19 pandemic J Am Acad Dermatol 83 2020 287 288 32339700 104 Elmets C.A. Lim H.W. Stoff B. Joint American Academy of Dermatology-National Psoriasis Foundation guidelines of care for the management and treatment of psoriasis with phototherapy J Am Acad Dermatol 81 2019 775 804 31351884 105 Centers for Disease Control and Prevention How to Protect Yourself & Others Available at: https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/prevention.html 2020 106 Raef H. Freeman E. Tan J. Skin care for health care workers during COVID-19. AAD.org: American Academy of Dermatology and the American Academy of Dermatology Association 2020 https://assets.ctfassets.net/1ny4yoiyrqia/17l8wipL9sbOuX42odjjDA/4c5afafa6c3b54853df6df47f2dbed17/20-341-CMM_COVID-19_-_Health_Care_Workers_infographic.pdf Accessed September 15, 2020 107 Thiers B.H. Tomecki K.J. Taylor S.C. Preventing and treating occupationally induced dermatologic conditions during COVID-19. A guide to preventing and treating occupationally induced dermatologic conditions during COVID-19. American Academy of Dermatology Available at: https://www.aad.org/public/diseases/coronavirus/occ-induced 108 Elmets M. Craig A. Korman M. Joint AAD-NPF Guidelines of care for the management and treatment of psoriasis with topical therapy and alternative medicine modalities for psoriasis severity measures J Am Acad Dermatol 2020 10.1016/j.jaad.2020.07.087 109 Park J.K. Lee Y.J. Shin K. Impact of temporary methotrexate discontinuation for 2 weeks on immunogenicity of seasonal influenza vaccination in patients with rheumatoid arthritis: a randomised clinical trial Ann Rheum Dis 77 2018 898 904 29572291 110 U.S. Food & Drug Administration Fact sheet for health care providers: Emergency use authorization (EUA) of Veklury® (remdesivir) Available at: https://www.fda.gov/media/137566/download 2020 111 Beigel J.H. Tomashek K.M. Dodd L.E. Remdesivir for the treatment of Covid-19—preliminary report N Engl J Med 2020 10.1056/NEJMoa2007764 112 RECOVERY Collaborative GroupHorby P. Lim W.S. Dexamethasone in hospitalized patients with Covid-19—preliminary report N Engl J Med 2020 10.1056/NEJMoa2021436 113 Mrowietz U. Domm S. Systemic steroids in the treatment of psoriasis: what is fact, what is fiction? J Eur Acad Dermatol Venereol 27 2013 1022 1025 22830601 114 U.S. Food & Drug Administration FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or 2020 115 U.S. Food & Drug Administration Letter revoking EUA for chloroquine phosphate and hydroxychloroquine sulfate Available at: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-revokes-emergency-use-authorization-chloroquine-and 2020 116 Bhimraj A. Morgan R.L. Shumaker A.H. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19 Clin Infect Dis 2020 10.1093/cid/ciaa478 117 National Institutes of Health Coronavirus Disease (COVID-19) treatment guidelines 2020 Available at: https://www.covid19treatmentguidelines.nih.gov/ 118 Qaseem A. Yost J. Etxeandia-Ikobaltzeta I. Humphrey L.L. Update alert 2: should clinicians use chloroquine or hydroxychloroquine alone or in combination with azithromycin for the prophylaxis or treatment of COVID-19? Living Practice Points From the American College of Physicians Ann Intern Med 173 5 2020 W88 W89 32730105 119 Ip A. Berry D.A. Hansen E. Hydroxychloroquine and tocilizumab therapy in COVID-19 patients-an observational study PLoS One 15 8 2020 e0237693 32790733 120 Rosenberg E.S. Dufort E.M. Udo T. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State JAMA 323 2020 2493 2502 32392282 121 Sbidian E. Josse J. Lemaitre G. Hydroxychloroquine with or without azithromycin and in-hospital mortality or discharge in patients hospitalized for COVID-19 infection: a cohort study of 4,642 in-patients in France [preprint] medRxiv 2020 10.1101/2020.06.16.20132597 122 Horby P. Mafham M. Linsell L. Effect of hydroxychloroquine in hospitalized patients with COVID-19: preliminary results from a multi-centre, randomized, controlled trial [preprint] medRxiv 2020 10.1101/2020.07.15.20151852 123 National Institutes of Health NIH halts clinical trial of hydroxychloroquine Available at: https://www.nih.gov/news-events/news-releases/nih-halts-clinical-trial-hydroxychloroquine 2020 124 World Health Organization “Solidarity” clinical trial for COVID-19 treatments Available at: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments 2020 125 Kutlu Ö. Metin A. A case of exacerbation of psoriasis after oseltamivir and hydroxychloroquine in a patient with COVID-19: will cases of psoriasis increase after COVID-19 pandemic? Dermatol Ther 2020 e13383 32259878 126 Sachdeva M. Mufti A. Maliyar K. Lytvyn Y. Yeung J. Hydroxychloroquine effects on psoriasis: a systematic review and a cautionary note for COVID-19 treatment J Am Acad Dermatol 83 2020 579 586 32442699 127 Ghalamkarpour F. Pourani M.R. Abdollahimajd F. Zargari O. A case of severe psoriatic erythroderma with COVID-19 J Dermatolog Treat 2020 1 3 128 Ozaras R. Berk A. Ucar D.H. Duman H. Kaya F. Mutlu H. Covid-19 and exacerbation of psoriasis Dermatol Ther 2020 e13632 32436303 129 Gananandan K. Sacks B. Ewing I. Guttate psoriasis secondary to COVID-19 BMJ Case Rep 13 2020 130 Centers for Disease Control and Prevention Discontinuation of isolation for persons with COVID-19 not in healthcare settings Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/disposition-in-home-patients.html 2020 131 Centers for Disease Control and Prevention Duration of isolation and precautions for adults with COVID-19 Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/duration-isolation.html 2020 132 Arons M.M. Hatfield K.M. Reddy S.C. Presymptomatic SARS-CoV-2 infections and transmission in a skilled nursing facility N Engl J Med 382 2020 2081 2090 32329971 133 Bullard J. Dust K. Funk D. Predicting infectious SARS-CoV-2 from diagnostic samples Clin Infect Dis 2020 10.1093/cid/ciaa638 134 van Kampen JJA van de Vijver D.A.M.C. Fraaij P.L.A. Shedding of infectious virus in hospitalized patients with coronavirus disease-2019 (COVID-19): duration and key determinants [preprint] medRxiv 2020 10.1101/2020.06.08.20125310 135 Brooks J.T. Butler J.C. Redfield R.R. Universal masking to prevent SARS-CoV-2 transmission—the time is now JAMA 324 7 2020 635 637 32663243 136 Centers for Disease Control and Prevention When to quarantine Available at: https://www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/quarantine.html 2020 137 Carfì A. Bernabei R. Landi F. Persistent symptoms in patients after acute COVID-19 JAMA 324 6 2020 603 605 32644129 138 Guyatt G. Oxman A.D. Akl E.A. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables J Clin Epidemiol 64 2011 383 394 21195583
PMC007xxxxxx/PMC7473026.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 Published by Elsevier on behalf of the American Academy of Dermatology. S0190-9622(20)32580-9 10.1016/j.jaad.2020.08.119 Research Letter Broad-spectrum abnormal localized photosensitivity syndrome Butt Sanaa BMBS a∗ Khalid Amina MRCP Derm a Alani Angela MRCP Derm a Fityan Adam FRCP b Fassihi Hiva MD c Dawe Robert MD a Ibbotson Sally MD a a Photobiology Unit, Dermatology Department, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom b Department of Dermatology, University Hospital Southampton National Health Service Foundation Trust, Southampton, Hampshire, UK c Department of Photodermatology, St John's Institute of Dermatology, Guy's and St Thomas' National Health Service Foundation Trust, London, United Kingdom ∗ Correspondence to: Sanaa Butt, BMBS NHS Tayside, Ninewells Hospital and Medical School, Dundee, Angus DD19SY, United Kingdom 4 9 2020 11 2021 4 9 2020 85 5 12981300 Crown Copyright © 2020 Published by Elsevier on behalf of the American Academy of Dermatology. All rights reserved. 2020 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTothe Editor: In recent years, we have been increasingly aware of patients presenting with severe abnormal photosensitivity recurrently affecting fixed and limited areas, which can be provoked at these sites through phototesting. Monochromator phototesting has shown severely abnormal photosensitivity across a broad spectrum of wavebands but only at affected sites. We thus coined the term broad-spectrum abnormal localized photosensitivity syndrome (BALPS) as a more accurate name. We have since realized that this condition has been described in the past and termed fixed sunlight sensitivity (FSS). We hope our suggested new diagnostic term better describes the clinical and photobiological features of this condition and leads to increased recognition. We retrospectively studied 10 cases of BALPS seen through 3 specialist photodiagnostic units over a 7-year period to investigate their clinical characteristics, photodiagnostic investigations, and histopathologic findings to enable phenotyping of this patient cohort (see the Supplemental Methods; available via Mendeley at https://doi.org/10.17632/4vzpx255mt.1). Eight of 10 patients were female. The mean age at onset was 37 years, with a mean time to presentation of 8 years after symptom onset. Limbs were a commonly affected site. Clinical features included erythema, edema, blistering, intense burning sensation, and pruritus (see Table I and the Supplemental Materials [available via Mendeley at https://doi.org/10.17632/4vzpx255mt.1] for further clinical features). Phototesting (Table I) showed broad-spectrum sensitivity at the affected sites with either normal or markedly less sensitivity noted at sites adjacent to these areas or at unaffected sites at 24 hours after irradiation (Fig 1 ). Common histopathologic findings were of epidermal spongiosis with lymphocyte exocytosis, mild dermal edema, and perivascular chronic lymphocytic infiltrates (for extended histopathology, see the Supplemental Materials).Table I Clinical features and phototesting results of patients with BALPS Patient Age/sex/skin type∗ Site Time to onset/clearance Clinical features Monochromator Nonaffected site Monochromator Affected site UVA provocation, nonaffected UVA provocation, affected Management Follow-up 1 64/M/III Right knee and right fifth finger, left forearm and lateral aspect of the wrist Hours/3-4 weeks Erythema; edema; tense, yellow, fluid-filled blisters; desquamation; and hypopigmentation Back and left knee: normal† Right knee: UVA/visible sensitivity (365-460 nm) 20 Jcm−2, negative Left forearm: 20 Jcm−2, grade 3 erythema Photoprotection‡ Prophylactic narrowband UVB, Psoracomb Dermalight 80 (UVB 311 nm; Dr Honle) Subjective: Improvement Objective: Improved, repeat testing showed only sensitivity at 365 nm and lesser degree 2 14/F/II Thighs 2 days/2 weeks Erythema, pruritus, edema Back: normal† Thigh: normal† Forearm: 20 Jcm−2, brown pigment (normal) Posterior thigh: 20 Jcm−2, grade 3 erythema Photoprotection‡ Prophylactic narrowband UVB Subjective: Improvement Objective: Worsened, 5 Jcm−2 UVA, grade 3 erythema + papules 3 43/F/II Axilla, groins, and abdomen Few hours/24 hours Erythema, edema, blistering, burning sensation Back: normal† Inner thigh: UVB/UVA sensitivity (305-365 nm) Right front aspect of the thigh: 10 Jcm−2, negative Right inner aspect of the thigh: 5 Jcm−2, grade 3 erythema Photoprotection‡ Prophylactic UVA1 Subjective: Improvement Objective: No change, repeat phototesting remained the same 4 52/M/II Right shin Hours/2 days Erythema, pruritus, blistering Left shin: normal† Right shin: UVB/UVA sensitivity (305-365 nm) Left shin: 5 Jcm−2, negative Right shin: 5 Jcm−2, grade 3 erythema Photoprotection‡ Clobetasol propionate 0.05% Subjective: Improvement Objective: No change, repeat phototesting remained the same 5 50/F/II Anterior and medial aspects of the thighs 1-2 days/6 weeks Erythema, pruritus, unilocular blistering Back: borderline at 305-400 nm Thighs: UVB/UVA/visible greater sensitivity (305-400 nm) Back: 5 Jcm−2, grade 3 erythema with papules Right inner aspect of the thigh: 5 Jcm−2, grade 4 response Right outer aspect of the thigh: 5 Jcm−2, grade 3 erythema Photoprotection‡ Clobetasol propionate 0.05% Subjective: Improvement with sunscreen Objective: No change, repeat phototesting remained the same 6 37/F/IV Buttocks and thighs 1 day/3-4days Burning sensation, macular erythema/purple discoloration Back: borderline at 335 nm Thighs: UVB/UVA/visible sensitivity (305-400 nm) Not done Not done Photoprotection‡ Further investigation and follow-up suspended because of coronavirus pandemic 7 50/F/II Buttocks, thighs, and flanks below the axillae 30 minutes/2 weeks Pruritus, erythema, burning sensation, urticated papules, resolves with purpuric change Back: normal† Buttock: UVB/UVA sensitivity (305, 365 nm) Not done Buttock: 10 Jcm−2, grade 3 erythema Photoprotection‡ Prophylactic narrowband UVB, Psoracomb Dermalight 80 (UVB 311 nm)—not tolerated Tacrolimus 0.1% Methotrexate 10 mg weekly Follow-up suspended because of coronavirus pandemic 8 56/F/II Legs, back of the thighs, knees, and abdomen unknown/2-3 weeks Erythema, papules, blistering Back: normal† Thigh: UVB/UVA/visible sensitivity (305-400 nm) Forearm: 10 Jcm−2, grade 1 erythema Back: 10 Jcm−2, grade 2 erythema and papules Thigh: 10 Jcm−2, grade 3 erythema Methotrexate 25 mg once weekly + IM glucocorticoid injection for alternative condition Photoprotection‡ Did not attend 9 31/F/II Right buttock, inner aspects of the thighs 2-3 days/4 weeks Pruritus, erythema, burning sensation, edema Back: normal† Buttock: UVB/UVA sensitivity (305-340 nm) Not done Not done Photoprotection‡ Clobetasol propionate 0.05% Subjective: Improvement 10 52/F/II Left buttock 18 hours/7 days Erythema, desquamation Back: minor UVB/UVA sensitivity (300-320 nm) Left buttock: UVB/UVA/visible sensitivity (300-400 nm) Not done Not done Photoprotection‡ Clobetasol propionate 0.05% Subjective: Improvement BALPS, Broad-spectrum abnormal localized photosensitivity syndrome; F, female; IM, intramuscular; M, male; UV, ultraviolet. ∗ Fitzpatrick skin phototype. † Within population reference range. ‡ Photoprotection advice includes behavioral modification, environmental, clothing, and topical sunscreen recommendations. Fig 1 Broad-spectrum abnormal localized photosensitivity syndrome. Localized and fixed photosensitivity, affecting only the lower portion of the right leg, with other sites unaffected. Monochromator phototesting on the affected sites showed abnormal delayed erythema in the ultraviolet (UV) B and UVA wavebands at 24 hours after irradiation. UVA provocation testing on the affected site was markedly abnormal (grade 3 erythema) at 5 J/cm2 (case 4, see Supplemental Fig 1 for further photos; available via Mendeley at https://doi.org/10.17632/4vzpx255mt.1). FSS was first reported in 1975 by Emmet,1 who described a case of itchy, erythematous papular rash localized to sun-exposed sites on the face, reproduced by photoprovocation with longwave ultraviolet light.1 Since then, a handful of reports have detailed a similar clinical pattern, where triggers including food and drugs were excluded, and only sunlight remained.2, 3, 4 Emmett noted the difficulty in classifying this condition because it shares various characteristics with well-recognized photodermatoses. One suggestion is to consider this as a localized form of CAD, given some similarities in phototesting and histopathology. However, typical photodistributed sites were not involved in our patients, and only reproducible bizarrely localized sites were affected. In 1 of our patients, ultraviolet A alone appeared to trigger the eruption, suggesting similarities to polymorphic light eruption; however, the clinical features did not correlate. BALPS is also akin to a fixed drug eruption (FDE), given the localized recurrent nature; hence, the term FSS used in the literature. In contrast to FDE, we have not noted hyperpigmentation, nor could we incriminate any culprit drugs. Immunologic memory is thought to be the pathogenesis implicated in FDE, with CD8+ T cells residing along the basement membrane primed and reactivated when reintroduced to the offending medication.5 There may be a shared underlying pathogenesis in the form of a currently unidentified chromophore depositing in the skin of these patients that absorbs the relevant wavelengths required to trigger a localized reaction. Because of the similar yet varied presentation of these cases, we wished to group them within this diagnostic entity of BALPS. We report on this diagnostic entity to raise awareness and facilitate identification of this fascinating patient cohort. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Emmett E.A. Fixed long ultraviolet eruption Arch Dermatol 111 2 1975 212 214 1115510 2 Valdivieso R. Cañarte C. It is not a fixed drug eruption, it is a fixed “sunlight” eruption Int J Dermatol 49 12 2010 1421 1423 21091679 3 Gamé D. Bassas J. Grau C. Fixed sunlight eruption: a new idiopathic photodermatosis rather than a variant of fixed drug eruption Photodermatol Photoimmunol Photomed 33 4 2017 222 224 28370395 4 Valdeolivas-Casillas N. Piteiro-Bermejo A.B. Trasobares-Marugán L. Fixed sunlight eruption: a case report J Eur Acad Dermatol Venereol 30 5 2016 894 895 25712699 5 Shiohara T. Fixed drug eruption: pathogenesis and diagnostic tests Curr Opin Allergy Clin Immunol 9 4 2009 316 321 19474709
PMC007xxxxxx/PMC7473138.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)32582-2 10.1016/j.jaad.2020.09.002 JAAD Online Authors' reply to the comment “Treatment considerations for patients with pemphigus during the COVID-19 pandemic” Shakshouk Hadir MBBS ab Daneshpazhooh Maryam MD c Murrell Dedee F. MD d Lehman Julia S. MD a∗ a Department of Dermatology, Mayo Clinic, Rochester, Minnesota b Department of Dermatology, Andrology and Venereology, Alexandria University, Egypt c Department of Dermatology, Autoimmune Bullous Diseases Research Center, Tehran University of Medical Sciences, Iran d Department of Dermatology, University of New South Wales, Sydney, Australia ∗ Correspondence to: Julia S. Lehman, MD, Department of Dermatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 4 9 2020 1 2021 4 9 2020 84 1 e61e62 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: We read with interest the thoughtful reply by Schultz et al to our previous correspondence regarding treatment considerations for patients with pemphigus during the coronavirus disease 2019 (COVID-19) pandemic.1 There is established agreement about the need to use caution when approaching iatrogenic immunosuppression, as is usually required in the management of pemphigus. Early in the pandemic, we had suggested postponing rituximab infusions when feasible, given the temporarily irreversible nature of B-cell depletion caused by rituximab, as well as the unknown effect of rituximab on susceptibility to and severity of infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Similar recommendations were made by Kasperkiewicz et al.2 Given that rituximab administration generally requires patients to attend a medical center, avoidance of this setting, particularly at the peak of the pandemic, would lessen the burden on health care systems and minimize mutual potential SARS-CoV-2 exposures at health care settings. Similarly, Kasperkiewicz et al2 speculated that rituximab could worsen severity of COVID-19, with this effect lasting for up to 1 year after administration. It has since become clear that in some countries, such as the United States, the COVID-19 pandemic is unlikely to abate in the near future, thus raising concern about the feasibility of continuing to postpone rituximab infusions. Fortunately, recent evidence has demonstrated that B-cell depletion may not affect the outcome in patients who develop COVID-19, perhaps because T cells play a major role in immunity against SARS-CoV-2.3 Published data from Italy showed that in a cohort of 371 patients with pemphigus, only 3 developed confirmed-positive COVID-19, and all recovered. Of the 12 patients in the study who had received rituximab, none had developed COVID-19.4 Although this preliminary report offers some reassurance, additional prospective experience will be necessary to fully understand the effect of rituximab in patients with pemphigus who develop COVID-19. Concern has been raised about rituximab potentially diminishing the immunologic response to the COVID-19 vaccine because it is known that patients receiving rituximab may have blunted immunoresponse to the vaccine that may persist for 6 to 12 months after rituximab infusions.3 It remains to be seen how rituximab may affect immunoresponse to any future COVID-19 vaccine. Given the well-demonstrated efficacy of rituximab in pemphigus, resuming this medication may be reasonable in patients without active COVID-19 infection, particularly if COVID-19 incidence is low in the patient's area. In patients with active pemphigus and COVID-19, systemic glucocorticoids at the lowest possible dose may be preferred, particularly given the promising results of dexamethasone in severe COVID-19 because of its anti-inflammatory effect against lung damage driven by the cytokine storm.5 Screening for SARS-CoV-2 infection by polymerase chain reaction before infusion of rituximab may also be a prudent practice to adopt. Patients must be counseled on basic infection-prevention principles, such as mask wearing, hand washing, and social distancing. Funding sources: None. Conflicts of interest: None disclosed. Reprints not available from the authors. ==== Refs References 1 Shakshouk H. Daneshpazhooh M. Murrell D.F. Lehman J.S. Treatment considerations for patients with pemphigus during the COVID-19 pandemic J Am Acad Dermatol 82 2020 e235 e236 32283243 2 Kasperkiewicz M. Schmidt E. Fairley J.A. Expert recommendations for the management of autoimmune bullous diseases during the COVID-19 pandemic J Eur Acad Dermatol Venereol 34 2020 e302 e303 32333823 3 Baker D. Roberts C.A. Pryce G. COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases Clin Exp Immunol 2020 10.1111/cei.13495 4 Di Altobrando A. Patrizi A. Abbenante D. Bardazzi F. Rituximab: a safe therapeutic option during the COVID-19 pandemic? J Dermatolog Treat 2020 10.1080/09546634.2020.1800565 5 Johnson R.M. Vinetz J.M. Dexamethasone in the management of covid -19 BMJ 370 2020 m2648 32620554
PMC007xxxxxx/PMC7474839.txt
==== Front Rev Fr Allergol (2009) Rev Fr Allergol (2009) Revue Francaise D'Allergologie (2009) 1877-0312 1877-0320 Elsevier Masson SAS. S1877-0320(20)30371-7 10.1016/j.reval.2020.07.003 Revue Générale Immunothérapie allergénique chez l’enfant et l’adolescent Allergic immunotherapy in children and adolescentsAmat F. a⁎ Labbé A. b a Service de pneumologie et d’allergologie pédiatrique-CRCM, hôpital Robert-Debré, Inserm UMRS1136 EPAR, Paris, France b UFR de médecine et des professions paramédicales, université Clermont-Auvergne, France ⁎ Auteur correspondant. 6 9 2020 October-November 2020 6 9 2020 60 6 554558 23 7 2020 29 7 2020 © 2020 Elsevier Masson SAS. All rights reserved. 2020 Elsevier Masson SAS Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. L’immunothérapie spécifique allergénique nécessite l’administration répétée d’allergènes dans le but de provoquer une tolérance clinique et immunologique. C’est la seule thérapeutique à visée étiologique qui permet de modifier l’évolution de la maladie en assurant une rémission après l’interruption de la procédure. La prévention de nouvelles sensibilisations par l’immunothérapie reste discutée. Nous envisagerons dans cette revue les principaux mécanismes immunologiques et les indications de l’immunothérapie chez l’enfant et l’adolescent. Specific allergic immunotherapy requires repeated administration of allergens in order to induce clinical and immunological tolerance. This is the only therapy with an aetiological aim that modifies the course of the disease by ensuring remission after the interruption of the procedure. The prevention of new sensitizations by immunotherapy is still under discussion. In this review we will consider the main immunological mechanisms and indications for immunotherapy in children and adolescents. Mots clés Enfant Adolescent Immunothérapie Asthme Rhinite Allergie alimentaire Keywords Children Adolescent Immunotherapy Asthma Rhinitis Food allergy ==== Body pmc1 Introduction L’immunothérapie allergénique anciennement appelée désensibilisation est une thérapeutique très ancienne puisqu’elle va avoir 100 ans [1]. Il a néanmoins fallu attendre de nombreuses années pour qu’elle obtienne ses lettres de noblesse et réponde aux standards scientifiques [2]. Les plus anciens d’entre nous se souviennent des premiers pas de l’immunothérapie dans les années 1970 marqués par l’empirisme et la difficulté d’obtenir des produits purifiés. C’est certainement ce qui a fait douter nombre de pneumologues de l’utilité de cette méthode thérapeutique jusqu’à la standardisation des allergènes et la réalisation d’études contrôlées [3], [4], [5]. Désormais l’immunothérapie fait partie de l’arsenal thérapeutique tout en ayant toujours des difficultés à s’imposer dans la prise en charge de l’asthme au niveau international comme le prouve la dernière édition du GINA [6]. Chez l’enfant le souhait de disposer d’une méthode curative et peut-être préventive s’est imposé à de nombreuses équipes au point de la proposer dès le plus jeune âge et d’élargir ses indications à l’allergie alimentaire. Dans cette courte revue nous exposerons seulement quelques aspects de cette technique largement connue de la plupart d’entre nous en insistant sur quelques éléments novateurs et moins abordés dans les publications générales sur ce sujet. 2 Mécanismes immunologiques de l’immunothérapie allergénique L’immunothérapie spécifique permet d’acquérir une tolérance vis-à-vis de l’allergène [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. Elle occasionne des modifications sensibles de la réponse immunitaire en agissant sur les mécanismes humoraux et cellulaires impliquées dans la réaction allergique (Fig. 1 ). Certains d’entre eux interviennent dès le début de la mise en route de l’immunothérapie. Cela concerne la diminution très précoce de la susceptibilité des cellules mastocytaires et des basophiles à la dégranulation malgré l’augmentation du taux d’IgE spécifiques. Ce processus initial de tolérance allergénique pourrait être lié aux récepteurs histaminiques de type 2 qui possèdent une très forte action de régulation immunitaire sur les lymphocytes T, les cellules dendritiques et les basophiles. L’immunothérapie allergénique induit également la production de lymphocytes T régulateurs (T reg). Les T reg jouent un rôle central dans l’induction de tolérance grâce à la libération d’IL 10 et de TGFß. Ils participent au rééquilibrage de la balance Th1/Th2 et empêchent la commutation de classe vers les IgE en favorisant celle conduisant à la production d’IgG4. Ils diminuent la circulation des cellules effectrices de l’allergie (mastocytes, polynucléaires basophiles, polynucléaires éosinophiles. L’indolamine 2,3 dioxygénase (IDO) est une enzyme catalytique intervenant dans la dégradation d’un acide aminé essentiel, le tryptophane. Présent dans les cellules dendritiques, son induction ou inhibition joue un rôle majeur dans les fonctions des lymphocytes T. L’interféron gamma produit par les Th1 agit sur les lymphocytes B, en particulier sur la commutation de classe des immunoglobulines réduisant ainsi la libération des IgE. La repolarisation Th1 a également pour conséquence l’augmentation des IgA et IgG4. L’immunothérapie régule les cellules lymphoïdes innées de type 2. Ces cellules jouent un rôle majeur dans la réponse allergique par la sécrétion d’IL-5 et d’IL-13. Il a été démontré que l’augmentation saisonnière des cellules lymphoïdes innées de type 2 est inhibée par l’immunothérapie sous cutanée [16]. Il persiste néanmoins encore des inconnues sur la tolérance à long terme induite par l’immunothérapie [17]. Il sera pourtant essentiel de comprendre, non seulement les mécanismes d’induction de tolérance, mais aussi ceux essentiels à la persistance de celle-ci afin de proposer des biomarqueurs de la réponse clinique.Fig. 1 Mécanismes immunologiques. Modification d’après Arasi et al. Italian J Pediatr 2018 : 44 :80. 3 Principales indications en pédiatrie 3.1 Aspects curatifs 3.1.1 Allergie respiratoire C’est dans le domaine de l’allergie respiratoire que l’immunothérapie s’est développée. De très nombreuses études ont été consacrées à l’analyse de l’efficacité de l’immunothérapie surtout pour la rhinite saisonnière [18], [19] mais aussi dans l’asthme [20], [21], [22]. Les contributions les plus solides concernent les allergies aux pollens et aux acariens [23], [24], alors que les travaux ayant trait aux moisissures et aux animaux domestiques sont beaucoup plus anecdotiques [25], [26] même si des travaux récents laissent supposer leur utilité pour le chat par voie injectable [27]. Les effets les plus démonstratifs de l’immunothérapie porte sur la rhinite pollinique [28], [29], [30], [31], [32] avec une réduction nette des coûts médicaux liés à la consommation médicamenteuse [33], [34], [35], [36]. L’efficacité est présente que le patient soit mono ou polysensibilisé. Il est établi que le bénéfice du traitement apparaît au bout d’un an et que 3 années complètes apportent un bénéfice supplémentaire qui perdure plusieurs saisons. Nous avons effectué une étude sur le devenir d’enfants désensibilisés par voie sous cutanée aux pollens de graminées que nous avons réévalué au moins trois ans après l’arrêt de l’immunothérapie [37]. Ces enfants avaient un asthme dans 85 % des cas et étaient polysensibilisés pour la moitié. Les scores symptomatiques restaient en dessous des scores cliniques moyens avant désensibilisation (p  < 0,0001). La toux sèche et/ou les crises d’asthme ne récidivaient par lors de la saison pollinique alors que les enfants gardaient des signes cliniques mineurs (rhinorhée, éternuement, irritation conjonctivale lors du pic pollinique). Les effets sur l’asthme sont plus difficiles à analyser, beaucoup d’études étant difficilement comparables du fait des critères d’inclusion et de l’absence souvent d’évaluation du contrôle [38], [39]. Toutefois plusieurs travaux, des méta-analyses et des essais randomisés permettent d’évaluer la place de l’immunothérapie dans l’asthme allergique. C’est le cas d’une revue Cochrane de 2010 basée sur l’analyse de 35 études qui démontre un effet significatif de la désensibilisation par voie sous cutanée aux pollens et aux acariens [40]. Pour l’immunothérapie par voie sublinguale le nombre d’études est moins important mais une revue systématique de 2013 publié dans le JAMA démontre un bénéfice dans le traitement des symptômes d’asthme, en particulier sur la diminution de scores symptomatiques [28]. Ceci est contredit par une nouvelle étude Cochrane e, 2015 [41] qui souligne le caractère imparfait de l’évaluation des asthmes et des scores symptomatiques. Plus récemment Rice JL et al. [42] ont effectué une revue synthétique de travaux pédiatriques (enfants et adolescents). Ils ont répertorié 40 travaux (17 en sous cutané, 11 par voie sublinguale, les autres étant mixtes). Ils retiennent un effet modéré de l’immunothérapie par voie sous cutanée sur l’utilisation à long terme des médicaments anti-asthmatiques avec un niveau de preuve faible sur l’effet sur la qualité de vie et la modification de la fonction respiratoire. Les résultats sont moins significatifs avec la voie sublinguale. Ils concluent que les effets ne sont pas démonstratifs sur les symptômes d’asthme et le recours au système de santé. C’est certainement une partie de ces travaux qui a conduit les rédacteurs de la nouvelle version du GINA 2020 à se montrer prudents sur le positionnement de l’immunothérapie dans la prise en charge de l’asthme [6]. 3.1.2 Allergie aux hyménoptères Pour l’allergie aux venins d’hyménoptères (guêpe ou abeille) la littérature est abondante et le recul suffisamment long pour arriver à un consensus [43], [44], [45], [46]. Chez l’adulte les indications sont unanimes en cas de réaction de type 3 ou 4 de la classification de Müller. Les techniques de rush et d’ultrarush vont partie de la prise en charge allergologique courante tout comme les doses d’entretien à 100 μg pour une durée très prolongée souvent de 5 ans. Chez l’enfant on retiendra que les patients atopiques, ou polysensibilisés, ou ceux vivant au contact des abeilles (parents apiculteurs) sont plus à risque de manifestations graves et donc plus candidats à l’immunothérapie. Par contre l’histoire naturelle de l’allergie aux venins est différente des adultes avec un risque plus modéré d’atteinte grave lors de piqûres successives (46). Il est donc admis que l’immunothérapie doit être réservé aux cas graves (réaction systémique de grade 3 ou 4), alors qu’une réaction urticarienne même généralisée mais isolée ne fait pas partie des indications habituelles. 3.1.3 Allergie alimentaire L’allergie alimentaire est probablement l’affection qui altère le plus la qualité de vie des enfants et de leur famille tant la crainte de réactions systémiques graves, les difficultés journalières de l’éviction rendent le quotidien problématique [47], [48], [49], [50], [51], [52]. Trois aliments (lait, œuf, arachide) sont le plus fréquemment en cause. L’European Academy of Allergy and Clinical Immunology (EAACI) a publié récemment des recommandations concernant l’immunothérapie dans l’allergie alimentaire IgE médiée [53]. Elle fait état des travaux publiés par voie orale, sublinguale et épicutanée pour les trois aliments précités. Elle met en garde sur le fait que le bénéfice après arrêt de la procédure n’est pas confirmé et que les effets secondaires sont souvent rapportés et parfois graves. Dans ces conditions elle restreint l’utilisation de ces techniques d’induction de tolérance aux centres de recherche et aux unités cliniques ayant une expérience exhaustive de l’immunothérapie dans l’allergie alimentaire. Ces conclusions ne font pas l’unanimité chez les allergologues, notamment sur l’impossibilité d’initier ce type de traitement en ambulatoire. Bien qu’il semble compliqué de prolonger cette analyse de la littérature après les travaux de l’EAACI, certaines publications très récentes méritent d’être discutées car elles apportent un éclairage intéressant dans ce domaine si particulier. D’abord il est essentiel de parler un langage commun et d’harmoniser la terminologie si on veut pouvoir comparer les études. C’est ce que propose Casale et al. [54] qui reviennent sur les termes utilisés lors des tests de provocation par voie orale qui sont essentiels pour initier et contrôler les immunothérapies. Ils proposent de différencier la dose réactive, la plus haute tolérée, la dose cumulative tolérée et la dose réactive cumulée (Fig. 2 ). Enfin, deux études sur l’allergie à l’arachide apportent des résultats intéressants, celle de Kim et al. [55] qui démontre clairement le bénéfice au long cours d’une désensibilisation par voie sublinguale, et celle de Fleicher et al. [56] qui montre l’intérêt de la voie épicutanée avec le même allergène.Fig. 2 Terminologie pour les tests de provocation par voie orale d’après Casale et al. [54]. 3.2 Aspects préventifs 3.2.1 Prévention de l’asthme Les enfants porteurs d’une rhinite allergique sont indiscutablement à risque d’asthme. Ce risque est clairement établi sans qu’il soit possible d’en établir l’incidence [57], [58], [59], [60], [61], [62]. L’étude GAP [32] a étudié l’efficacité d’un lyophylisat sublingual d’extrait de pollen de phléoles des prés (Grazax® Laboratoire ALK-Abello 75000sQ-T par lyophylisat) administré durant 3 ans contre placebo suivi d’une surveillance de deux ans après l’arrêt. Aucun de ces enfants n’était asthmatique au départ de l’étude. Les résultats sont significatifs en terme de réduction des symptômes de la rhino-conjontivite et des médicaments utilisés à cet effet (différence de 22 et 27 % vs placebo). Le traitement réduit également de façon significative le risque d’avoir des symptômes d’asthme et l’utilisation des médicaments de secours. Par contre, il n’y a pas d’effet sur le délai de survenue de l’asthme, mais établi selon des critères probablement assez loin des réalités de terrain. En effet, l’asthme était défini de façon assez complexe, par trois conditions : au moins un épisode de sifflement, difficulté respiratoire et une réversibilité du VEMS de plus de 12 % après bronchodilatateur, ou sifflements avec ou sans phase expiratoire prolongée lors d’un examen clinique avec prise de bronchodilatateur d’effet démontré, ou sifflements avec ou sans phase expiratoire prolongée lors d’un examen clinique et réversibilité du VEMS de plus de 12 % après bronchodilatateur. 3.2.2 Prévention des sensibilisations L’effet préventif de l’immunothérapie allergénique a été rapporté dans de nombreuses revues et conférence de consensus. Toutefois, cela représente en réalité peu d’études contrôlées chez l’enfant et l’adulte. Di Bona et al. [63] ont donc décidé d’aller plus loin dans l’analyse des données sur ce sujet en réexaminant les travaux publiés et en étudiant la réalité des conclusions au vu du risque de biais, de la consistance et de l’importance de l’effet. Dix-huit études (1049 enfants et 10 057 adultes) répondaient aux critères de sélection. Le risque de biais est élevé dans toutes les études sauf une. Une évidence faible est en faveur de la prévention de la survenue de nouvelles sensibilisations par l’immunothérapie allergénique, avec 10 des 18 études qui rapportent une réduction de la survenue de nouvelles sensibilisations chez les patients traités par immunothérapie versus placebo. Les études de moindres effectifs effectuées sur les périodes les plus courtes retrouvaient les bénéfices les plus importants. 4 Conclusion En conclusion, si l’immunothérapie est devenue incontournable chez l’enfant et si les preuves scientifiques de son efficacité ne sont plus discutables de nombreux points restent à découvrir ou à approfondir. Il y a certainement des progrès à faire pour individualiser des marqueurs biologiques d’efficacité cliniques. Le développement de nouveaux produits risque de souffrir de la concurrence des recherches actuelles sur le vaccin du Covid-19. D’ici là d’autres progrès peuvent intervenir notamment sur la place de l’immunothérapie préventive dans l’asthme du petit enfant et bien sur dans le domaine de l’allergologie alimentaire. Déclaration de liens d’intérêts Les auteurs déclarent ne pas avoir de liens d’intérêts. ==== Refs Références 1 Noon L. Prophylactic inoculation against hay fever Lancet 1 1911 1572 1573 2 Lowell F.C. Franklin W. A double-blind study of the effectiveness and specificity of injecton therapy in ragweed hay fever N Engl J Med 273 1965 675 679 5318212 3 Chapman M.D. Briza P. Molecular approaches to allergen standardization Curr Allergy Asthma Rep 12 2012 478 484 22740009 4 Jutel M. Agache I. Bonini S. Burks W. Calderon M. Canonica W. International consensus on allergen immunotherapy II: mechanisms, standardization, and pharmacoeconomics J Allergy Clin Immunol 137 2016 358 368 26853128 5 Burks A.W. Calderon M.A. Casale T. Cox L. Demoly P. Jutel M. Update on allergy immunotherapy: American Academy of Allergy, Asthma & Immunology/European Academy of Allergy and Clinical Immunology/PRACTALL consensus report J Allergy Clin Immunol 131 2013 1288 1296 [e3] 23498595 6 Global initiative for asthma. Global stategy for asthma managemeny and prévention 2020 [www.ginasthma.org] 7 Jutel M. Akdis C.A. Immunological mechanisms of allergen-specific immunotherapy Allergy 66 2011 725 732 21466562 8 Johnson B.A. Baban B. Mellir A.L. Targeting the immunoregulatory indoeamine 2,3 dioxygenase pathway in immunotherapy Immunotherapy 1 2009 645 661 20161103 9 Arasi S. Corsello G. Villani A. Pajno G.B. The future outlook on allergen immunotherapy in children: 2018 and beyond Italian J Ped 44 2018 80 10 Uermosi C. Zabel F. Manolova V. Bauer M. Beerli R.R. Senti G. IgG-mediated down-regulation of IgE bound to mast cells: a potential novel mechanism of allergen-specific desensitization Allergy 69 2014 338 347 24354793 11 Akdis M. Akdis C.A. Mechanisms of allergen-specific immunotherapy: multiple suppressor factors at work in immune tolerance to allergens J Allergy Clin Immunol 133 2014 621 631 24581429 12 Novak N. Mete N. Bussmann C. Maintz L. Bieber T. Akdis M. Early suppression of basophil activation during allergen-specific immunotherapy by histamine receptor 2 J Allergy Clin Immunol 130 2012 1153 1158 22698521 13 Shamji M.H. Ljorring C. Francis J.N. Calderon M.A. Larche M. Kimber I. Functional rather than immunoreactive levels of IgG4 correlate closely with clinical response to grass pollen immunotherapy Allergy 67 2012 217 222 22077562 14 Lou W. Wang C. Wang Y. Han D. Zhang L. Responses of CD4(1) CD25(1) Foxp3(1) and IL-10-secreting type I T regulatory cells to cluster-specific immunotherapy for allergic rhinitis in children Pediatr Allergy Immunol 23 2012 140 149 22192331 15 Tsai Y.G. Lai J.C. Yang K.D. Hung C.H. Yeh Y.J. Lin C.Y. Enhanced CD46-induced regulatory T cells suppress allergic inflammation after Dermatophagoides pteronyssinus-specific immunotherapy J Allergy Clin Immunol 134 2014 1206 1209 [e1] 25065720 16 Lao-Araya M. Steveling E. Scadding G.W. Durham S.R. Shamji M.H. Seasonal increases in peripheral innate lymphoid type 2 cells are inhibited by subcutaneous grass pollen immunotherapy J Allergy Clin Immunol 134 2014 1193 1195 [e4] 25212194 17 Cappella A. Durham S.R. Allergen immunotherapy for allergic respiratory diseases Human Vaccines Immunother 8 10 2012 1499 1512 18 Dretzke J. Meadows A. Novielli N. Huissoon A. Fry-Smith A. Meads C. Sucutaneous and sublingual immunotherapy for seasonal allergic rhinitis: a systematic review and indirect comparison J Allergy Clin Immunol 131 2013 1361 1366 23557834 19 Durham RS, Walker SM, Varga EM, Jacobson MR, O’Brien F, Nobel W, et al. Long-Term clinical efficay of grass pollen immunotherapy. N Engl J Med 199; 341: 468-75. 20 Frew A.J. Allergen immunotherapy J Allergy Clin Immunol 125 2010 306 313 21 Cox L. Nelson H. Lockey R. Calabria C. Chacko T. Finegold I. Allergen immunotherapy: a practice parameter third update J Allergy Clin Immunol 127 Suppl 1 2011 1 55 22 Marchal O. Allali D. Place de l’immunothérapie dans l’asthme allergique Rev Med Suisse 14 2018 731 734 29620295 23 Eifan A.O. Akkoc T. Yildiz A. Keles S. Ozdemir C. Bahceciler N.N. Clinical efficacy and immunological mechanisms of sublingual and subcutaneous immunotherapy in asthmatic/rhinitis children sensitized to house dust mite: an open randomized controlled trial Clin Exp Allergy 40 2010 922 932 20100188 24 Karakoc-Aydiner E. Eifan A.O. Baris S. Gunay E. Akturk E. Akkoc T. Long-term effect of sublingual and subcutaneous immunotherapy in dust mite-allergic children with asthma/rhinitis: a 3-year prospective randomized controlled trial J Investig Allergol Clin Immunol 25 2015 334 342 25 Bozek A. Pyrkosz K. Immunotherapy of mold allergy: a review Human Vaccines Immunother 13 2017 2397 2401 26 Di Bona D. Frisenda F. Albanesi M. Di Lorenzo G. Caiaffa M.F. Macchia L. Efficacy and safety of allergen immunotherapy in patients with allergy to molds Clin Exp Allergy 48 2018 1391 1401 30079619 27 Uriarte S. Sastre J. Safety of an Ultrarush (4 hours) Subcutaneous immunotherapy schedule with cat and dog extracts using an infusion pump J Investig Allergol Clin Immunol 28 2018 430 432 28 Lin S.Y. Erekosima N. Kim J.M. Ramanathan M. Suarez-Cuervo C. Chelladurai Y. Sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis and asthma: a systematic review JAMA 309 2013 1278 1288 23532243 29 Blaiss M. Maloney J. Nolte H. Gawchik S. Yao R. Skoner D.P. Efficacy and safety of timothy grass allergy immunotherapy tablets in North American children and adolescents J Allergy Clin Immunol 127 2011 64 71 21211642 30 Wahn U. Tabar A. Kuna P. Efficacy and safety of 5-grass-pollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis J Allergy Clin Immunol 123 2009 160 166 19046761 31 Durham S.R. Emminger W. Kapp A. de Monchy J.G. Rak S. Scadding G.K. SQ-standardized sublingual grass immunotherapy: confirmation of disease modification 2 years after 3 years of treatment in a randomized trial J Allergy Clin Immunol 129 2012 717 725 22285278 32 Valovirta E. Petersen T.H. Piotrowska T. Laursen M.K. Andersen J.S. Sørensen H.F. Results from the 5-year SQ grass sublingual immunotherapy tablet asthma prevention (GAP) trial in children with grass pollen allergy J Allergy Clin Immunol 141 2018 529 538 28689794 33 Berto P. Passalacqua G. Crimi N. Frati F. Ortolani C. Senna G. Economic evaluation of sublingual immunotherapy vs symptomatic treatment in adults with pollen-induced respiratory allergy: the sublingual immunotherapy pollen allergy Italy (SPAI) study Ann Allergy Asthma Immunol 97 2006 615 621 17165269 34 Meadows A. Kaambwa B. Novielli N. Huissoon A. Fry-Smith A. Meads C. A systematic review and economic evaluation of subcutaneous and sublingual allergen immunotherapy in adults and children with seasonal allergic rhinitis Health Technol Assess 17 2013 1 322 35 Omnes L.F. Bousquet J. Scheinmann P. Neukirch F. Jasso-Mosqueda G. Chicoye A. Pharmacoeconomic assessment of specific immunotherapy versus current symptomatic treatment for allergic rhinitis and asthma in France Eur Ann Allergy Clin Immunol 39 2007 148 156 17626329 36 Westerhout K.Y. Verheggen B.G. Schreder C.H. Augustin M. Cost effectiveness analysis of immunotherapy in patients with grass pollen allergic rhinoconjunctivitis in Germany J Med Econ 15 2012 906 917 22533527 37 Sablayrolles V. Pereira B. Petit I. Fauquert J.L. Labbé A. Désensibilisation au pollen de graminées chez l’enfant : quels symptômes trois ans après l’arrêt du traitement Rev Fr Allergol 52 2012 311 316 38 Jacobsen L. Niggemann B. Dreborg S. Ferdousi H.A. Halken S. Høst A. Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study Allergy 62 2007 943 948 17620073 39 Đurić-Filipović I. Caminati M. Kostić G. Filipović Đ. Živković Z. Allergen specific sublingual immunotherapy in children with asthma and allergic rhinitis World J Pediatr 12 2016 283 290 27351563 40 Abramson M.J. Puy R.M. Weiner J.M. Injection allergy immunotherapy for asthma Cochrane Database Syst Rev 8 2010 CD001186 41 Normansell R. Kew R.M. Bridgman A. Sublingual immunotherapy for asthma Cochrane Database Syst Rev 2015 CD011293 26315994 42 Rice J.L. Diette G.B. Suarez-Cuervo C. Brigham E.P. Lin S.Y. Ramannthan M. Allergen-specific immunotherapy in the treatment of pediatric asthma: a systematic review Pediatrics 141 2018 e20173833 29572287 43 Bilo M.B. Pravettoni V. Bigardi D. Bonadonna P. Mauro M. Novembre E. Hymenoptera venom allergy management of children and adults in clinical pratice J Investig Allergol Immunol 29 2019 180 205 44 Ludman S.W. Boyle R.J. Stinging insect allergy: current perspectives on venom immunotherapy J Asthma Allergy 23 2015 75 86 45 Confino-Cohen R. Rosman Y. Goldberg A. Rush venom immunotherapy in children J Allergy Clin Immunol Pract 5 2016 799 803 27914814 46 Lange J. Cichoca-Janosz E. Marczak H. Krauze A. Tarczon I. Swiebocka E. Natural history of hymenoptera venom allergy in children not treated with immunotherapy Ann Allergy Asthma Immunol 116 2016 225 229 26945496 47 Cook Q.S. Kim E.H. Update on peanut allergy: prevention and immunotherapy Allergy Asthma Proc 40 2019 14 20 30582491 48 Nurmatov U. Dhami S. Arasi S. Pajno G.B. Fernandez-Rivas M. Muraro A. Allergen immunotherapy for IgE-mediated food allergy: a systematic review and meta-analysis Allergy 72 2017 1133 1147 28058751 49 Chipps B.E. Ciaccio C.E. Rosén K. Haselkorn T. Zigmont E. Casale T.B. Realworld attitudes among allergists/immunologists regarding oral immunotherapy and preferred terminology J Allergy Clin Immunol Pract 7 2019 721 723 30557711 50 Virkud Y.V. Burks A.W. Steele P.H. Edwards L.J. Berglund J.P. Jones S.M. Novel Baseline predictors of adverse évents during oral immunotherapy in children with peanuts allergy J Allergy Clin Immunol 139 2017 882 888 27609653 51 Vickery B.P. Vereda A. Casale T.B. Beyer K. du Toit G. Hourihane J.O. AR101 oral immunotherapy for peanut allergy N Engl J Med 379 2018 1991 2001 30449234 52 Jones S.M. Sicherer S.H. Burks A.W. Leung D.Y. Lindblad R.W. Dawson P. Epicutaneous immunotherapy for the treatment of peanut allergy in children and young adults J Allergy Clin Immunol 139 2017 1242 1252 [e9] 28091362 53 Pajno G.B. Fernández-Rivas M. Arasi S. Roberts G. Akdis C.A. Alvaro-Lozano M. EAACI Guidelines on allergen immunotherapy: IgE-mediated food allergy Allergy 73 2018 799 815 29205393 54 Casale T.B. Haselkern T. Ciaccio C. Sriarnoon P. Harmonization of terminology for tolerated and reactive dose in food allergy immunotherapy J Allergy Clin Immunol Pract 7 2019 389 392 30557719 55 Kim E.H. Yang L. Ye P. Guo R. Quefeng Li Q. Kulis Long-term sublingual immunotherapy for peanuts allergy in children: clinical and immunologic evidence of desensitization J Allergy Clin Immunol 144 2019 1320 1326 31493887 56 Fleischer D.M. Shreffler W.G. Campbell D.E. Green T.D. Anvari S. Assa’ad A. Long-term, open-label extension study of the efficacy and safety of epicutaneous immunotherapy for peanut allergy in children: PEOPLE 3-year results J Allergy Clin Immunol 2020 10.1016/j.jaci.2020.06.028 57 Settipane R.J. Hagy G.W. Settipane G.A. Long-term risk factors for developing asthma and allergic rhinitis: a 23-year follow-up study of college students Allergy Proc 15 1994 21 25 8005452 58 Demoly P. Bousquet P.J. Links between allergic rhinitis and asthma still reinforced Allergy 63 2008 251 254 18269672 59 Burgess J.A. Walters E.H. Byrnes G.B. Matheson M.C. Jenkins M.A. Wharton C.L. Childhood allergic rhinitis predicts asthma incidence and persistence to middle age: a longitudinal study J Allergy Clin Immunol 120 2007 863 869 17825896 60 Saranz R.J. Lozano A. Caceres M.E. Arnolt R.G. Maspero J.F. Bozzola C.M. Allergen immunotherapy for prevention and treatment of respiratory allergy in childhood Arch Argent Pediatr 108 2010 258 265 20544144 61 Zuberbier T. Bachert C. Bousquet P.J. Passalacqua G. Walter Canonica G. Merk H. GA2 LEN/EAACI pocket guide for allergen-specific immunotherapy for allergic rhinitis and asthma Allergy 65 2010 1525 1530 21039596 62 Cox L. Nelson H. Lockey R. Calabria C. Chacko T. Finegold I. Allergen immunotherapy: a practice parameter third update J Allergy Clin Immunol 127 2011 S1 S55 21122901 63 Di Bona D. Plaia A. Leto-Barone M.S. La Piana S. Macchia L. Di Lorenzo G. Efficacy of allergen immunotherapy in reducing the likelihood of developping new allergen sensitizations: a systematic review Allergy 72 2017 691 702 27926981
PMC007xxxxxx/PMC7484621.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)32600-1 10.1016/j.jaad.2020.09.015 JAAD Online Male balding as a major risk factor for severe COVID-19: A possible role for targeting androgens and transmembrane protease serine 2 to protect vulnerable individuals Wambier Carlos Gustavo MD, PhD a∗ McCoy John PhD b Goren Andy MD b a Department of Dermatology, Alpert Medical School of Brown University, Providence, Rhode Island b Applied Biology, Inc, Irvine, California ∗ Correspondence to: Carlos Gustavo Wambier, MD, PhD, Department of Dermatology, Rhode Island Hospital, 593 Eddy St, APC building, 10th Floor, Providence, RI 02903 11 9 2020 12 2020 11 9 2020 83 6 e401e402 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: We would like to praise Lee et al1 for extra data to support the role of androgens in the COVID-19 pandemic. Lee et al showed increased positivity for COVID-19 among individuals previously self-identified as having pattern 4 baldness. Pattern 4 (frontal plus vertex) baldness could be interpreted as very severe baldness or Hamilton-Norwood scale score of 4 to 7.2 They further showed in multivariate logistic regression that very severe baldness had a higher odds ratio for COVID-19 positivity than hypertension, dyslipidemia, diabetes, obesity per body mass index, or age.1 It is noteworthy that severe baldness was reported to be a better predictor of test result positivity than obesity, because there are many reports linking obesity to COVID-19 disease severity. This underscores the need for further studies and the communication of these findings beyond the dermatology community. In the context of symptomatic presentations reported by Lee et al,1 the baldness survey was conducted many years ago. Some patients who initially self-reported as having frontal baldness or vertex baldness (patterns 2 or 3, respectively) could have developed pattern 4 by 2020. Therefore, we believe the numbers with very severe baldness may be even greater than what was reported. The main evidence of vulnerability is the clinical outcome during the course of COVID-19, particularly intensive care unit (ICU) admission and fatality rates. Severe baldness, the Gabrin sign (Hamilton-Norwood scale score of 3 to 7), has been associated with both increased ICU admissions and increased death rates.2 Understanding the mechanisms leading to host susceptibility provides an opportunity for pharmacologic interventions to protect vulnerable individuals. We have proposed that androgen sensitivity is associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, possibly through androgen-promoted transmembrane protease serine 2 (TMPRSS2).3 Recently, results of a study using bromhexine hydrochloride, a common over-the-counter cough medication only available outside the United States, were reported. Bromhexine was the first drug identified to be a TMPRSS2 inhibitor. The open-label, randomized, standard protocol-controlled trial enrolled 78 patients for treatment of clinical and radiologic pneumonia suspected to be due to COVID-19.4 The arm with bromhexine was superior to the standard protocol, with only 2 patients admitted to the ICU and 0 deaths versus 11 patients admitted to the ICU (P = .006) and 5 deaths in the standard protocol arm (P = .027).4 Reduced expression of TMPRSS2 is also achieved by blocking androgens with medications commonly used in dermatology.3 Results of our recent COVID-19 prospective cohort study involving 77 hospitalized men were also particularly encouraging: only 1 out of 12 individuals was admitted to the ICU (8%) in the cohort of men using 5-alpha-reductase inhibitors or other antiandrogen drugs (dutasteride, n = 9; finasteride, n = 2; and spironolactone, n = 1) versus 38 out of 65 men (58%) not taking antiandrogens (P = .0015).5 Raw data available via Mendeley at https://doi.org/10.17632/6gpc32dyy7.2. Medications that target TMPRSS2 have shown improved COVID-19 outcomes in clinical studies and have the potential to protect vulnerable individuals during the pandemic. We hope that in the near future, more data will be available regarding interventions focused on inhibiting host factors that increase susceptibility to SARS-COV-2, such as the androgen-TMPRSS2 pathway. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Lee J. Yousaf A. Fang W. Kolodney M. Male balding is a major risk factor for severe COVID-19 J Am Acad Dermatol 83 2020 e353 e354 32707256 2 Wambier C.G. Vaño-Galván S. McCoy J. Pai S. Dhurat R. Goren A. Androgenetic alopecia in COVID-19: compared to age-matched epidemiologic studies and hospital outcomes with or without the Gabrin sign J Am Acad Dermatol 2020 10.1016/j.jaad.2020.07.099 3 Wambier C.G. Goren A. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is likely to be androgen mediated J Am Acad Dermatol 83 2020 308 309 32283245 4 Ansarin K. Tolouian R. Ardalan M. Effect of bromhexine on clinical outcomes and mortality in COVID-19 patients: a randomized clinical trial BioImpacts 10 4 2020 209 215 32983936 5 Goren A. Wambier C.G. Herrera S. Anti-androgens may protect against severe COVID-19 outcomes: results from a prospective cohort study of 77 hospitalized men J Eur Acad Dermatol Venereol Published online September 25, 2020 10.1111/jdv.16953
PMC007xxxxxx/PMC7484689.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)32604-9 10.1016/j.jaad.2020.09.019 Research Letter Understanding the impact of teledermatology on no-show rates and health care accessibility: A retrospective chart review Franciosi Ellen B. BA a Tan Alice J. BS a Kassamali Bina BS b O'Connor Daniel M. MD c Rashighi Mehdi MD a LaChance Avery H. MD, MPH b∗ a Department of Dermatology, University of Massachusetts Medical School, Worcester, Massachusetts b Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts c Harvard Combined Dermatology Residency Program, Boston, Massachusetts ∗ Correspondence to: Avery LaChance, MD, MPH, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Ave, Boston, MA 02115 11 9 2020 3 2021 11 9 2020 84 3 769771 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcAt the onset of the COVID-19 pandemic, emergency legislation expanding the coverage of telehealth service swept across the nation to allow for continued access to medical care despite strict shelter-in-place guidelines.1 In the wake of this, telehealth usage has increased dramatically.2 Dermatology, in particular, is uniquely amenable to virtual visits, and teledermatology has the potential to become a permanent platform from which we provide specialty care. As telehealth expands, additional data are needed on the impact of telehealth on health equity. Missed appointments, or no-shows, are a measure of health disparity, with low-income, Medicaid, and minority patients traditionally having the highest no-show rates.3 Given the ability of teledermatology to theoretically improve patient convenience and eliminate potential barriers to care, we sought to investigate the impact of telehealth on no-show rates and patient access at a large academic medical center. The institutional review board of the University of Massachusetts designated this study exempt from institutional review as a quality improvement project. A retrospective chart review was conducted on all patients with completed or no-show appointments with a dermatologist at the UMass Memorial Hahnemann Campus during the months of May and June of 2019 and 2020. Procedural appointments were excluded. In-person visits and televisits, which were conducted using Doximity (San Francisco, CA) or AmWell (Boston, MA) software, were included. Clinic and televisit no-show rates were calculated using data from 2019 and 2020, respectively. Statistical analysis was performed with the Fisher exact test and 2-tailed P values < .05 were considered statistically significant. The Bonferroni method was applied to correct P values where indicated. Compared with clinic visits, televisits had significantly lower no-show rates, with the greatest reductions seen for Black or African American, LatinX, and primary non–English-speaking patients (Fig 1 , Table I ). Compared with clinic visits, televisits served a greater percentage of Medicaid enrollees and patients under 50 years of age (Table I). There was no significant difference in the racial/ethnic background of patients seen via the 2 platforms, with a similar proportion of minority patients seen in televisits versus clinic visits (504 of 1568 [32.1%] vs 1581 of 5315 [29.7%]; P = .19).Fig 1 No-show rates between clinic and teledermatology visits for all patients and stratified by patient demographic subgroups: gender, primary language, and race/ethnicity. Error bars show the standard error of the mean. Table I Comparison of patient composition and no-show rates in clinic versus teledermatology visits for all patients and stratified by patient demographic subgroups Patient demographics Percent no-show (no-show visits/total visits) Televisits Clinic visits P value All 4.0% (63/1568) 13.4% (711/5315) <.0001∗ Gender  Female 4.9% (47/969) 14.2% (423/2992) <.0001∗  Male 2.7% (16/599) 12.4% (288/2322) <.0001∗ Primary language  Non-English 5.6% (8/143) 12.5% (174/742) <.0001∗  English 3.9% (55/1425) 11.8% (538/4573) <.0001∗ Race/Ethnicity Adjusted P value  Asian 2.9% (2/69) 14.2% (24/169) .15  Black or African American 2.6% (2/77) 30.4% (68/224) .0006∗  LatinX 7.0% (17/242) 27.7% (229/826) .0006∗  Other 6.6% (4/61) 25.1% (53/211) .04  Unknown 1.8% (1/55) 13.3% (20/151) .18  White 3.5% (37/1064) 8.5% (318/3734) .0006∗ Age, y  <50 4.3% (41/964) 18.7% (423/2268) <.0001∗  ≥50 3.6% (22/604) 8.6% (289/3372) <.0001∗ Insurance payer Completed televisits Completed clinic visits Adjusted P value  Private 60.6% (975/1607) 54.5% (2462/4514) .08  Medicaid 25.5% (410/1607) 19.6% (885/4514) .0003∗  Medicare 13.8% (222/1607) 25.9 % (1167/4514) .0003∗  Total 1607 4514 ∗ Statistically significant. The data show a particularly striking reduction in no-show rates for minority patients seen via teledermatology. At the same time, both platforms served a similar population of patients with respect to race/ethnicity, while televisits saw a greater percentage of Medicaid but smaller percentage of Medicare enrollees, possibly reflecting age-dependent differences in comfort with virtual visits. Lack of private transportation, access to childcare, and inflexible work schedules contribute to higher no-show rates in minority patients and patients with Medicaid.4 , 5 Significant reductions in no-show rates with teledermatology suggest that televisits may help mitigate barriers to care and improve access for these patients. Limitations of this study include its small sample size and single institution experience. However, this study provides early evidence that teledermatology may play an important role in mitigating no-show rates and improving access to our most vulnerable populations. Further investigation into the impact of telehealth on health inequity is vital to informing future policy making regarding continued insurance coverage of telemedicine moving forward. Funding: Supported by 10.13039/100007299 Harvard Catalyst , The Harvard Clinical and Translational Science Center (10.13039/100006108 National Center for Advancing Translational Sciences , 10.13039/100000002 National Institutes of Health Award UL 1TR002541) and financial contributions from 10.13039/100007229 Harvard University and its affiliated academic health care centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, or the National Institutes of Health. Conflicts of interest: None declared. IRB status: The institutional review board of the University of Massachusetts designated this study exempt from institutional review as a quality improvement project. Reprints not available from the authors. ==== Refs References 1 Kassamali B. Haddadi N.S. Rashighi M. Cavanaugh-Hussey M. LaChance A. Telemedicine and the battle for health equity: translating temporary regulatory orders into sustained policy change J Am Acad Dermatol 2020 10.1016/j.jaad.2020.08.016 2 Newswire P.R. Telehealth claim lines increase 4,347 percent nationally from March 2019 to March 2020 Available at: https://www.prnewswire.com/news-releases/telehealth-claim-lines-increase-4-347-percent-nationally-from-march-2019-to-march-2020--301069182.html 3 Dantas L.F. Fleck J.L. Cyrino Oliveira F.L. Hamacher S. No-shows in appointment scheduling - a systematic literature review Health Policy 122 2018 412 421 29482948 4 Syed S.T. Gerber B.S. Sharp L.K. Traveling towards disease: transportation barriers to health care access J Community Health 38 2013 976 993 23543372 5 Sharp D.J. Hamilton W. Non-attendance at general practices and outpatient clinics BMJ 323 2001 1081 1082 11701560
PMC007xxxxxx/PMC7484805.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)32593-7 10.1016/j.jaad.2020.09.009 Original Article Clinical outcomes of COVID-19 in patients taking tumor necrosis factor inhibitors or methotrexate: A multicenter research network study Yousaf Ahmed BA a Gayam Swapna MD b Feldman Steve MD c Zinn Zachary MD a∗ Kolodney Michael MD, PhD a a Department of Dermatology, West Virginia University, Morgantown, West Virginia b Section of Gastroenterology and Hepatology, West Virginia University, Morgantown, West Virginia c Center for Dermatology Research, Department of Dermatology, Pathology, and Social Sciences and Health Policy, Wake Forest University School of Medicine, Winston-Salem, North Carolina ∗ Reprint requests: Zachary Zinn, MD, Department of Dermatology, West Virginia University, 1 Medical Center Dr, HSC PO Box 9158, Morgantown, WV 26506-9158. 11 9 2020 1 2021 11 9 2020 84 1 7075 3 9 2020 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Background Data on the impact of biologics and immunomodulators on coronavirus disease 2019 (COVID-19)–related outcomes remain scarce. Objective We sought to determine whether patients taking tumor necrosis factor inhibitors (TNFis) or methotrexate are at increased risk of COVID-19–related outcomes. Methods In this large comparative cohort study, real-time searches and analyses were performed on adult patients who were diagnosed with COVID-19 and were treated with TNFis or methotrexate compared with those who were not treated. The likelihood of hospitalization and mortality were compared between groups with and without propensity score matching for confounding factors. Results More than 53 million (53,511,836) unique patient records were analyzed, of which 32,076 (0.06%) had a COVID-19–related diagnosis documented starting after January 20, 2020. Two hundred fourteen patients with COVID-19 were identified with recent TNFi or methotrexate exposure compared with 31,862 patients with COVID-19 without TNFi or methotrexate exposure. After propensity matching, the likelihood of hospitalization and mortality were not significantly different between the treatment and nontreatment groups (risk ratio = 0.91 [95% confidence interval, 0.68-1.22], P = .5260 and risk ratio = 0.87 [95% confidence interval, 0.42-1.78], P = .6958, respectively). Limitations All TNFis may not behave similarly. Conclusion Our study suggests that patients with recent TNFi or methotrexate exposure do not have increased hospitalization or mortality compared with patients with COVID-19 without recent TNFi or methotrexate exposure. Key words coronavirus COVID-19 methotrexate TNF-alpha tumor necrosis factor–alpha inhibitor ==== Body pmc Capsule Summary • To date, there is insufficient real-world evidence to determine whether patients taking tumor necrosis factor inhibitors or methotrexate are at increased risk of worse COVID-19–related outcomes. • This study supports the ongoing use of tumor necrosis factor inhibitors or methotrexate therapy. Coronavirus disease 2019 (COVID-19) is a global pandemic caused by the respiratory droplet transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As of September 20, 2020, there have been more than 6.7 million cases and 199,000 deaths in the United States alone. Given lack of effective vaccines or highly efficacious medical therapy, a global strategy of social distancing and quarantining has been implemented. High-risk patient characteristics include advanced age and various underlying comorbidities. The effect of immunosuppressive medications on COVID-19–related outcomes remains largely unknown.1 Tumor necrosis factor inhibitors (TNFis) and methotrexate (MTX) are used extensively in autoimmune inflammatory diseases, including rheumatoid arthritis, psoriasis, psoriatic arthritis, inflammatory bowel disease, ankylosing spondylitis, and others. Infliximab, adalimumab, etanercept, certolizumab, and golimumab are the 5 most commonly prescribed TNFis, and MTX is the most commonly prescribed disease-modifying antirheumatic drug (DMARD) in the United States. TNFis increase the risk of certain infections, such as upper respiratory infections, and cause flaring of pre-existing infectious diseases, such as tuberculosis.2 Likewise, MTX, a DMARD used as monotherapy or in conjunction with biologic agents, such as TNFi, can suppress immune function and increase infection risk.3 There are little data on SARS-CoV-2 risk in patients who are taking TNFis or MTX. The U.S. Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) did not issue guidelines regarding the usage of biologics including TNFis or immunomodulators including MTX during the COVID-19 pandemic. Medical societies such as the American College of Gastroenterology, American College of Rheumatology, and American Academy of Dermatology released guidelines on medication usage, although guidelines were based largely on expert opinion given the paucity of available information on SARS-CoV-2. The effect of TNFi or MTX usage on COVID-19–related outcomes remains poorly characterized. We tested the hypothesis that TNFi or MTX usage increases the risk of report hospitalization and mortality from COVID-19 using data from a global health research network. Methods Patient population TriNetX (Cambridge, MA) is a global federated health research network providing access to statistics on electronic medical records, including diagnoses, procedures, medications, laboratory values, and genomic information. The COVID-19 research network includes approximately 53 million unique patient records from 2009 to 2020 across 42 large health care organizations, predominantly from the United States (91%) but including Italy, Spain, the United Kingdom, India, Malaysia, and Australia. TriNetX fast-tracked data inflow into the COVID-19 research network to add COVID-19 diagnoses and terminology following WHO and CDC guidelines. Importantly, TriNetX allows International Classification of Diseases, 10th Revision, Clinical Modification queries for comorbid diagnoses. As a federated network, TriNetX received a waiver from the Western Institutional Review Board (Olympia, WA) because only aggregated counts and statistical summaries of deidentified information are distributed, no protected health information is received, and no study-specific activities are performed in retrospective analyses. COVID-19 patients ≥18 years of age were queried on June 11, 2020 using International Classification of Diseases, 10th Revision, Clinical Modification diagnoses and terminology recommended by the WHO and CDC (Supplementary Appendix available via Mendeley at https://data.mendeley.com/datasets/wgbv9mdv9x/1). Only patients diagnosed with a documented code after January 20, 2020 were included, following the first U.S. confirmed case.4 We captured patients with COVID-19 who were taking TNFis or MTX by requiring any instance of a documented TNFi (adalimumab, infliximab, etanercept, certolizumab, or golimumab) or MTX within 1 year of contracting COVID-19. Baseline characteristics were reported from documentation any time 6 months before the COVID-19 diagnosis. The index event was defined as contracting COVID-19. Outcomes The observation period for outcome analysis was defined as the date from the index event to 45 days after the index event. Primary outcomes studied were, from any cause, hospitalization and mortality. Outcomes analysis restricted the time window to capture primary outcomes related to COVID-19. TriNetX provided specific inclusion criteria defining each outcome (Supplementary Appendix). Statistical analysis A 1:1 propensity score match was performed for confounding variables previously found to be associated with COVID-19.5 Independent variables were chosen to assess for demographic disparities, including age at index event, gender, and race. Summary statistics were generated for all variables included in the propensity score match. A greedy nearest-neighbor matching algorithm was used with a caliper of 0.1 times the standard deviation. Chi-square analysis was conducted to determine significant differences between the TNFi or MTX cohort and the nontreatment cohort. Significance was set to an alpha level of 0.05 a priori. All statistical analyses were conducted on TriNetX. Results Patient population More than 53 million (53,511,836) patient records were on the COVID-19 research network across 42 health care organizations, of which 32,076 (0.06%) had a COVID-19–related diagnosis documented starting after January 20, 2020. Among the COVID-19 population, 214 (0.7%) had either a documented TNFi or MTX exposure within 1 year of the COVID-19 diagnosis. One hundred and two (0.3%) patients were documented with a TNFi and 128 (0.4%) with methotrexate within 1 year before the COVID-19 diagnosis. (Patients with exposure to both TNFi and MTX were counted once in the combined TNFi or MTX group.) Baseline characteristics Patients in the TNFi/MTX group had a nonsignificant age difference (55.1 ± 15.8 years vs 53.2 ± 18.9 years, P = .1540) when compared with the non-TNFi/MTX group (Tables I and II ). Patients were more frequently female (66.4%) and white (42.5%) in the TNFi/MTX group compared with the non-TNFi/MTX group (54.6% and 34.4%, respectively). The TNFi/MTX group had substantially more comorbidities compared with the non-TNFi/MTX group. A greater proportion of the TNFi/MTX group was diabetic (20.6%) and obese (18.7%) compared with the non- TNFi/MTX group (12.5% and 9.1%, respectively).Table I Unmatched baseline characteristics and outcomes Characteristics Before propensity matching P value TNFi plus MTX (n = 214) No TNFi or MTX (n = 31,862) Demographics  Age at index, y ± SD 55.1 ± 15.8 53.2 ± 18.9 .1540  Female, n (%) 142 (66.4) 17,393 (54.6) .0006  White, n (%) 91 (42.5) 10,958 (34.4) .0126 Comorbidities, n (%)  Diseases of the digestive system 106 (49.5) 5537 (17.4) <.0001  Diseases of the musculoskeletal system and connective tissue 143 (66.8) 6366 (20.0) <.0001  Diseases of the nervous system 94 (43.9) 5247 (16.5) <.0001  Diseases of the blood and blood-forming organs 88 (41.1) 4037 (12.7) <.0001  Diseases of the circulatory system 131 (61.2) 9526 (29.9) <.0001  Diseases of the skin and subcutaneous tissue 59 (27.6) 2307 (7.2) <.0001  Diabetes mellitus 44 (20.6) 3992 (12.5) .0004  Body mass index 30-39.9 kg/m2 40 (18.7) 2909 (9.1) <.0001 45-day outcomes, n (%)  Hospitalization 61 (28.5) 6325 (19.9) .0016  Death 13 (6.1) 1963 (6.2) .9583 MTX, Methotrexate; SD, standard deviation; TNFi, tumor necrosis factor inhibitor. Table II Subgroup analysis of unmatched baseline characteristics and outcomes Characteristics Before propensity matching P value TNFi (n = 102) No TNFi (n = 32,057) P value MTX (n = 128) No MTX (n = 31982) Demographics  Age at index, y ± SD 49.7 ± 15.6 53.2 ± 18.9 .0606 58.7 ± 14.9 53.2 ± 18.9 .0011  Female, n (%) 62 (60.7) 17540 (54.7) .2189 93 (72.7) 17461 (54.6) <.0001  White, n (%) 46 (45.1) 11040 (34.4) .0237 53 (41.4) 11011 (34.4) .0974 Comorbidities, n (%)  Diseases of the digestive system 51 (50.0) 5615 (17.5) <.0001 62 (48.4) 5599 (17.5) <.0001  Diseases of the musculoskeletal system and connective tissue 58 (56.9) 6490 (20.3) <.0001 98 (76.6) 6424 (20.1) <.0001  Diseases of the nervous system 38 (37.3) 5326 (16.6) <.0001 63 (49.2) 5286 (16.5) <.0001  Diseases of the blood and blood-forming organs 37 (36.3) 4115 (12.8) <.0001 58 (45.3) 4084 (12.8) <.0001  Diseases of the circulatory system 50 (49.0) 9644 (30.1) <.0001 88 (68.8) 9581 (30.0) <.0001  Diseases of the skin and subcutaneous tissue 28 (27.5) 2351 (7.3) <.0001 36 (28.1) 2339 (7.3) <.0001  Diabetes mellitus 11 (10.8) 4037 (12.6) .5824 33 (25.8) 4007 (12.5) <.0001  Body mass index 30-39.9 kg/m2 18 (17.6) 2945 (9.2) .0032 25 (19.5) 2930 (9.2) <.0001 45-day outcomes, n (%)  Hospitalization 24 (23.5) 6378 (19.9) .3588 40 (31.3) 6349 (19.9) .0013  Death N/A∗ 1979 (6.2) - 12 (9.4) 1964 (6.1) .1286 MTX, Methotrexate; N/A, not available; SD, standard deviation; TNFi, tumor necrosis factor inhibitor. ∗ TriNetX obfuscates patient counts ≤10 to safeguard protected health information. Patients in the MTX subgroup were older than the non-MTX group (58.7 ± 14.9 years vs 53.2 ± 18.9 years, P = .0011). In both TNFi and MTX subgroups, the demographic trends of more female and white patients remained, as did having substantially more comorbidities. Therefore, a 1:1 propensity score match was performed for all significant comorbidities, as well as age, gender, race, diabetes, and obesity. Outcomes at 45 days Propensity score matching in the TNFi/MTX group yielded n = 213 in both TNFi/MTX and non- TNFi/MTX groups. After matching, the groups were well balanced in age, gender, race, and all comorbidities. The likelihood of hospitalization was similar for the TNFi/MTX group and the non-TNF/MTX group (risk ratio = 0.91 [95% confidence interval {CI} 0.68-1.22], P = .5260). This trend remained when subgroup analysis was performed in the TNFi (risk ratio = 0.73 [95% CI 0.47-1.14], P = .1594) and MTX (risk ratio = 0.87 [95% CI 0.62-1.23], P = .4272) groups. Matching did not change the overall outcome results for death, remaining nonsignificant in the TNFi/MTX group when compared with the non-TNFi/MTX group (risk ratio = 0.87 [95% CI 0.42-1.78], P = .6958, Tables III and IV ).Table III Matched characteristics and outcomes Characteristics After propensity matching TNFi plus MTX (n = 213) No TNFi or MTX (n = 213) P value Demographics  Age at index, y ± SD 55.1 ± 15.8 54.9 ± 16.2 .9301  Female, n (%) 141 (66.2) 139 (65.3) .8382  White, n (%) 91 (42.7) 81 (38.0) .3234 Comorbidities, n (%)  Diseases of the digestive system 105 (49.3) 97 (45.5) .4376  Diseases of the musculoskeletal system and connective tissue 142 (66.7) 149 (70.0) .4660  Diseases of the nervous system 93 (43.7) 81 (38.0) .2369  Diseases of the blood and blood-forming organs 87 (40.9) 89 (41.8) .8440  Diseases of the circulatory system 130 (61.0) 123 (57.8) .4898  Diseases of the skin and subcutaneous tissue 58 (27.2) 50 (23.5) .3729  Diabetes mellitus 44 (20.7) 39 (18.3) .5408  Body mass index 30-39.9 kg/m2 40 (18.8) 32 (15.0) .3010 45-day outcomes, n (%)  Hospitalization 61 (28.6) 67 (31.5) .5260  Death 13 (6.1) 15 (7.0) .6958 MTX, Methotrexate; SD, standard deviation; TNFi, tumor necrosis factor inhibitor. Table IV Subgroup analysis of matched baseline characteristics and outcomes Characteristics After propensity matching TNFi (n = 101) No TNFi (n = 101) P value MTX (n = 128) No MTX (n = 128) P value Demographics  Age at index, y ± SD 49.7 ± 15.7 52.0 ± 18.5 .3304 58.7 ± 14.9 58.7 ± 16.7 .9968  Female, n (%) 61 (60.4) 67 (66.3) .3809 94 (73.4) 94 (73.4) .8880  White, n (%) 46 (45.5) 48 (47.5) .7779 53 (41.4) 53 (41.4) 1.0000 Comorbidities, n (%)  Diseases of the digestive system 50 (49.5) 51 (50.5) .8881 62 (48.4) 62 (48.4) 1.0000  Diseases of the musculoskeletal system and connective tissue 57 (56.4) 59 (58.4) .7760 98 (76.6) 99 (77.3) .8820  Diseases of the nervous system 37 (36.6) 34 (33.7) .6584 63 (49.2) 55 (43.0) .3158  Diseases of the blood and blood-forming organs 36 (35.6) 35 (34.7) .8828 58 (45.3) 53 (41.4) .5283  Diseases of the circulatory system 49 (48.5) 44 (43.6) .4803 88 (68.8) 96 (75.0) .2661  Diseases of the skin and subcutaneous tissue 27 (26.7) 27 (26.7) 1.0000 36 (28.1) 32 (25) .5714  Diabetes mellitus 11 (10.9) N/A∗ — 33 (25.8) 32 (25) .8858  Body mass index 30-39.9 kg/m2 18 (17.8) 12 (11.9) .2352 25 (19.5) 24 (18.8) .8738 45-day outcomes, n (%)  Hospitalization 24 (23.8) 33 (32.7) .1594 40 (31.3) 46 (35.9) .4272  Death N/A∗ N/A∗ — 12 (9.4) N/A∗ — MTX, Methotrexate; N/A, not available; SD, standard deviation; TNFi, tumor necrosis factor inhibitor. ∗ TriNetX obfuscates patient counts ≤10 to safeguard protected health information. Discussion Outcome-based data on the effect of recent anticytokine biologic or immunomodulator exposure in the setting of COVID-19 infection are limited. SARS-CoV-2 can induce a cytokine storm syndrome that worsens symptoms in the form of fevers, confusion, and coagulopathy.6 Initial hypotheses maintained that cytokine inhibition may worsen COVID-19–related outcomes via general immune suppression; however, more recent hypotheses suggest that inhibition of a cytokine storm may actually be beneficial. Anticytokine biologic therapies may prevent cytokine storm syndrome, which is the rationale for use of interleukin-6 inhibitors for treating COVID-19.7 , 8 Real-world evidence-based data are needed on COVID-19–related outcomes in the setting of TNFi or MTX exposure. Two hundred fourteen of 32,076 patients with COVID-19 had TNFi or MTX treatment within 12 months of COVID-19 infection and comprised the treatment group. Thirty-one thousand eight hundred sixty-two patients with COVID-19 infection had no TNFi or MTX exposure within the same time period and comprised the nontreatment group. The likelihood of hospitalization and mortality were compared between groups with and without propensity score matching for confounding factors. After propensity matching, the likelihood of hospitalization and mortality were not significantly different between the treatment and nontreatment group (risk ratio = 0.91 [95% CI 0.68-1.22], P = .5260 and risk ratio = 0.87 [95% CI 0.42-1.78], P = .6958, respectively). Subgroup analysis of TNFi exposure also showed no significant difference in likelihood of hospitalization compared with patients with COVID-19 without TNFi exposure (risk ratio = 0.73 [95% CI 0.47-1.14], P = .1594). Likewise, MTX exposure alone showed no statistically significant difference in the likelihood of hospitalization compared with patients who were not exposed to MTX (risk ratio = 0.87 [95% CI 0.62-1.23], P = .4272). There were insufficient data to calculate mortality for TNFi and MTX individually. In summary, our data showed similar likelihoods of hospitalization and mortality in the TNFi or MTX treatment group versus the nontreatment group. These results stood with and without propensity score matching for confounding factors. Our study builds upon a case series from New York by Haberman et al1 that concluded that baseline anticytokine biologic use did not correlate with worse COVID-19–related outcomes. While hospitalization rates were similar in the anticytokine biologic treatment cohort compared with patients with COVID-19 in the general population of New York City, their limited sample size made conclusions on mortality untenable. This study reviewed >53 million patients from 42 health care organizations, permitting a large enough sample size to conclude mortality likelihood differences and to control for confounding factors. Haberman et al1 included patients taking 5 different classes of anticytokine therapy (Janus kinase inhibitor, TNFi, interleukin-17 blocker, interleukin-23 blocker, and interleukin-12/23 blocker) with outcome data interpreted in aggregate. As a result, COVID-19–related outcomes related to a specific class of anticytokine biologics could not be evaluated. This study evaluated only 1 class of anticytokine biologics, the TNFis, and only 1 DMARD, MTX, to avoid influences of aggregating immunosuppressive medications. Nonetheless, the present study provides practical information to the clinician treating patients who are taking these medications. Adalimumab, etanercept, infliximab, certolizumab, golimumab, and MTX were included in the study. This group includes 3 of the most commonly prescribed biologics (adalimumab, etanercept, and infliximab) and the most commonly prescribed DMARD (MTX) in the United States. Such a selection makes our study relevant to dermatologists, gastroenterologists, rheumatologists, and other specialists who routinely prescribe these medications.9 The large cohort is a strength of this study. Limitations of our study include an inclusion criteria window for TNFi or MTX exposure within 12 months of COVID-19 infection that may have captured some patients who were no longer taking the medication of concern at the onset of COVID-19 infection. Some patients in the data set were taking a TNFi and MTX and therefore may have been included twice in the subgroup analysis. Diagnostic indication for TNFi and MTX prescription was not available for subgroup analyses. Furthermore, patients that took both TNFi and MTX may have taken both drugs concurrently or at different times during the 12-month window, and actual biologic exposure may differ from what is reflected in the electronic medical record. The present study did not control for the use of medications in other classes, which may affect the results of the study. In addition, all TNFis may not behave similarly and inclusion of multiple TNFis together may create bias; however, this bias is presumably to a lesser magnitude than studies that aggregate anticytokine biologics across multiple classes. COVID-19 infection may also have been misclassified in some patients given limitations of COVID-19 confirmatory testing, although COVID-19–specific diagnoses and terminology recommended by the WHO and CDC were used in our inclusion criteria. Finally, propensity score matching may not account for all possible confounders. Because the COVID-19 pandemic is ongoing, there is desperate need for evidence-based data on biologic and immunomodulator exposure in the setting of COVID-19 infection. Current guidelines regarding COVID-19 and the use of biologics are largely based on expert opinion rather than rigorous statistical analysis. Our study supports the ongoing use of TNFi or MTX therapy and argues against the interruption of treatment because of the fear of possibly worse COVID-19–related outcomes. Funding sources: None. Conflicts of interest: None declared. IRB status: Not applicable. ==== Refs References 1 Haberman R. Axelrad J. Chen A. Covid-19 in immune-mediated inflammatory diseases—case series from New York N Engl J Med 383 2020 85 88 32348641 2 Bongartz T. Sutton A.J. Sweeting M.J. Buchan I. Matteson E.L. Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials JAMA 295 2006 2275 2285 16705109 3 McLean-Tooke A. Aldridge C. Waugh S. Spickett G.P. Kay L. Methotrexate, rheumatoid arthritis and infection risk—what is the evidence? Rheumatology 48 2009 867 871 19447771 4 Holshue M.L. DeBolt C. Lindquist S. First case of 2019 novel coronavirus in the United States N Engl J Med 382 2020 e53 5 Jordan R.E. Adab P. Cheng K.K. Covid-19: risk factors for severe disease and death BMJ 368 2020 m1198 32217618 6 Wang D. Hu B. Hu C. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China JAMA 323 2020 1061 1069 32031570 7 Henriksen M. Anti-il6 treatment of serious COVID-19 disease with threatening respiratory failure (TOCIVID) Available at: https://www.clinicaltrials.gov/ct2/show/NCT04322773 8 Regeneron Pharmaceuticals Evaluation of the efficacy and safety of sarilumab in hospitalized patients with COVID-19 Available at: https://clinicaltrials.gov/ct2/show/NCT04315298 9 Biologic drugs set to top 2012 sales Nat Med 18 2012 636
PMC007xxxxxx/PMC7485548.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)32597-4 10.1016/j.jaad.2020.09.012 Research Letter A deep learning algorithm with high sensitivity for the detection of basal cell carcinoma in Mohs micrographic surgery frozen sections Campanella Gabriele MS ab Nehal Kishwer S. MD c Lee Erica H. MD c Rossi Anthony MD c Possum Brandon HT c Manuel Genna HT c Fuchs Thomas J. PhD ab Busam Klaus J. MD b∗ a Weill Cornell Graduate School of Medical Sciences, New York, New York b Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York c Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York ∗ Correspondence to: Klaus J. Busam, MD, Department of Pathology, Rm C530, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 11 9 2020 11 2021 11 9 2020 85 5 12851286 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: Advances in digital pathology with rapid slide scanning of whole slide images (WSIs)1 , 2 and artificial intelligence (AI) offer opportunities for improved accuracy and real-time quality assurance of histopathologic interpretations, which could be used for intraoperative frozen section margin assessment of skin cancer. A recent study explored an AI algorithm for detecting basal cell carcinoma (BCC) in digital images of Mohs micrographic surgery slides using a total of 100 cases: 60 for training, 20 for validation, and 20 for testing.3 The final model's sensitivity was 70.6%; its specificity was 79.1%. We also performed a retrospective study (under institutional review board protocol 18-013) on the feasibility of detecting BCC in Mohs micrographic surgery sections but used a deep learning system under the multiple instance learning assumption that was trained on thousands of WSIs.4 Six thousand two hundred fifty-two WSIs were used during the learning phase: 4699 for training and 1553 for validation and model selection. Of the entire cohort, 1154 WSIs were positive for BCC. An additional 200 Mohs micrographic surgery sections were used to fine-tune the model. The final test set consisted of 100 frozen sections from 50 patients. Thirty-six sections had BCC and 64 were benign. The model used was a ResNet34 convolutional neural network that was pretrained on natural images. We compared the algorithm's performance to that of 3 Mohs surgeons reading individually the same 100 WSIs on a screen. Our algorithm performed with high sensitivity (Fig 1 ). It correctly identified all sections with BCC. There were 4 false positive results (specificity 94%). The specificity of the surgeons ranged from 91.4% to 100%. Two of 3 surgeons achieved a specificity of 100% (all margins scored as positive contained BCC). The sensitivity of the surgeons in detecting BCC on the scanned images varied from 90% to 97.3% (failure to detect BCC in 1, 2, and 4 cases, respectively). The area under the curve performance of the surgeons compared with the algorithm is shown in Fig 2 .Fig 1 Performance of the proposed algorithm. Receiver operating characteristic curves for the final prediction and individual models trained at different magnifications. AUC, Area under the curve; MPP, microns per pixel. Fig 2 Comparison of the performance of the algorithm with that of 3 dermatologic surgeons. AUC, Area under the curve. When comparing the algorithm to the surgeons, one needs to bear in mind that our test conditions do not mirror clinical practice. Scanned images were used, not slides. In addition, when a microscopic finding of uncertain significance is encountered in clinical practice, one is not limited to rendering a best guess based on 1 slide alone. Additional histologic sections can be obtained for more clues. Nonetheless, assistance from a second reader during Mohs micrographic surgery, such as an AI algorithm, could have clinical value. A discordance between the algorithm and a physician could prompt a second look at a particular slide in real time to ensure that no positive margin is missed. While our findings document clinical grade high sensitivity of our deep learning algorithm, a major limitation of the current study is the binary classification of BCC present versus absent. More studies are needed to assess how the algorithm performs for the detection of other tumors, such as squamous cell carcinoma. It is possible that different models may be required for various diagnostic problems. Prospective studies are needed to assess the practicality of integrating AI in clinical practice and how it affects outcomes. We thank the Warren Alpert Center for Digital and Computational Pathology, in particular Christina Virgo, for assistance with the slide scanning. We also thank Yesenia Gonzalez for additional support with the slide management, preparation, and submission of this research letter. Funding: Supported in part by the Cancer Center Support Grant of 10.13039/100000002 National Institutes of Health /10.13039/100000054 National Cancer Institute grant P30CA008748. Conflicts of interest: Dr Fuchs owns equity of PAIGE.AI. All other authors have no conflicts of interest to declare. IRB status: Approved. Reprints not available from the authors. ==== Refs References 1 Hanna M.G. Reuter V.E. Hameed M.R. Whole slide imaging equivalency and efficiency study: experience at a large academic center Mod Pathol 32 2019 916 928 30778169 2 Hanna M.G. Reuter V.E. Ardon O. Validation of a digital pathology system including remote review during the COVID-19 pandemic Mod Pathol 2020 10.1038/s41379-020-0601-5 3 Sohn G.K. Sohn J.H. Yeh J. Chen Y. Brian Jiang S.I. A deep learning algorithm to detect the presence of basal cell carcinoma on Mohs micrographic surgery frozen sections J Am Acad Dermatol 2020 10.1016/j.jaad.2020.06.080 4 Campanella G. Hanna M.G. Geneslaw L. Clinical-grade computational pathology using weakly supervised deep learning on whole slide images Nat Med 25 2019 1301 1309 31308507
PMC007xxxxxx/PMC7491373.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)32615-3 10.1016/j.jaad.2020.09.029 Research Letter Patient and physician perspectives on teledermatology at an academic dermatology department amid the COVID-19 pandemic Asabor Emmanuella Ngozi MPhil ab Bunick Christopher G. MD, PhD c Cohen Jeffrey M. MD c Perkins Sara H. MD c∗ a Yale School of Medicine, Yale University, New Haven, Connecticut b Department of Epidemiology of Microbial Diseases, Yale School of Public Health, Yale University, New Haven, Connecticut c Department of Dermatology, Yale School of Medicine, Yale University, New Haven, Connecticut ∗ Reprint requests: Sara H. Perkins, MD, 333 Cedar St, LCI 501, PO Box 208059, New Haven, CT 06520-8059 15 9 2020 1 2021 15 9 2020 84 1 158161 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: In the era of COVID-19, dermatology practices have rapidly adopted teledermatology.1 , 2 Prepandemic research showed physician and patient satisfaction; however, these studies included groups who chose the telemedicine medium.3 , 4 Pandemic-related restrictions on in-person care catalyzed a broader adoption of telemedicine among both physicians and patients. This study examines the experiences of both groups with teledermatology during the COVID-19 pandemic. We surveyed the clinical faculty in the Department of Dermatology at Yale School of Medicine and patients seen via Epic MyChart (Epic, Verona, WI) synchronous video visits from mid-March to mid-May 2020. We performed an ordinal logistic regression using the polr package in R, version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria) to compare patient and physician perceptions. We excluded all unable to answer responses from the regression analysis. Faculty were amenable to managing many skin conditions solely by telemedicine or by telemedicine in conjunction with in-person visits. However, 23 of 24 faculty members (96%) believed that total body skin examination should only be managed through in-person visits (Fig 1 ).Fig 1 Faculty management preferences for managing various dermatologic conditions via telemedicine versus in-person visits. Table I summarizes physician and patient perspectives on virtual care; 50% of faculty reported prior experience with teledermatology, although the majority had used only store-and-forward.5 Table I Patient and physician perspectives on telemedicine care Question posed to patients and/or physicians Patients, n (%) (N = 548) Physicians, n (%) (N = 24) Odds ratio 95% CI P value The MyChart App made it easy to have a video visit 4.46 2.05-9.71 .001  Strongly agree 365 (67.1) 7 (30.4)  Agree 137 (25.2) 11 (47.8)  Disagree 14 (2.6) 2 (8.7)  Strongly disagree 21 (3.9) 3 (13.0)  Unable to answer 7 (1.3) 0 The video visit picture and audio quality were good 18.05 8.56-38.75 <.001  Strongly agree 324 (59.2) 0 (0)  Agree 169 (30.9) 9 (37.5)  Disagree 24 (4.4) 10 (41.7)  Strongly disagree 16 (2.9) 5 (20.8)  Unable to answer 14 (2.6) 0 Patient received/I am able to provide the same quality of care during our video visit as an office visit 48.28 19.55-128.40 <.001  Strongly agree 234 (42.8) 1 (4.2)  Agree 213 (38.9) 2 (8.3)  Disagree 61 (11.2) 11 (45.8)  Strongly disagree 7 (1.3) 10 (41.7)  Unable to answer 32 (5.9) 0 I am interested in using video visits for future appointments 1.33 0.62-2.85 .47  Strongly agree 223 (40.8) 8 (33.3)  Agree 238 (43.6) 13 (54.2)  Disagree 53 (9.7) 3 (12.5)  Strongly disagree 10 (1.8) 0  Unable to answer 22 (4.0) 0 My family member or I would be more likely to choose a provider who offered video visits — — —  Strongly agree 195 (35.8) —  Agree 233 (42.8) —  Disagree 72 (13.2) —  Strongly disagree 9 (1.7) —  Unable to answer 35 (6.4) — How much time did you save by having a video visit? (includes travel, wait, time off of work) — — —  Less than 1 hour 192 (35.0) —  1-2 hours 267 (48.7) —  2-4 hours 67 (12.2) —  More than 4 hours 22 (4.0) — My patients appreciated the ability to have a video visit — — —  Strongly agree — 14 (60.9)  Agree — 9 (39.1)  Disagree — 0  Strongly disagree — 0  Unable to answer — 0 Offering video visits during the pandemic allowed me to feel that I was participating in the overall effort to decrease the need for in-person care — — —  Strongly agree — 18 (78.3)  Agree — 5 (21.7)  Disagree — 0  Strongly disagree — 0  Unable to answer — 0 Patients were generally understanding of the situation and our effort to conduct care using telemedicine — — —  Strongly agree — 12 (50)  Agree — 12 (50)  Disagree — 0  Strongly disagree — 0  Unable to answer — 0 I believe that some of my patients' skin cancer, or skin disease, has progressed as a result of avoiding interaction with the medical system during the COVID-19 pandemic — — —  Strongly agree — 5 (21.7)  Agree — 15 (65.2)  Disagree — 2 (8.7)  Strongly disagree — 1 (4.3)  Unable to answer — 0 Did you have experience offering teledermatology services before the COVID-19 pandemic? — — —  Yes, store-and-forward, physician-to-physician (eConsults) — 9 (38)  Yes, live synchronous (video visits) — 2 (8)  Yes, store-and-forward, direct-to-patient — 1 (4)  No — 12 (50) CI, Confidence interval. All physician respondents believed that teledermatology allowed them to contribute to efforts to reduce in-person care; however, 87% of physicians responded that some patients' skin cancer or skin disease likely progressed because of COVID-related avoidance of interaction with in-office medical care (Table I). Finally, most patients reported that teledermatology was time saving. Including travel, wait time, and time off from work, 65% of patients reported saving at least 1 hour of time (Table I). Patients were nearly 50 times more likely than faculty to agree or strongly agree that the quality of care during a telemedicine visit was equal to an in-office visit (odds ratio, 48.28; 95% confidence interval, 19.55-128.40; P < .001). Patients were nearly 20 times as likely as faculty to agree or strongly agree that the picture and video quality during the video visit were good (odds ratio, 18.05; 95% CI, 8.56-38.75; P < .001). The majority of both patients and physicians reported future interest in video visits (P = .47) (Table I). Our study indicates that patients and physicians are overwhelmingly interested in teledermatology in the future. Although most physicians had limited previous experience, the majority believed that teledermatology allowed them to contribute to COVID-19 control efforts and that many conditions could be managed by telemedicine alone or by telemedicine in conjunction with office visits. However, our study highlights important discrepancies between physician and patient perceptions and emphasizes significant concerns among physicians regarding the quality of virtual care provision. They also suggest that patients, compared to physicians, value convenience when thinking about quality. These insights represent opportunities for technologic innovation but also indicate a need for caution as we integrate this care modality. Our study is limited by our sample size of 572 and the fact that patients who did not schedule video visits could not be included. Larger, multi-institutional studies are needed to better understand the limitations of, and opportunities afforded by, teledermatology during the public health crisis and beyond. Author Asabor would like to thank the Black Health Scholars Network for their support of this work. Drs Cohen and Perkins contributed equally to this article. Funding sources: None. Disclosure: Dr Perkins is a clinical advisor for Hims/Hers. Dr Bunick is a consultant for Teladoc. Author Asabor and Dr Cohen have no conflicts of interest to declare. IRB approval status: Reviewed and approved by Yale University Institutional Review Board (protocol ID 2000028082). ==== Refs References 1 McGee J.S. Reynolds R.V. Olbricht S.M. Fighting COVID-19: early teledermatology lessons learned J Am Acad Dermatol 83 2020 1224 1225 32553677 2 Perkins S. Cohen J.M. Nelson C.A. Bunick C.G. Teledermatology in the era of COVID-19: experience of an academic department of dermatology J Am Acad Dermatol 83 1 2020 e43 e44 32305442 3 Wang Y.C. Ganzorig B. Wu C.C. Patient satisfaction with dermatology teleconsultation by using MedX Comput Methods Programs Biomed 167 2018 37 42 30501858 4 Coustasse A. Sarkar R. Abodunde B. Metzger B.J. Slater C.M. Use of teledermatology to improve dermatological access in rural areas Telemed J E Health 25 11 2019 1022 1032 30741608 5 Deeds S.A. Dowdell K.J. Chew L.D. Ackerman S.L. Implementing an opt-in eConsult program at seven academic medical centers: a qualitative analysis of primary care provider experiences J Gen Intern Med 34 8 2019 1427 1433 31197734
PMC007xxxxxx/PMC7527280.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)32678-5 10.1016/j.jaad.2020.09.077 JAAD Online COVID-19 compels closer scrutiny of disparities in dermatology Temiz Laurie A. BA a McKinley-Grant Lynn MD b Glass Donald A. II MD, PhD c Harvey Valerie M. MD, MPH d∗ a Meharry Medical College, Nashville, Tennessee b Department of Dermatology, Howard University College of Medicine, Washington, DC c Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas d Hampton University Skin of Color Research Institute, Hampton University, Virginia ∗ Correspondence to: Valerie M. Harvey, MD, MPH, Hampton University Skin of Color Research Institute, 100 William Harvey Way, Hampton, VA 23668 1 10 2020 2 2021 1 10 2020 84 2 e103e104 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: The coronavirus disease 2019 (COVID-19) pandemic has had profound impact. As of August 22, 2020, the United States (US) has reported 5,686,305 cases and 176,583 deaths.1 Beyond the substantial health and economic consequences, COVID-19 has exposed the profound health disparities that have long plagued the US, illuminating the disproportionate suffering of minorities and other marginalized populations. Blacks comprise a disparate number of COVID-19 hospitalizations and deaths. In New Orleans, 76.9% of COVID-19 hospitalizations and 70.6% of deaths were among Blacks, although they only comprised 31% of that health system's population.2 The reasons for increased COVID-19 severity among minorities are multifactorial, including a higher prevalence of comorbidities (ie, diabetes, hypertension, obesity) and longer waits to access health care. Moreover, Blacks are more likely than Whites to hold occupations (ie, restaurants, retail, hospitality) and reside in housing (multigenerational homes, public housing) that facilitate community transmission, rendering strategies to prevent COVID-19 spread (social distancing, teleworking) less feasible.2 The pandemic has not only provoked national discourse on inequities in health care but also calls for more rigorous examination of this topic in dermatology. The Department of Health and Human Services' Healthy People 2020 defines a health disparity as…a particular type of health difference that is closely linked with social, economic, and/or environmental disadvantage. Health disparities adversely affect groups of people who have systematically experienced greater obstacles to health based on their racial or ethnic group; religion; socioeconomic status; . . . or other characteristics historically linked to discrimination or exclusion.3 Expectedly, the limited studies probing disparities in dermatologic outcomes reveal existing inequities. For example, minority patients diagnosed with melanoma are 2- to 4-times more likely than Whites to receive an advanced-stage diagnosis.4 Privately and publicly insured outpatient dermatology visits are less common for Blacks and Latinx compared with Whites after adjustments for patient demographics and primary diagnosis.4 However, the individual, contextual, and structural determinants of these disparities and the pathways through which they operate are unknown. With US demographics shifting toward a minority-majority by 2045 and recognizing the profound impact of cutaneous disorders on health and quality of life, there is an urgent need to drive health disparity inquiry to the forefront of the research agenda. Based on the conceptual framework of Kilbourne et al,5 a basic strategic roadmap should include detecting disparities, understanding their determinants, and implementing evidence-based policies to eliminate inequities. At a minimum, a requisite series of actions must occur. Dermatologists must begin the difficult task of evidence generation by supporting investigators who study disparities. Dermatology leadership, nationally and institutionally, should intensify longitudinal pipeline efforts to diversify the dermatology workforce, because under-represented minorities are more likely to practice in underserved communities. There must be a contemporaneous and explicit effort to mentor and develop under-represented minorities to assume academic and nonacademic leadership positions, because this will broaden and balance research and policy directives. COVID-19 has highlighted the pervasiveness of disparities in medicine that we, as dermatologists can no longer ignore. The disproportionate suffering by any population from any condition, including skin diseases, is simply unacceptable. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Johns Hopkins University & Medicine COVID-19 World Map Available at: https://coronavirus.jhu.edu/map.html 2020 2 Price-Haywood E.G. Burton J. Fort D. Seoane L. Hospitalization and mortality among black patients and white patients with Covid-19 N Engl J Med 382 26 2020 2534 2543 32459916 3 Office of Disease Prevention and Promotion Disparities Healthy People 2020 Available at: https://www.healthypeople.gov/2020/about/foundation-health-measures/Disparities#:∼:text=Healthy%20People%202020%20defines%20a,%2C%20and%2For%20environmental%20disadvantage 4 Harvey V.M. Paul J. Boulware L.E. Racial and ethnic disparities in dermatology office visits among insured patients, 2005-2010 J Health Disparities Res Pract 9 2 2016 93 131 5 Kilbourne A.M. Switzer G. Hyman K. Crowley-Matoka M. Fine M.J. Advancing health disparities research within the health care system: A conceptual framework Am J Public Health 9 2 2006 96 2121
PMC007xxxxxx/PMC7528834.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)32654-2 10.1016/j.jaad.2020.09.058 Research Letter Cross-sectional survey shows that price and wait time affect patient preferences for delivery of dermatologic care Nellore Aditya BA a Grace Shane A. MD b∗ Dittmer Martin R. MD b Armbrecht Eric S. PhD c Abate Mallory S. MD b a School of Medicine, Saint Louis University, Saint Louis, Missouri b Department of Dermatology, Saint Louis University, Saint Louis, Missouri c Center for Health Outcomes Research, Saint Louis University, Saint Louis, Missouri ∗ Correspondence to: Shane A. Grace, MD, Department of Dermatology, Saint Louis University, 1755 S Grand Blvd, Saint Louis, MO 63104 1 10 2020 11 2021 1 10 2020 85 5 13091311 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: The coronavirus disease 2019 pandemic has forced the unprecedented adoption of telemedicine services across medical specialties, making it more important than ever to understand patient preferences and what factors influence them. The purpose of this study was to identify which delivery modality is preferred by patients: face-to-face versus store-and-forward versus live video, and how out-of-pocket cost, lack of access to a face-to-face visit, wait time, and demographic variables influence this preference. We performed a cross-sectional survey study that was approved by Saint Louis University's institutional review board. A 14-question survey was created via Qualtrics and disseminated via Amazon Mechanical Turk, an online marketplace for participants to take surveys (Supplemental Fig 1 available via Mendeley at https://data.mendeley.com/datasets/5f7hbhsrwr/1). Each participant was paid $0.10. Responses were recorded anonymously. Descriptive statistics were calculated for each survey item. The Pearson χ2 test was used for statistical analysis. The sample size for analysis was N = 433, based on the number of responses recorded via Qualtrics. Among the 433 online surveys completed, 108 were eliminated because of missing data. The mean age of our study population was 35 years (Supplemental Fig 2 available via Mendeley at https://data.mendeley.com/datasets/5f7hbhsrwr/1). Most participants owned a smartphone (97%) and would therefore have access to applications necessary for telemedicine. Our analysis revealed several statistically significant findings. For example, our data suggest that when patients are required to pay for an evaluation, store-and-forward may be the preferred option, even when face-to-face is available (Table I ). When face-to-face was not an option, participants did not have a strong preference between the two virtual methods when they are free; however, when asked to pay for a virtual visit, 64% choose store-and-forward for $50 over live video for $75. This suggests that the distinction between store-and-forward or live video may not be as important to patients as the overall cost of health care.Table I Price and wait time influence patient choice of delivery method (N = 325) Choice Scenarios Price Free with no wait FTF $100 vs pay for virtual FTF $100 with 1-hour wait vs virtual for free FTF not an option vs virtual for free FTF not an option vs pay for virtual FTF $0 67% — — — — FTF $100 — 37% — — — FTF with 1-hour wait $100 — — 31% — — LV $0 12% — — 54% — LV $75 — 15% 39% — 36% SAF $0 21% — — 46% — SAF $50 — 48% 30% — 64% — 100% 100% 100% 100% 100% FTF, Face-to-face; LV, live video; SAF, store-and-forward. We also found that income level was statistically significant in influencing participant choice. Our findings suggest that patients with lower household income might value face-to-face interaction more than those with higher incomes, who seem to prefer the store-and-forward method (Table II ). Town type, insurance type, education level, age, and gender were not found to be statistically significant influencing factors in choice of delivery in any scenario.Table II Income level influences patient preference of delivery of dermatologic care∗ Free with no wait P value FTF (n = 216) SAF (n = 70) LV (n = 39) Overall (N = 325) 67% 21% 12% — Income group .026  <$20,000 (n = 55) 75% 16% 9% —  $20,000-$44,999 (n = 107) 67% 20% 13% —  $45,000-$139,999 (n = 127) 67% 19% 14% —  ≥$140,000 (n = 36) 50% 44% 6% — Town type .333  Rural (n = 49) 63% 27% 10% —  Small town (n = 77) 70% 23% 7% —  Medium-sized city (n = 102) 61% 23% 17% —  Urban (n = 97) 71% 16% 13% — FTF for $100 vs paying for virtual FTF $100 (n = 120) SAF $50 (n = 155) LV $75 (n = 50) Overall (N = 325) 37% 48% 15% — Income group .030  <$20,000 (n = 55) 35% 51% 15% —  $20,000-$44,999 (n = 107) 42% 44% 14% —  $45,000-$139,999 (n = 127) 43% 37% 20% —  ≥$140,000 (n = 36) 25% 72% 3% — Town type .697  Rural (n = 49) 41% 47% 12% —  Small town (n = 77) 34% 54% 12% —  Medium-sized city (n = 102) 39% 42% 19% —  Urban (n = 97) 35% 48% 17% — Bold indicates statistical significance. FTF, Face-to-face; LV, live video; SAF, store-and-forward. ∗ Note that rurality does not influence the choice. P values were calculated using the Pearson χ2 test. P < .05 tells us that the percentage distributions that we see across demographic groups is statistically significant. When participants were asked about perceived diagnostic accuracy between face-to-face versus virtual, 70% of participants thought their dermatologist's diagnostic ability was better with a face-to-face interaction. Only a participant's highest education level was found to be a statistically significant influencing factor in this choice, with 71% of college graduates thinking their dermatologist's diagnostic ability was better face-to-face versus only 49% of high school graduates. The main limitation in our study is that our survey population may not be representative of a dermatology practice population because we surveyed an online marketplace. With telemedicine use on the rise, the landscape of dermatology practice as we know it is changing. To adapt to this dynamic environment, it is imperative that physicians determine which delivery modality is preferred by patients and what factors influence this preference. Our study is just the beginning of this process. Author Nellore and Dr Grace contributed equally to this article. Funding sources: None. Conflicts of interest: None declared. IRB approval status: Approved by Saint Louis University Institutional Review Board (30758).
PMC007xxxxxx/PMC7583646.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)32854-1 10.1016/j.jaad.2020.10.042 Research Letter COVID-19 and health care disparities: Innovative ways to meet the dermatologic needs of patients experiencing homelessness Guhan Samantha M. BA a Nathan Neera R. MD, MSHS b Raef Haya BA c Cavanaugh-Hussey Margaret MD, MPH df Tan Jennifer K. MD ef∗ a Harvard Medical School, Boston, Massachusetts b Harvard Combined Dermatology Residency, Harvard Medical School, Boston, Massachusetts c Tufts University School of Medicine, Boston, Massachusetts d Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts e Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts f Boston Health Care for the Homeless Program, Boston, Massachusetts ∗ Correspondence to: Jennifer K. Tan, MD, Dermatology Department, Massachusetts General Hospital, 50 Staniford St, 2nd Floor, Boston, MA 02114 23 10 2020 2 2021 23 10 2020 84 2 511513 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: The coronavirus disease 2019 (COVID-19) pandemic has affected every aspect of global society. The homeless population in the United States, which included 568,000 Americans on any given day in 2019,1 is disproportionately affected by this crisis and faces unique obstacles to combating the spread of disease.2 People experiencing homelessness have limited access to resources necessary to prevent severe acute respiratory syndrome coronavirus 2. Guidelines to slow transmission, including social distancing and frequent handwashing, inherently present barriers to individuals who shelter in congregate settings and are often unable to procure face masks, soap, or hand sanitizer. Many people experiencing homelessness are also older adults from socially disadvantaged minority populations, who data suggest are at increased risk of COVID-19 mortality.1 , 3 The medical community has taken multiple steps to increase access to care for this vulnerable population, such as creating facilities that offer isolation and treatment for people experiencing homelessness who have COVID-19. We hypothesized that dermatologists can further aid this population by mobilizing critical supplies commonly found in their offices and using the generosity of local companies to create COVID-19 care kits, which contain items necessary to protect people experiencing homelessness from disease. Goals of distribution included not only increased access to basic hygienic products but also acknowledgment of our common humanity during a time of crisis. Before supply collection, local shelters were contacted to identify the most useful items to patients. As dermatologists, we were especially well positioned to obtain products such as soap and hand sanitizer because of preexisting relationships with skin care companies. Local volunteers contributed face masks and donors provided additional funds for entertainment items, COVID-19 safety brochures, and packaging. The final kits contained soap, hand sanitizer, moisturizer, dental care products, puzzles, headphones, a COVID-19 informational pamphlet, and other personal hygiene items (Fig 1 ). To minimize the number of people in contact with patients, kits were delivered to a contact person at each shelter, who later distributed the kits.Fig 1 COVID-19 care kits consisting of soap, hand sanitizer, moisturizer, dental care products, puzzles, headphones, a COVID-19 informational pamphlet, and other personal hygiene items. The success of this endeavor was measured by the number of kits distributed to local shelters. Greater than 1000 kits were assembled between March and June. This program is sustainable through the generosity of skin care companies, fund-raising efforts, and the incorporation of staff and trainees into the collection and assembly process. Limitations include distribution to a single geographic area and variation in supply of donated items. Building on relationships we already have as dermatologists, we were able to create a COVID-19 kit donation program that provided people experiencing homelessness with necessary supplies to minimize the spread of disease. In the post–COVID-19 era, this effort will be expanded to involve the assembly of kits containing over-the-counter products to treat common skin conditions, including acne, atopic dermatitis, and xerosis. We propose a call to action for the dermatology community to create similar programs to aid this critically marginalized population. To identify a clinic or shelter with which to partner, the following resources may be useful: National Health Care for the Homeless Council Respite and Grantee directories (http://www.nhchc.org), http://www.findahealthcenter.hrsa.gov, and http://www.homelessshelterdirectory.org. Funding sources: Supported by L’Oreal Active Cosmetics, Tom's of Maine, Fabrizia Spirits, The Tufts Medical Alumni Association CSL Funds, The Tufts CSL Community Response Mini-Grants, and private contributions. Conflicts of interest: Dr Tan is a consultant for Purity Brands. Drs Nathan and Cavanaugh-Hussey and Authors Guhan and Raef have no conflicts of interest to declare. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Henry M. Watt R. Mahathey A. Ouellette J. Sitler A. Abt Associates The 2019 Annual Homeless Assessment Report (AHAR) to Congress Available at: https://www.huduser.gov/portal/sites/default/files/pdf/2019-AHAR-Part-1.pdf Accessed May 10, 2020 2 Mosites E. Parker E.M. Clarke K.E.N. Assessment of SARS-CoV-2 infection prevalence in homeless shelters - four U.S. cities, March 27-April 15, 2020 MMWR Morb Mortal Wkly Rep 69 2020 521 522 32352957 3 Shah M. Sachdeva M. Dodiuk-Gad R.P. COVID-19 and racial disparities J Am Acad Dermatol 83 1 2020 e35 32305444
PMC007xxxxxx/PMC7585496.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)32872-3 10.1016/j.jaad.2020.10.060 Original Article Mucocutaneous disease and related clinical characteristics in hospitalized children and adolescents with COVID-19 and multisystem inflammatory syndrome in children Rekhtman Sergey MD, PharmD, MPH Tannenbaum Rachel BS Strunk Andrew MA Birabaharan Morgan MD Wright Shari BS Garg Amit MD ∗ Department of Dermatology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New Hyde Park, New York ∗ Correspondence to: Amit Garg, MD, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 1991 Marcus Avenue, Suite 300, New Hyde Park, NY, 11042. 24 10 2020 2 2021 24 10 2020 84 2 408414 8 10 2020 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Background Little is known about mucocutaneous disease in acutely ill children and adolescents with COVID-19 and multisystem inflammatory syndrome in children (MIS-C). Objective To characterize mucocutaneous disease and its relation to clinical course among hospitalized patients with COVID-19 and MIS-C. Methods Descriptive cohort study of prospectively and consecutively hospitalized eligible patients between May 11, 2020 and June 5, 2020. Results In COVID-19 patients, 4 of 12 (33%) had rash and/or mucositis, including erythema, morbilliform pattern, and lip mucositis. In MIS-C patients, 9 of 19 (47%) had rash and/or mucositis, including erythema, morbilliform, retiform purpura, targetoid and urticarial patterns, along with acral edema, lip mucositis, tongue papillitis, and conjunctivitis. COVID-19 patients with rash had less frequent respiratory symptoms, pediatric intensive care unit admission, invasive ventilation, and shorter stay versus COVID-19 patients without rash. MIS-C patients with rash had less frequent pediatric intensive care unit admission, shock, ventilation, as well as lower levels of C-reactive protein, ferritin, D-dimer, and troponin (vs MIS-C without rash). Neutrophil-to-lymphocyte ratio was similar for patients with and without rash in both groups. None of the MIS-C patients met criteria for Kawasaki disease. Limitations Small sample sizes. Conclusions Mucocutaneous disease is common among children and adolescents with COVID-19 and MIS-C. Laboratory trends observed in patients with rash may prognosticate a less severe course. Key words COVID-19 Kawasaki MIS-C multisystem inflammatory syndrome in children pediatrics prevalence rash SARS-CoV-2 Abbreviations used IQR interquartile range KD Kawasaki disease MIS-C multisystem inflammatory syndrome in children PCR polymerase chain reaction ==== Body pmc Capsule Summary • Little is known about the morphologic spectrum of mucocutaneous disease and its relation to clinical course in acutely ill children with COVID-19 or multisystem inflammatory syndrome in children (MIS-C). • This study highlights novel mucocutaneous observations associated with SARS-CoV-2 infection, which may support recognition of infection and its potential relevance to prognosis and the development of diagnostic criteria for MIS-C. Introduction COVID-19 has variability within its constellation of findings among children and adolescents.1, 2, 3, 4, 5 In addition to fever and respiratory symptoms, pediatric patients infected with SARS-CoV-2, the pathogen in COVID-19, also get eruptions and mucositis. Yet, little is understood about the morphologic spectrum of mucocutaneous disease and its relation to outcomes among acutely ill children and adolescents with COVID-19, or its presumed sequela, multisystem inflammatory syndrome in children (MIS-C). The New York metropolitan area was an epicenter for the pandemic in the United States,6 which provided an opportunity to characterize mucocutaneous disease in pediatric hospitalized patients with COVID-19 and MIS-C. The purpose of this study was to estimate prevalence of integumentary findings in hospitalized patients with COVID-19 and MIS-C, characterize their morphologic patterns, evaluate whether rash prognosticates clinical course, and determine how closely features in MIS-C align with Kawasaki disease (KD). Methods This study was performed at Cohen Children's Hospital (Northwell Health), a tertiary hospital located in Queens, New York. The study sample consisted of all hospitalized patients between May 11, 2020 and June 5, 2020 who were 18 years and younger and who were suspected of having COVID-19 or MIS-C. Criteria for confirming the diagnosis of MIS-C included age less than 21 years, fever for 24 hours or more, clinically severe illness requiring hospitalization, multisystem organ involvement, no alternative plausible diagnosis, and exposure to a suspected or confirmed COVID-19 case or positive SARS-CoV-2 infection by polymerase chain reaction (PCR)/serology testing.7 The sample was limited to patients who had (1) diagnosis of MIS-C based on all 6 criteria above, and this group comprised the MIS-C cohort or (2) positive COVID-19 PCR test among those not meeting the definition of MIS-C, and this group comprised the COVID-19 cohort. Consecutive prospective skin examinations were performed for eligible patients, and photographs of mucocutaneous findings were taken as part of their care. Morphologic patterns and locations of rash were assessed based on photographs collected during clinical evaluation and were independently classified by two raters. Differing classifications were adjudicated via discussion. For each patient, raters also determined whether each mucocutaneous finding was pre-existing or likely to be unrelated to SARS-CoV-2 infection. Examples included observations of atopic eczema, furunculosis, and scar. All patients who had mucocutaneous manifestations without an otherwise known etiology were considered to have a COVID-19-related rash. For their description, patients with COVID-19 and MIS-C were further stratified according to presence of at least one COVID-19–related rash. We categorized COVID-19 and MIS-C patients separately because these diseases have different clinical characteristics and disease courses and because MIS-C is considered to be a later, noninfectious complication of COVID-19. Data analysis Given the anticipated sample size, and consequently low statistical power, the intent of our analysis was descriptive and hypothesis generating. Medians (interquartile range [IQR]) were used to describe continuous variables, and frequencies (percentages) were used to describe categorical variables. This study was approved by the institutional review board at the Feinstein Institutes of Medical Research at Northwell Health. Results Of 39 hospitalized pediatric patients identified as possible COVID-19 or MIS-C cases during the study period, 31 were eligible for inclusion. Six patients did not test positive for SARS-CoV-2 by PCR and were also ruled out for MIS-C prior to discharge. Others excluded were 1 child whose family deferred skin examination and 1 newborn having limb necrosis with negative SARS-CoV-2 PCR and IgM antibody who was felt to have fetal compartment syndrome. Demographic characteristics for 12 patients classified as COVID-19 and 19 patients classified as MIS-C are listed in Table I .Table I Demographics and characteristics of mucocutaneous disease Characteristic COVID-19 with mucocutaneous disease n = 4 COVID-19 without mucocutaneous disease n = 8 MIS-C with mucocutaneous disease n = 9 MIS-C without mucocutaneous disease n = 10 Age 5 (1.75, 10) 10 (7.25, 16) 8 (7, 10) 10.5 (10, 13) Male sex (%) 1 (25) 5 (63) 7 (78) 6 (60) Race∗ n = 7 n = 8 n = 8  African American 0 (0) 1 (14) 4 (50) 1 (13)  Asian 0 (0) 1 (14) 1 (13) 1 (13)  White 0 (0) 0 (0) 1 (13) 1 (13)  Other/multiracial 4 (100) 5 (71) 2 (25) 5 (63) Cutaneous morphologic patterns  Nonspecific erythema 3 (75) — 3 (33) —  Morbilliform 1 (25) — 1 (11) —  Retiform purpura 0 (0) — 1 (11) —  Targetoid 0 (0) — 1 (11) —  Urticarial 0 (0) — 1 (11) —  Edema (acral) 0 (0) — 1 (11) —  Pernio-like lesions 0 (0) — 0 (0) — Mucositis  Lip cracking or fissuring 1 (25) — 4 (44) —  Papillitis of tongue 0 (0) — 2 (22) —  Conjunctivitis 0 (0) — 2 (22) — Note. Percentages may not sum to 100 due to rounding. Continuous variables are presented as median (IQR). Categorical variables are presented as frequency (percent). ∗ Self-reported race. COVID-19 cohort In patients with COVID-19, 4 of 12 (33%) had rash and/or mucositis (Supplemental Fig 1; available at: https://data.mendeley.com/datasets/wrzffv27cx/1). Those with rash were younger (Table I). Only 3 of 12 (25%) were febrile (≥100.4°F) during hospitalization. Type and frequencies of morphologic patterns observed in patients with COVID-19 are described in Table I. None of the hospitalized COVID-19 patients with rash had pernio-like lesions of the toes or fingers, and none had conjunctivitis. Locations and frequencies of mucocutaneous eruptions in patients with COVID-19 are described in Fig 1 .Fig 1 Frequencies of children with mucocutaneous disease in COVID-19 and MIS-C by area of involvement. Compared with COVID-19 patients without rash, those with rash were observed to have less frequent respiratory symptoms, admission to the pediatric intensive care unit, ventilation, and shorter length of hospital stay. Maximum neutrophil-to-lymphocyte ratio (NLR) observed during hospitalization was similar for patients with and without rash (Table I). MIS-C cohort In patients with MIS-C, 9 of 19 (47%) had rash and/or mucositis. (Fig 2 ; Supplemental Fig 2; available at: https://data.mendeley.com/datasets/wrzffv27cx/1). All 19 patients (100%) were febrile during hospitalization.Fig 2 A and B, Mucocutaneous disease in children and adolescents with MISC-C. A, Retiform purpura, arm. B, Targetoid erythema, arm. Morphologic patterns were heterogeneous (Table I). Lip fissuring or cracking was present in 44% (4 of 9), whereas papillitis of the tongue was present in 22% (2 of 9). Conjunctivitis was present in 22% (2 of 9) of patients with rash. Locations and frequencies of mucocutaneous eruptions in patients with MIS-C are described in Fig 1. Compared with MIS-C patients without rash, those with rash were observed to have less frequent pediatric intensive care unit admission, shock, and requirement for invasive mechanical ventilation. Patients with rash also had lower levels of inflammatory markers. Maximum NLR observed during hospitalization was similar for patients with and without rash (Table II ).Table II Clinical characteristics of patients with and without mucocutaneous disease COVID-19 with mucocutaneous disease n = 4 COVID-19 without mucocutaneous disease n = 8 MIS-C with mucocutaneous disease n = 9 MIS-C without mucocutaneous disease n = 10 Fever, peak 99.8 (99.4, 100.6) 99.8 (99.6, 100.3) 103.1 (102.9, 103.6) 103.4 (103.1, 104.8) Fever ≥5 consecutive days 0 (0) 0 (0) 3 (33) 2 (20) Laterocervical lymphadenopathy 0 (0) 0 (0) 1 (11) 1 (10) Respiratory symptoms 0 (0) 3 (38) 5 (56) 6 (60) Gastrointestinal symptoms 3 (75) 4 (50) 9 (100) 10 (100) Shock 0 (0) 1 (13) 3 (33) 8 (80) Coronary aneurysm or pericardial effusion 0 (0) 1 (13) 4 (44) 6 (60) Myocardial infarction 0 (0) 0 (0) 0 (0) 0 (0) Venous thrombosis or thromboembolism 0 (0) 0 (0) 0 (0) 0 (0) Arterial thrombosis 0 (0) 1 (13) 0 (0) 0 (0) Treatment with intravenous immunoglobulin 0 (0) 0 (0) 9 (100) 10 (100) Treatment with aspirin 0 (0) 1 (13) 9 (100) 9 (90) Admission to pediatric intensive care unit 0 (0) 3 (38) 3 (33) 9 (90) Ventilation 0 (0) 1 (13) 1 (13) 4 (40) Hospital length of stay,∗ days 2.5 (2, 6) 5 (1.5, 17) 7 (5, 9) 7 (5, 10) Lymphocyte count, minimum† 1.23 (0.34, 4.70)‡ 1.50 (0.97, 2.17) 0.61 (0.48, 0.93) 0.58 (0.44, 0.87) Neutrophil count, maximum 4.20 (0.31, 8.02)‡ 7.62 (3.39, 11.57) 17.00 (10.26, 19.37) 18.85 (14.31, 24.22) Neutrophil/lymphocyte ratio, maximum¶ 0.84 (0.58, 6.52)‡ 3.51 (1.76, 8.69) 15.01 (8.62, 17.18) 13.21 (8.66, 23.04) C-reactive protein, maximum, mg/dL 1.4 (1.2, 3.9)‡ 1.6 (0.8, 2.2)§ 15.2 (15, 17) 26.3 (19.1, 28.2) Ferritin, maximum, ng/mL (normal, 30-400) 731 (93, 3024) 200 (144, 369)§ 578 (370, 1091) 1457 (808, 2214) Lactate dehydrogenase, maximum, U/L (normal, 50-242) 263 (197, 465) 257 (202, 650)‡ 346 (233, 533) 322 (260, 415) Albumin, minimum, g/dL (normal, 3.5-5.0) 3.7 (3.5, 3.8) 3.5 (3.3, 4.1) 2.6 (2.1, 2.8) 2.1 (1.8, 2.7) Procalcitonin, maximum, ng/mL (normal, 0.02-0.10) 0.22 (0.17, 0.53)‡ 0.13 (0.08, 0.24)‡ 6.24 (2.00, 14.44) 9.4 (3.4, 29.0) D-Dimer, maximum, ng/mL (normal, ≤229) 570 (439, 952) 300 (263, 904) 1492 (1287, 2681) 4147 (2538, 5011) Fibrinogen, maximum, mg/dL (normal, 300-520) 525 (486, 577) 510 (506, 535) 718 (698, 884) 802 (713, 908) Troponin, maximum, ng/L (normal, <6-14) 5 (5, 15)‡ 8 (5, 11)§ 18 (8, 38) 70 (17, 114) proBNP, maximum, pg/mL (normal, <300) 172 (21, 326) 545 (10, 909)‡ 3946 (3351, 6455) 5065 (2754, 10980) SarsCOV2 + PCR, % 4 (100) 8 (100) 3 (33) 2 (20) SarsCOV2 + IgM/IgG, % 2 (50) 2 (25) 7 (78) 10 (100) proBNP, N-terminal pro b-type natriuretic peptide. ∗ Median length of stay (25th percentile, 75th percentile) calculated using the Kaplan-Meier survival estimate to account for patients who were not discharged as of the date of chart abstraction. † Maximum and minimum refer to each patient's maximum or minimum value during hospitalization. The summary measure represents the median across all of the individual patient maximums/minimums. Continuous variables are presented as median (IQR). Categorical variables are presented as frequency (percent). ‡ Based on 3 non-missing values. Raw data values are reported, rather than median and IQR. § Based on 4 non-missing values. ¶ Ratio was calculated by dividing the neutrophil count by the lymphocyte count from the same test result. The maximum ratio during hospitalization for each patient was then selected and summarized by group using the median and IQR. Among the 19 patients with MIS-C, none met 2017 American Heart Association criteria for KD.8 With requirement for fever of at least 5 consecutive days in the stem, only 1 (5.3%) patient met at least 3 of 5 criteria and only the same patient (1/19; 5.3%) met at least 2 of 5 criteria. With inclusion of coronary aneurysm as an additional sub-criterion, still none met at least 4 of 6 criteria for KD diagnosis. In this expanded construct, 1 (5.3%) patient met at least 3 of 6 criteria and only 2 (10.5%) patients met at least 2 of 6 criteria. Among the 19 MIS-C patients, 5 (26.3%) had fever for 5 or more days, 2 (10.5%) had cervical lymphadenopathy, 2 (10.5%) had edema or erythema of hands or feet, and 2 (10.5%) had a morbilliform or erythema-multiforme–like eruption. Discussion Although presence of rash in MIS-C patients has been reported,9, 10, 11 morphologic characterization of mucocutaneous eruptions in hospitalized pediatric patients with COVID-19 and MIS-C is otherwise absent to date. In this analysis, we estimated prevalence of rash and/or mucositis among hospitalized pediatric patients with COVID-19 and MIS-C. We have characterized morphologic features and distributions of these eruptions, and we distinguished subtypes that occurred only in MIS-C patients. We observed that presence of rash appears to predict a less-severe clinical course. Finally, we observed that MIS-C and KD might be more dissimilar than presently postulated. Although disease-defining integumentary patterns did not emerge in either group, some patterns of mucocutaneous disease appeared to have distinguished MIS-C from COVID-19. Retiform purpura, targetoid, urticarial, acral edema or erythema, papillitis of the tongue, and conjunctivitis were observed only among MIS-C patients. The observation of unilateral retiform purpura of the arm in a patient suggests potential for endothelial cell involvement or injury of cutaneous vessels by the virus or the presence of coagulopathy induced by the infection. Vessel involvement through endothelial cell infection of the kidney and lung in adults has been seen,12 , 13 and this phenomenon warrants further study in children. Presence of nonspecific erythema, morbilliform eruption, or lip mucositis did not distinguish COVID-19 and MIS-C. Pernio-like patches and plaques on the fingers or toes were not observed in either group, which reinforces the suggestion that patients with this presentation tend to have mild disease course.14 Almost all hospitalized COVID-19 patients with rash had involvement of at least the face. Rash among MIS-C patients was most often peripherally distributed. Although lips were frequently involved in MIS-C patients, tongue and eye involvement were less frequent. Continued localization of mucocutaneous disease in COVID-19 and MIS-C may identify distinct patterns that differentiate the 2 conditions. Several clinical and laboratory indicators suggested that pediatric patients with COVID-19 and MIS-C with rash may have less severe disease course. MIS-C patients with rash may have a modified and/or muted cytokine response, which preferentially involves the integument and which may result in a less severe course. Whether presence of rash in COVID-19 and MIS-C can predict prognosis in children and adolescents and the basis for preferential involvement of skin warrants further study. The NLRs were similar between COVID-19 patients with and without rash and between MIS-C patients with and without rash. We did observe, however, higher NLR in MIS-C patients compared with COVID-19 patients, and this may prove to be a useful differentiating marker. In adults, NLR has been observed to distinguish mild from severe cases of COVID-19.15, 16, 17 There are shared features between MIS-C and KD, including presence of mucocutaneous disease, although the distinction between MIS-C and KD remains uncertain.18 None of the MIS-C in our sample met criteria for KD, and few met partial criteria, even when criteria were expanded to include coronary aneurysm. Only 5 patients met criterion for fever of greater than 5 consecutive days, and few had lymphadenopathy or edema/erythema of hands or feet. Although there may exist some overlapping features between MIS-C and KD, our observations suggest that MIS-C may warrant development of distinct criteria, which should include broadening the morphologic patterns of mucocutaneous disease observed. Here we provided detailed morphologic characterization of mucocutaneous findings in prospectively and consecutively examined patients with confirmed diagnoses of COVID-19 and MIS-C. Limitations to this study include the fact that most pediatric patients with COVID-19 have a course that does not require hospitalization, and there were fewer hospitalized cases of MIS-C in mid May and June of 2020 in the New York metropolitan area. As such, we had inadequate power to perform hypothesis tests, and we cannot rule out that differences observed between groups were due to chance. However, the finding of less-severe course was observed across several indicators among both COVID-19 and MIS-C patients with rash. Pathology was not obtained, as there was no clear indication this could specify diagnoses or change the courses of care. Mucocutaneous disease is common among children and adolescents with COVID-19 and MIS-C. Trends observed in pediatric patients with rash may suggest a less-severe clinical course, although confirmatory studies are required to assess the generalizability of these observations. This study highlights several novel observations in hospitalized children and adolescents with COVID-19 and MIS-C, many of which will support the research agenda to further characterize mucocutaneous disease associated with SARS-CoV-2, to recognize its potential relevance in prognosticating disease courses, and to develop diagnosis criteria for MIS-C. Funding sources: None. Conflicts of interest: Dr Garg has received honoraria from AbbVie, Amgen, Boehringer Ingelheim, Incyte, Janssen, Novartis, Pfizer, UCB, and Viela Bio. The rest of the authors have no conflicts to disclose. IRB approval status: This investigation was approved by the Human Subjects Committee at the Feinstein Institute for Medical Research at the Northwell Health. Reprints not available from the authors. ==== Refs References 1 Lu X. Zhang L. Du H. Chinese Pediatric Novel Coronavirus Study Team SARS-CoV-2 infection in children N Engl J Med 382 17 2020 1663 1665 32187458 2 Dong Y. Mo X. Hu Y. Epidemiology of COVID-19 among children in China Pediatrics 145 6 2020 e20200702 32179660 3 Wu Z. McGoogan J.M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention JAMA 323 13 2020 1239 1242 32091533 4 Tagarro A. Epalza C. Santos M. Screening and severity of coronavirus disease 2019 (COVID-19) in children in Madrid, Spain JAMA Pediatr 2020 e201346 10.1001/jamapediatrics.2020.1346 32267485 5 Qiu H. Wu J. Hong L. Luo Y. Song Q. Chen D. Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study Lancet Infect Dis 20 6 2020 689 696 32220650 6 NYC Department of Health Coronavirus disease 2019 (COVID-19) Available at: https://www1.nyc.gov/site/doh/covid/covid-19-main.page 7 Centers for Disease Control and Prevention Multisystem Inflammatory Syndrome in Children (MIS-C) Available at: https://www.cdc.gov/mis-c/hcp/ 8 McCrindle B.W. Rowley A.H. Newburger J.W. American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the YoungCouncil on Cardiovascular and Stroke NursingCouncil on Cardiovascular Surgery and AnesthesiaCouncil on Epidemiology and Prevention Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association Circulation 135 17 2017 e927 e999 28356445 9 Verdoni L. Mazza A. Gervasoni A. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study Lancet 395 10239 2020 1771 1778 32410760 10 Cheung E.W. Zachariah P. Gorelik M. Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents in New York City JAMA 324 3 2020 294 296 32511676 11 Whittaker E. Bamford A. Kenny J. Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 JAMA 324 3 2020 259 269 32511692 12 Freeman E.E. McMahon D.E. Lipoff J.B. Pernio-like skin lesions associated with COVID-19: a case series of 318 patients from 8 countries J Am Acad Dermatol 83 2 2020 486 492 32479979 13 Ackermann M. Verleden S.E. Kuehnel M. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19 N Engl J Med 383 2 2020 120 128 32437596 14 Varga Z. Flammer A.J. Steiger P. Endothelial cell infection and endotheliitis in COVID-19 Lancet 395 10234 2020 1417 1418 32325026 15 Wang D. Hu B. Hu C. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China JAMA 323 11 2020 1061 1069 32031570 16 Qin C. Zhou L. Hu Z. Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China Clin Infect Dis 71 15 2020 762 768 32161940 17 Chen G. Wu D. Guo W. Clinical and immunological features of severe and moderate coronavirus disease 2019 J Clin Invest 130 5 2020 2620 2629 32217835 18 McCrindle B.W. Manlhiot C. SARS-CoV-2-related inflammatory multisystem syndrome in children: different or shared etiology and pathophysiology as Kawasaki disease? JAMA 324 3 2020 246 248 32511667
PMC007xxxxxx/PMC7585501.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)32863-2 10.1016/j.jaad.2020.10.051 JAAD Online A response to “Male balding is a major risk factor for severe COVID-19” Thatiparthi Akshitha BS a Liu Jeffrey BS b Martin Amylee BS c Wu Jashin J. MD d∗ a College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA b Keck School of Medicine, University of Southern California, Los Angeles, CA c School of Medicine, University of California, Riverside, CA d Dermatology Research and Education Foundation, Irvine, CA ∗ Correspondence to: Jashin J. Wu, MD, Dermatology Research and Education Foundation, Irvine, CA 92620 24 10 2020 2 2021 24 10 2020 84 2 e87e88 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: We read with great interest Male Balding is a Major Risk Factor for Severe COVID-19 by Lee et al1 regarding androgenic alopecia as a risk factor for COVID-19 severe symptomatology. A recent study by Wambier et al2 observed similar findings regarding androgenic alopecia and COVID-19. Yet, the relationship between scalp health, androgenic alopecia, and COVID-19 has not been explored. We examined the current, yet limited, literature regarding the role of the scalp in preventing transmission of COVID-19. Trüeb et al3 describes the importance of scalp and hair health. The scalp has a large number of terminal hairs and microbes creating a unique microenvironment. Hair is a mechanical barrier, blocking ultraviolet radiation from reaching the scalp skin and facilitates moisture retention.3 Aging and male sex hormones can compromise hair growth, resulting in androgenic alopecia. Alteration of hair production and pre-existing photo-aging results in scalp atrophy and increased exposure to ultraviolet radiation.3 These effects change scalp volume, alter cellularity of the epidermis, and elevate dermal inflammatory cells.3 Premature balding increases risk of scalp damage, as there is a loss of elasticity and moisturized protective barrier. Furthermore, scalp balding increases the expression of oxidative stress markers resulting in DNA damage.3 The combination of factors sensitizes scalp skin environmental stress and pathogens, including viruses such as COVID-19.1, 2, 3, 4 COVID-19 is spread via mucosal and skin barriers. ACE2 was recently identified as a vital receptor for cell entry of SARS-CoV-2.4 Cells with high levels of ACE2 expression, such as pulmonary pneumocytes and keratinocytes, are vulnerable to infections.2 , 4 Increased expression of ACE2 in epidermal keratinocyte cells has been indicated as a possible transmission route of SARS-CoV-2, particularly in conditions compromising skin barrier function.4 ACE2 receptor expression is influenced by male sex hormones.2 Androgenic hormones play a central role in the pathogenesis of androgenic alopecia, which results in loss of an important scalp protective barrier. Scalp health may be preventative against the transmission of COVID-19, as male pattern balding has been implicated in the development of severe symptomology.1, 2, 3 Through suppression of male sex hormones, medications preventing androgenic alopecia may alter ACE2 receptor expression. Accordingly, maintenance of scalp health may be essential in preventing transmission by sustaining a robust skin barrier.2 Scalp hair is a potential protective factor against COVID-19 transmission. Studies are needed to evaluate this relationship, as understanding the link will aid in the creation of appropriate public health measures and treatment options. Potential considerations for exploration include the association between COVID-19 and the effects in other etiologies of alopecia including alopecia areata and frontal fibrosing alopecia. Lastly, human culture determines body coverage with clothes; however, the scalp is usually exposed, and, along with the face and acral areas, become the only zones of temperature control. Thus, there may be a link between neurovascular responses to temperature changes from the scalp and disease incidence that peak seasonally in subtropical areas including human coronavirus strains and potentially COVID-19.5 Further research is warranted to study the link between hair coverage and systemic disease. Funding sources: None. Conflicts of interest: Dr Wu is or has been an investigator, consultant, or speaker for AbbVie, Almirall, Amgen, Arcutis, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Dermavant, Dermira, Dr. Reddy's Laboratories, Eli Lilly, Janssen, LEO Pharma, Novartis, Regeneron, Sanofi Genzyme, Sun Pharmaceutical, UCB, and Valeant Pharmaceuticals North America LLC. The rest of the authors have no conflicts to disclose. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Lee J. Yousaf A. Fang W. Kolodney M. Male balding is a major risk factor for severe COVID-19 J Am Acad Dermatol 83 5 2020 e353 e354 32707256 2 Wambier C.G. Vaño-Galván S. McCoy J. Androgenetic alopecia present in the majority of hospitalized COVID-19 patients - the “Gabrin sign.” J Am Acad Dermatol 83 2 2020 680 682 32446821 3 Trüeb R.M. Henry J.P. Davis M.G. Schwartz J.R. Scalp condition impacts hair growth and retention via oxidative stress Int J Trichology 10 6 2018 262 270 30783333 4 Xue X. Mi Z. Wang Z. Pang Z. Liu H. Zhang F. High Expression of ACE2 on keratinocytes reveals skin as a potential target for SARS-CoV-2 J Invest Dermatol 141 1 2021 206 209.e1 32454066 5 Kissler S.M. Tedijanto C. Goldstein E. Grad Y.H. Lipsitch M. Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period Science 368 6493 2020 860 868 32291278
PMC007xxxxxx/PMC7598361.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)32891-7 10.1016/j.jaad.2020.10.070 A Clinician's Perspective Evidence following guidelines: Another COVID-19 paradox Heymann Warren R. MD ∗ Cooper Medical School of Rowan University, Marlton, New Jersey ∗ Correspondence to: Warren R. Heymann, MD, 100 Brick Rd, Ste 306, Marlton, NJ 08053. 29 10 2020 1 2021 29 10 2020 84 1 3738 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Key words biologics COVID-19 immunosuppressives ==== Body pmcEvidence-based medicine is predicated on the concept of making clinical decisions based on the best available clinical evidence. One of the great concerns for dermatologists at the onset of the pandemic was to determine how to treat patients with psoriasis, atopic dermatitis, autoimmune bullous disorders, and connective tissue diseases who were prescribed immunosuppressants or immunomodulators.1 In the topsy-turvy COVID-19 universe, guidelines needed to be developed posthaste, based on expert opinion rather than data. Gadarowski et al2 (p1) note that “in March 2020, it was unclear whether dermatology patients on biologics or other forms of systemic therapy should continue medication, or whether it would be inappropriate to initiate such treatment in an at-risk cohort.” The essence of the American Academy of Dermatology guidelines (https://www.aad.org/member/practice/coronavirus/clinical-guidance/biologics) is that patients on these agents should not discontinue them unless testing positive for COVID-19; they may be readministered after COVID-19 resolution. Initiation of such therapy is based on disease severity and comorbidities, with postponement of administration for high-risk patients (>60 years old; diabetes, cardiovascular, hepatic, renal, or respiratory disease). Guidelines from multiple international organizations all concurred that patients should not discontinue treatment without first speaking with their providers.2 Entering year 2 of the pandemic, data are beginning to accrue that will help confirm or deny the validity of these guidelines. Haberman et al3 performed a prospective study on 86 patients with immune-mediated inflammatory diseases on biologics and immunomodulatory therapies who were confirmed to have COVID-19 (59 patients) or highly suspected to have the infection (27 patients). Only 14 of the 86 patients required hospitalization, which was similar to the general population. The authors concluded that the baseline use of biologics was not associated with worsened outcomes while acknowledging that their study was small.3 Gisondi et al4 performed a retrospective study of 5206 patients with psoriasis on biologics (tumor necrosis factor [TNF], interleukin (IL) 17, IL-12/23, and IL-23 inhibitors) during the Italian pandemic. Only 4 patients, all with COVID-19 risk factors, required hospitalization for pneumonia; none died. Despite the limitations of this study, the results were reassuring for the continued use of biologic agents during the pandemic.4 In this issue of the Journal of the American Academy of Dermatology, Yousaf et al5 evaluated whether patients on TNF inhibitors and/or methotrexate are at increased risk of COVID-19–related outcomes. A total of 214 patients with COVID-19 were identified with recent TNF inhibitor or methotrexate exposure and compared to 31,862 patients with COVID-19 without TNF inhibitor or methotrexate exposure. After propensity matching, the likelihoods of hospitalization and mortality were not significantly different between the treatment and nontreatment groups, allowing the investigators to conclude that patients with recent TNF inhibitor and/or methotrexate exposure do not have increased hospitalization or mortality compared to patients with COVID-19 without recent TNF inhibitor and/or methotrexate exposure. I applaud every dermatologist involved with the rapid development of the thoughtful American Academy of Dermatology guidelines for COVID-19 that allowed us to navigate unchartered seas. The coming year(s) will bring us multiple studies that may modify these guidelines accordingly. It is imperative that we all keep abreast of these developments in real time. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the author. ==== Refs References 1 Drenovska K. Schmidt E. Vassileva S. Covid-19 pandemic and the skin Int J Dermatol 2020 10.1111/ijd.15189 2 Gadarowski M.B. Balogh E.A. Bashyam A.M. Feldman S.R. Examining recommendations for the use of biologics and other systemic therapies during COVID-19: a review and comparison of available dermatology guidelines and patient registries J Dermatolog Treat 2020 10.1080/09546634.2020.1808154 3 Haberman R. Axelrad J. Chen A. Covid-19 in immune-mediated inflammatory diseases—case series from New York N Engl J Med 383 1 2020 85 88 32348641 4 Gisondi P. Facheris P. Dapavo P. The impact of the COVID-19 pandemic on patients with chronic plaque psoriasis being treated with biological therapy: the Northern Italy experience Br J Dermatol 183 2 2020 373 374 32343839 5 Yousaf A. Gayam S. Feldman S. Zinn Z. Kolodney M. Clinical outcomes of COVID-19 in patients taking tumor necrosis factor inhibitors and/or methotrexate: a multi-center research network study J Am Acad Dermatol 2021 10.1016/j.jaad.2020.09.009
PMC007xxxxxx/PMC7598732.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 Published by Elsevier on behalf of the American Academy of Dermatology, Inc. S0190-9622(20)32896-6 10.1016/j.jaad.2020.10.075 JAAD Online Toward a COVID-19 vaccine strategy for patients with pemphigus on rituximab Waldman Reid A. MD a∗ Creed Marina APRN, FNP b Sharp Kelley BSN c Adalsteinsson Jonas MD, PhD a Imitola Jaime MD b Durso Timothy MD d Lu Jun MD a a Department of Dermatology, University of Connecticut Health Center, Farmington, Connecticut b University of Connecticut Health Comprehensive Multiple Sclerosis Center, Department of Neurology, University of Connecticut Health Center, Farmington, Connecticut c Quinnipiac School of Medicine, North Haven, Connecticut d Division of Dermatology, Joint Base Andrews–Naval Air Facility Washington, Prince George's County, Maryland ∗ Correspondence to: Reid A. Waldman, MD, University of Connecticut, Department of Dermatology, 21 South Road, Farmington, CT 06032 29 10 2020 4 2021 29 10 2020 84 4 e197e198 © 2020 Published by Elsevier on behalf of the American Academy of Dermatology, Inc. 2020 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: Shakshouk et al and Schultz et al discuss the potential impact of rituximab-induced peripheral B-cell depletion on future COVID-19 vaccine response. Their articles highlight the need for emergent study of anti-CD20 therapy's impact on COVID-19 vaccine response. Here, we review existing data surrounding the vaccination of individuals receiving anti-CD20 monoclonal antibodies. The effect of rituximab and other anti-CD20 monoclonal antibodies on vaccine response has been studied for inactivated vaccines, including those for seasonal influenza, hepatitis B, tetanus, shingles, pneumococcus, and Haemophilus influenzae type b.1 , 2 These studies suggest that rituximab recipients mount attenuated yet meaningful vaccine responses.1 Additionally, these studies indicate that rituximab recipients are not at increased risk of inactivated vaccine-related adverse effects.3 Recently, a prospective clinical trial evaluated the effect of ocrelizumab (humanized anti-CD20 antibody) on the immunogenicity of several vaccines that were administered 12 weeks after infusion.4 This study showed increased seroprotection rates across all studied vaccines in ocrelizumab recipients, although these conversion rates are lower than those observed in control individuals. Consensus guidelines recommend administering routine vaccinations (eg, tetanus, diphtheria, and pertussis [TDaP]) at least 4 weeks before rituximab initiation.3 Notably, they recommend administering inactivated influenza vaccine even in individuals undergoing active treatment with rituximab, because patients face imminent risk of contracting influenza, which outweighs the minimal risks associated with vaccination.3 Importantly, there are no studies addressing the immunogenicity of live attenuated vaccines, given theoretical safety concerns regarding the use of live attenuated vaccines in rituximab recipients.3 Additionally, there are no studies that have evaluated the safety and immunogenicity of messenger RNA vaccines or viral vector vaccines, which are among the leading COVID-19 vaccine candidates, because no vaccines in these classes are commercially available. How should dermatologists approach vaccination of rituximab recipients with a future COVID-19 vaccine? Although the answer will depend on the type(s) of vaccine(s) that reach the market, inoculation with vaccines that do not contain live virus particles (eg, inactivated vaccines, messenger RNA vaccines) should be considered in the absence of postmarketing data or vaccine trial signals suggesting previously unforeseen risk.5 We assess that COVID-19 vaccine recommendations similar to influenza vaccine recommendations are sensible until COVID-19 vaccine response data for individuals receiving rituximab emerges. The ideal timing of vaccination is unknown; however, individuals who have not initiated rituximab therapy are typically vaccinated at least 4 weeks before rituximab infusion. Individuals who are actively receiving rituximab are often vaccinated against influenza 12 to 20 weeks after completion of a treatment cycle so that patients have 4 weeks or longer before their next infusion (assuming dosing every 6 months) to mount an immune response.3 Extending rituximab dosing intervals to enhance vaccine response should be weighed against the risk of disease recurrence. Although vaccine response may be attenuated and may occur at lower rates in rituximab recipients, vaccine response can be quantified with titers, which may be helpful for guiding decisions to revaccinate patients after humoral immune reconstitution (approximately 6-9 months after rituximab discontinuation). Until COVID-19 vaccines arrive, the data encourage careful use of anti-CD20 therapy for skin disease. When vaccines are available, dermatologists can consider vaccinating patients 12 to 20 weeks after the completion of a treatment cycle or extending rituximab dosing intervals. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Baker D. Roberts C.A.K. Pryce G. COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases Clin Exp Immunol 202 2 2020 149 161 32671831 2 Houot R. Levy R. Cartron G. Armand P. Could anti-CD20 therapy jeopardise the efficacy of a SARS-CoV-2 vaccine? Eur J Cancer 136 2020 4 6 32619884 3 Mohme S. Schmalzing M. Müller C.S.L. Vogt T. Goebeler M. Stoevesandt J. Immunizations in immunocompromised patients: a guide for dermatologists J Dtsch Dermatol Ges 18 7 2020 699 723 4 Bar-Or A. Calkwood J.C. Chognot C. Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis: the VELOCE study Neurology 95 14 2020 e1999 e2008 32727835 5 Pardi N. Hogan M.J. Porter F.W. Weissman D. mRNA vaccines—a new era in vaccinology Nat Rev Drug Discov 17 4 2018 261 279 29326426
PMC007xxxxxx/PMC7657845.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. Published by Elsevier Inc. S0190-9622(20)32656-6 10.1016/j.jaad.2020.09.060 Research Letter Impact of the COVID-19 pandemic on inpatient dermatology consult patterns at a tertiary care hospital: A retrospective cohort study Rogers Meredith C. MD, PhD a Wallace Matthew M. MD a Wheless Lee MD, PhD ab Dewan Anna K. MD, MHS a∗ a Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee b Data Science Institute, Vanderbilt University Medical Center, Nashville, Tennessee ∗ Correspondence to: Anna K. Dewan, MD, MHS, Vanderbilt University Medical Center, 719 Thompson Lane, Ste 26300, Nashville, TN 37204 12 11 2020 1 2021 12 11 2020 84 1 156158 © 2020 by the American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: The early phase of the coronavirus disease 2019 (COVID-19) pandemic had a profound global impact on medical practice and patient behaviors.1 The impact of the pandemic on inpatient dermatology consultations in the United States has not been reported, to our knowledge. We analyzed all patients who received a dermatology consultation at our hospital from March to May 2020 compared with the same period in 2019. After obtaining Institutional Review Board approval, we retrospectively analyzed electronic medical records of adult patients who received a dermatology consult at Vanderbilt University Medical Center during an inpatient admission or from the emergency department between March 15 and May 31 for the years 2019 and 2020. Differences were tested using the χ2, t test, or Mann-Whitney test via GraphPad Prism 8 software (GraphPad Software, San Diego, CA). A total of 106 dermatology consults were seen during the study period in 2020 compared with 149 in 2019 (Table I ).2 In 2020, 42% of consults were completed via teledermatology (Table II ).2 The mean number of consults per week was significantly reduced in 2020 compared with 2019 (9.5 vs 13.5, P = .04). There was a significant reduction in consults for patients who presented for a primary dermatologic complaint in 2020 (23% vs 52%, P < .01). In contrast, the frequency of consults for patients who originally presented to the hospital for a nondermatologic problem was not significantly different (7.4 vs 6.5 consults per week, P = .5).Table I Demographics and characteristics of patients who received a dermatology consult between March 15 and May 31 Variable∗ All consults P value† Presentation for primary dermatologic problem P value† Non-dermatologic presentation P value† 2019 2020 2019 2020 2019 2020 Total, No. 149 106 77 24 72 82 Consults/week, mean (SD), No. 13.5 (4.4) 9.5 (4.1) .04‡ 6.9 (2.7) 2.2 (1.2) <.01‡ 6.5 (2.8) 7.4 (3.2) .53‡ Age, mean (SD), y 53.7 (16.9) 52.5 (17.3) .57‡ 52.2 (18.5) 56.0 (17.5) .36‡ 55.4 (14.8) 51.5 (17.3) .13‡ Male sex 74 (49.7) 52 (49.1) .92§ 34 (44.2) 9 (37.5) .58§ 40 (55.6) 43 (52.4) .70§ Uninsured 18 (12.1) 17 (16.0) .37§ 12 (15.6) 4 (16.7) .90§ 6 (8.3) 13 (15.9) .16§ Primary dermatologic problem 77 (51.7) 24 (22.6) <.01§ … … … … … … Presented through ED¶ 70 (47.0) 33 (31.1) .01§ 38 (49.4) 8 (33.3) .17§ 32 (44.4) 25 (30.5) .07§ ED consult 18 (12.1) 18 (17.0) .27§ 16 (20.8) 12 (50.0) <.01§ 2 (2.8) 6 (7.3) .21§ Length of stay (admitted pts), mean (SD), d 12.4 (25.4) 12.1 (20.4) .53∥ 5.1 (3.8) 3.4 (2.6) .06∥ 19.7 (34.3) 14.6 (22.5) .43∥ Common outpatient diagnosis# 64 (43.0) 24 (22.6) <.01§ 29 (37.7) 5 (20.8) .13§ 35 (48.6) 19 (23.2) <.01§ Life-threatening diagnosis∗∗ 11 (7.4) 13 (12.3) .19§ 5 (6.5) 3 (12.5) .34§ 6 (8.3) 10 (12.2) .43§ Follow-up recommended 37 (26.4) 41 (40.6) .02§ 23 (31.5) 15 (65.2) <.01§ 14 (20.9) 26 (33/3) .09§ ED, Emergency department; No., number; pts, patient. ∗ Categorical data are presented as number (%) and continuous data as indicated. † Bold P values are statistically significant. ‡ Unpaired t test with the Welch correction. § χ2 test. ∥ Mann-Whitney test ¶ ED presentations compared with direct admissions (scheduled operations and clinic admissions) and transfers from other hospitals. # Outpatient diagnoses were defined as nonerythrodermic eczematous dermatoses (including atopic dermatitis, contact dermatitis, seborrheic dermatitis, stasis dermatitis, and eczematous dermatitis not otherwise specified), nonerythrodermic psoriasis vulgaris, cutaneous malignant neoplasms, cutaneous benign neoplasms, rosacea, acne vulgaris, hidradenitis suppurativa, acne conglobata, dissecting cellulitis, lichen simplex chronicus, lichen planus, alopecia, dyspigmentation, folliculitis, arthropod assault, scabies, tinea, onychomycosis, verrucae, intertrigo, and urticaria. These diagnoses were chosen based on literature review2 and clinical judgment. Diseases that have a wide spectrum of severity (eg, cellulitis) were not grouped with outpatient diagnoses because the severity of presentation could not be reliably determined by chart review. ∗∗ Life-threatening diagnoses were defined as Stevens–Johnson/toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, toxic shock syndrome, staphylococcal scalded skin syndrome, angioinvasive fungal infection, medium vessel vasculitis, calciphylaxis, purpura fulminans, metastatic malignancy, leukemia cutis, and erythroderma of any type. Table II Comparison of in-person vs virtual dermatology consults during the COVID-19 pandemic between March 15 and May 31 Variable∗ In-person Virtual P value† Total, No. 61 45 Age, mean (SD), y 54.4 (16.7) 49.9 (18.0) .19‡ Male sex 27 (44.3) 25 (55.6) .25§ Primary dermatologic problem 9 (14.8) 15 (33.3) .024§ Presented through ED¶ 23 (37.7) 10 (22.2) .09§ ED consult 6 (9.8) 12 (26.7) .023§ ED discharge after ED consult 2 (33.3) 3 (25) .71§ Length of stay (admitted pts), mean (SD), d 12.6 (23.8) 11.5 (14.6) .29∥ Common outpatient diagnosis# 14 (23.0) 10 (22.2) .93§ Life-threatening diagnosis∗∗ 10 (16.4) 3 (6.7) .13§ Follow-up recommended 23 (39.0) 18 (42.9) .70§ Consult for known dermatologic diagnosis 12 (19.7) 10 (22.2) .75§ Virtual consults later seen in person 11 (24.4) In-person visit delayed due to pending/positive COVID 7 (63.6) Presumed virtual diagnosis changed after in-person visit 5 (45.4) Mean (SD) number of derm notes 2.3 (1.8) 2.0 (1.2) .49§ Mean (SD) number of derm notes (minus virtual consults later seen in person) 2.3 (1.8) 1.5 (0.8) .017∥ Biopsy done 33 (54.1) 12 (26.7) <.01§ Biopsy by derm 32 (97.0) 8 (67.7) <.01§ Definitive diagnosis made†† 55 (90.2) 27 (60) <.01§ ED, Emergency department; No., number; pts, patient. ∗ Categorical data are presented as number (%) and continuous data as indicated. † Bold P values are statistically significant. ‡ Unpaired t test with the Welch correction. § χ2 test. ∥ Mann-Whitney test ¶ ED presentations compared with direct admissions (scheduled surgeries and clinic admissions) and transfers from other hospitals. # Outpatient diagnoses were defined as: nonerythrodermic eczematous dermatoses (including atopic dermatitis, contact dermatitis, seborrheic dermatitis, stasis dermatitis, and eczematous dermatitis not otherwise specified), nonerythrodermic psoriasis vulgaris, cutaneous malignant neoplasms, cutaneous benign neoplasms, rosacea, acne vulgaris, hidradenitis suppurativa, acne conglobata, dissecting cellulitis, lichen simplex chronicus, lichen planus, alopecia, dyspigmentation, folliculitis, arthropod assault, scabies, tinea, onychomycosis, verrucae, intertrigo, and urticaria. These diagnoses were chosen based on literature review2 and clinical judgment. Diseases that have a wide spectrum of severity (eg, cellulitis) were not grouped with outpatient diagnoses as the severity of presentation could not be reliably determined by chart review. ∗∗ Life-threatening diagnoses were defined as Stevens–Johnson/toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, toxic shock syndrome, staphylococcal scalded skin syndrome, angioinvasive fungal infection, medium vessel vasculitis, calciphylaxis, purpura fulminans, metastatic malignancy, leukemia cutis, and erythroderma of any type. †† “Definitive diagnosis” was defined as a single diagnosis listed on the consult note or final progress note, or pathology report with a single diagnosis listed. Almost 25% of virtual consults were later seen in person, with a change of diagnosis in nearly half of cases. Ultimately, virtual consultations resulted in significantly reduced diagnostic certainty, with only 60% of consults resulting in a definitive diagnosis compared with 90% of in-person consults. When looking at only the subset of virtual consultations that were never seen in-person, a definitive diagnosis was made less than half of the time. During the early phase of the COVID-19 pandemic, our inpatient dermatology consult service shifted to include care via teledermatology. We found no evidence that patients with severe dermatologic illness avoided the hospital. Completion of a virtual consult during the COVID-19 pandemic was associated with decreased diagnostic certainty compared with in-person consults. A prospective study on teledermatology found that the primary diagnosis given by a virtual consult was concordant with that of an in-person consult in 67% of cases.3 Although the methodologies of our study and the study by Gabel et al3 are too disparate to directly compare results, our experience indicates that further research on inpatient teledermatology and the criteria for which it might be safely and effectively used is warranted. It is our opinion that the in-person examination remains important for inpatient dermatology, as highlighted by a recent case report of an incidental melanoma that would have been missed had an inpatient consult been conducted via teledermatology during the pandemic.4 Our consultation service similarly found an incidental melanoma during an in-patient visit that would have been missed via teledermatology. Further studies will be needed to understand how reduced overall emergency department visits for dermatologic complaints and an increased incidence of virtual consults during this period will affect long-term outcomes for patients. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Reviewed and approved by the Vanderbilt University Medical Center Institutional Review Board. ==== Refs References 1 Hartnett K.P. Kite-Powell A. DeVies J. Impact of the COVID-19 Pandemic on Emergency Department Visits—United States, January1, 2019–May 30, 2020 MMWR Morb Mortal Wkly Rep 69 2020 699 704 32525856 2 Wilmer E.N. Gustafson C.J. Ahn C.S. Davis S.A. Feldman S.R. Huang W.W. Most common dermatologic conditions encountered by dermatologists and nondermatologists Cutis 94 2014 285 292 25566569 3 Gabel C.K. Nguyen E. Karmouta R. Use of teledermatology by dermatology hospitalists is effective in the diagnosis and management of inpatient disease J Am Acad Dermatol 2020 10.1016/j.jaad.2020.04.171 4 Deacon D.C. Madigan L.M. Inpatient teledermatology in the era of COVID-19 and the importance of the complete skin examination JAAD Case Rep 6 10 2020 977 978 32837991
PMC007xxxxxx/PMC7718581.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)30538-7 10.1016/j.jaad.2020.03.111 JAAD Online Clinical Pearl An alternative application of tissue paper Bu Wenbo MD a Zhang Mengli MD b Fang Fang MD a∗ Wang Qiang MD a∗ a Department of Dermatologic Surgery, Hospital of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, People's Republic of China b Department of Cosmetic Laser Surgery, Hospital of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, People's Republic of China ∗ Correspondence to: Fang Fang, MD, Department of Dermatologic Surgery, Hospital of Dermatology, 12 Jiang-wang-miao Street, Nanjing, Jiangsu, China 210042. ∗ Qiang Wang, MD, Department of Dermatologic Surgery, Hospital of Dermatology, 12 Jiang-wang-miao Street, Nanjing, Jiangsu, China 210042. 5 12 2020 1 2021 5 12 2020 84 1 e1e1 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcClinical challenge With the outbreak of the novel coronavirus disease 2019 (COVID-19), front-line medical personnel are required to don surgical masks and goggles for personal protection. However, goggles are prone to fogging when worn for extended periods, affecting the vision of medical workers and posing inconvenience in clinical work. Solution Tissue paper (Fig 1 , A) can be used in combination with surgical masks to reduce the fogging of goggles through the absorption of water vapor exhaled from the mouth and nose. First, a piece of tissue paper is folded in half 2 or 3 times to achieve a certain thickness and water vapor absorption ability. The folded tissue paper should preferably be rectangular, with its long edge shorter than the top edge of the surgical mask and its short edge slightly longer than the distance from the mask pressure point on the nose to the nostrils. It can then be placed on the mask inner surface, with its long edge aligned with the top edge of the mask (Fig 1, B). Subsequently, the mask with the added tissue paper layer can be adjusted to produce an optimum fit. The top edges of the tissue paper and mask should remain aligned; the bottom edge of the tissue paper should be positioned slightly lower than the nostrils (Fig 1, C). Finally, goggles should be worn properly (Fig 1, D) to allow water vapor absorption by the folded tissue paper. This will prevent fogging of the goggles and reduce compression of the skin on the nose.Fig 1 Combined use of tissue paper and surgical mask. (A) Tissue paper. (B) The bottom edge of the tissue paper should partially cover the nostrils. (C) The folded tissue paper is placed on the inner surface of the surgical mask. (D) The surgical mask and goggles should be worn properly. Drs Bu and Zhang contributed equally to this work. Funding sources: Supported by the 10.13039/501100001809 National Nature Science Foundation of China (81703142). Conflicts of interest: None disclosed. IRB approval status: Not applicable.
PMC007xxxxxx/PMC7797175.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 Published by Elsevier on behalf of the American Academy of Dermatology, Inc. S0190-9622(21)00110-9 10.1016/j.jaad.2020.10.098 Research Letter Chronic hydroxychloroquine therapy and COVID-19 outcomes: A retrospective case-control analysis Rangel Lauren K. BA Shah Payal BS Lo Sicco Kristen MD Caplan Avrom S. MD Femia Alisa MD ∗ Ronald O. Perelman Department of Dermatology, New York University Grossman School of Medicine, New York, New York ∗ Correspondence to: Alisa Femia, MD, New York University Dermatology, 240 E 38th St, 11th fl, New York, NY 10016 10 1 2021 6 2021 10 1 2021 84 6 17691772 © 2021 Published by Elsevier on behalf of the American Academy of Dermatology, Inc. 2021 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: Hydroxychloroquine (HCQ) has failed to show significant therapeutic benefit for patients with coronavirus disease-2019 (COVID-19) in recent studies, although interest in this medication's potential pre- and postprophylactic efficacy remains, with 1 retrospective study showing reduced COVID-19 infection among patients taking chronic HCQ.1 , 2 In this study, we sought to evaluate COVID-19 clinical outcomes in patients taking chronic HCQ for an underlying condition as well as in a matched cohort not taking HCQ at time of COVID-19 diagnosis. We identified all patients with severe acute respiratory syndrome coronavirus 2 seen at New York University from March to April 2020 using International Classification of Diseases, 10th revision codes and included patients taking HCQ for ≥6 weeks before their COVID-19 diagnosis. Control subjects were randomly selected from the remaining severe acute respiratory syndrome coronavirus 2–positive patients with automated matching for age, gender, and immunosuppressive medication using SPSS software (SPSS Inc, Chicago, IL). Baseline clinical characteristics and outcomes were compared using Pearson χ2, independent sample t test, and Mann–Whitney tests using 2-tailed significance (significance set as P < .05). We identified 50 patients taking chronic HCQ for ≥6 weeks before their COVID-19 diagnosis and 103 matched control subjects who were not taking HCQ at the time of their COVID-19 diagnosis (Table I ). There was no significant difference in age, sex, overall use of iatrogenic immunosuppressive medications, or COVID-19 risk factors between the groups (Table II ). However, in the control group, there was a significantly higher rate of organ transplantation (2.0% vs 26.2%, P < .001), and consequently a higher rate of chronic tacrolimus and mycophenolate use in this group (Supplemental Table I available via Mendeley at https://data.mendeley.com/datasets/6gmpg43rvm/1); subgroup analysis excluding patients taking tacrolimus or mycophenolate was performed. COVID-19 therapies were statistically similar other than lopinavir/ritonavir (more frequent in the chronic HCQ group) and interleukin-6 inhibitors (more common in the control group; Table II). All patients on chronic HCQ continued to take HCQ upon COVID-19 diagnosis, and 60 control subjects (58.3%) were treated with HCQ for COVID-19.Table I Hydroxychloroquine indication, dosage, and duration at time of COVID-19 diagnosis HCQ indication, dosage, and duration (N = 50) n (%) HCQ indication  Systemic lupus erythematosus 17 (34.0)  Rheumatoid arthritis 11 (22.0)  Connective tissue disease overlap syndromes 9 (18.0)  Sjögren syndrome 6 (12.0)  Mixed connective tissue disease 2 (4.0)  Undifferentiated connective tissue disease 1 (2.0)  Erythema nodosum during pregnancy 1 (2.0)  Carcinoid 1 (2.0)  Myalgic encephalomyelitis/chronic fatigue syndrome 1 (2.0)  Acquired hypogammaglobulinemia 1 (2.0) HCQ dosage  200 mg HCQ daily 13 (36.0)  200 mg HCQ 2 times daily (400 mg total) 36 (72.0)  200 mg HCQ 3 times daily (600 mg total) 1 (2.0) Mean duration of HCQ therapy before COVID-19 diagnosis (IQR) 28 (14.25-44.25) months COVID-19, Coronavirus disease-2019; HCQ, hydroxychloroquine; IQR, interquartile range. Table II Demographics and clinical outcomes of the study population Pre-exposure HCQ (N = 50) Matched no pre-exposure HCQ (N = 103) P value Mean age, y (±SD) 47.2 ± 2.4 49.8 ± 1.4 .282 Sex, n (%)  Male 8 (16.0) 24 (23.3) .197  Female 42 (84.0) 79 (76.7) Race, n (%)  White 29 (58.0) 49 (47.6) .624  Black 15 (30.0) 24 (23.3)  Asian 2 (4.0) 7 (6.8)  Other (Pacific Islander, Native American) 0 (0.0) 0 (0.0)  Unknown 4 (8.0) 14 (13.6) Ethnicity, n (%)  Hispanic 14 (28.0) 25 (24.3) .959  Non-Hispanic 36 (72.0) 64 (62.1) Taking immunosuppressant 28 (56.0) 55 (53.4) .762 Comorbidities, n (%)  Mean BMI, kg/m2 (±SEM) 31.7 ± 1.2 30.5 ± 0.7 .347  Cancer 2 (4.0) 3 (2.9) .972  Hypertension 21 (42.0) 44 (42.7) .933  Coronary artery disease 4 (8.0) 7 (6.8) .787  Congestive heart failure 0 (0.0) 6 (5.8) .082  Asthma 9 (16.0) 13 (12.6) .454  Chronic obstructive pulmonary disease 1 (2.0) 3 (2.9) .740  Obstructive sleep apnea 5 (10.0) 10 (9.7) .955  Chronic kidney disease 5 (9.8) 12 (11.7) .761  End-stage renal disease 4 (8.0) 16 (15.5) .195  Diabetes mellitus 7 (14.0) 28 (27.2) .053  Organ transplant 1 (2.0) 27 (26.2) <.001  HIV 0 (0.0) 2 (1.9) .321  Autoimmune disease 47 (94.0) 30 (28.3) <.001  Pregnant 3 (6.0) 4 (3.9) .584 Mean no. of days of COVID-19 symptoms before diagnosis (IQR) 4 (2-8) 4 (2-7) .932 Level of care, n (%)  Not hospitalized/ambulatory 29 (58.0) 52 (49.1) .468  Hospitalized 17 (34.0) 45 (42.5)  ICU 4 (8.0) 9 (8.5) Mean no. of days of duration of stay (IQR)  Full hospitalization 5.0 (3.0-11.0) 8.5 (5.8-18.0) .123  ICU stay 9.0 (6.5-24.5) 17.0 (7.5-26.5) .825 COVID-19 treatment, n (%)  Glucocorticoids 2 (4.0) 3 (2.9) .723  Chloroquine 0 (0.0) 0 (0.0) —  Hydroxychloroquine 50 (100.0) 60 (58.3) <.001  Azithromycin 28 (54.0) 55 (53.4) .855  Lopinavir/ritonavir 6 (12.0) 2 (1.9) .009  Remdesivir 0 (0.0) 1 (1.0) .485  Interleukin-6 inhibitor 1 (2.0) 15 (14.6) .017  Convalescent plasma 0 (0.0) 2 (1.9) .321  Ceftriaxone∗ 6 (12.0) 16 (15.5) .559 Complications among hospitalized patients, n (%) n = 21 n = 54  Invasive mechanical ventilation 4/21 (19.0) 10/54 (18.5) .958  Hemodialysis 0/21 (0.0) 7/54 (13.0) .083  ECMO 0/21 (0.0) 1/54 (1.9) .530  Venous thromboembolism 1/21 (4.8) 6/54 (11.1) .396  Disseminated intravascular coagulation 0/21 (0.0) 0/54 (0.0) — Disposition, n (%)  Discharged 16/21 (76.2) 43/54 (79.6) .250  Death 4/21 (19.0) 11/54 (20.4) .601 BMI, Body mass index; COVID-19, coronavirus disease-2019; ECMO, extracorporeal membrane oxygenation; HCQ, hydroxychloroquine; ICU, intensive care unit; IQR, interquartile range; SD, standard deviation; SEM, standard error of the mean. ∗ Empiric use for bacterial pneumonia prophylaxis or treatment. Clinical outcomes between groups did not differ on any parameter (Table II). Specifically, level of care (34.0% vs 42.5% requiring hospital admission; 8.0% vs 8.5% intensive care unit admission, P = .468), length of hospital stay (5.0 vs 8.5 days, P = .123), length of stay in the intensive care unit (9.0 vs 17.0 days, P = .825), hospital complications (intubation for example: 19% vs 18.5%, P = .958), and mortality (19% vs 20.4%, P = .250) did not differ (Table II). Three separate subgroup analyses were performed: excluding all those 1) undergoing chronic immunosuppressive therapy, 2) taking chronic tacrolimus or mycophenolate, and 3) taking lopinavir/ritonavir or anti–interleukin-6 treatment. Outcomes did not differ across any outcome upon subgroup analysis. This retrospective case-control study from a large hospital system at the epicenter of the COVID-19 pandemic found that chronic HCQ was not associated with improved clinical outcomes of COVID-19. Thus, similar to studies showing no treatment or postexposure benefit to HCQ,1 , 3 this study suggests no pre-exposure prophylactic benefit, particularly among those with autoimmune disease. Moreover, while patients with autoimmune disease may have worse viral illness outcomes,4 our results suggest that those taking chronic HCQ do not experience worse COVID-19 outcomes. Our study's retrospective design limits its generalizability. In addition, the relatively small cohort size, heterogeneity of groups, and inability to perfectly match groups inherently influences results and reduces power to detect smaller differences in outcomes. Notably, there was a higher rate of organ transplantation in the control group; however, subgroup analysis excluding those taking chronic tacrolimus or mycophenolate did not alter results. Moreover, HCQ was commonly administered for an autoimmune condition rather than as pre-exposure prophylaxis. In addition, several control subjects did receive HCQ therapy for COVID-19, potentially limiting the detection of differences between groups. Finally, dosing of chronic HCQ therapy and HCQ for pre-exposure prophylaxis may differ, although the former is typically higher.5 Therefore, while our results did not find a benefit to chronic HCQ therapy before COVID-19 infection, larger prospective studies of the general population or select high-risk populations may be warranted to evaluate the efficacy of HCQ dosed specifically as a form of pre-exposure prophylaxis. Conflicts of interest None disclosed. Funding sources: None. IRB approval status: Reviewed and approved by the New York University Grossman School of Medicine. ==== Refs References 1 Elavarasi A. Prasad M. Seth T. Chloroquine and hydroxychloroquine for the treatment of COVID-19: a systematic review and meta-analysis J Gen Intern Med 35 2020 3308 3314 32885373 2 Ferreira A. Oliveira-E-Silva A. Bettencourt P. Chronic treatment with hydroxychloroquine and SARS-CoV-2 infection J Med Virol 93 2021 755 759 32644224 3 Boulware D.R. Pullen M.F. Bangdiwala A.S. A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19 N Engl J Med 383 2020 517 525 32492293 4 Zandman-Goddard G. Shoenfeld Y. Infections and SLE Autoimmunity 38 2005 473 485 16373252 5 Al-Kofahi M. Jacobson P. Boulware D.R. Finding the dose for hydroxychloroquine prophylaxis for COVID-19: the desperate search for effectiveness Clin Pharmacol Ther 108 2020 766 769 32344449
PMC007xxxxxx/PMC7808898.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 Mosby S0190-9622(21)00013-X 10.1016/j.jaad.2021.01.003 This month in JAAD case reports This Month in JAAD Case Reports: March 2021 Sloan Brett MD ∗ Department of Dermatology, University of Connecticut School of Medicine, Farmington, Connecticut ∗ Correspondence to: Brett Sloan, MD, Department of Dermatology, 555 Willard Ave, VA Connecticut Healthcare System, Newington, CT 06111. 15 1 2021 3 2021 15 1 2021 84 3 611611 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Abbreviation used ITP immune thrombocytopenic purpura ==== Body pmcCoronavirus disease 19 (COVID-19) has rarely been associated with immune thrombocytopenic purpura (ITP). Of the few cases reported, >90% had at least 1 symptom of COVID-19.1 In the November edition of JAAD Case Reports, Lobos et al2 reported a 22 year old healthy active male who presented via a tele-dermatology consultation with an asymptomatic petechial eruption on his lower extremities after vigorous exercise. His review of symptoms was negative for COVID-19 symptoms yet he had reported gingival bleeding and a buccal hematoma after a dental procedure 1 day prior. A full laboratory workup revealed a platelet count of 1000/μL and an oropharyngeal swab positive for SARS-Cov-2. Fortunately, he remained asymptomatic of COVID-19 symptoms and his platelet count and petechial eruption improved after receiving intravenous immunoglobulin and eltrombopag. Numerous cutaneous eruptions have been associated with COVID-19. Given the well-known association of viruses with ITP, it is not surprising that SARS-Cov-2 is added to this list. The case presented by Lobos et al2 is a great example of the utility of tele-dermatology during this pandemic and a stark reminder to have a low threshold on thoroughly investigating any petechial eruption regardless of symptomology. Conflicts of interest None to report. Funding sources: None. IRB approval status: Not applicable. Reprints not available from the author. ==== Refs References 1 Bhattacharjee S. Banerjee M. Immune thrombocytopenia secondary to COVID-19: a systematic review SN Compr Clin Med 2 2020 2048 2058 32984764 2 Lobos P. Lobos C. Aravena P. Immune thrombocytopenic purpura associated with coronavirus disease 2019 infection in an asymptomatic young healthy patient JAAD Case Rep 6 11 2020 1129 1131 32923567
PMC007xxxxxx/PMC7816618.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(21)00196-1 10.1016/j.jaad.2021.01.047 Review An evidence-based guide to SARS-CoV-2 vaccination of patients on immunotherapies in dermatology Gresham Louise M. MD a Marzario Barbara MD a Dutz Jan MD, FRCPC b Kirchhof Mark G. MD, PhD, FRCPC a∗ a Division of Dermatology, Department of Medicine, University of Ottawa and The Ottawa Hospital, Ottawa, Canada b Department of Dermatology and Skin Sciences, University of British Columbia, Vancouver, Canada ∗ Reprint requests: Mark G. Kirchhof, MD, PhD, FRCPC, Division of Dermatology, Department of Medicine, University of Ottawa and The Ottawa Hospital, 737 Parkdale Ave, Ottawa, Ontario, Canada K1Y 4E9. 19 1 2021 6 2021 19 1 2021 84 6 16521666 15 1 2021 © 2021 by the American Academy of Dermatology, Inc. 2021 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Immune-mediated diseases and immunotherapeutics can negatively affect normal immune functioning and, consequently, vaccine safety and response. The COVID-19 pandemic has incited research aimed at developing a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. As SARS-CoV-2 vaccines are developed and made available, the assessment of anticipated safety and efficacy in patients with immune-mediated dermatologic diseases and requiring immunosuppressive and/or immunomodulatory therapy is particularly important. A review of the literature was conducted by a multidisciplinary committee to provide guidance on the safety and efficacy of SARS-CoV-2 vaccination for dermatologists and other clinicians when prescribing immunotherapeutics. The vaccine platforms being used to develop SARS-CoV-2 vaccines are expected to be safe and potentially effective for dermatology patients on immunotherapeutics. Current guidelines for the vaccination of an immunocompromised host remain appropriate when considering future administration of SARS-CoV-2 vaccines. Key words COVID-19 immunomodulatory therapy immunosuppressive therapy SARS-CoV-2 vaccine Abbreviations used IL interleukin mRNA messenger RNA SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 TNF tumor necrosis factor VAERD vaccine-associated enhanced respiratory disease ==== Body pmc Capsule Summary • The safety and efficacy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients with immune-mediated dermatologic diseases requiring immunotherapeutics is unknown. • The SARS-CoV-2 vaccines approved and distributed are expected to be safe for patients on immunotherapeutics with some variability in efficacy, depending on the degree of immunosuppression and type of vaccine given. Patients with immune-mediated dermatologic diseases can require treatment with short-term and long-term immunosuppressive and/or immunomodulatory therapy. Immune-mediated diseases and immunotherapeutics can negatively affect normal immune functioning, placing these patients at increased risk of infection.1, 2, 3 However, patients on immunotherapies for dermatologic and rheumatologic disease do not appear to be more susceptible to COVID-19.4 Vaccines protect against infection by provoking a protective humoral and cellular immune response.5 , 6 Assessment of vaccine safety is largely derived from observational studies,7 whereas the efficacy of vaccination is commonly investigated by using postimmunization antibody titers as correlates of protection.6 , 8, 9, 10 For patients on immunotherapeutics, clinical decision making regarding vaccination must weigh the anticipated disease protection achieved by immunization against the risk of vaccine-induced adverse events. Meanwhile, the risk of discontinuation or temporary withdrawal of therapy must also be considered because some immunotherapies can carry the risk of increased disease activity, relapse, or loss of response.3 , 11 The COVID-19 pandemic has included a rapid increase in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) research around the globe, particularly research aimed at developing a SARS-CoV-2 vaccine. SARS-CoV-2 vaccination research has resulted in the development of novel vaccine platforms (ie, RNA, DNA, nonreplicating viral vectors, etc).12 , 13 Furthermore, SARS-CoV-2 is a novel vaccine target. As SARS-CoV-2 vaccines are developed and made available, the assessment of potential safety and efficacy in this population is particularly important. The launch of SARS-CoV-2 vaccines creates a unique clinical challenge for dermatologists and other clinicians when prescribing immunotherapeutics. We aim to provide guidance on the safety and efficacy of SARS-CoV-2 vaccination for dermatology patients on immunotherapeutics as an adjunct to existing guidelines, including the Infectious Diseases Society of America “Clinical Practice Guideline for Vaccination of the Immunocompromised Host.”14 Specifically, this review is intended to serve as a point of reference to assist dermatologists and clinicians when approaching SARS-CoV-2 vaccination and their patients receiving immunotherapeutics through (1) a review of the SARS-CoV-2 vaccines now authorized for distribution (Moderna messenger RNA [mRNA] and Pfizer-BioNTech mRNA) as well as those under development and an outline of the potential risks to patients receiving immunotherapeutics, (2) a summary of current evidence pertaining to the safety and efficacy of nonviral vaccines in patients receiving immunotherapeutics, and (3) an extrapolation of these data to comment on the anticipated safety and efficacy outcomes with the novel SARS-CoV-2 vaccines. Methods A review of the literature was conducted by a multidisciplinary committee comprising dermatologists (MGK, JD), immunologists (MGK, JD), a rheumatologist (JD), dermatology residents (LMG, BM) and a specialist in virology and vaccination (MS). Studies were identified by performing a search across electronic databases (MEDLINE, Embase, PubMed) and divided into 3 areas of focus based on major search terms in addition to advanced searching within these databases using the following Medical Subject Headings terms: (1) “SARS-CoV-2” or “COVID-19” and “vaccine” or “vaccination”; (2) “vaccine” or “vaccination” and “glucocorticoid” or “prednisone” or “corticosteroid,” as well as “vaccine” or “vaccination” and specific systemic immunotherapy (“apremilast,” “azathioprine,” “cyclosporine,” “methotrexate,” “mycophenolate mofetil,” and “JAK inhibitors”); (3) “vaccine” or “vaccination” and specific biologic agent (“adalimumab,” “certolizumab,” “etanercept,” “infliximab,” “ustekinumab,” “brodalumab,” “ixekizumab,” “secukinumab,” “guselkumab,” “risankizumab,” “tildrakizumab,” “rituximab,” “anakinra,” “dupilumab,” “omalizumab,” and “IVIG”). Additional relevant studies were identified from the reference lists of primary studies and reviews and included based on relevance to these major search terms. Published studies including clinical trials, meta-analyses, systematic reviews, case series, and case reports were reviewed and assessed for content and grading of quality of evidence adapted from Robinson et al15 to support recommendations. Data were extracted from individual studies and synthesized into tables. Results and discussion Review of SARS-CoV-2 vaccines under development To properly assess risks of vaccines against SARS-CoV-2 to patients on immunotherapeutics, it is important to understand the basic mechanisms of the vaccines' platforms. There are more than 90 vaccines against SARS-CoV-2 in development; the wide range of strategies used to stimulate the immune system to develop protective antibodies is summarized in Table I .5 Live attenuated vaccines are weakened wild-type viruses that have accumulated mutations to diminish their ability to cause disease and therefore pose the highest risk to dermatology patients on immunotherapeutics because of the rare risk of reversion to the original pathogenic infectious agent.3 , 16 However, currently, there are no live attenuated SARS-CoV-2 vaccines in phase 2 or phase 3 trials.Table I Review of COVID-19 vaccines in development Type of vaccine (approved examples) Description Example companies and phase of development Anticipated risk to patients on immunotherapeutics Inactivated virus SARS-CoV-2 is allowed to replicate in cells and then killed by using chemicals, heat, or radiation • Sinovac: approved (not in United States) • Sinopharm: approved (not in United States) None Live, attenuated virus SARS-CoV-2 is genetically engineered to limit infection and reproduction • Serum Institute and Codagenix: phase 1 Low Protein subunit SARS-CoV-2 protein is engineered and produced to stimulate antiviral antibodies • Novavax (NVX-CoV2373): phase 3 None Virus-like particles Virus-like structures enter cells like virus to deliver SARS-CoV-2 protein subunit to stimulate immune response • Medicago/GlaxoSmithKline: phase 3 None Nonreplicating viral vectors Nonreplicating engineered viruses, such as adenovirus or vaccinia, that carry genetic code for proteins of the SARS-CoV-2 virus to stimulate an immune response • University of Oxford/AstraZeneca (ChAdOx1/AZD1222): approved (expected in United States) • Johnson & Johnson (JNJ-78436735): approved in United States None to minimal Replicating viral vectors Weakened versions of carrier viruses, like influenza or measles, that can replicate in the body and carry genetic code for a protein of SARS-CoV-2. Do not usually cause symptoms. • University of Pittsburgh/Themis Biosciences/Institut Pasteur/Merck: phase 2 Minimal RNA RNA is injected into the body that codes for a SARS-CoV-2 protein that is then produced and leads to antibody development. • Moderna/National Institute of Allergy and Infectious Diseases (mRNA-1273): approved in United States • BioNTech/Fosun Pharma/Pfizer (BNT162): approved in United States None DNA DNA is injected into the body, often in the form of a plasmid, that codes for a SARS-CoV-2 protein that is then produced and leads to antibody development. • Inovio/International Vaccine Institute: phase 3 • Cadila Healthcare: phase 2 • Osaka University/AnGes/Takara Bio: phase 2 None SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2. Otherwise, there are 3 principal vaccine platforms that have been used to develop already approved vaccines and are considered safe for patients on immunotherapeutics: inactivated vaccines, protein subunit vaccines, and virus-like particle vaccines. These platforms have been used to develop pertussis vaccines, hepatitis B vaccines, and human papilloma virus vaccines. With regard to developmental SARS-CoV-2 vaccines, there is currently 1 protein subunit vaccine in phase 3 trials (NVX-CoV2373, Novavax), which, based on phase 1 and 2 data, appears to be safe, and elicits a strong antibody response.17 Nonreplicating viral vectors and RNA/DNA vaccines are in phase 3 trials or have completed phase 3 trials and represent novel methods of vaccination.18, 19, 20 Results suggest that these vaccines are safe and have the ability to produce protective antibody responses.18, 19, 20, 21, 22, 23, 24 The data from phase 2 and 3 trials of ChAdOx1/AZD1222 (Oxford-AstraZeneca) (nonreplicating viral vector) and phase 3 trials of mRNA-1273 (Moderna) (mRNA vaccine) and BNT162 (Pfizer-BioNTech) (mRNA vaccine) indicate that these vaccines are safe, with mild to moderate adverse events and the development of antibody responses that are above convalescent serum controls.18, 19, 20 The US Government has prepurchased mRNA-1273 (mRNA vaccine), BNT162 (mRNA vaccine), JNJ-78436735 (Johnson & Johnson) (nonreplicating viral vector), ChAdOx1/AZD1222 (nonreplicating viral vector), NVX-CoV2373 (Novavax) (protein subunit vaccine), and a protein subunit vaccine from Sanofi/GlaxoSmithKline. Systemic immunotherapies and vaccines The following dermatology-relevant immune-targeting therapies were reviewed in the setting of studies evaluating the safety and efficacy of nonviral and live vaccines: apremilast, azathioprine, cyclosporine, methotrexate, mycophenolate mofetil, systemic corticosteroids, and JAK inhibitors. No studies evaluated vaccination in patients receiving thalidomide or apremilast; safety has been addressed in the literature on the basis of expert opinion only.25 Safety of vaccines in patients receiving nonbiologic systemic immunotherapy Based on available studies, detailed in Table II ,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 the majority of vaccines are safe in patients receiving nonbiologic immunotherapy. There is ultimately good evidence for the safety of nonviral vaccines in patients with dermatologic, autoimmune, or inflammatory disease treated with standard dermatologic doses of immunosuppressive agents, and these are generally well tolerated (Table II). These findings are aligned with current guideline recommendations.3 , 70 , 71 Table II Review of data on systemic immune targeting therapies and vaccines (see Table 2 in van Riel and de Wit12) Drug Type of vaccination Adverse events Effects on immunity Level of evidence Systemic corticosteroids (prednisone) Influenza26, 27, 28, 29, 30, 31, 32, 33, 34,73,75,82,113,116,121 PPSV2335,36,101,117,119,120 Hepatitis B37 HPV38 Herpes/varicella zoster (LZV)39,40,145 Yellow fever41 Safe, generally well tolerated. Increased frequency of moderate/severe local reactions compared to healthy control individuals have been observed; as well as a few reports of increased incidence of clinical and/or biochemical parameters of disease flare30 or increased herpes zoster risk observed in patients on immune-suppressive therapy39 Variable effect on immunity: adequate seroprotection and/or no significant suppression of response in several studies and associated with doses up to <10-20 mg/day.37,38 Reduced seroconversion rates and/or impaired immune response/humoral response noted in a number of studies and, in particular, associated with a high-dose regimen of >20 mg/day.27,29,35,116 In VZV, long-term seroprotection for VZV at the 2-year follow-up was also observed.40,145 A-B Methotrexate Influenza: trivalent,42,43,79,80,146 pandemic (A/H1N1)44,45,73,76,78,82, 83, 84 PPSV2343,111 PCV7/1346,120,143 HAV86,99 HBV100 Tetanus/diphtheria102 MMR1,47, 48, 49,74 Herpes/varicella zoster (LZV,39,50, 51, 52,85,93,145 RZV92) Yellow fever53, 54, 55, 56,129 Safe, generally well tolerated with both nonviral and live-attenuated/live vaccines7,56,57,∗,† Rare risk of systemic rash and fever with live-attenuated/live vaccine (ie, MMR48,49 and HZV39,145) Variable effect on immunity: Most studies involving live-virus vaccines showed no significant effect on children and adult populations and satisfactory vaccine response/adequate seroprotection with a methotrexate dose of 10-25 mg/week. There is some support for improved response with temporary discontinuation and/or second dose. Nonviral vaccine is overall associated with a negative effect on immunogenicity, including reduced humoral response and insufficient protection with a single dose, with the exception of HBV (no significant effect).86,99,100 A-B Azathioprine Influenza: trivalent,32,58, 59, 60 pandemic (A/H1N1)61,62,82,84 PPSV23110,118 PCV1363,118 HAV131 HBV97,100 Tetanus, pertussis107 Herpes/varicella zoster (LZV)39,64, 65, 66,92 RZV92 Yellow fever61 Safe, consistently well tolerated with nonviral vaccines and live-attenuated/live vaccines Variable effects on immune response for nonviral and live-attenuated/live vaccines described. Most studies report blunted to impaired immunogenicity for nonviral and live vaccines (eg, reduced humoral response). Comparable response to healthy control individuals also has been observed in pandemic influenza strains61,82 and HAV131 B Cyclosporine Influenza: trivalent62 Pandemic (A/H1N1)44,61,84 Herpes/varicella zoster (LZV)39,145 Yellow fever61 PPSV2372 HAV67 Tetanus toxoid72 Safe, consistently well tolerated with nonviral vaccines and live-attenuated/live vaccines. Consistent findings describing overall negative effect on immune response with nonviral and live-attenuated/live vaccines (ie, reduced recall humoral response, reduced rates of seroconversion, in vitro cellular immune response). A-B Mycophenolate mofetil Influenza: trivalent,59,87 pandemic (A/H1N1)68,84,88 PPSV2372 Tetanus toxoid72 Yellow fever61 Safe, generally well tolerated (few reports of mild adverse effects) Variable effects on immune response described in the literature. Most studies describe reduced immunogenicity/reduced humoral response with nonviral vaccines and worse with doses >2 g/day. Some support for antibody response comparable to healthy control individuals or nonsignificantly reduced/improved response with second dose. No studies evaluating immunogenicity in live-attenuated or live vaccines. A-B JAK inhibitors Influenza (trivalent)95 PPSV2389,94,95 Tetanus toxoid89,95 Herpes/varicella zoster69,91,92 No reports of clinically significant adverse effects Evidence is limited. Overall consistently preserved immunogenicity with nonviral and live-attenuated/live vaccine (ie, LZV†); sustained/long-term seroprotection may be inadequate.‡ B HAV, Hepatitis A vaccine; LZV, live zoster vaccine; MMR, measles, mumps, rubella; PPSV, pneumococcal polysaccharide vaccine; RZV, recombinant zoster vaccine; VZV, Varicella zoster virus. ∗ No significant adverse effects and no reports of increased clinical or laboratory index of disease activity. No exacerbation of disease activity in a number for autoimmune/inflammatory diseases. No adverse effects in function or graft failure in solid organ transplant recipients. One case report of fatal vaccine-associated viscerotropic disease.74,83 † In a cohort of patients vaccinated 2 to 3 weeks before starting tofacitinib treatment. ‡ Diminished humoral response to tetanus toxoid vaccine at week 12 and only 60% mounting 4-fold response to tetanus toxoid vaccine in patients with psoriasis on JAK inhibitors. Efficacy of vaccines in patients receiving systemic immunotherapies There is a trend toward a decreased immune response and vaccine immunogenicity in patients on systemic immunotherapies, particularly patients receiving azathioprine, cyclosporine, methotrexate, mycophenolate mofetil, or JAK inhibitors (Table II). Studies evaluating vaccine efficacy in patients receiving mycophenolate mofetil and cyclosporine have been primarily conducted in kidney transplant recipients and/or solid organ transplant recipients, in whom the immunosuppressive regimens result in severely disturbed primary and secondary humoral responses and, therefore, an impaired ability to mount a protective immune response.72 This may not be generalized to patients with dermatology immune disease on dermatologic doses of immunotherapies. The efficacy of inactivated, attenuated, and recombinant vaccines (ie, trivalent [A/H1N1, H3N2, B strain] and pandemic [A/H1N1] influenza vaccine) has been evaluated in patients receiving methotrexate.73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83 A significant reduction of inactivated and subunit vaccine antibody titers84 and inadequate sustained response or nonprotective titers on follow-up (at 4 to 12 weeks) has been reported in patients treated with methotrexate.85 On the other hand, the response appears to improve with second vaccination in studies evaluating influenza85 and hepatitis A86 vaccines in patients receiving methotrexate (15-20 mg per week),85 , 86 azathioprine, or cyclosporine.85 , 87 , 88 Satisfactory immune responses to influenza vaccine and nonviral vaccine (PPSV23, tetanus toxoid) in JAK inhibitor–treated patients with rheumatoid arthritis89 and inflammatory bowel disease have been observed when vaccines were administered either before the initiation of therapy90, 91, 92, 93 or after temporary withdrawal of JAK inhibitors 2 to 3 weeks before vaccination,89 , 94 , 95 which is consistent with most consensus guideline recommendations.3 , 70 , 71 Overall, vaccine efficacy may be reduced in patients receiving systemic immune-targeting therapies because of the impaired immune response in these patients; however, temporary withdrawal and/or additional vaccinations may be considered to achieve adequate protection. Vaccines and biologics The majority of primary data on the safety and efficacy of vaccines in patients exposed to biologics focuses on tumor necrosis factor (TNF) alpha inhibitors (primarily infliximab and etanercept) and the anti-CD20 monoclonal antibody rituximab.74 , 76 , 77 , 79 , 80 , 83 , 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145 Patients with rheumatoid arthritis and inflammatory bowel disease were the most frequently studied populations.76 , 77 , 83 , 97, 98, 99, 100, 101 , 103 , 105 , 108, 109, 110 , 113 , 114 , 116 , 117 , 120, 121, 122 , 124 , 126 , 127 , 129, 130, 131 , 133, 134, 135, 136, 137 , 139 , 140 , 142, 143, 144, 145, 146 No studies on the safety or efficacy of vaccination in patients exposed to the following biologics were identified: brodalumab, anakinra, omalizumab, guselkumab, risankizumab, or tildrakizumab (Table III ).147, 148, 149, 150, 151, 152 Table III Review of data on vaccines and biologics∗,† Drug Type of vaccination Adverse events Effects on immunity Level of evidence Adalimumab (TNF inhibitor) PPSV23117 Influenza117,156 HBV114,133 Safe, generally well tolerated Variable; some studies show no significant effect on humoral response,117,133 while others show reduced humoral response.114,117,156 A-B Certolizumab (TNF inhibitor)121 Influenza PPSV23 Safe, generally well tolerated No significant effect on humoral response A Etanercept (TNF inhibitor) MMR74 PPSV2396,125 PCV13134 Influenza106 HBV114,136 Safe, generally well tolerated No increase in disease activity Variable; most studies showed no significant effect on humoral response,96,125,134 while some showed reduced humoral response.73,106,114 A-B Infliximab (TNF inhibitor) Influenza76,105,109,113,124 HBV97,114,133,136 Yellow fever129,139 PPSV23110,143 Safe, generally well tolerated No increase in disease activity Variable efficacy for trivalent influenza and PPSV23 vaccination. Some studies show no significant effect on humoral response,76,109,124 while others show reduced humoral response.105,110,113,124 Most studies showed reduced humoral response to HBV vaccination.97,114,133 Adequate humoral response to yellow fever vaccination. A-B C∗ TNF inhibitors grouped HBV100,133,138 HAV99,103,131 HZ145 PPSV23103,120,123,138 PCV13115,118,126,128,147 Tdap102,107 Influenza79,80,115,116,122,137,140,154 Pandemic (A/H1N1)77,83,103 Safe, well tolerated No increase in disease activity Variable; some studies show no significant effect on humoral response, while others show reduced humoral response. Vaccine possibly associated with lower HZ incidence 2 years after vaccination.145 No significant difference in humoral response to PPSV23 vaccine between infliximab or etanercept treated patients.138 A-B Ustekinumab (IL-12/23 inhibitor) Influenza156 PPSV23155 Tetanus toxoid155 HBV114 N/A Nonimpaired immune response and efficacy of inactivated influenza vaccine. No significant effect on humoral response to PPSV23 and tetanus vaccination. Possible reduced humoral response to HBV vaccination A-B Ixekizumab (IL-17 inhibitor) PPSV23148 Tetanus toxoid148 Well tolerated No significant effect to humoral response A Secukinumab (IL-17 inhibitor) Meningococcal C Conjugate149 Trivalent influenza136,149,150 Well tolerated No increase in disease activity No significant effect to humoral response A-B Rituximab (anti–CD-20) Influenza98,104,108,111,115,116,122,130,135,142,144 PPSV23101,115,135 PCV13112,126, 127, 128 PCV7157 TdaP102 Yellow fever129 HBV136 HZ145 Well tolerated No increase in disease activity The majority of studies found a reduced humoral response to influenza, pneumococcal, HBV, and TdaP vaccine. Vaccination possibly associated with significantly lower HZ incidence 2 years after vaccination.145 No significant effect on humoral response to yellow fever vaccination. A-B C∗ Dupilumab (IL-4/13 inhibitor) TdaP MPSV4153 Safe, well tolerated No significant effect on humoral response A IVIG MMR151 Influenza152 N/A No significant effect on humoral response when vaccination occurs before IVIG administration. Decreased humoral response when vaccination occurs after IVIG administration. B HAV, Hepatitis A vaccine; HBV, hepatitis B virus; HZ, herpes zoster; IL, interleukin; IVIG, intravenous immunoglobulin; MMR, measles, mumps, rubella; MPSV, meningococcal polysaccharide vaccine; N/A, not applicable; PCV, pneumococcal conjugate vaccine; PPSV, pneumococcal polysaccharide vaccine; TdaP, tetanus/diphtheria/pertussis; TNF, tumor necrosis factor. ∗ The only study with level of evidence C is Oliveira et al.129 † There were no studies identified evaluating vaccine safety and/or efficacy with following biologics: brodalumab (IL-17 inhibitor), guselkumab (IL-23 inhibitor), risankizumab (IL-23 inhibitor), tildrakizumab (IL-23 inhibitor), anakinra (IL-1 inhibitor), omalizumab. Vaccination safety in patients on biologics There have been few serious adverse events reported with vaccination and patients on biologic therapies, and the majority of reported adverse events were unrelated to vaccination.96 , 117 , 121 , 153 Aikawa et al96 reported 1 serious adverse event in a patient on TNF inhibitor therapy who developed invasive pneumococcal disease with bacterial pneumonia 5 months after vaccination, despite seroconverting 6 out of 7 polysaccharide serotypes analyzed. Blauvelt et al153 reported 1 treatment-related serious event in their dupilumab treatment group: a serum sickness-like reaction that resolved without sequelae. Vaccine efficacy in patients on biologics Data pertaining to vaccine efficacy are heterogeneous. Good antibody levels are observed after vaccination for patients on interleukin (IL) 17 (brodalumab, ixekizumab, secukinumab) and IL-4/13 inhibitors (dupilumab). Anti-TNF (adalimumab, certolizumab, etanercept) and anti–IL-12/23 (ustekinumab) biologics have been associated with a significant decrease in antibody levels. Variable data are observed for rituximab. Exposure to TNF inhibitors did not have a significant effect on humoral responses to pneumococcal (PPS23 and PCV13) or influenza vaccination in patients with rheumatoid arthritis.76 , 79 , 83 , 96 , 109 , 115 , 117 , 120 , 121 , 125 , 134 , 137 , 143 , 154 Curiously, TNF inhibitor exposure was associated with a reduced humoral response to pneumococcal and influenza vaccination in patients with inflammatory bowel disease.103 , 105 , 110 , 113 , 123 , 124 Belle et al100 found that treatment with immunomodulators and TNF inhibitors in patients with inflammatory bowel disease did not influence humoral response to hepatitis B vaccination compared to healthy control individuals.100 Patients with moderate to severe psoriasis treated with ustekinumab did not experience a change in humoral response to PPSV23 and tetanus toxoid vaccination.155 This is further supported by a recent study showing decreased efficacy of influenza vaccination in patients treated with adalimumab but not ustekinumab.156 In patients exposed to rituximab, most studies found a reduced humoral response to pneumococcal,101 , 112 , 115 , 126, 127, 128 , 135 , 157 hepatitis B,136 and influenza vaccination.73 , 108 , 111 , 116 , 122 , 130 , 142 , 144 Rituximab exposure did not significantly affect humoral response to seasonal influenza vaccination in patients with autoimmune blistering disease.104 Blauvelt et al153 found that patients with moderate to severe atopic dermatitis treated with dupilumab did not have a decreased humoral response to meningococcal and tetanus/diphtheria/pertussis vaccination. SARS-CoV-2 candidate vaccines and immunotherapeutics: estimating risk and response It is not possible to determine the true risk associated with any potential SARS-CoV-2 vaccine until it has gone through all phases of clinical trials and real-world evidence has been gathered from a widely distributed and adopted vaccination program. Nonetheless, we are able to estimate risk from the limited trial data for the SARS-CoV-2 vaccines and from a review of the literature for patients on immunotherapeutics and established vaccines (Fig 1 ). Considering the immunologic basis of the SARS-CoV-2 vaccine platforms in late-stage development, the estimated risk to patients on immunotherapies is low. From the review of the literature, patients on biologics have no abnormal immune responses leading to detrimental outcomes (Table III). The safety of a potential SARS-CoV-2 vaccine can be estimated based on the mechanism of action of the biologic or on inferences from the limited data on other biologics. For instance, there are no safety or efficacy data for vaccination of patients on anti–IL-23 biologics, but we can infer the safety profile from vaccination of patients on anti–IL-17 biologics and anti–IL-12/23 biologics. Omalizumab, which blocks immunoglobulin E, is also regarded as safe based on the mechanism of action. For the systemic immunotherapeutics, systemic corticosteroids, methotrexate, and JAK inhibitors appear to have the highest risk of reduced antibody production. However, it should be noted that in previous reviews, methotrexate and JAK inhibitors were considered safe therapies during the COVID-19 pandemic and, in fact, are being studied as potential treatments for COVID-19.158 , 159 Fig 1 Summary of the safety and efficacy for potential SARS-CoV-2 vaccines for patients on immunotherapeutics. ∗Insufficient data. There were no studies evaluating the safety and/or efficacy of vaccination in patients receiving thalidomide, apremilast, IVIg, or the following biologics: brodalumab, anakinra, omalizumab, guselkumab, risankizumab, or tildrakizumab. Data on apremilast has been addressed in the literature on the basis of expert opinion only. With regard to vaccine-generated antibody response, data generally support a possible decrease in antibody titers with the TNF-αbiologics, rituximab, ustekinumab, and many of the oral immunotherapies.3 Given the possibility of decreased antibody titers to vaccination with some of these treatments, there have been suggestions for withholding immunotherapeutics at the time of vaccination to promote a better vaccine response.157 For instance, a 2-week temporary withdrawal of methotrexate after vaccination for influenza has been shown to result in higher antibody titers in patients with rheumatoid arthritis.160 It would thus be prudent to check the titers after vaccination for any patients on a immunotherapeutic because they might require a booster to establish or maintain protective antibody titers. If protective antibody titers are inadequate and skewed to a T helper type 2 phenotype, vaccine-associated enhanced respiratory disease (VAERD) can develop.161 VAERD is a condition in which vaccination makes subsequent infections with the same virus worse. VAERD has been noted with vaccines to respiratory syncytial virus162 and measles,163 as well as vaccination in animal models of Middle East respiratory syndrome coronavirus (MERS-CoV).164 Based on the data from the current SARS-CoV-2 vaccines, the risk of VAERD appears to be low in the absence of immune modulatory therapy,22, 23, 24 , 165 but the possibility of T helper type 2 deviation may need to be considered. Otherwise, general considerations of vaccine safety need to be considered, such as allergic or anaphylactic reactions and exuberant inflammatory responses with fever and systemic symptoms. The benefit-to-risk ratio for vaccinating patients for SARS-CoV-2 is ultimately a discussion that needs to involve informed clinicians and patients. Study limitations This article provides an overview of current evidence on the administration of existing approved vaccines in patients receiving immunotherapy. Consequently, information is subject to process bias secondary to the methodology of the review. Existing evidence is frequently of low/limited quality with a lack of control groups, insufficient sample size and therefore limited power, and/or inconsistent findings. There is a paucity of data pertaining to vaccination in patient populations on immunosuppressive and immunomodulatory therapies, especially patients with dermatologic disease. Moreover, there is variability of underlying disease or treatment in study populations, which reflects the current diversity of immunosuppressive and immunomodulatory medications and the range of combinations in treatment regimens. Recommendations and conclusions The data reviewed in this article support the safety and potential efficacy of SARS-CoV-2 vaccines for our dermatology patients on immunotherapies (Box 1 ). The SARS-CoV-2 vaccines currently approved (Moderna/NIAID mRNA-1273, Pfizer/BioNTech/Fosun Pharma BNT162) and most likely to be approved (Astra-Zeneca/University of Oxford ChAdOx1/AZD1222, Johnson & Johnson JNJ-78436735, Novavax NVX-CoV2373) in North America are vaccine platforms (ie, RNA, protein subunit, and nonreplicating viral vectors) that are expected to be safe for patients on immunotherapeutics. The anticipated efficacy is variable in the setting of systemic immunotherapies. Although most biologics are associated with good (anti-IL-17, anti-IL-4/13) to fair (anti-TNF, anti-IL-12/23) antibody response to all vaccine subtypes, there is paucity in data for a number of agents. The current Infectious Diseases Society of America “Clinical Practice Guideline for Vaccination of the Immunocompromised Host” remains appropriate when considering future administration of a SARS-CoV-2 vaccine,14 although additional vaccinations and monitoring antibody titers can be considered.Box 1 Summary of the recommendations for vaccination as applied to a potential SARS-CoV-2 vaccine 1. Nonviral or inactivated SARS-CoV-2 vaccine subtypes may be considered before, during, or after immunosuppressive therapy in patients receiving systemic immunosuppressant or immune-targeting therapy without significant modification of ongoing treatments.1.1. Safety: minimal to no risk of adverse events 1.2. Efficacy: variable antibody levels expected depending on vaccine and immunotherapy 2. Nonviral SARS-CoV-2 vaccine subtypes may be considered in patients receiving biologic therapy without significant modification of ongoing immune therapy.2.1. Safety: minimal to no risk of adverse events 2.2. Efficacy: at least fair to good antibody response for most biologics 3. The risk-to-benefit ratio may favor immunization if immunosuppression is low and there is significant risk of disease development. 4. Consider checking antibody titers after vaccination and using additional vaccinations, if needed, to boost the level of protective antibodies. SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2. Conflicts of interest None disclosed. We would like to acknowledge the help of Dr Manish Sadarangani, director, Vaccine Evaluation Center, BC Children's Hospital, Sauder Family Chair in Pediatric Infectious Diseases, University of British Columbia. He reviewed the manuscript and provided helpful comments and suggestions. Funding sources: None. IRB approval status: Not applicable. ==== Refs References 1 Huber F. Ehrensperger B. Hatz C. Chappuis F. Bühler S. Eperon G. Safety of live vaccines on immunosuppressive or immunomodulatory therapy—a retrospective study in three Swiss travel clinics J Travel Med 25 1 2018 1 8 2 McKinnon J.E. Maksimowicz-McKinnon K. Autoimmune disease and vaccination: impact on infectious disease prevention and a look at future applications Transl Res 167 1 2016 46 60 26408802 3 Papp K.A. Haraoui B. Kumar D. Vaccination guidelines for patients with immune-mediated disorders on immunosuppressive therapies J Cutan Med Surg 23 1 2019 50 74 30463418 4 Jessica Chang T.Y. Pope J.E. How COVID-19 affects patients receiving anticytokine and JAK inhibitors in rheumatology and dermatology Immunotherapy 12 2020 1115 1119 32640861 5 Callaway E. The race for coronavirus vaccines: a graphical guide Nature 580 7805 2020 576 577 32346146 6 Plotkin S.A. Correlates of protection induced by vaccination Clin Vaccine Immunol 17 7 2010 1055 1065 20463105 7 Croce E. Hatz C. Jonker E.F. Visser L.G. Jaeger V.K. Bühler S. Safety of live vaccinations on immunosuppressive therapy in patients with immune-mediated inflammatory diseases, solid organ transplantation or after bone-marrow transplantation—a systematic review of randomized trials, observational studies and case reports Vaccine 35 9 2017 1216 1226 28162821 8 Amanna I.J. Messaoudi I. Slifka M.K. Protective immunity following vaccination: how is it defined? Hum Vaccin 4 4 2008 316 319 18398296 9 Andrews N.J. Waight P.A. Burbidge P. Serotype-specific effectiveness and correlates of protection for the 13-valent pneumococcal conjugate vaccine: a postlicensure indirect cohort study Lancet Infect Dis 14 9 2014 839 846 25042756 10 Taranger J. Trollfors B. Lagergård T. Correlation between pertussis toxin IgG antibodies in postvaccination sera and subsequent protection against pertussis J Infect Dis 181 3 2000 1010 1013 10720524 11 Blauvelt A. Papp K.A. Sofen H. Continuous dosing versus interrupted therapy with ixekizumab: an integrated analysis of two phase 3 trials in psoriasis J Eur Acad Dermatol Venereol 31 6 2017 1004 1013 28190255 12 van Riel D. de Wit E. Next-generation vaccine platforms for COVID-19 Nat Mater 19 8 2020 810 812 32704139 13 Abbasi J. COVID-19 and mRNA vaccines—first large test for a new approach JAMA 324 12 2020 1125 1127 32880613 14 Rubin L.G. Levin M.J. Ljungman P. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host Clin Infect Dis 58 3 2014 e44 e100 24311479 15 Robinson J.K. Dellavalle R.P. Bigby M. Callen J.P. Systematic reviews: grading recommendations and evidence quality Arch Dermatol 144 1 2008 97 99 18209174 16 Introduction of inactivated poliovirus vaccine into oral poliovirus vaccine-using countries Wkly Epidemiol Rec 78 28 2003 241 250 15571166 17 Keech C. Albert G. Cho I. Phase 1–2 trial of a SARS-CoV-2 recombinant spike protein nanoparticle vaccine N Engl J Med 383 2020 2320 2332 32877576 18 Baden L.R. El Sahly H.M. Essink B. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine N Engl J Med 384 5 2021 403 416 33378609 19 Polack F.P. Thomas S.J. Kitchin N. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine N Engl J Med 383 27 2020 2603 2615 33301246 20 Ramasamy M.N. Minassian A.M. Ewer K.J. Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial Lancet 396 10267 2021 1979 1993 33220855 21 Bar-Zeev N. Moss W.J. Encouraging results from phase 1/2 COVID-19 vaccine trials Lancet 396 2020 448 449 32702300 22 Callaway E. Coronavirus vaccine trials have delivered their first results—but their promise is still unclear Nature 581 7809 2020 363 364 32433634 23 Folegatti P.M. Ewer K.J. Aley P.K. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial Lancet 396 2020 467 478 32702298 24 Corbett K.S. Flynn B. Foulds K.E. Evaluation of the mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates N Engl J Med 383 2020 1544 1555 32722908 25 Baumrin E. Van Voorhees A. Garg A. Feldman S.R. Merola J.F. A systematic review of herpes zoster incidence and consensus recommendations on vaccination in adult patients on systemic therapy for psoriasis or psoriatic arthritis: from the Medical Board of the National Psoriasis Foundation J Am Acad Dermatol 81 1 2019 102 110 30885757 26 Abu-Shakra M. Press J. Varsano N. Specific antibody response after influenza immunization in systemic lupus erythematosus J Rheumatol 29 12 2002 2555 2557 12465151 27 Borba E.F. Saad C.G. Pasoto S.G. Influenza A/H1N1 vaccination of patients with SLE: can antimalarial drugs restore diminished response under immunosuppressive therapy? Rheumatology (Oxford) 51 6 2012 1061 1069 22298793 28 Chalmers A. Scheifele D. Patterson C. Immunization of patients with rheumatoid arthritis against influenza: a study of vaccine safety and immunogenicity J Rheumatol 21 7 1994 1203 1206 7966058 29 Crowe S.R. Merrill J.T. Vista E.S. Influenza vaccination responses in human systemic lupus erythematosus: impact of clinical and demographic features Arthritis Rheum 63 8 2011 2396 2406 21598235 30 Del Porto F. Laganà B. Biselli R. Influenza vaccine administration in patients with systemic lupus erythematosus and rheumatoid arthritis. Safety and immunogenicity Vaccine 24 16 2006 3217 3223 16466833 31 Herron A. Dettleff G. Hixon B. Influenza vaccination in patients with rheumatic diseases. Safety and efficacy JAMA 242 1 1979 53 56 312949 32 Holvast A. Stegeman C.A. Benne C.A. Wegener's granulomatosis patients show an adequate antibody response to influenza vaccination Ann Rheum Dis 68 6 2009 873 878 18625625 33 Louie J.S. Nies K.M. Shoji K.T. Clinical and antibody responses after influenza immunization in systemic lupus erythematosus Ann Intern Med 88 6 1978 790 792 307356 34 Williams G.W. Steinberg A.D. Reinertsen J.L. Klassen L.W. Decker J.L. Dolin R. Influenza immunization in systemic lupus erythematosus. A double-blind trial Ann Intern Med 88 6 1978 729 734 352210 35 Fischer L. Gerstel P.F. Poncet A. Pneumococcal polysaccharide vaccination in adults undergoing immunosuppressive treatment for inflammatory diseases—a longitudinal study Arthritis Res Ther 17 1 2015 151 26048579 36 Ulinski T. Leroy S. Dubrel M. Danon S. Bensman A. High serological response to pneumococcal vaccine in nephrotic children at disease onset on high-dose prednisone Pediatr Nephrol 23 7 2008 1107 1113 18324419 37 Sempere L. Almenta I. Barrenengoa J. Factors predicting response to hepatitis B vaccination in patients with inflammatory bowel disease Vaccine 31 30 2013 3065 3071 23664999 38 Mok C.C. Ho L.Y. Fong L.S. To C.H. Immunogenicity and safety of a quadrivalent human papillomavirus vaccine in patients with systemic lupus erythematosus: a case-control study Ann Rheum Dis 72 5 2013 659 664 22589375 39 Cheetham T.C. Marcy S.M. Tseng H.F. Risk of herpes zoster and disseminated varicella zoster in patients taking immunosuppressant drugs at the time of zoster vaccination Mayo Clin Proc 90 7 2015 865 873 26051268 40 Russell A.F. Parrino J. Fisher C.L. Jr. Safety, tolerability, and immunogenicity of zoster vaccine in subjects on chronic/maintenance corticosteroids Vaccine 33 27 2015 3129 3134 25964168 41 Kernéis S. Launay O. Ancelle T. Safety and immunogenicity of yellow fever 17D vaccine in adults receiving systemic corticosteroid therapy: an observational cohort study Arthritis Care Res (Hoboken) 65 9 2013 1522 1528 23554297 42 Park J.K. Lee Y.J. Shin K. Impact of temporary methotrexate discontinuation for 2 weeks on immunogenicity of seasonal influenza vaccination in patients with rheumatoid arthritis: a randomised clinical trial Ann Rheum Dis 77 6 2018 898 904 29572291 43 Mori S. Ueki Y. Akeda Y. Pneumococcal polysaccharide vaccination in rheumatoid arthritis patients receiving tocilizumab therapy Ann Rheum Dis 72 8 2013 1362 1366 23345600 44 Guissa V.R. Pereira R.M. Sallum A.M. Influenza A H1N1/2009 vaccine in juvenile dermatomyositis: reduced immunogenicity in patients under immunosuppressive therapy Clin Exp Rheumatol 30 4 2012 583 588 22931582 45 Elkayam O. Caspi D. Reitblatt T. Charboneau D. Rubins J.B. The effect of tumor necrosis factor blockade on the response to pneumococcal vaccination in patients with rheumatoid arthritis and ankylosing spondylitis Semin Arthritis Rheum 33 4 2004 283 288 14978666 46 Kapetanovic M.C. Nagel J. Nordström I. Saxne T. Geborek P. Rudin A. Methotrexate reduces vaccine-specific immunoglobulin levels but not numbers of circulating antibody-producing B cells in rheumatoid arthritis after vaccination with a conjugate pneumococcal vaccine Vaccine 35 6 2017 903 908 28081972 47 Heijstek M.W. Kamphuis S. Armbrust W. Effects of the live attenuated measles-mumps-rubella booster vaccination on disease activity in patients with juvenile idiopathic arthritis: a randomized trial JAMA 309 23 2013 2449 2456 23780457 48 Heijstek M.W. Pileggi G.C. Zonneveld-Huijssoon E. Safety of measles, mumps and rubella vaccination in juvenile idiopathic arthritis Ann Rheum Dis 66 10 2007 1384 1387 17284544 49 Uziel Y. Moshe V. Onozo B. Live attenuated MMR/V booster vaccines in children with rheumatic diseases on immunosuppressive therapy are safe: multicenter, retrospective data collection Vaccine 38 9 2020 2198 2201 31987692 50 Groot N. Pileggi G. Sandoval C.B. Varicella vaccination elicits a humoral and cellular response in children with rheumatic diseases using immune suppressive treatment Vaccine 35 21 2017 2818 2822 28412076 51 El-Darouti M.A. Hegazy R.A. Abdel Hay R.M. Abdel Halim D.M. Live attenuated varicella vaccine: a new effective adjuvant weapon in the battlefield against severe resistant psoriasis, a pilot randomized controlled trial J Am Acad Dermatol 66 3 2012 511 513 22342019 52 El-Darouti M.A. Hegazy R.A. Abdel Hay R.M. Rashed L.A. Study of T helper (17) and T regulatory cells in psoriatic patients receiving live attenuated varicella vaccine therapy in a randomized controlled trial Eur J Dermatol 24 4 2014 464 469 25119950 53 Wieten R.W. Jonker E.F. Pieren D.K. Comparison of the PRNT and an immune fluorescence assay in yellow fever vaccinees receiving immunosuppressive medication Vaccine 34 10 2016 1247 1251 26845742 54 Wieten R.W. Goorhuis A. Jonker E.F.F. 17D yellow fever vaccine elicits comparable long-term immune responses in healthy individuals and immune-compromised patients J Infect 72 6 2016 713 722 27017899 55 Stuhec M. Yellow fever vaccine used in a psoriatic arthritis patient treated with methotrexate: a case report Acta Dermatovenerol Alp Pannonica Adriat 23 3 2014 63 64 25242163 56 Whittembury A. Ramirez G. Hernández H. Viscerotropic disease following yellow fever vaccination in Peru Vaccine 27 43 2009 5974 5981 19679215 57 Winthrop K.L. Yamanaka H. Valdez H. Herpes zoster and tofacitinib therapy in patients with rheumatoid arthritis Arthritis Rheumatol 66 10 2014 2675 2684 24943354 58 Holvast A. Huckriede A. Wilschut J. Safety and efficacy of influenza vaccination in systemic lupus erythematosus patients with quiescent disease Ann Rheum Dis 65 7 2006 913 918 16322083 59 Keshtkar-Jahromi M. Argani H. Rahnavardi M. Antibody response to influenza immunization in kidney transplant recipients receiving either azathioprine or mycophenolate: a controlled trial Am J Nephrol 28 4 2008 654 660 18322360 60 Salles M.J. Sens Y.A. Boas L.S. Machado C.M. Influenza virus vaccination in kidney transplant recipients: serum antibody response to different immunosuppressive drugs Clin Transplant 24 1 2010 E17 E23 19758368 61 Azevedo L.S. Gerhard J. Miraglia J.L. Seroconversion of 2009 pandemic influenza A (H1N1) vaccination in kidney transplant patients and the influence of different risk factors Transpl Infect Dis 15 6 2013 612 618 24134688 62 Versluis D.J. Beyer W.E. Masurel N. Wenting G.J. Weimar W. Impairment of the immune response to influenza vaccination in renal transplant recipients by cyclosporine, but not azathioprine Transplantation 42 4 1986 376 379 3532450 63 Dotan I. Werner L. Vigodman S. Normal response to vaccines in inflammatory bowel disease patients treated with thiopurines Inflamm Bowel Dis 18 2 2012 261 268 21438101 64 Wasan S.K. Zullow S. Berg A. Cheifetz A.S. Ganley-Leal L. Farraye F.A. Herpes zoster vaccine response in inflammatory bowel disease patients on low-dose immunosuppression Inflamm Bowel Dis 22 6 2016 1391 1396 27057679 65 Winthrop K.L. Baddley J.W. Chen L. Association between the initiation of anti-tumor necrosis factor therapy and the risk of herpes zoster JAMA 309 9 2013 887 895 23462785 66 Guthridge J.M. Cogman A. Merrill J.T. Herpes zoster vaccination in SLE: a pilot study of immunogenicity J Rheumatol 40 11 2013 1875 1880 24037550 67 Jeon H.J. Ro H. Jeong J.C. Efficacy and safety of hepatitis A vaccination in kidney transplant recipients Transpl Infect Dis 16 3 2014 511 515 24750343 68 Egli A. Humar A. Widmer L.A. Effect of immunosuppression on T-helper 2 and B-cell responses to influenza vaccination J Infect Dis 212 1 2015 137 146 25589334 69 Winthrop K.L. Curtis J.R. Lindsey S. Herpes zoster and tofacitinib: clinical outcomes and the risk of concomitant therapy Arthritis Rheumatol 69 10 2017 1960 1968 28845604 70 Canadian immunization guide: part 3—vaccination of specific populations; immunization of immunocompromised persons. Government of Canada Published 2017. Updated 2018. Accessed September 12, 2020. Available at: www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-3-vaccination-specific-populations/page-8-immunization-immunocompromised-persons.html 71 Poelman S.M. Keeling C.P. Metelitsa A.I. Practical guidelines for managing patients with psoriasis on biologics: an update J Cutan Med Surg 23 1_suppl 2019 3S 12S 72 Struijk G.H. Minnee R.C. Koch S.D. Maintenance immunosuppressive therapy with everolimus preserves humoral immune responses Kidney Int 78 9 2010 934 940 20703211 73 Adler S. Krivine A. Weix J. Protective effect of A/H1N1 vaccination in immune-mediated disease—a prospectively controlled vaccination study Rheumatology (Oxford) 51 4 2012 695 700 22171015 74 Borte S. Liebert U.G. Borte M. Sack U. Efficacy of measles, mumps and rubella revaccination in children with juvenile idiopathic arthritis treated with methotrexate and etanercept Rheumatology (Oxford) 48 2 2009 144 148 19074187 75 Elkayam O. Amir S. Mendelson E. Efficacy and safety of vaccination against pandemic 2009 influenza A (H1N1) virus among patients with rheumatic diseases Arthritis Care Res (Hoboken) 63 7 2011 1062 1067 21425247 76 Fomin I. Caspi D. Levy V. Vaccination against influenza in rheumatoid arthritis: the effect of disease modifying drugs, including TNF alpha blockers Ann Rheum Dis 65 2 2006 191 194 16014674 77 França I.L. Ribeiro A.C. Aikawa N.E. TNF blockers show distinct patterns of immune response to the pandemic influenza A H1N1 vaccine in inflammatory arthritis patients Rheumatology (Oxford) 51 11 2012 2091 2098 22908326 78 Iwamoto M. Homma S. Onishi S. Low level of seroconversion after a novel influenza A/H1N1/2009 vaccination in Japanese patients with rheumatoid arthritis in the 2009 season Rheumatol Int 32 11 2012 3691 3694 21881985 79 Kapetanovic M.C. Saxne T. Nilsson J.A. Geborek P. Influenza vaccination as model for testing immune modulation induced by anti-TNF and methotrexate therapy in rheumatoid arthritis patients Rheumatology (Oxford) 46 4 2007 608 611 17114801 80 Kobie J.J. Zheng B. Bryk P. Decreased influenza-specific B cell responses in rheumatoid arthritis patients treated with anti-tumor necrosis factor Arthritis Res Ther 13 6 2011 R209 22177419 81 Mori S. Ueki Y. Hirakata N. Oribe M. Hidaka T. Oishi K. Impact of tocilizumab therapy on antibody response to influenza vaccine in patients with rheumatoid arthritis Ann Rheum Dis 71 12 2012 2006 2010 22887851 82 Pasoto S.G. Ribeiro A.C. Viana V.S. Short and long-term effects of pandemic unadjuvanted influenza A(H1N1)pdm09 vaccine on clinical manifestations and autoantibody profile in primary Sjögren's syndrome Vaccine 31 14 2013 1793 1798 23395584 83 Ribeiro A.C. Guedes L.K. Moraes J.C. Reduced seroprotection after pandemic H1N1 influenza adjuvant-free vaccination in patients with rheumatoid arthritis: implications for clinical practice Ann Rheum Dis 70 12 2011 2144 2147 21859696 84 Gabay C. Bel M. Combescure C. Impact of synthetic and biologic disease-modifying antirheumatic drugs on antibody responses to the AS03-adjuvanted pandemic influenza vaccine: a prospective, open-label, parallel-cohort, single-center study Arthritis Rheum 63 6 2011 1486 1496 21384334 85 Pileggi G.S. de Souza C.B. Ferriani V.P. Safety and immunogenicity of varicella vaccine in patients with juvenile rheumatic diseases receiving methotrexate and corticosteroids Arthritis Care Res (Hoboken) 62 7 2010 1034 1039 20235203 86 Rosdahl A. Herzog C. Frösner G. Norén T. Rombo L. Askling H.H. An extra priming dose of hepatitis A vaccine to adult patients with rheumatoid arthritis and drug induced immunosuppression—a prospective, open-label, multi-center study Trav Med Infect Dis 21 2018 43 50 87 Baluch A. Humar A. Eurich D. Randomized controlled trial of high-dose intradermal versus standard-dose intramuscular influenza vaccine in organ transplant recipients Am J Transplant 13 4 2013 1026 1033 23406320 88 Siegrist C.A. Ambrosioni J. Bel M. Responses of solid organ transplant recipients to the AS03-adjuvanted pandemic influenza vaccine Antivir Ther 17 5 2012 893 903 22544169 89 Winthrop K.L. Bingham C.O. 3rd Komocsar W.J. Evaluation of pneumococcal and tetanus vaccine responses in patients with rheumatoid arthritis receiving baricitinib: results from a long-term extension trial substudy Arthritis Res Ther 21 1 2019 102 30999933 90 Measles pneumonitis following measles-mumps-rubella vaccination of a patient with HIV infection, 1993 MMWR Morb Mortal Wkly Rep 45 28 1996 603 606 8676852 91 Calabrese L.H. Abud-Mendoza C. Lindsey S.M. Live zoster vaccine in patients with rheumatoid arthritis treated with tofacitinib with or without methotrexate, or adalimumab with methotrexate: a post hoc analysis of data from a phase IIIb/IV randomized study Arthritis Care Res 72 3 2020 353 359 92 Satyam V.R. Li P.H. Reich J. Safety of recombinant zoster vaccine in patients with inflammatory bowel disease Dig Dis Sci 65 2020 2986 2991 31897892 93 Winthrop K.L. Wouters A.G. Choy E.H. The safety and immunogenicity of live zoster vaccination in patients with rheumatoid arthritis before starting tofacitinib: a randomized phase II trial Arthritis Rheumatol 69 10 2017 1969 1977 28845577 94 Winthrop K.L. Korman N. Abramovits W. T-cell-mediated immune response to pneumococcal conjugate vaccine (PCV-13) and tetanus toxoid vaccine in patients with moderate-to-severe psoriasis during tofacitinib treatment J Am Acad Dermatol 78 6 2018 1149 1155.e1 29080806 95 Winthrop K.L. Silverfield J. Racewicz A. The effect of tofacitinib on pneumococcal and influenza vaccine responses in rheumatoid arthritis Ann Rheum Dis 75 4 2016 687 695 25795907 96 Aikawa N.E. França I.L. Ribeiro A.C. Sallum A.M. Bonfa E. Silva C.A. Short and long-term immunogenicity and safety following the 23-valent polysaccharide pneumococcal vaccine in juvenile idiopathic arthritis patients under conventional DMARDs with or without anti-TNF therapy Vaccine 33 5 2015 604 609 25554240 97 Andrade P. Santos-Antunes J. Rodrigues S. Lopes S. Macedo G. Treatment with infliximab or azathioprine negatively impact the efficacy of hepatitis B vaccine in inflammatory bowel disease patients J Gastroenterol Hepatol 30 11 2015 1591 1595 25967740 98 Arad U. Tzadok S. Amir S. The cellular immune response to influenza vaccination is preserved in rheumatoid arthritis patients treated with rituximab Vaccine 29 8 2011 1643 1648 21211590 99 Askling H.H. Rombo L. van Vollenhoven R. Hepatitis A vaccine for immunosuppressed patients with rheumatoid arthritis: a prospective, open-label, multi-centre study Travel Med Infect Dis 12 2 2014 134 142 24529746 100 Belle A. Baumann C. Bigard M.A. Impact of immunosuppressive therapy on hepatitis B vaccination in inflammatory bowel diseases Eur J Gastroenterol Hepatol 27 8 2015 877 881 26121376 101 Bingham C.O. 3rd Looney R.J. Deodhar A. Immunization responses in rheumatoid arthritis patients treated with rituximab: results from a controlled clinical trial Arthritis Rheum 62 1 2010 64 74 20039397 102 Bühler S. Jaeger V.K. Adler S. Safety and immunogenicity of tetanus/diphtheria vaccination in patients with rheumatic diseases-a prospective multi-centre cohort study Rheumatology (Oxford) 58 9 2019 1585 1596 30877773 103 Cao Y. Zhao D. Xu A.T. Shen J. Ran Z.H. Effects of immunosuppressants on immune response to vaccine in inflammatory bowel disease Chin Med J (Engl) 128 6 2015 835 838 25758282 104 Cho A. Bradley B. Kauffman R. Robust memory responses against influenza vaccination in pemphigus patients previously treated with rituximab JCI Insight 2 12 2017 e93222 28614800 105 deBruyn J. Fonseca K. Ghosh S. Immunogenicity of influenza vaccine for patients with inflammatory bowel disease on maintenance infliximab therapy: a randomized trial Inflamm Bowel Dis 22 3 2016 638 647 26595551 106 Dell' Era L. Esposito S. Corona F. Principi N. Vaccination of children and adolescents with rheumatic diseases Rheumatology (Oxford) 50 8 2011 1358 1365 21482543 107 Dezfoli S. Horton H.A. Thepyasuwan N. Combined immunosuppression impairs immunogenicity to tetanus and pertussis vaccination among patients with inflammatory bowel disease Inflamm Bowel Dis 21 8 2015 1754 1760 25985242 108 Eisenberg R.A. Jawad A.F. Boyer J. Rituximab-treated patients have a poor response to influenza vaccination J Clin Immunol 33 2 2013 388 396 23064976 109 Elkayam O. Bashkin A. Mandelboim M. The effect of infliximab and timing of vaccination on the humoral response to influenza vaccination in patients with rheumatoid arthritis and ankylosing spondylitis Semin Arthritis Rheum 39 6 2010 442 447 19246078 110 Fiorino G. Peyrin-Biroulet L. Naccarato P. Effects of immunosuppression on immune response to pneumococcal vaccine in inflammatory bowel disease: a prospective study Inflamm Bowel Dis 18 6 2012 1042 1047 21674732 111 Gelinck L.B. van der Bijl A.E. Visser L.G. Synergistic immunosuppressive effect of anti-TNF combined with methotrexate on antibody responses to the 23 valent pneumococcal polysaccharide vaccine Vaccine 26 27-28 2008 3528 3533 18502006 112 Gorelik M. Elizalde A. Wong Williams K. Gonzalez E. Cole J.L. Immunogenicity of sequential 13-valent conjugated and 23-valent unconjugated pneumococcal vaccines in a population of children with lupus Lupus 27 14 2018 2228 2235 30380992 113 Hagihara Y. Ohfuji S. Watanabe K. Infliximab and/or immunomodulators inhibit immune responses to trivalent influenza vaccination in adults with inflammatory bowel disease J Crohns Colitis 8 3 2014 223 233 24011513 114 Haykir Solay A. Eser F. High dose hepatitis B vaccine is not effective in patients using immunomodulatory drugs: a pilot study Hum Vaccin Immunother 15 5 2019 1177 1182 30676860 115 Hua C. Barnetche T. Combe B. Morel J. Effect of methotrexate, anti-tumor necrosis factor α, and rituximab on the immune response to influenza and pneumococcal vaccines in patients with rheumatoid arthritis: a systematic review and meta-analysis Arthritis Care Res (Hoboken) 66 7 2014 1016 1026 24339395 116 Huang Y. Wang H. Wan L. Lu X. Tam W.W. Is systemic lupus erythematosus associated with a declined immunogenicity and poor safety of influenza vaccination? A systematic review and meta-analysis Medicine (Baltimore) 95 19 2016 e3637 27175678 117 Kaine J.L. Kivitz A.J. Birbara C. Luo A.Y. Immune responses following administration of influenza and pneumococcal vaccines to patients with rheumatoid arthritis receiving adalimumab J Rheumatol 34 2 2007 272 279 17304653 118 Kantsø B. Halkjær S.I. Thomsen O. Immunosuppressive drugs impairs antibody response of the polysaccharide and conjugated pneumococcal vaccines in patients with Crohn's disease Vaccine 33 41 2015 5464 5469 26275480 119 Kapetanovic M.C. Roseman C. Jönsson G. Truedsson L. Saxne T. Geborek P. Antibody response is reduced following vaccination with 7-valent conjugate pneumococcal vaccine in adult methotrexate-treated patients with established arthritis, but not those treated with tumor necrosis factor inhibitors Arthritis Rheum 63 12 2011 3723 3732 21834061 120 Kapetanovic M.C. Saxne T. Sjöholm A. Truedsson L. Jönsson G. Geborek P. Influence of methotrexate, TNF blockers and prednisolone on antibody responses to pneumococcal polysaccharide vaccine in patients with rheumatoid arthritis Rheumatology (Oxford) 45 1 2006 106 111 16287919 121 Kivitz A.J. Schechtman J. Texter M. Fichtner A. de Longueville M. Chartash E.K. Vaccine responses in patients with rheumatoid arthritis treated with certolizumab pegol: results from a single-blind randomized phase IV trial J Rheumatol 41 4 2014 648 657 24584918 122 Lakota K. Perdan-Pirkmajer K. Sodin-Šemrl S. The immunogenicity of seasonal and pandemic influenza vaccination in autoimmune inflammatory rheumatic patients—a 6-month follow-up prospective study Clin Rheumatol 38 5 2019 1277 1292 30761436 123 Lee C.K. Kim H.S. Ye B.D. Patients with Crohn's disease on anti-tumor necrosis factor therapy are at significant risk of inadequate response to the 23-valent pneumococcal polysaccharide vaccine J Crohns Colitis 8 5 2014 384 391 24144611 124 Mamula P. Markowitz J.E. Piccoli D.A. Klimov A. Cohen L. Baldassano R.N. Immune response to influenza vaccine in pediatric patients with inflammatory bowel disease Clin Gastroenterol Hepatol 5 7 2007 851 856 17544875 125 Mease P.J. Ritchlin C.T. Martin R.W. Pneumococcal vaccine response in psoriatic arthritis patients during treatment with etanercept J Rheumatol 31 7 2004 1356 1361 15229957 126 Nguyen M.T.T. Lindegaard H. Hendricks O. Jørgensen C.S. Kantsø B. Friis-Møller N. Initial serological response after prime-boost pneumococcal vaccination in rheumatoid arthritis patients: results of a randomized controlled trial J Rheumatol 44 12 2017 1794 1803 28966211 127 Nived P. Jönsson G. Settergren B. Prime-boost vaccination strategy enhances immunogenicity compared to single pneumococcal conjugate vaccination in patients receiving conventional DMARDs, to some extent in abatacept but not in rituximab-treated patients Arthritis Res Ther 22 1 2020 36 32087733 128 Nived P. Nagel J. Saxne T. Immune response to pneumococcal conjugate vaccine in patients with systemic vasculitis receiving standard of care therapy Vaccine 35 29 2017 3639 3646 28552512 129 Oliveira A.C. Mota L.M. Santos-Neto L.L. Simões M. Martins-Filho O.A. Tauil P.L. Seroconversion in patients with rheumatic diseases treated with immunomodulators or immunosuppressants, who were inadvertently revaccinated against yellow fever Arthritis Rheumatol 67 2 2015 582 583 25418753 130 Oren S. Mandelboim M. Braun-Moscovici Y. Vaccination against influenza in patients with rheumatoid arthritis: the effect of rituximab on the humoral response Ann Rheum Dis 67 7 2008 937 941 17981914 131 Park S.H. Yang S.K. Park S.K. Efficacy of hepatitis A vaccination and factors impacting on seroconversion in patients with inflammatory bowel disease Inflamm Bowel Dis 20 1 2014 69 74 24284413 132 Polachek A. Korobko U. Mader-Balakirski N. Immunogenicity and safety of vaccination against seasonal 2012 influenza virus among patients with psoriatic arthritis and psoriasis Clin Exp Rheumatol 33 2 2015 181 186 25738420 133 Pratt P.K. Jr. David N. Weber H.C. Antibody response to hepatitis B virus vaccine is impaired in patients with inflammatory bowel disease on infliximab therapy Inflamm Bowel Dis 24 2 2018 380 386 29361083 134 Rákóczi É. Perge B. Végh E. Evaluation of the immunogenicity of the 13-valent conjugated pneumococcal vaccine in rheumatoid arthritis patients treated with etanercept Joint Bone Spine 83 6 2016 675 679 26995488 135 Rehnberg M. Brisslert M. Amu S. Zendjanchi K. Håwi G. Bokarewa M.I. Vaccination response to protein and carbohydrate antigens in patients with rheumatoid arthritis after rituximab treatment Arthritis Res Ther 12 3 2010 R111 20529331 136 Richi P. Alonso O. Martín M.D. Evaluation of the immune response to hepatitis B vaccine in patients on biological therapy: results of the RIER cohort study Clin Rheumatol 39 2020 2751 2756 32248433 137 Salemi S. Picchianti-Diamanti A. Germano V. Influenza vaccine administration in rheumatoid arthritis patients under treatment with TNFα blockers: safety and immunogenicity Clin Immunol 134 2 2010 113 120 19846344 138 Salinas G.F. De Rycke L. Barendregt B. Anti-TNF treatment blocks the induction of T cell-dependent humoral responses Ann Rheum Dis 72 6 2013 1037 1043 22968102 139 Scheinberg M. Guedes-Barbosa L.S. Mangueira C. Yellow fever revaccination during infliximab therapy Arthritis Care Res (Hoboken) 62 6 2010 896 898 20535801 140 Shirai S. Hara M. Sakata Y. Immunogenicity of quadrivalent influenza vaccine for patients with inflammatory bowel disease undergoing immunosuppressive therapy Inflamm Bowel Dis 24 5 2018 1082 1091 29538682 141 van Aalst M. Lötsch F. Spijker R. Incidence of invasive pneumococcal disease in immunocompromised patients: a systematic review and meta-analysis Travel Med Infect Dis 24 2018 89 100 29860151 142 van Assen S. Holvast A. Benne C.A. Humoral responses after influenza vaccination are severely reduced in patients with rheumatoid arthritis treated with rituximab Arthritis Rheum 62 1 2010 75 81 20039396 143 Visvanathan S. Keenan G.F. Baker D.G. Levinson A.I. Wagner C.L. Response to pneumococcal vaccine in patients with early rheumatoid arthritis receiving infliximab plus methotrexate or methotrexate alone J Rheumatol 34 5 2007 952 957 17444589 144 Westra J. van Assen S. Wilting K.R. Rituximab impairs immunoglobulin (Ig)M and IgG (subclass) responses after influenza vaccination in rheumatoid arthritis patients Clin Exp Immunol 178 1 2014 40 47 24889761 145 Zhang J. Xie F. Delzell E. Association between vaccination for herpes zoster and risk of herpes zoster infection among older patients with selected immune-mediated diseases JAMA 308 1 2012 43 49 22760290 146 Kapetanovic M.C. Kristensen L.E. Saxne T. Aktas T. Mörner A. Geborek P. Impact of anti-rheumatic treatment on immunogenicity of pandemic H1N1 influenza vaccine in patients with arthritis Arthritis Res Ther 16 1 2014 R2 24383620 147 van Aalst M. Langedijk A.C. Spijker R. de Bree G.J. Grobusch M.P. Goorhuis A. The effect of immunosuppressive agents on immunogenicity of pneumococcal vaccination: a systematic review and meta-analysis Vaccine 36 39 2018 5832 5845 30122649 148 Gomez E.V. Bishop J.L. Jackson K. Muram T.M. Phillips D. Response to tetanus and pneumococcal vaccination following administration of ixekizumab in healthy participants BioDrugs 31 6 2017 545 554 29116597 149 Chioato A. Noseda E. Stevens M. Gaitatzis N. Kleinschmidt A. Picaud H. Treatment with the interleukin-17A-blocking antibody secukinumab does not interfere with the efficacy of influenza and meningococcal vaccinations in healthy subjects: results of an open-label, parallel-group, randomized single-center study Clin Vaccine Immunol 19 10 2012 1597 1602 22875601 150 Furer V. Zisman D. Kaufman I. Immunogenicity and safety of vaccination against seasonal influenza vaccine in patients with psoriatic arthritis treated with secukinumab Vaccine 38 4 2020 847 851 31767465 151 Tacke C.E. Smits G.P. van der Klis F.R. Kuipers I.M. Zaaijer H.L. Kuijpers T.W. Reduced serologic response to mumps, measles, and rubella vaccination in patients treated with intravenous immunoglobulin for Kawasaki disease J Allergy Clin Immunol 131 6 2013 1701 1703 23498596 152 Tamez R.L. Tan W.V. O’Malley J.T. Influenza B virus infection and Stevens-Johnson syndrome Pediatr Dermatol 35 1 2018 e45 e48 29282756 153 Blauvelt A. Simpson E.L. Tyring S.K. Dupilumab does not affect correlates of vaccine-induced immunity: a randomized, placebo-controlled trial in adults with moderate-to-severe atopic dermatitis J Am Acad Dermatol 80 1 2019 158 167 30092324 154 Kubota T. Nii T. Nanki T. Anti-tumor necrosis factor therapy does not diminish the immune response to influenza vaccine in Japanese patients with rheumatoid arthritis Mod Rheumatol 17 6 2007 531 533 18084712 155 Brodmerkel C. Zhu Y. Jiao Q. Effects of ustekinumab administration on primate/human antigen-recall and humoral immune response functions J Drugs Dermatol 9 6 2010 677 683 20645530 156 Doornekamp L. Goetgebuer R.L. Schmitz K.S. High immunogenicity to influenza vaccination in Crohn's disease patients treated with ustekinumab Vaccines (Basel) 8 3 2020 455 32824111 157 Crnkic Kapetanovic M. Saxne T. Jönsson G. Truedsson L. Geborek P. Rituximab and abatacept but not tocilizumab impair antibody response to pneumococcal conjugate vaccine in patients with rheumatoid arthritis Arthritis Res Ther 15 5 2013 R171 24286269 158 Ghazawi F.M. Lim M. Dutz J.P. Kirchhof M.G. Infection risk of dermatologic therapeutics during the COVID-19 pandemic: an evidence-based recalibration Int J Dermatol 59 2020 1043 1056 32621284 159 Zahedi Niaki O. Anadkat M.J. Chen S.T. Navigating immunosuppression in a pandemic: a guide for the dermatologist from the COVID Task Force of the Medical Dermatology Society and Society of Dermatology Hospitalists J Am Acad Dermatol 83 2020 1150 1159 32569797 160 Park J.K. Choi Y. Winthrop K.L. Song Y.W. Lee E.B. Optimal time between the last methotrexate administration and seasonal influenza vaccination in rheumatoid arthritis: post hoc analysis of a randomised clinical trial Ann Rheum Dis 78 9 2019 1283 1284 30904830 161 Polack F.P. Atypical measles and enhanced respiratory syncytial virus disease (ERD) made simple Pediatr Res 62 1 2007 111 115 17515829 162 Kim H.W. Canchola J.G. Brandt C.D. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine Am J Epidemiol 89 4 1969 422 434 4305198 163 Fulginiti V.A. Eller J.J. Downie A.W. Kempe C.H. Altered reactivity to measles virus. Atypical measles in children previously immunized with inactivated measles virus vaccines JAMA 202 12 1967 1075 1080 6072745 164 Scobey T. Yount B.L. Sims A.C. Reverse genetics with a full-length infectious cDNA of the Middle East respiratory syndrome coronavirus Proc Natl Acad Sci U S A 110 40 2013 16157 16162 24043791 165 Xia S. Duan K. Zhang Y. Effect of an inactivated vaccine against SARS-CoV-2 on safety and immunogenicity outcomes: interim analysis of 2 randomized clinical trials JAMA 324 10 2020 951 960 32789505
PMC007xxxxxx/PMC7816892.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(21)00166-3 10.1016/j.jaad.2021.01.023 Original Article The clinical spectrum of COVID-19–associated cutaneous manifestations: An Italian multicenter study of 200 adult patients Marzano Angelo Valerio MD ab∗ Genovese Giovanni MD ab Moltrasio Chiara MRes ac Gaspari Valeria MD d Vezzoli Pamela MD e Maione Vincenzo MD f Misciali Cosimo MD d Sena Paolo MD e Patrizi Annalisa MD d Offidani Annamaria MD g Quaglino Pietro MD h Arco Renato MSc i Caproni Marzia MD j Rovesti Miriam MD k Bordin Giorgio MD l Recalcati Sebastiano MD m Potenza Concetta MD n Guarneri Claudio MD o Fabbrocini Gabriella MD p Tomasini Carlo MD q Sorci Mariarita MD r Lombardo Maurizio MD s Gisondi Paolo MD t Conti Andrea MD u Casazza Giovanni PhD v Peris Ketty MD wx Calzavara-Pinton Piergiacomo MD f Berti Emilio MD ab Italian Skin COVID-19 Network of the Italian Society of Dermatology and Sexually Transmitted Diseases a Dermatology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy b Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy c Institute for Maternal and Child Health–IRCCS “Burlo Garofolo”, Trieste, Italy d Dermatology Unit, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy e Dermatology Unit, ASST Papa Giovanni XXIII Hospital, Bergamo, Italy f Department of Dermatology, Spedali Civili, Brescia, Italy g Dermatological Unit, Department of Clinical and Molecular Sciences, Polytechnic Marche University, Ancona, Italy h Section of Dermatology, Department of Medical Sciences, University of Turin, Turin, Italy i Statistician, Italian Ministry of Universities and Research, Milan, Italy j Division of Dermatology, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy k Section of Dermatology, Department of Medicine and Surgery, University of Parma, Parma, Italy l Internal Medicine, Piccole Figlie Hospital, Parma, Italy m Dermatology Unit, ASTT Lecco, Alessandro Manzoni Hospital, Lecco, Italy n D. Innocenzi Dermatology Unit, Sapienza University of Rome, Polo Pontino, Rome, Italy o Department of Dermatology, University of Messina, Messina, Italy p Section of Dermatology, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy q Institute of Dermatology, Department of Clinical-Surgical, Diagnostic, and Pediatric Science, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy r Dermatology Unit, Department of Surgery, Infermi Hospital Rimini, AUSL Romagna, Rimini, Italy s Dermatology Department, Ospedale di Circolo e Fondazione Macchi, Varese, Italy t Section of Dermatology and Venereology, Department of Medicine, University of Verona, Verona, Italy u Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, Dermatology Unit, University of Modena and Reggio Emilia, Modena, Italy v L. Sacco Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, Milan, Italy w Institute of Dermatology, Catholic University of Rome, Rome, Italy x Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy ∗ Correspondence to: Angelo Valerio Marzano, MD, Dermatology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Pace 9, 20122 Milano, Italy. 18 1 2021 5 2021 18 1 2021 84 5 13561363 6 1 2021 © 2021 by the American Academy of Dermatology, Inc. 2021 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Background COVID-19 is associated with a wide range of skin manifestations. Objective To describe the clinical characteristics of COVID-19–associated skin manifestations and explore the relationships among the 6 main cutaneous phenotypes and systemic findings. Methods Twenty-one Italian Dermatology Units were asked to collect the demographic, clinical, and histopathologic data of 200 patients with COVID-19–associated skin manifestations. The severity of COVID-19 was classified as asymptomatic, mild, moderate, or severe. Results A chilblain-like acral pattern was significantly associated with a younger age (P < .0001) and, after adjusting for age, significantly associated with less severe COVID-19 (P = .0009). However, the median duration of chilblain-like lesions was significantly longer than that of the other cutaneous manifestations taken together (P < .0001). Patients with moderate/severe COVID-19 were more represented than those with asymptomatic/mild COVID-19 among the patients with cutaneous manifestations other than chilblain-like lesions, but only the confluent erythematous/maculo-papular/morbilliform phenotype was significantly associated with more severe COVID-19 (P = .015), and this significance disappeared after adjustment for age. Limitations Laboratory confirmation of COVID-19 was not possible in all cases. Conclusions After adjustment for age, there was no clear-cut spectrum of COVID-19 severity in patients with COVID-19–related skin manifestations, although chilblain-like acral lesions were more frequent in younger patients with asymptomatic/pauci-symptomatic COVID-19. Key words coronavirus COVID-19 infection skin manifestations SARS-CoV-2 Abbreviations used CI confidence interval IQR interquartile range OR odds ratio SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 ==== Body pmc Capsule Summary • There are 6 main COVID-19–related cutaneous phenotypes, but only the chilblain-like acral pattern was significantly associated with younger age. • After adjustment for patient age, there was no spectrum of COVID-19 severity in relation to cutaneous phenotypes, although the longer-lasting chilblain-like acral pattern was significantly associated with milder disease. COVID-19 is an infectious illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that may affect multiple organs, including the skin (the prevalence of cutaneous involvement was 7.8% in a binational Chinese-Italian cohort of 678 hospitalized adults with laboratory-confirmed disease).1 A number of skin manifestations have been described in individual case reports and nationwide case series. Galván Casas et al2 published the first large clinical study of 375 patients with various COVID-19–associated skin manifestations and, on the basis of the available literature and direct clinical experience, 3 of the authors of this article (AVM, GG, and CM) have identified 6 main phenotypes: (1) urticarial rash, (2) confluent erythematous/maculopapular/morbilliform rash, (3) papulovesicular exanthem, (4) a chilblain-like acral pattern, (5) a livedo reticularis/racemosa-like pattern, and (6) a purpuric vasculitic pattern.3 However, there have been reports of a miscellany of other cutaneous presentations that cannot be included in this classification, including erythema multiforme–like,4 pityriasis rosea–like,5 and Grover disease–like manifestations.6 Galván Casas et al2 found that maculopapular eruptions accounted for almost half of the cutaneous manifestations in their study, but the majority of published studies have focused on chilblain-like acral lesions,7, 8, 9, 10 which are generally associated with a benign clinical course and more frequently reported in children.11, 12, 13 The aim of this nationwide multicenter study was to provide clinical data concerning COVID-19–associated skin manifestations to improve the clinical and demographic characterization of the cutaneous phenotypes that have been defined only on the basis of previously published preliminary data.3 The main study objective was to explore the possible associations between these phenotypes, extracutaneous symptoms, and the severity of COVID-19. Materials and methods Patients With the support of the Italian Society of Dermatology and Sexually Transmitted Diseases, 21 Italian dermatology units contributed to collecting the clinical data of patients with COVID-19–associated skin manifestations who were examined between March 1 and 18, 2020. The data included sex, age at the time of onset of COVID-19, the presence/absence of comorbidities, cutaneous patterns, the presence/absence of mucous lesions, the duration of skin manifestations, skin-related symptoms, systemic symptoms, the duration of systemic symptoms, the latency between the cutaneous manifestations and systemic symptoms, death, and the severity of COVID-19. Each participating center was asked to provide data on the basis of the following patient inclusion criteria: (1) an age of 18 years or older, (2) probable or laboratory-confirmed COVID-19, and (3) the presence of COVID-19–related skin manifestations confirmed by an expert dermatologist. A COVID-19 diagnosis was considered to be laboratory confirmed in the case of a nasopharyngeal swab with a positive result for SARS-CoV-2 RNA or positive serology result for anti–SARS-CoV-2 IgG/IgM antibodies. COVID-19 was considered probable in any patient meeting the clinical criteria (dry cough, fever, dyspnea, the sudden onset of hyposmia or hypogeusia) who had been in close contact with someone with confirmed COVID-19 in the 14 days before symptom onset. A history of new medications in the 15 days before the onset of the skin manifestations was considered an exclusion criterion. Clinical assessment Systemic symptoms were taken from the charts of hospitalized patients or reported by outpatients and assessed by a physician (a pulmonologist or a specialist in internal/emergency medicine or infectious diseases). The duration of the skin manifestations was directly evaluated by a dermatologist in the case of hospitalized patients or reported by outpatients. Each patient was examined at least twice (during the period of skin manifestations and after their resolution). The severity of COVID-19 was classified as asymptomatic, mild (in the presence of fever, cough, and/or gastrointestinal symptoms with no imaging sign of pneumonia), moderate (in the presence of dyspnea and/or radiologic findings of pneumonia), or severe (a need for invasive assisted ventilation, the occurrence of thromboembolic events, or death)14 and was assessed by considering the worst systemic symptoms over the entire course of the disease, as shown in hospital records or self-reported by outpatients. Statistical analysis Continuous variables are expressed as median values and interquartile ranges (IQRs), and dichotomous variables are provided as absolute numbers and percentages. Quantitative variables (disease severity, symptoms, cutaneous phenotypes) were compared between groups using the nonparametric Wilcoxon-Mann-Whitney test. Logistic regression analysis was used to assess the role of the 6 predefined skin phenotypes as risk factors for extracutaneous symptoms (fever, cough, dyspnea, pneumonia, gastrointestinal symptoms, hyposmia/hypogeusia) and the severity of COVID-19 (dichotomized as asymptomatic or mild vs moderate or severe). Univariate logistic regression models of each cutaneous phenotype were fitted by considering the severity of COVID-19 and the 6 extracutaneous symptoms as dependent variables (7 separate models); the phenotype was considered an independent variable. In addition, age-adjusted logistic regression analyses were made because of the possible confounding effect of age on symptoms and the severity of COVID-19. Odds ratios (ORs) and their 95% confidence intervals (CIs) were obtained from the estimates of the logistic model parameters. Differences in the prevalence of symptoms among phenotypes were assessed by using chi-square tests. Given the small number of patients with a livedo reticularis-like/racemosa-like pattern, only 5 phenotypes were considered (the purpuric and reticularis/racemosa-like patterns were merged). Patients with more than 1 cutaneous phenotype were not included in the statistical analyses, which were performed with SAS statistical software, release 9.4 (SAS Institute, Inc). A 2-sided P value of less than .05 was considered statistically significant. Ethical approval and consent to participate The study was conducted in accordance with the Declaration of Helsinki, and the full protocol was approved by the institutional review board of the ethics committee of the principal investigator's center (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; protocol no. 464_2020). All of the participants enrolled in the study gave their written informed consent. Results Patients and cutaneous manifestations The demographic and clinical features of the 200 patients are summarized in Table I . The patients were predominantly male (n = 108; 54%), and their median age at the time of the diagnosis of COVID-19 was 57 years (IQR, 40.25-72.25). Eighty-six of the 195 patients with available data (43%) had experienced at least 1 comorbidity.Table I Demographic data and clinical features of 200 patients with COVID-19–associated cutaneous manifestations Analyzed parameters Values Age at the time of the onset of COVID-19, y, median (IQR) 57 (40.25-72.25) Male, n (%) 108 (54) Female, n (%) 92 (46) Latency between cutaneous manifestations and systemic symptoms, days, median (IQR)∗ 14 (4-27) Duration of cutaneous manifestations, days, median (IQR)† 12 (8-20) Cutaneous phenotypes, n (%)  Urticarial rash‡ 19 (10.2)  Confluent erythematous/maculopapular/morbilliform rash‡ 48 (25.7)  Papulovesicular exanthem‡ 29 (15.5)  Chilblain-like acral pattern‡ 46 (24.6)  Livedo reticularis-like/racemosa-like pattern‡ 4 (2.1)  Purpuric vasculitic pattern‡ 13 (6.9)  Other cutaneous phenotypes‡ 28 (15)  More than 1 phenotype 13 (6.5) Duration of cutaneous manifestations, days, median (IQR)  Urticarial rash 8 (5-13)§  Confluent erythematous/maculopapular/morbilliform rash 10 (7-14.5)װ  Papulovesicular exanthem 10 (7-14)¶  Chilblain-like acral pattern 22 (15-32)#  Livedo reticularis/racemosa-like pattern 14 (5-27)∗∗  Purpuric vasculitic pattern 11 (6.5-15.5)†† Latency between cutaneous manifestations and systemic symptoms, days, median (IQR)  Urticarial rash 12 (5-23)‡‡  Confluent erythematous/maculopapular/morbilliform rash 21.5 (12-28.75)§§  Papulovesicular exanthem 4 (1.25-8)װװ  Chilblain-like acral pattern 16 (9-39)¶¶  Livedo reticularis/racemosa-like pattern 24.5 (4-48.25)##  Purpuric vasculitic pattern 16 (3.5-34)∗∗∗ Skin-related symptoms, n (%)  Pruritus 81 (40.5)  Pain/burning 22 (11) Data were available for the following numbers of patients: 155,∗ 171,† 19,§ 49,ǁ 21,¶ 43,# 5,∗∗ 17,†† 24,‡‡ 44,§§ 28,ǁǁ 23,¶¶ 6,## and 17.∗∗∗ ‡ Percentages of 187 patients (excluding the 13 with more than 1 cutaneous phenotype). Thirteen patients (6.5%) presented with more than 1 cutaneous phenotype. Of the 187 patients with only 1 phenotype, 19 (10.2%) developed urticarial rash; 48 (25.7%) confluent erythematous/maculo-papular/morbilliform rash; 29 (15.5%) papulovesicular exanthem; 46 (24.6%) a chilblain-like acral pattern; 4 (2.1%) a livedo reticularis/racemosa-like pattern; and 13 (6.9%) a purpuric vasculitic pattern (Supplemental Fig 1; available via Mendeley at https://doi.org/10.17632/tj6m9v2gky.1). Cutaneous manifestations other than those included in the classifications mentioned3 were observed in 28 patients (15.0%): pityriasis rosea–like lesions in 10; erythema multiforme–like lesions in 8; erythema nodosum–like lesions in 4; panniculitis in 4; and angioedema in 2. No mucosal lesions were recorded. The most frequent skin-related symptom was pruritus (n = 81; 40.5%), followed by pain/burning (n = 22; 11%). Among the 168 patients for whom data were available, the median duration of the skin manifestations was 12 days (IQR, 8-20). However, the median duration of chilblain-like acral lesions was significantly longer than that of the other cutaneous manifestations taken together (21.5 [15-31] vs 10 [7-15] days; P < .0001). The median latency between the cutaneous manifestations and systemic symptoms was 14 days (IQR, 4-27) in the 155 patients for whom the data were available. The median duration of the individual skin manifestations and the latency between these and systemic symptoms are detailed in Table I. Interestingly, the median (IQR) age of patients with a chilblain-like acral pattern was significantly lower than that of patients with all of the other cutaneous phenotypes taken together (38.5 [23-55] vs 60 [50-75] years; P < .0001). The median (IQR) age of the patients with purpuric and livedo reticularis–like/racemosa-like patterns was significantly higher than that of patients with the other manifestations taken together (66 [58-84] vs 55 [39-71] years; P = .0022), and the median (IQR) age of the patients with confluent erythematous/maculopapular/morbilliform rash was also significantly higher than that of the patients with the other manifestations taken together (61 [51.5-78] vs 55 [36-71] years; P = .029). There was no statistically significant association with age in the case of the papulovesicular and urticarial phenotypes. As shown in Table II , the median (IQR) age of patients with moderate/severe COVID-19 was significantly higher than that of those with asymptomatic/mild COVID-19 (64 [54.5-78] vs 40 [27-57] years; P < .0001). It was also significantly higher in the patients with fever than in those without (59 [50-75] vs 38 [26-61] years; P < .0001), in those with cough than in those without (58.5 [50-74] vs 52 [30-71] years; P = .0077), in those with dyspnea than in those without (65 [55-78] vs 49 [30.5-63] years; P < .0001), and in those with pneumonia than in those without (65 [55-80] vs 41.5 [28-57] years; P < .0001). There was no statistically significant difference in median age in the case of gastrointestinal symptoms or hypogeusia/hyposmia.Table II Comparison of the median age of patients with COVID-19–associated skin manifestations (n = 187)∗ Analyzed parameters Median (IQR) P value Cutaneous phenotypes  Urticarial rash  Yes (n = 19) 54 (36-58) .1663  No (n = 168) 57.5 (41-74)  Confluent erythematous/maculopapular/morbilliform rash  Yes (n = 48) 61 (51.5-78) .029  No (n = 159) 55 (36-71)  Papulovesicular exanthem  Yes (n = 29) 57 (44-75) .4863  No (n = 158) 57 (40-73)  Chilblain-like acral pattern  Yes (n = 46) 38.5 (23-55) <.0001  No (n = 141) 60 (50-75)  Livedo reticularis/racemosa-like and purpuric vasculitic pattern  Yes (n = 17) 66 (58-84) .0022  No (n = 170) 55 (39-71) Disease severity  Asymptomatic status and mild COVID-19 (n = 75) 40 (27-57) <.0001  Moderate and severe COVID-19 (n = 112) 64 (54.5-78) Systemic symptoms  Fever  Yes (n = 136) 59 (50-75) <.0001  No (n = 51) 38 (26-61)  Cough  Yes (n = 102) 58.5 (50-74) .0077  No (n = 85) 52 (30-71)  Dyspnea  Yes (n = 71) 65 (55-78) <.0001  No (n = 116) 49 (30.5-63)  Pneumonia  Yes (n = 101) 65 (55-80) <.0001  No (n = 86) 41.5 (28-57)  Hyposmia/hypogeusia  Yes (n = 41) 55 (44-65) .3337  No (n = 146) 57.5 (40-75)  Gastrointestinal symptoms  Yes (n = 43) 55 (44-71) .9462  No (n = 144) 57 (38.5-73.5) IQR, Interquartile range. ∗ Patients with more than 1 cutaneous phenotype were excluded from the statistical analysis. Clinical features of COVID-19 COVID-19 was laboratory confirmed in 124 patients and was regarded as probable in the remaining 73 (Table III ). Thirty-one patients (15.5%) were asymptomatic, 51 (25.5%) had mild disease, 95 (47.5%) had moderate disease, and 23 (11.5%) had severe disease. Among the 124 patients for whom the data were available, the median duration of systemic symptoms was 23 days (IQR, 12-31).Table III The severity of COVID-19 and the clinical features of its systemic symptoms Analyzed parameters Values Patients with at least 1 comorbidity, n (%)∗ 86 (43) Median duration of systemic symptoms, days (IQR)† 23 (12-31) Systemic symptoms, n (%)  Fever 146 (73)  Cough 108 (54)  Pneumonia 106 (53)  Dyspnea 77 (38.5)  Gastrointestinal symptoms 46 (23)  Hypogeusia/hyposmia 44 (22) Thromboembolic complications 11 (5.5) Death 7 (3.5) Disease severity, n (%)  Asymptomatic 31 (15.5)  Mild 51 (25.5)  Moderate 95 (47.5)  Severe 23 (11.5) Diagnosis of COVID-19, n (%)  Suspected 73 (36.5)  Laboratory confirmed 127 (63.5) Duration of systemic symptoms, days, median (IQR)  Urticarial rash‡ 21 (11-39.5)  Confluent erythematous/maculopapular/morbilliform rash§ 28 (19-38)  Papulovesicular exanthemaǁ 19 (12-28.5)  Chilblain-like acral pattern¶ 13 (7-21)  Livedo reticularis/racemosa-like pattern# 26 (11.75-48.25)  Purpuric vasculitic pattern∗∗ 22 (8.75-33.5) Data were available for the following numbers of patients: 195,∗ 124,† 17,‡ 39,§ 13,ǁ 21,¶ 6,# and 12.∗∗ Skin signs predated systemic symptoms in 11 patients; among the remaining 189, they followed (n = 186) or were concomitant with systemic symptoms (n = 3). Fever was the most frequent systemic symptom (n = 146; 73%), followed by cough (n = 108; 54%), pneumonia (n = 106; 53%), dyspnea (n = 77; 38.5%), gastrointestinal symptoms (n = 46; 23%), and hypogeusia/hyposmia (n = 44; 22%). Thromboembolic complications occurred in 11 patients (5.5%) and death in 7 (3.5%). The median duration of systemic symptoms by each cutaneous phenotype is detailed in Table III. Relationships between cutaneous phenotypes and the severity of COVID-19/extracutaneous features As shown in Table IV , it is worth noting that, after adjustment for age, chilblain-like acral lesions were associated with a decreased risk of experiencing more severe COVID-19 (OR, 0.23; 95% CI, 0.09-0.55; P = .0009). On the other hand, confluent erythematous/maculopapular/morbilliform rash was associated with more severe COVID-19 before (OR, 2.49; 95% CI 1.19-5.18; P = .015) but not after adjustment for age (OR, 1.9; 95% CI, 0.83-4.37; P = .1307).Table IV Age-adjusted ORs and 95% CIs of COVID-19 severity and systemic symptoms by skin phenotype in patients with COVID-19–associated skin manifestations (n = 187)∗ Cutaneous phenotypes Moderate/severe COVID-19 Fever Cough Dyspnea Pneumonia Hyposmia/hypogeusia Gastrointestinal symptoms OR (95% CI) P value OR (95% CI) P value OR (95% CI) P value OR (95% CI) P value OR (95% CI) P value OR (95% CI) P value OR (95% CI) P value Urticarial rash 1.24 (0.43-3.62) .6938 2.69 (0.72-10.10) .1418 1.036 0.394 2.723 .9433 1.78 (0.63-5.02) .2781 1.351 0.4673.906 .579 2.23 (0.81-6.12) .1196 6.10 (2.25-16.59) .0004 Confluent erythematous/maculopapular/morbilliform rash 1.9 (0.83-4.37) .1307 0.83 (0.37-1.87) .6462 2.25 (1.1-4.63) .0269 2.05 (0.99-4.24) .0519 1.5 (0.7-3.3) .3121 0.67 (0.28-1.59) .3632 0.82 (0.37-1.85) .6391 Papulovesicular exanthem 1.44 (0.55-3.79) .4565 2.44 (0.77-7.71) .1283 0.96 (0.42-2.16) .9185 0.71 (0.29-1.74) .4507 1.34 (0.53-3.41) .5387 1.83 (0.76-4.41) .1814 0.65 (0.23-1.82) .4154 Chilblain-like acral pattern 0.23 (0.09-0.55) .0009 0.21 (0.1-0.46) .0001 0.28 (0.13-0.6) .001 0.2 (0.07-0.56) .0024 0.29 (0.12-0.70) .0063 0.19 (0.06-0.61) .0054 0.51 (0.2-1.30) .1579 Livedo reticularis/racemosa-like and purpuric vasculitic pattern 1.05 (0.25-4.39) .9462 1.18 (0.24-5.85) .8382 1.5 (0.43-5.18) .5223 4.17 (1.05-16.5) .0420 0.6 (0.17-2.16) .4302 1.19 (0.30-4.64) .8054 0.25 (0.03-1.97) .1864 CI, Confidence interval; OR, odds ratio. ∗ Patients with more than 1 cutaneous phenotype were excluded from the statistical analysis. Although patients with moderate/severe COVID-19 were more represented than those with asymptomatic/mild COVID-19 among patients with cutaneous phenotypes other than chilblain-like lesions, there was no statistically significant association with the severity of COVID-19. After adjustment for age, confluent erythematous/maculopapular/morbilliform rash was identified as a significant risk factor for cough (OR, 2.25; 95% CI, 1.1-4.63; P = .0269), the urticarial pattern as a significant risk factor for gastrointestinal symptoms (OR, 6.10; 95% CI, 2.25-16.59; P = .0004), and the livedo-like/vasculitic pattern as a significant risk factor for dyspnea (OR, 4.17; 95% CI, 1.05-16.5; P = .042). Discussion With the exponential increase in the number of patients with COVID-19 worldwide, the clinical features of the disease are being better defined, and a number of reports have documented the occurrence of various cutaneous manifestations. In our nationwide cohort, patients mainly presented with the 6 cutaneous phenotypes previously identified by our group.3 The most frequent cutaneous phenotypes were confluent erythematous/maculopapular/morbilliform rash and a chilblain-like acral pattern, which affected, respectively, 25.7% and 24.6% of the 187 patients included in the statistical analysis, whereas the least frequent was a livedo reticularis-like/racemosa-like pattern (2.1%). The median latency between the onset of the cutaneous manifestations and systemic symptoms was 14 days (varying from 4 days in the case of papulovesicular exanthem to 24.5 days in the case of a livedo reticularis-like/racemosa-like pattern). The median duration of the cutaneous manifestations was 12 days (ranging from 8 days in the case of urticarial rash to 22 days in the case of a chilblain-like acral pattern). Pityriasis rosea–like and erythema multiforme–like patterns were the most frequently reported skin manifestations falling outside our classification, but it is still debated whether the former is directly mediated by SARS-CoV-2 or caused by COVID-19–related immune system dysfunction leading to human herpes virus 6/7 reactivation5 , 15 , 16 and whether the latter is triggered by SARS-CoV-2 or other viruses.4 In line with previous observations, none of our patients experienced mucous membrane lesions.17 Although the angiotensin-converting enzyme 2 (ACE2) receptor of the spike protein of SARS-CoV-2 has been described as being not only expressed on keratinocytes18 but also in the oral cavity,16 mucous membrane lesions have very rarely been reported in patients with COVID-19.17 The main strength of this study is our exploration of the relationships between cutaneous phenotypes and the severity of COVID-19. Two studies of large cohorts of patients with COVID-19–related skin manifestations have found a gradient of increasingly severe systemic symptoms, going from chilblain-like lesions to a livedo/necrotic pattern.2 , 19 However, unlike these studies, our study adjusted for patient age and failed to confirm this spectrum. Only the chilblain-like acral phenotype was significantly associated with less severe COVID-19 and although patients with severe disease were prevalent in each of the other 5 phenotypic categories, none of them was significantly associated with an increased risk of more severe COVID-19. Moreover, in line with the findings of other studies,7 the chilblain-like acral phenotype was associated with a younger age at the time of COVID-19 diagnosis, whereas the livedo-like/vasculitic and maculopapular phenotypes were associated with an older age at the time COVID-19 diagnosis. The pathologic mechanisms underlying these relationships remain unclear but, in line with the acknowledged correlation between age and COVID-19 severity,20 we found that patients with more severe disease, fever, or respiratory symptoms (cough, dyspnea, and pneumonia) had a higher median age, thus confirming the need for careful observation and an early intervention to prevent the development of severe COVID-19 in the elderly. The close association between the urticarial phenotype and gastrointestinal symptoms found in our study is intriguing and suggests that this phenotype is predictive of COVID-19–related gastrointestinal involvement. The pathophysiologic link between skin and digestive manifestations needs further investigation, but it is likely that SARS-CoV-2 is a triggering factor for both. The main limitation of this study is the absence of laboratory confirmation of COVID-19 in 73 patients (36.5%), which was mainly due to the fact that asymptomatic and pauci-symptomatic patients did not undergo SARS-CoV-2 testing during the first wave of COVID-19 in Italy for economic reasons. Selection bias due to the fact that the study included only patients whose COVID-19–related skin lesions had been evaluated by an expert dermatologist may be considered another limitation, but we believe that this is actually a strength insofar as it avoided the misdiagnoses that may have been made by nonspecialists. In conclusion, this study further defines the demographic and clinical features of the 6 main clinical phenotypes of COVID-19–associated skin manifestations by assessing the relationship between them and the extracutaneous symptoms and severity of COVID-19. The only correlation between the cutaneous phenotype and the severity of COVID-19 was observed in the case of chilblain-like acral lesions, a phenotype that is generally associated with the benign/subclinical course of COVID-19. Conflicts of interest None disclosed. The authors would like to thank the following collaborators for their help in data collection and patient management: Carlo Alberto Maronese, Mauro Alaibac, Maria Carmela Annunziata, Alessandro Borghi, Giuseppe Argenziano, Caterina Cariti, Andrea Carugno, Annunziata Dattola, Federico Diotallevi, Maria Concetta Fargnoli, Claudio Feliciani, Astrid Lappi, Ylenia Natalini, Mauro Panigada, Manuela Papini, Pietro Rubegni, and Marina Venturini. Drs Calzavara-Pinton and Berti contributed equally to this article. Funding sources: None. IRB approval status: Reviewed and approved by all participating sites and the IRB of the principal investigator's center (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan: protocol no. 464_2020). Reprints not available from the authors. ==== Refs References 1 De Giorgi V. Recalcati S. Jia Z. Cutaneous manifestations related to coronavirus disease 2019 (COVID-19): a prospective study from China and Italy J Am Acad Dermatol 83 2020 674 675 32442696 2 Galván Casas C. Català A. Carretero Hernández G. Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases Br J Dermatol 183 2020 71 77 32348545 3 Marzano A.V. Cassano N. Genovese G. Cutaneous manifestations in patients with COVID-19: a preliminary review of an emerging issue Br J Dermatol 183 2020 431 442 32479680 4 Torrelo A. Andina D. Santonja C. Erythema multiforme-like lesions in children and COVID-19 Pediatr Dermatol 37 2020 442 446 32445583 5 Ehsani A.H. Nasimi M. Bigdelo Z. Pityriasis rosea as a cutaneous manifestation of COVID-19 infection J Eur Acad Dermatol Venereol 34 2020 e436 e437 32359180 6 Gianotti R. Veraldi S. Recalcati S. Cutaneous clinico-pathological findings in three COVID-19-positive patients observed in the metropolitan area of Milan, Italy Acta Derm Venereol 100 2020 adv00124 32315073 7 Freeman E.E. McMahon D.E. Lipoff J.B. Pernio-like skin lesions associated with COVID-19: a case series of 318 patients from 8 countries J Am Acad Dermatol 83 2020 486 492 32479979 8 de Masson A. Bouaziz J.D. Sulimovic L. Chilblains is a common cutaneous finding during the COVID-19 pandemic: a retrospective nationwide study from France J Am Acad Dermatol 83 2020 667 670 32380219 9 Fernandez-Nieto D. Jimenez-Cauhe J. Suarez-Valle A. Characterization of acute acral skin lesions in nonhospitalized patients: a case series of 132 patients during the COVID-19 outbreak J Am Acad Dermatol 83 2020 e61 e63 32339703 10 Kanitakis J. Lesort C. Danset M. Chilblain-like acral lesions during the COVID-19 pandemic (“COVID toes”): histologic, immunofluorescence, and immunohistochemical study of 17 cases J Am Acad Dermatol 83 2020 870 875 32502585 11 Colonna C. Genovese G. Monzani N.A. Outbreak of chilblain-like acral lesions in children in the metropolitan area of Milan, Italy, during the COVID-19 pandemic J Am Acad Dermatol 83 2020 965 969 32534082 12 El Hachem M. Diociaiuti A. Concato C. A clinical, histopathological and laboratory study of 19 consecutive Italian paediatric patients with chilblain-like lesions: lights and shadows on the relationship with COVID-19 infection J Eur Acad Dermatol Venereol 34 2020 2620 2629 32474947 13 Piccolo V. Neri I. Filippeschi C. Chilblain-like lesions during COVID-19 epidemic: a preliminary study on 63 patients J Eur Acad Dermatol Venereol 34 2020 e291 e293 32330334 14 Diagnosis and treatment protocol for novel coronavirus pneumonia (trial version 7) Chin Med J (Engl) 133 2020 1087 1095 32358325 15 Marzano A.V. Genovese G. Response to “Reply to ‘Varicella-like exanthem as a specific COVID-19-associated skin manifestation: multicenter case series of 22 patients': to consider varicella-like exanthem associated with COVID-19, virus varicella zoster and virus herpes simplex must be ruled out.” J Am Acad Dermatol 83 2020 e255 e256 32442697 16 Novak N. Peng W. Naegeli M.C. SARS-CoV-2, COVID-19, skin and immunology—what do we know so far? Allergy 76 2021 698 713 32658359 17 Zhou G. Chen S. Chen Z. Advances in COVID-19: the virus, the pathogenesis, and evidence-based control and therapeutic strategies Front Med 14 2020 117 125 32318975 18 Xue X. Mi Z. Wang Z. Pang Z. Liu H. Zhang F. High expression of ACE2 on keratinocytes reveals skin as a potential target for SARS-CoV-2 J Invest Dermatol 141 2020 206 209 32454066 19 Freeman E.E. McMahon D.E. Lipoff J.B. The spectrum of COVID-19-associated dermatologic manifestations: an international registry of 716 patients from 31 countries J Am Acad Dermatol 83 2020 1118 1129 32622888 20 Li X. Xu S. Yu M. Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan J Allergy Clin Immunol 146 2020 110 118 32294485
PMC007xxxxxx/PMC7817517.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(21)00082-7 10.1016/j.jaad.2020.12.065 Research Letter The magnitude of COVID-19's effect on the timely management of melanoma and nonmelanoma skin cancers Marson Justin W. MD a∗ Maner Brittany S. BS, MBS b Harding Tanner P. BS c Meisenheimer John VII BS d Solomon James A. MD, PhD b Leavitt Matt DO e Levin Nicole J. BS f Dellavalle Robert MD, PhD, MSPH g Brooks Ian PhD h Rigel Darrell S. MD, MS i a National Society for Cutaneous Medicine, New York, New York b Ameriderm Research, Ormond Beach, Florida c University of Central Florida College of Medicine, Orlando, Florida d Morsani College of Medicine at University of South Florida, Tampa, Florida e Advanced Dermatology and Cosmetic Surgery, Maitland, Florida f Florida Atlantic University Charles E. Schmidt College of Medicine, Boca Raton, Florida g University of Colorado, School of Medicine, and the Colorado School of Public Health, Aurora h Center for Health Informatics, School of Information Sciences, University of Illinois at Urbana-Champaign, Champaign i Department of Dermatology, NYU Grossman School of Medicine, New York, New York ∗ Correspondence to: Justin W. Marson, MD, 35 E 35th St #208, New York, NY 10016 19 1 2021 4 2021 19 1 2021 84 4 11001103 © 2021 by the American Academy of Dermatology, Inc. 2021 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Key words basal cell carcinoma COVID-19 cutaneous melanoma cutaneous squamous cell carcinoma diagnostic delay nonmelanoma skin cancer ==== Body pmcTo the Editor: The coronavirus disease 2019 (COVID-19) pandemic substantially reduced patient volumes or caused full closings of many US dermatology practices.1 , 2 Given reduced access to care and National Comprehensive Cancer Network guidelines to defer surgical management,3 concerns have been raised that patients with potential skin cancers had material delays in care. This study assessed the magnitude of delays in initial skin cancer diagnosis and management owing to COVID-19. With institutional review board approval, data from January 2019 to August 2020 were analyzed from available outpatient-chart reviews of 143 US dermatology practices (350 providers) covering 4.7 million patients across 13 geographically distributed states. The number of diagnosed cutaneous melanomas, cutaneous squamous cell carcinomas (cSCCs), and basal cell carcinomas (BCCs) was determined. Data from 2020 were aggregated into pre–COVID-19 (January to February), initial to peak COVID-19 (March to May), and COVID-19 recovery (June to August). Analysis of variance with Tukey-Kramer testing was performed for multiple comparisons. Average monthly number of skin cancers diagnosed significantly decreased during March to May 2020 compared with both before March 2020 (cutaneous melanoma mean difference –126.5, cSCC –2086.6, and BCC –3305.8) and the immediate recovery period (cutaneous melanoma –144.7, cSCC –2057.7, and BCC –3370.0) (Fig 1 ). Skin cancers diagnosed in March to May 2020 were materially lower than from March to May 2019, with diagnoses decreased by 43.1% in cutaneous melanomas, 44.1% in cSCCs, and 51.2% in BCCs (Table I ). The largest decreases were observed during April 2020 (cutaneous melanomas –69.6%, SCCs –77.7%, and BCCs –85.9%). As COVID-19's effect on dermatology practices decreased, the number of skin cancers diagnosed from June to August 2020 was only slightly higher than during June to August 2019 (cutaneous melanomas 9.2%, cSCCs 3.1%, and BCCs 1.4%). However, total 2020 skin cancer diagnoses continued to trail that of 2019, with 279 fewer cutaneous melanomas, 6000 fewer cutaneous SCCs, and 9914 fewer BCCs detected. Extrapolating these findings to the full US population (≈330 million), an estimated 19,600 cutaneous melanomas, 421,300 cSCCs, and 696,100 BCCs have had materially delayed initial diagnosis or treatment.Fig 1 Mean difference in skin cancer diagnoses owing to COVID-19. Across the different types of skin cancers, there was a significant decrease in average number of diagnoses from the initial to peak COVID-19 pandemic (March to May 2020) compared with pre–COVID-19 (before March 2020) and the immediate COVID-19 recovery period (June to August 2020). BCC, Basal cell carcinoma; CI, confidence interval; COVID-19, coronavirus disease 2019; cSCC, cutaneous squamous cell carcinoma. ∗Analysis of variance with post hoc Tukey-Kramer, P < .01. Table I Percentage changes in skin cancers diagnosed by month in 2020 versus 2019 Cutaneous melanoma cSCC BCC Period Month 2019, n = 2228 2020, n = 1944 Change, no. (%) 2019, n = 38,432 2020, n = 32,164 Change, no. (%) 2019, n = 51,991 2020, n = 42,958 Change, no. (%) Pre–COVID-19 January 292 262 –30 (–1.0) 5135 5047 –88 (–1.7) 6385 6824 439 (6.9) February 298 323 25 (8.4) 4790 4610 –180 (–3.8) 6164 6606 442 (7.2) Total 590 585 –5 (–0.9) 9925 9657 –268 (–2.7) 12,549 13,430 881 (7.0) Initial to peak COVID-19 March 293 240 –53 (–18.1) 4575 3073 –1502 (–32.8) 6103 4271 –1832 (–30.0) April 257 78 –179 (–69.6) 5069 1154 –3915 (–77.7) 6952 982 –5970 (–85.9) May 271 149 –122 (–45.0) 4959 3940 –1019 (–20.5) 6834 4456 –2378 (–34.8) Total 821 467 –354 (–43.1) 14,603 8167 –6436 (–44.1) 19,889 9709 –10,180 (–51.2) COVID-19 recovery June 276 301 25 (9.1) 4442 5164 722 (16.3) 6171 7163 992 (16.1) July 289 339 50 (17.3) 4685 4595 –90 (–1.9) 6584 6442 –142 (–2.2) August 261 261 0 4777 4581 –196 (–4.1) 6798 6214 –584 (–8.6) Total 817 892 75 (9.2) 13,904 14,340 436 (3.1) 19,553 19,819 266 (1.4) March–August 1647 1368 –279 (–16.9) 28,507 22,507 –6000 (–21.0) 39,442 29,528 –9914 (–25.1) BCC, Basal cell carcinoma; COVID-19, coronavirus disease 2019; cSCC, cutaneous squamous cell carcinoma. Analysis of the data found a backlog of 279 cutaneous melanomas, 6000 cSCC, and 9914 BCCs that would have been expected to be diagnosed but have not yet been observed. This study demonstrates COVID-19's ongoing effect on skin cancer diagnosis and management. Although skin cancer diagnoses have returned to the same-month 2019 baseline, our findings suggest that a large backlog of skin cancers remains undiagnosed. Assuming a best-case scenario wherein all delayed cancers were diagnosed at the first opportunity during the recovery period, there would still be an average diagnostic delay of 1.8 months for cutaneous melanomas, 2.1 months for cSCCs, and 1.9 months for BCCs. These delays in initial diagnosis and treatment may lead to skin cancers presenting at more advanced stages,4 with potential increased morbidity and worse cutaneous melanomas survival outcomes.5 Limitations include data homogenization because US regions were temporally differentially affected by the COVID-19 pandemic. Sampling or ascertainment bias could affect these findings, but the patient base represented a large, diverse group (4.7 million persons). Given lacking socioeconomic data, results may not capture the pandemic's full magnitude and effect. Furthermore, although our findings suggest material delays existed in initial skin cancer diagnosis and management, further large-scale studies may be necessary to quantify the effect on health care costs, morbidity, and survival. Our findings suggest that COVID-19 has materially delayed diagnosis and care for patients with skin cancer. Although the number of diagnoses returned to the approximate June to August 2019 baseline, a substantial backlog of undiagnosed cases still remains, with associated delay implications. Further studies may determine whether these delays will materially affect the stage at which subsequent skin cancers present and the potential associated increases in morbidity and mortality that may occur. Conflicts of interest None disclosed. Funding sources: None. IRB approval status: Approved by University of Central Florida IRB (approval 00000863). ==== Refs References 1 Litchman G.H. Rigel D.S. The immediate impact of COVID-19 on US dermatology practices J Am Acad Dermatol 83 2 2020 685 686 32422226 2 Litchman G.H. Marson J.W. Rigel D.S. The continuing impact of COVID-19 on dermatology practice: office workflow, economics and future implications J Am Acad Dermatol 84 2 2021 576 579 33010326 3 COVID-19 resources. National Comprehensive Cancer Network Accessed September 25, 2020. Available at: https://www.nccn.org/covid-19/ 4 Tejera-Vaquerizo A. Nagore E. Estimated effect of COVID-19 lockdown on melanoma thickness and prognosis: a rate of growth model J Eur Acad Dermatol Venereol 34 8 2020 e351 e353 32362041 5 Pacifico M.D. Pearl R.A. Grover R. The UK government two-week rule and its impact on melanoma prognosis: an evidence-based study Ann R Coll Surg Engl 89 2007 609 615 18201477
PMC007xxxxxx/PMC7831642.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)32687-6 10.1016/j.jaad.2020.09.086 Research Letter Chilblain-like lesions and COVID-19 infection: A prospective observational study at Spain's ground zero Feito-Rodríguez Marta PhD a∗ Mayor-Ibarguren Ander MD a Cámara-Hijón Carmen PhD b Montero-Vega Dolores MD c Servera-Negre Guillermo MD a Ruiz-Bravo Elena MD d Nozal Pilar MD b Rodríguez-Peralto José Luis PhD e Enguita Ana Belén PhD e Bravo-Gallego Luz Yadira MD b Granados-Fernández Marí MD f Fernández-Alcalde Celia MD f Fernández-Heredero Álvaro MD g Alonso-Riaño Marina MD e Jiménez-Yuste Víctor PhD h Nuño-González Almudena PhD a De Lucas-Laguna Raúl MD a López-Granados Eduardo PhD b Herranz-Pinto Pedro PhD a a Department of Dermatology, La Paz University Hospital, Madrid, Spain b Department of Clinical Immunology, La Paz University Hospital, Madrid, Spain c Department of Microbiology, La Paz University Hospital, Madrid, Spain d Department of Pathology, La Paz University Hospital, Madrid, Spain e Department of Pathology, Doce de Octubre University Hospital, Madrid, Spain f Department of Ophthalmology, La Paz University Hospital, Madrid, Spain g Department of Vascular Surgery, La Paz University Hospital, Madrid, Spain h Department of Hematology, La Paz University Hospital, Madrid, Spain ∗ Correspondence to: Marta Feito-Rodríguez, PhD, Department of Dermatology, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain 3 10 2020 2 2021 3 10 2020 84 2 507509 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: Chilblain-like lesions (CBLL) have been related to severe acute respiratory coronavirus 2 (SARS-CoV-2) infection,1 although solid microbiological confirmation is still lacking. We present a prospective cohort study of 37 patients (median age, 14 years) presenting new-onset CBLL during the COVID-19 outbreak in Spain that included (1) SARS-CoV-2 testing (nasopharyngeal polymerase chain reaction [PCR] and serologies) and immunologic profiles for all patients, (2) custom recall antigen experiments and intracellular cytokine production evaluation in selected cases, and (3) skin biopsy for histopathology and immunochemistry (11 samples) and SARS-CoV-2 PCR and electron microscopy (3 cases) (Supplemental Tables I-IV; available via Mendeley at https://doi.org/10.17632/vgvxtcb82c.1). CBLL mainly affected the toes (Table I ), with other features including dusky erythematoedematous changes on the dorsal surfaces of the toes and fingers (24.32%), purpuric macules (37.83%), and blisters (10.81%). Two patients presented with more obvious signs of distal skin ischemia (Supplemental Figs 1-3; available via Mendeley at https://doi.org/10.17632/vgvxtcb82c.1). In most cases, the lesions fully/partially remitted with topical therapy or no therapy. Only 1 patient presented with signs of retinal vasculitis. Vascular pulses and Doppler ultrasonography showed normal blood flows in the entire series. All biopsy specimens were consistent with pernio, and 54.5% showed complement C3d and C4d deposition around small vessels (Supplemental Fig 4; available via Mendeley at https://doi.org/10.17632/vgvxtcb82c.1). Nasopharyngeal PCR had positive results in 8.1%, and SARS-CoV-2 serology results were positive in just 8.1% of patients. Recall antigen assays showed positive responses in the 3 patients who underwent them (2 with negative SARS-CoV-2 serologies). Five of the 37 patients presented mild anticardiolipin titer elevation. Interferon (IFN) alfa levels were increased in only 1 of 24 tested patients, whereas the rest of the cytokines remained within normal or undetectable levels. No virus was detected on electron microscopy or PCR testing in skin samples.Table I Summary of demographic and clinical features of the patients presenting chilblain-like lesions (N = 37) Sex, n (%)  Female 20 (54.05)  Male 17 (45.95) Mean age, y, mean ± SD 22.08 ± 15.46 Median age, y 14 Latency between systemic symptoms and skin lesions, days 21.76 ± 23.01 Affected areas, n (%)  Toes only 15 (40.55)  Fingers only 10 (27.03)  Toes and sides of feet 7 (18.92)  Toes and heels 2 (5.40)  Toes and fingers 2 (5.40)  Toes, fingers, and sides of feet 1 (2.70) Associated signs and symptoms, n (%)  Purpuric macules 14 (37.83)  Erythema 6 (16.21)  Pruritus 5 (13.51)  Cold skin 5 (13.51)  Blisters 4 (10.81)  Pain 3 (8.10)  Edema 3 (8.10)  Ulceration and/or necrosis 2 (5.40) History of systemic symptoms, n (%) 17 (45.95) Evolution of the lesions (+2 weeks), n (%)  Complete resolution 16 (43.24)  Partial resolution 14 (37.84)  Persistence 4 (10.81)  Worsening 3 (8.11) Prescribed therapy, n (%)  None 24 (64.86)  Topical corticosteroids 8 (21.63)  Oral corticosteroids 1 (2.70)  Pentoxifylline 4 (10.81) SD, Standard deviation. Our patients presented with CBLL in striking parallel to the rise and fall of the COVID-19 pandemic in Madrid, but approximately 2 weeks later (Fig 1 ). The low proportion of positive SARS-CoV-2 serology test results would argue against the idea of a causal relationship between CBLL and SARS-CoV-2 infection. Lack of serologic test accuracy and a more prominent innate immune response might explain this discrepancy.2 However, our preliminary results with SARS-CoV-2 assays suggest that patients could have been exposed to SARS-CoV-2 despite negative routine serologic test results. These patients might have had mild SARS-CoV-2 infection, although the upregulation of the type I IFN pathway could have resulted in the onset of CBLL in genetically predisposed patients. The lower rate of measured IFN alfa could be due to the fact that we measured it in a late phase of infection, according to PCR test results.Fig 1 Chilblain-like lesions: the incidence at our center compared with confirmed COVID-19 cases over time in Madrid. The exact role of SARS-CoV-2 in the development of CBLL, if any, remains unclear.3 We were unable to detect the virus in skin samples; however, the SARS-CoV-2 spike protein has been shown in the endothelial and epithelial cells of eccrine glands.4 Additionally, immune complex deposition can lead to tissue injury through various mechanisms, including complement activation, which could contribute to their pathogenesis.5 In conclusion, if CBLL were secondary to SARS-CoV-2, absence of a more evident humoral response would be highlighted. Recall antigen assays could help clarify this association. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Reviewed and approved by the IRB of La Paz University Hospital, Madrid, Spain. Reprints not available from the authors. ==== Refs References 1 Colmenero I. Santonja C. Alonso-Riaño M. SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultrastructural study of seven paediatric cases Br J Dermatol 183 4 2020 729 737 32562567 2 Netea M.G. Joosten L.A.B. Trained immunity and local innate immune memory in the lung Cell 175 2018 1463 1465 30500533 3 Kanitakis J. Lesort C. Danset M. Jullien D. Chilblain-like acral lesions during the COVID-19 pandemic (“COVID toes”): histologic, immunofluorescence and immunohistochemical study of 17 cases J Am Acad Dermatol 83 2020 870 875 32502585 4 Torrelo A. Andina D. Santonja C. Erythema multiforme-like lesions in children and COVID-19 Pediatr Dermatol 37 2020 442 446 32445583 5 Rojko J.L. Evans M.G. Price S.A. Formation, clearance, deposition, pathogenicity, and identification of biopharmaceutical-related immune complexes: review and case studies Toxicol Pathol 42 2014 725 764 24705884
PMC007xxxxxx/PMC7832011.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 Mosby S0190-9622(20)32869-3 10.1016/j.jaad.2020.10.057 This month in JAAD case reports January 2021: Skin of color images Sloan Brett MD ∗ Department of Dermatology, University of Connecticut School of Medicine, Farmington, Connecticut ∗ Correspondence to: Steven Brett Sloan, MD, Department of Dermatology, 555 Willard Ave, VA Connecticut Healthcare System, Newington, CT 06111. 24 10 2020 1 2021 24 10 2020 84 1 3535 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcAccording to the Centers for Disease Control and Prevention COVID Data Tracker, 52% of all US coronavirus disease 2019 (COVID-19) cases had reported racial demographic data. Of these, 46.2% of all COVID-19 cases and 37.1% of all COVID-19–related deaths were in black or Hispanic patients.1 As of July 2016, blacks represented 13.4% and Hispanics represented 18.5% of the US population.2 The reasons why minority populations are disproportionally affected by COVID-19 are complex, with disparities in health care representing one major facet. In 2019, Lester et al3 eloquently illustrated the disparities and subsequent effects in recognizing diseases in skin of color. They pointed out the lack of representation of images of skin of color in major textbooks and teaching sets and proposed a proactive approach to photographing and publishing more images of diseases in patients with darker skin types. Earlier this year, Lester et al4 searched 36 publications with 130 photographs of COVID-19–related skin findings. Of these published photographs, 92% (120 of 130) were of skin types I to III, only 6% (7 of 130) were of skin type IV, and none were of skin types V to VI. In the September edition of JAAD Case Reports, Daneshjou et al5 attempted to narrow this practice gap by presenting a case series documenting 15 images of pernio-like eruptions in 7 persons with Fitzpatrick III to V skin. They pointed out that red and pink hues are more difficult to appreciate in darker skin types, potentially delaying a diagnosis.5 The clinical importance of this article and the practice gap highlighted by Lester et al5 have prompted JAAD Case Reports to develop a skin of color collection. In an attempt to narrow this gap, the collection will provide an ongoing repository of case reports and images in darker skin types. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 CDC COVID data tracker https://covid.cdc.gov/covid-data-tracker/#demographics 2 2016 American Community Survey 1-Year Estimates. U.S. Census Fact Finder. American Community Survey. Accessed October 11, 2020. 3 Lester J. Taylor S. Chren M.M. Under-representation of skin of colour in dermatology images: not just an educational issue Br J Dermatol 180 2019 1521 1522 31157429 4 Lester J. Jia J. Zhang L. Okoye G. Linos E. Absence of images of skin of colour in publications of COVID-19 skin manifestations Br J Dermatol 183 2020 593 595 32471009 5 Daneshjou R. Rana J. Dickman M. Yost J.M. Chiou A. Ko J. Pernio-like eruption associated with COVID-19 in skin of color JAAD Case Rep 6 9 2020 892 897 32835046
PMC007xxxxxx/PMC7832803.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)30996-8 10.1016/j.jaad.2020.05.120 JAAD Online Comment on “Characterization of acute acro-ischemic lesions in non-hospitalized patients: A case series of 132 patients during the COVID-19 outbreak” Fernandez-Nieto Diego MD ∗ Jimenez-Cauhe Juan MD Suarez-Valle Ana MD Moreno-Arrones Oscar M. MD, PhD Saceda-Corralo David MD, PhD Arana-Raja Arantxa MD Ortega-Quijano Daniel MD Dermatology Department, Ramon y Cajal University Hospital, Alcala University, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain ∗ Correspondence to: Diego Fernandez-Nieto, MD, Dermatology Department, Ramon y Cajal University Hospital, Carretera Colmenar Viejo km 9.100, 28034 Madrid, Spain 1 6 2020 9 2020 1 6 2020 83 3 e241e241 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: We thank Dr. Ruggiero and colleagues1 for their interest in our article. We read their study of erythema perniolike lesions in the Italian pediatric population during the coronavirus disease 2019 (COVID-19) outbreak. They described findings regarding the distribution and duration of skin lesions that were similar to those of our Spanish cohort, and also described a low rate for systemic symptoms or positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction test results. They also reported the use of a wide variety of treatments in 74 of 100 cases (74%), including topical steroids, antibiotics, and heparin. There were no consistent differences between the improvement rates at day 12, although physicians' choice for treatment may have been biased by the severity of the disease. We are struggling with uncertainty in these challenging times. On one hand, there are severely ill COVID-19 patients who may present with ischemic acral lesions that may progress to gangrene2 because of COVID-19–induced coagulopathy and thrombotic microangiopathy. On the other hand, there are asymptomatic young patients with subtle ecchymotic and vesicular acral lesions, which have been associated with viral hypersensitivity reactions, microthrombi, overexpression of interferon 1, and immune vasculitis.3 , 4 The latter are not usually associated with COVID-19 pneumonia or thromboembolic events. However, overlapping features may coexist. In fact, both groups of patients may represent the mild and severe ends of the spectrum of COVID-associated coagulopathy.5 We must take into account that a causal relation between acral skin lesions and SARS-CoV-2 has not been fully established yet. These lesions have been increasingly reported in several countries coincident with the COVID-19 pandemic spread. However, most studies report a low positive test-result rate for SARS-CoV-2 polymerase chain reaction, with little access to diagnostic tests. We believe that these skin manifestations are delayed COVID-19 manifestations; hence, the negative results. Serologic studies will be needed to elucidate this point. What should we do with these patients? Because the epidemic curve is slowly declining worldwide, confinement measures are being relaxed. These skin manifestations could be of great value in identifying primary cases, permitting the health care system to implement control and prevention measures and thus avoiding the spread of the virus. Until we have more information about the risk of SARS-CoV-2 transmission in these patients, we should recommend maintenance of isolation measures, especially if diagnostic tests are unavailable. Funding sources: None. Conflicts of interest: None disclosed. Reprints not available from the authors. ==== Refs References 1 Ruggiero G. Arcangeli F. Lotti T. Reply to: “Characterization of acute acro-ischemic lesions in non-hospitalized patients: a case series of 132 patients during the COVID-19 outbreak” J Am Acad Dermatol 83 1 2020 e61 e63 32339703 2 Zhang Y. Cao W. Xiao M. Clinical and coagulation characteristics of 7 patients with critical COVID-2019 pneumonia and acro-ischemia Zhonghua Xue Ye Xue Za Zhi 41 0 2020 E006 32220276 3 Kolivras A. Dehavay F. Delplace D. Coronavirus (COVID-19) infection-induced chilblains: a case report with histopathologic findings JAAD Case Rep 6 6 2020 489 492 32363225 4 Suchonwanit P. Leerunyakul K. Kositkuljorn C. Cutaneous manifestations in COVID-19: lessons learned from current evidence J Am Acad Dermatol 83 1 2020 e57 e60 32339706 5 Zhang Y. Xiao M. Zhang S. Coagulopathy and antiphospholipid antibodies in patients with COVID-19 N Engl J Med 382 17 2020 e38 32268022
PMC007xxxxxx/PMC7833840.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)33143-1 10.1016/j.jaad.2020.11.064 Research Letter Impact of the Paycheck Protection Program on dermatology practices during the COVID-19 pandemic Benlagha Imene MD ∗ Nguyen Bichchau Michelle MD, MPH, MBA Tufts University School of Medicine/Tufts Medical Center, Boston, Massachusetts ∗ Correspondence to: Imene Benlagha, MD, 25 Brooks Park, Medford, MA 02155 10 12 2020 3 2021 10 12 2020 84 3 775777 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: In addition to life losses and health care system collapse, the COVID-19 pandemic caused a profound economic impact. Social distancing and isolation were advised as preventative measures to limit COVID-19 spread but caused worldwide economic slowdown. In the United States, the major outbreak in March 2020 prompted the government to declare a national state of emergency, which came with substantial economic detriment.1 Many dermatologists had to close their practices to reduce the risk of transmission, a rational decision from a public health standpoint but financially devastating. In response, the US Congress passed the Paycheck Protection Program (PPP) to provide financial support for small businesses, including dermatology practices.2 We analyzed the economic impact of COVID-19 on dermatology practice by identifying practices that benefited from the PPP. We identified 1066 dermatology practices that received loans of $0.15 million or greater, representing 5% of medical practices included in this program. The number of dermatologists who benefited from this program was 3719, representing 19.7% of all dermatologists. The majority of loans went to corporations, limited liability companies (LLCs), and subchapters. More than 75% of the loans benefited practices located in the US Southeast, Northeast, and West regions. More than 80% of the loans went to practices with 5 or fewer physicians and 49 or fewer employees (Table I ).Table I Characteristics of loan recipients Characteristics n % Business type  Corporation 404 37.9  Limited liability company 281 26.4  Subchapter corporation 276 25.9  Professional association 42 3.9  Partnership 31 2.9  Sole proprietor 16 1.5  Limited liability partnership 11 1  Cooperative 3 0.3  Nonprofit organization 2 0.2 US geographic region  Southeast 347 32.6  Northeast 236 22.1  West 220 20.6  Midwest 152 14.3  Southwest 111 10.4 Race  White 94 8.8  Asian 16 1.5  Black 1 0.1  Hispanic 8 0.8  American Indian or Alaska Native 1 0.1  Unanswered 946 88.7 Sex  Female 83 7.8  Male 180 16.9  Unanswered 803 75.3 Number of medical providers in practice  1 327 30.7  2-5 566 53.1  6-10 135 12.7  >10 38 3.6 Jobs retained  <10 116 11.7  10-49 708 71.4  50-250 160 16.1  >250 7 0.7 The majority of loans were $0.35 million or less, and more than 90% were less than $1 million. The loans of $2 million and more exclusively benefited LLCs, corporations, and subchapter corporations. Sole proprietor businesses received loans of only $0.35 million or less. More than 50% of the loans of $1 million to $5 million went to the US Southeast and Southwest regions (Table II ). Spearman rank correlation coefficients were 0.49 and 0.45, respectively, for the number of physician providers and jobs retained in practice and the loan range, which shows a positive correlation.Table II Loan distribution, n (%) Loan range $5-$10 million $2-$5 million $1-$2 million $0.35-$1 million $0.15-$0.35 million P value (chi-square test) Total 1 (0.09) 11 (1.03) 43 (4.03) 345 (32.36) 666 (62.48) Business type .1339  Limited liability company 1 (100) 3 (27.3) 9 (20.9) 75 (21.7) 193 (28.9)  Corporation — 6 (54.5) 19 (44.2) 145 (42) 234 (35.1)  Professional association — — 3 (7) 17 (4.9) 22 (3.3)  Partnership — — 2 (4.7) 11 (3.2) 18 (2.7)  Sole proprietor — — — — 16 (2.4)  Subchapter corporation — 2 (18.2) 9 (20.9) 91 (26.4) 174 (26.1)  Limited liability partnership — — — 6 (1.7) 5 (0.8)  Cooperative — — — — 3 (0.5)  Nonprofit organization — — 1 (2.3) — 1 (0.2) US geographic region .4552  Southeast — 5 (45.5) 19 (44.2) 112 (32.5) 211 (31.7)  West 1 (100) 1 (9) 4 (9.3) 64 (18.5) 150 (22.5)  Northeast — — 11 (25.6) 81 (23.5) 144 (21.6)  Midwest — 2 (18.2) 6 (13.9) 54 (15.6) 90 (13.5)  Southwest — 3 (27.3) 3 (7) 34 (9.9) 71 (10.7) Number of medical providers in practice <2.2e-16  1 — 1 (9.1) — 48 (13.9) 278 (41.7)  2-5 — — 5 (11.6) 194 (56.2) 367 (55.1)  6-10 — 2 (18.2) 19 (44.2) 93 (26.9) 21 (3.2)  >10 1 (100) 8 (72.7) 19 (44.2) 10 (3) — Jobs retained <2.2e-16  <10 (micro) — 2 (18.2) 4 (9.3) 30 (8.7) 80 (12)  10-49 (small) — 1 (2.3) 176 (33) 531 (79.7)  50-249 (medium) — 6 (54.5) 36 (83.7) 114 (51) 4 (0.6)  >250 (large) 1 (100) 3 (27.3) — 2 (0.6) 1 (0.2)  Unanswered — — 2 (4.7) 23 (6.7) 50 (7.5) In dermatology, a significant decrease of outpatients was registered during the pandemic.3 This may be explained by the nonemergent character of most outpatient visits, which led to a significant drop in dermatologists’ activity and, therefore, income. The necessity of close contact during dermatologic inspection also may have discouraged patients from seeking care. Most loan recipients were corporations, LLCs, and subchapters, which may reflect the distribution of health care organizations business structures. The geographic distribution of loans mostly in the US East and West regions may be explained by the presence of major cities with greater numbers of practices. Another factor could be the stay-at-home order that was issued in all US West and East states, whereas it was not or was partially issued in states of the US Midwest and Southwest regions.4 Loans of $1 million and greater were surprisingly less distributed in the US West and Northeast. To support this finding, economic analysts noted that banks in major areas like New York City prioritized large food service companies to the detriment of smaller businesses like health care organizations.5 Most of loan beneficiaries were small practices, which is consistent with the distribution of dermatology practices by size. Another factor to consider is that solo and small medical practices were disproportionally affected because of lack of financial resources to guarantee sustainability. Conflicts of interest None disclosed. Funding sources: None. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Trump D.J. Proclamation on declaring a national emergency concerning the novel coronavirus disease (COVID-19) outbreak Available at: https://www.whitehouse.gov/presidential-actions/proclamation-declaring-national-emergency-concerning-novel-coronavirus-disease-covid-19-outbreak/ 2020 2 CARES Act, S.3548, 116th Congress Available at: https://www.congress.gov/bill/116th-congress/senate-bill/3548/text 2020 3 Gisondi P. Piaserico S. Conti A. Dermatologists and SARS-CoV-2: the impact of the pandemic on daily practice J Eur Acad Dermatol Venereol 34 6 2020 1196 1201 32320091 4 Wu J. Smith S. Mansee K. Corky S. DeJesus-Banos B. Stay-at-home orders across the country. NBC News Available at: https://www.nbcnews.com/health/health-news/here-are-stay-home-orders-across-country-n1168736 2020 5 Pines G. Here’s a state-by-state breakdown of PPP funding and how far it went. Money Available at: https://money.com/state-by-state-ppp-funding/ 2020
PMC007xxxxxx/PMC7833847.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)31148-8 10.1016/j.jaad.2020.06.050 JAAD Online International collaboration and rapid harmonization across dermatologic COVID-19 registries Freeman Esther E. MD, PhD ab∗ McMahon Devon E. BA a Hruza George J. MD, MBA c Irvine Alan D. MD, FRCP, MRCP d Spuls Phyllis I. MD, PhD e Smith Catherine H. MD f Mahil Satveer K. MD, PhD f Castelo-Soccio Leslie MD, PhD g Cordoro Kelly M. MD h Lara-Corrales Irene MD, MSc i Naik Haley B. MD, MHSc h Alhusayen Raed MBBS, MSCE j Ingram John R. MD, PhD k Feldman Steven R. MD, PhD l Balogh Esther A. MD l Kappelman Michael D. MD, MPH m Wall Dmitri MD no Meah Nekma MD p Sinclair Rodney MBBS, MD, FACD p Beylot-Barry Marie MD, PhD q Fitzgerald Matthew DrPH r French Lars E. MD s Lim Henry W. MD t Griffiths Christopher E.M. MD u Flohr Carsten MD, PhD v a Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts b Medical Practice Evaluation Center, Mongan Institute, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts c Department of Dermatology, Saint Louis University School of Medicine, Saint Louis, Missouri d Clinical Medicine, Trinity College Dublin, Dublin, Ireland e Department of Dermatology, Public Health and Epidemiology; Immunity and Infections, Amsterdam University Medical Centers, location Academic Medical Center, Amsterdam, the Netherlands f St John's Institute of Dermatology, King's College London and Guy's & St Thomas' National Health Service Foundation Trust, London, United Kingdom g Section of Pediatric Dermatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania h Department of Dermatology, University of California, San Francisco, San Francisco, California i Section of Pediatric Dermatology, Hospital for Sick Children, Toronto, Ontario, Canada j Sunnybrook Research Institute, Dermatology Division, Department of Medicine, University of Toronto, Toronto, Ontario, Canada k Division of Infection and Immunity, Department of Dermatology & Academic Wound Healing, Cardiff University, Cardiff, United Kingdom l Center for Dermatology Research, Department of Dermatology, Wake Forest School of Medicine, Winston-Salem, North Carolina m Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina n Hair Restoration Blackrock, Dublin, Ireland o National and International Skin Registry Solutions (NISR), Charles Institute of Dermatology, Dublin, Ireland p Sinclair Dermatology, East Melbourne, Victoria, Australia q French Society of Dermatology and Department of Dermatology, University Hospital of Bordeaux, Bordeaux, France r American Academy of Dermatology, Rosemont, Illinois s Department of Dermatology, University Hospital, Munich University of Ludwig Maximilian, Munich, Germany t Department of Dermatology, Henry Ford Health System, Detroit, Michigan u Dermatology Centre, Salford Royal Hospital, National Institute for Health Research, Manchester Biomedical Research Centre, University of Manchester, Manchester, United Kingdom v Unit for Population-Based Dermatology Research, St John's Institute of Dermatology, King's College London and Guy's & St Thomas' National Health Service Foundation Trust, London, United Kingdom ∗ Correspondence to: Esther Freeman, MD, PhD, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114 17 6 2020 9 2020 17 6 2020 83 3 e261e266 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: Across specialties, coronavirus disease-2019 (COVID-19) has ushered in an unprecedented time for international collaboration. As COVID-19 has spread around the world, there has been a movement among dermatologists to better understand the effects of the virus on their patients as well as potential dermatologic manifestations of the disease. During March and April 2020, 8 dermatologic registries focused on COVID-19 were launched worldwide to address these issues (Table I ).1, 2, 3 We developed a rapid consensus among registry leaders to foster collaboration and data harmonization.Table I General, demographic, and medical information included in coronavirus disease 2019 (COVID-19) dermatology registries Variable PsoProtect COVIDSKIN French registry SECURE Psoriasis SECURE AD Global HS COVID-19 Registry SECURE Alopecia AAD/ILDS Dermatology COVID Registry PeDRA Date initiated March 27, 2020 March 30, 2020 April 1, 2020 April 1, 2020 April 6, 2020 April 8, 2020 April 8, 2020 April 20, 2020 Website hosted on www.psoprotect.org https://bit.ly/COVIDSKINSFD covidpso.org covidderm.org https://hscovid.ucsf.edu securealopecia.covidderm.org www.aad.org/covidregistry pedsderm.net; pedraresearch.org Server platform REDCap∗ sfdermato.org REDCap OpenApp: Clinical Insight† REDCap OpenApp: Clinical Insight REDCap REDCap Languages available English only French only English only English, Chinese, Spanish, French, Russian English only English only English only English only Inclusion criteria  Person entering data Health care professional or patients Health care professional Health care professional Health care professional or patients Health care professional or patients Health care professional Health care professional Health care professional  COVID-19 laboratory confirmed ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓  COVID-19 suspected ✓ ✓ … ✓ ✓ ✓ ✓ ✓  Patients on systemic medication included ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓  Patients not on systemic medication included ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ Patient demographics  Date of entry into study ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓  Sex ✓ ✓ ✓ ✓ ✓ ✓ ✓ Assigned at birth ✓ Assigned at birth  Age/year of birth ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓  Country of residence ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓  State of residence ✓ ✓ US only ✓ US/Australia ✓ ✓ US/Australia ✓ US only ✓ US States/Canadian Provinces  Ethnicity ✓ ✓ US census categories ✓ WHO categories ✓ Originally US Census; changed to WHO categories 4/26/20 ✓ WHO categories ✓ Originally US census; changed to WHO 4/20/20 ✓ Currently US census categories General medical information  Height ✓ ✓ ✓ ✓  Weight ✓ ✓ ✓ ✓  Comorbidities (eg asthma, COPD, heart disease, DM) ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓  Smoking status ✓ ✓ ✓ ✓ ✓ ✓  Alcohol intake ✓ ✓  NSAIDS ✓ ✓ ✓ ✓ Existing dermatologic condition  Primary dermatologic condition ✓ Only psoriasis ✓ ✓ Only psoriasis ✓ Only AD ✓ ✓ Only alopecia ✓ ✓  Subspecialty disease subtype ✓ ✓ Psoriasis subtype ✓ Alopecia subtypes ✓  Year of dermatologic diagnosis ✓ ✓ ✓  Name of dermatologic medication ✓ ✓ ✓ Psoriasis medications only ✓ ✓ ✓ ✓  Systemic medication:  Name ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓  Dose and frequency ✓ ✓ ✓ ✓ ✓  Length of treatment ✓ ✓ ✓ ✓  Stopped or tapered during COVID-19 infection ✓ ✓ ✓ ✓ ✓  Symptom activity at time of COVID-19 diagnosis ✓ ✓ ✓ ✓ ✓ ✓  Associated skin disease flare with COVID-19 ✓ ✓ ✓ ✓ ✓ ✓  Skin disease severity during COVID-19 flare ✓ ✓ ✓ ✓ ✓ AAD, American Academy of Dermatology; AD, atopic dermatitis; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; DM, diabetes mellitus; HS, hidradenitis suppurativa; ILDS, International League of Dermatological Societies; NSAIDS, nonsteroidal anti-inflammatory drugs; PeDRA, Pediatric Dermatology Research Alliance; SECURE, Surveillance Epidemiology of Coronavirus (COVID 19) Under Research Exclusion; REDCap, Research Electronic Data Capture; US, United States; WHO, World Health Organization. ∗ Vanderbilt University, Nashville, Tennessee. † OpenApp, Dublin, Ireland. Members from each international registry came together in a virtual consensus meeting in April 2020, facilitated by the American Academy of Dermatology and the International League of Dermatologic Societies. Models of collaboration discussed were (1) linking data across registries for overlapping conditions at the point of data entry and (2) harmonizing data post hoc, using shared variables across registries. As a first step, each dermatologic registry provided a list of the variables they collect across several domains, including registry information, patient demographics, general medical information, prior dermatologic conditions, new-onset skin manifestations in the setting of COVID-19, and COVID-19–related history and outcomes (Supplemental Table I available via Mendeley at https://data.mendeley.com/datasets/zh6bw88xhc). This effort formed the basis for a meta-catalog containing all registry variables so that commonalities and variables in need of harmonization between studies could be easily identified (Supplemental Appendix). As a result of this harmonization process, 2 registries have, for example, changed how they collect demographics to harmonize with other international registries. Additionally, the registries now link to each other to facilitate collaboration at the time of data entry. Registry leaders also discussed challenges in collaboration, particularly double data entry across different registries.4 To address this concern, registries added a question at the point of data collection about whether a provider entered a case in another registry and to identify that registry. This additional information will enhance our ability to track double case reporting during analysis, although it is not possible to fully verify deidentified patient data. An additional limitation is that registries have, thus far, originated from North America, Europe, and Australia. Even though many of these registries are open to global submissions, most are only available in English, which may hinder participation. Active work is needed to include a broader representation of global dermatologists as well as inclusion of patients from all racial/ethnic and socioeconomic groups within each country.5 Ultimately, the reports generated from these registries will only be as good as the data entered. As physicians and researchers, we must strive to include diversity in these reports so that data collected are representative of the global patient community we look after. Communication and transparency in data sharing, which may take the form of regularly posted aggregate data from the registries as well as periodic update newsletters to dermatology societies internationally, may be a motivator for the dermatology community and may encourage engagement and reporting of cases. Together, we are most powerful when our collective knowledge is used to inform the management and care of our patients affected by COVID-19. The Surveillance Epidemiology of Coronavirus (COVID 19) Under Research Exclusion (SECURE)-Atopic Dermatitis (AD) Registry would like to acknowledge key support through Steering Group and patient partners Bernd Arents and Tim Burton as well as their Statistical Lead David Prieto-Merino and Steering Group members Drs Annelie H. Musters, Angela Bosma, Aaron Drucker, Kenji Kabashima, and Ching-Chi Chi. SECURE-AD and SECURE-Alopecia wish to acknowledge the support of the not-for-profit company, National and International Skin Registry solutions (NISR) in establishing and maintaining their registries. The Global Hidradenitis Suppurativa COVID-19 Registry would like to acknowledge instrumental Steering Committee members, including John W. Frew, MBBS, MMed, MSc, Sandra Guilbault, Michelle A. Lowes, MBBS, PhD, and Christine A. Yannuzzi, BA. The American Academy of Dermatology/International League of Dermatologic Societies registry would like to thank the staff of the American Academy of Dermatology and the staff of the International League of Dermatologic Societies for their support. All registries would like to thank health care providers worldwide for entering cases. Funding sources: There were no funding sources specifically for this collaboration. Please see conflicts of interest and disclosures below for funding sources for individual authors. Conflicts of interest and disclosures: Drs Freeman and Hruza are part of the American Academy of Dermatology (AAD) COVID-19 Ad Hoc Task Force. Drs Smith and Mahil are supported by the 10.13039/501100000272 National Institute for Health Research (NIHR) 10.13039/100014461 Biomedical Research Centre at Guy's and St Thomas' National Health Service Foundation Trust and 10.13039/100012980 King's College , London, United Kingdom, and the 10.13039/100013126 Psoriasis Association , United Kingdom. Drs Castelo-Soccio, Cordoro, and Lara-Corrales are part of the Pediatric Dermatology Research Alliance COVID-19 Response Task Force, a collaboration between the Society for Pediatric Dermatology (SPD) and the Pediatric Dermatology Research Alliance (PeDRA). Dr Naik is a board member of the Hidradenitis Suppurativa Foundation. Raed Alhusayen is a member of the Canadian Dermatology Association (CDA) COVID-19 Task-Force and president of the Canadian Hidradenitis Suppurativa Foundation. Dr Feldman has received research, speaking, and/or consulting support from a variety of companies, including Galderma, GSK/Stiefel, Almirall, Alvotech, LEO Pharma, BMS, Boehringer Ingelheim, Mylan, Celgene, Pfizer, Ortho Dermatology, AbbVie, Samsung, Janssen, Lilly, Menlo, Merck, Novartis, Regeneron, Sanofi, Novan, Qurient, National Biological Corporation, Caremark, Advance Medical, Sun Pharma, Suncare Research, Informa, UpToDate, and the National Psoriasis Foundation. Dr Feldman also consults for others through Guidepoint Global, Gerson Lehrman, and other consulting organizations. Dr Feldman is founder and majority owner of www.DrScore.com and is founder and part owner of Causa Research, a company dedicated to enhancing patients' adherence to treatment. Dr Kappelman has consulted for AbbVie, Janssen, and Takeda, is a shareholder in Johnson & Johnson, and has received research support from 10.13039/100006483 AbbVie and Janssen. Dr Beylot-Barry is president of the French Society of Dermatology. Dr French is president and Dr Lim is a board member of the International League of Dermatological Societies (ILDS). Dr Griffiths is president of the European Society for Dermatological Research and is funded in part by the National Institute for Health Research Manchester Biomedical Research Centre. Dr Flohr is president of the British Society for Paediatric Dermatology and chief investigator of the UK-Irish Atopic eczema Systemic TherApy Register (A-STAR; ISRCTN11210918). Dr Flohr and the patient-facing part of the SECURE-AD registry are supported by the National Institute for Health Research Biomedical Research Centre at Guy's and St Thomas' National Health Service Foundation Trust, London, United Kingdom. Devon McMahon and Drs Irvine, Spuls, Ingram, Balogh, Wall, Meah, Sinclair, and Fitzgerald have no conflicts of interest to disclose. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Freeman E.E. McMahon D.E. Fitzgerald M.E. The AAD COVID-19 Registry: crowdsourcing dermatology in the age of COVID-19 J Am Acad Dermatol 83 2 2020 509 510 32305438 2 Mahil S.K. Yiu Z.Z.N. Mason K.J. Global reporting of cases of COVID-19 in psoriasis and atopic dermatitis: an opportunity to inform care during a pandemic [e-pub ahead of print]. Br J Dermatol 10.1111/bjd.19161 2020 3 Balogh E.A. Heron C. Feldman S.R. Huang W.W. SECURE-Psoriasis: a de-identified registry of psoriasis patients diagnosed with COVID-19 J Dermatolog Treat 31 4 2020 327 32266851 4 Bauchner H. Golub R.M. Zylke J. Editorial concern–possible reporting of the same patients with COVID-19 in different reports JAMA 323 13 2020 1256 32176775 5 Khunti K. Singh A.K. Pareek M. Hanif W. Is ethnicity linked to incidence or outcomes of COVID-19? BMJ 369 2020 m1548 32312785
PMC007xxxxxx/PMC7834601.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)33225-4 10.1016/j.jaad.2020.12.034 Research Letter The impact of the COVID-19 pandemic on the presentation status of newly diagnosed melanoma: A single institution experience Shannon Adrienne B. MD a∗ Sharon Cimarron E. MD a Straker Richard J. III MD a Miura John T. MD b Ming Michael E. MD c Chu Emily Y. MD, PhD cd Karakousis Giorgos C. MD b a Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia b Division of Endocrine and Oncologic Surgery, Hospital of the University of Pennsylvania, Philadelphia c Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia d Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia ∗ Correspondence to: Adrienne Shannon, 3400 Spruce St, 4 Maloney, Philadelphia, PA 19104 25 12 2020 4 2021 25 12 2020 84 4 10961098 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: The COVID-19 pandemic has had a significant impact on cancer care.1 Some have projected up to a 10% increase in mortality for specific malignancies due to delays in care caused by the COVID-19 pandemic, but the pandemic's impact on melanoma has yet to be defined.2 , 3 Delays in diagnosis could result in thicker melanomas at presentation and profound effects on patient outcomes. This study evaluates the presentation status of melanoma lesions before and after a period of pandemic restrictions, which limited dermatologic evaluation to define the pandemic's impact on melanoma care. Patients referred to the University of Pennsylvania's Dermatopathology Department for pathologic slide review and/or Division of Endocrine and Oncologic Surgery (handling most of the institutional resection volume) for definitive resection of nonmetastatic primary melanomas were identified from a 2-month period after clinical resurgence at our institution (June 15-August 15, 2020; the COVID-19 era cohort) and a corresponding period in the pre–COVID-19 era (June 15-August 15, 2019). Patient and tumor characteristics were analyzed by univariate analyses. All tests were 2-sided, and P values less than .05 were considered statistically significance. Analyses were performed in Stata for Windows version 16.1. Of all melanomas evaluated at our institution, 358 and 298 patients were evaluated in the pre–COVID-19 era cohort and COVID-19 era cohort, respectively. There were no differences in patient characteristics and tumor type (invasive melanoma versus melanoma in situ) between the 2 cohorts. After exclusion of melanoma in situ lesions, 172 and 153 patients with invasive melanoma were evaluated in the pre–COVID-19 and COVID-19 era cohorts, respectively (Table I ). Patients in the COVID-19 era cohort were more likely to have satellitosis (3.9% vs 0%, P = .001) compared with pre–COVID-19 era patients. Among patients evaluated by the oncologic surgery department, specifically, COVID-19 era (N = 56) patients had higher median tumor Breslow depth (1.4 mm vs 0.87 mm; P = .013) and a higher proportion of patients with mitotic count greater than 1/mm2 (58.9% vs 35.3%; P = .018), satellitosis (8.9% vs 0%; P = .029), and pT3/pT4 tumors (35.7% vs 19.1%; P = .037) compared with pre–COVID-19 era patients (N = 68) (Table II ).Table I Patient and tumor characteristics of all melanomas examined by dermatopathology and oncologic surgery from June 15 to August 15, 2019 and June 15 to August 15, 2020 Pre–COVID-19 COVID-19 P value N = 172 (52.9%) N = 153 (47.1%) Age (median, IQR) 68 (16.5) 68 (18) .518  <50 y 24 (14.0) 23 (15.0)  50-59 y 22 (12.8) 30 (19.6)  60-69 y 48 (27.9) 38 (24.8)  70-79 y 56 (32.6) 43 (28.1)  ≥80 y 22 (12.8) 19 (12.4) Sex .757  Male 96 (55.8) 88 (57.5)  Female 76 (44.2) 65 (42.5) Race .257  White 138 (80.2) 116 (75.8)  Black 2 (1.2) 0 (0.0)  Asian 0 (0.0) 1 (0.7)  Unknown 32 (18.6) 36 (23.5) Immune compromise 1 (0.6) 4 (2.6) .137 Tumor depth (median, IQR) 0.5 (0.7) 0.6 (0.9) .171 pT staging group .900  1/2 147 (85.5) 130 (85.0)  3/4 25 (14.5) 23 (15.0) Clark level .880  Level II 57 (33.1) 47 (30.7)  Level III 52 (30.2) 41 (26.8)  Level IV 56 (32.6) 58 (37.9)  Level V 4 (2.3) 4 (2.6)  Unknown 3 (1.7) 3 (2.0) Lymphovascular invasion 6 (3.5) 4 (2.6) .092  Unknown 5 (2.9) 0 (0.0) Ulceration 14 (8.1) 22 (14.4) .165  Unknown 3 (1.7) 4 (2.6) Tumor-infiltrating lymphocytes .537  Brisk 18 (10.5) 14 (9.2)  Nonbrisk 92 (53.5) 88 (57.5)  Unknown 28 (16.3) 17 (11.1) Vertical growth 114 (66.3) 98 (64.1) .673  Unknown 8 (4.7) 5 (3.3) Regression 48 (27.9) 32 (20.9) .162  Unknown 4 (2.3) 8 (5.2) Satellitosis 0 (0.0) 6 (3.9) .001∗  Unknown 5 (2.9) 14 (9.2) Perineural invasion 3 (1.7) 4 (2.6) .080  Unknown 8 (4.7) 1 (0.7) Mitotic count .240  None 97 (56.4) 79 (51.6)  ≤1 33 (19.2) 24 (15.7)  >1 42 (24.4) 50 (32.7) Residual tumor 50 (29.1) 47 (30.7) .691  Unknown 58 (33.7) 56 (36.6) Source .587  Dermatopathology only 104 (60.5) 97 (63.4)  Surgery 68 (39.5) 56 (36.6) IQR, Interquartile range. ∗ Indicates significance. Table II Patient and tumor characteristics of all melanomas examined by oncologic surgery from June 15 to August 15, 2019 and June 15 to August 15, 2020 Pre–COVID-19 COVID-19 P value N = 68 (54.8%) N = 56 (45.2%) Age (median, IQR) 65 (19) 66.5 (14.5) .699  <50 y 11 (16.2) 7 (12.5)  50-59 y 10 (14.7) 12 (21.4)  60-69 y 22 (32.4) 17 (30.4)  70-79 y 18 (26.5) 17 (30.4)  ≥80 y 7 (10.3) 3 (5.4) Sex .504  Male 36 (52.9) 33 (58.9)  Female 32 (47.1) 23 (41.1) Race .085  White 59 (86.8) 54 (96.4)  Black 2 (2.9) 0 (0.0)  Asian 0 (0.0) 1 (1.8)  Unknown 7 (10.3) 1 (1.8) Immune compromise 0 (0.0) 3 (5.4) .053 Tumor depth (median, IQR) 0.8 (1.0) 1.4 (3.0) .013∗ pT staging group .037∗  1/2 55 (80.9) 36 (64.3)  3/4 13 (19.1) 20 (35.7) Clark level .006∗  Level II 14 (20.6) 3 (5.4)  Level III 23 (33.8) 11 (19.6)  Level IV 28 (41.2) 36 (64.3)  Level V 3 (4.4) 3 (5.4)  Unknown 0 (0.0) 3 (5.4) Lymphovascular invasion 0 (0.0) 2 (3.6) .130  Unknown 2 (2.9) 0 (0.0) Ulceration 12 (17.7) 15 (26.8) .327  Unknown 1 (1.5) 0 (0.0) Tumor-infiltrating lymphocytes .764  Brisk 11 (16.2) 6 (10.7)  Nonbrisk 38 (55.9) 36 (64.3)  Unknown 10 (14.7) 7 (12.5) Vertical growth 50 (73.5) 46 (82.1) .492  Unknown 6 (8.8) 4 (7.1) Regression 24 (35.3) 12 (21.4) .239  Unknown 1 (1.5) 1 (1.8) Satellitosis 0 (0.0) 5 (8.9) .029∗  Unknown 1 (1.5) 0 (0.0) Perineural invasion 2 (2.9) 3 (5.4) .734  Unknown 2 (2.9) 1 (1.8) Mitotic count .018∗  None 29 (42.7) 12 (21.4)  ≤1/mm2 15 (22.1) 11 (19.6)  >1/mm2 24 (35.3) 33 (58.9) Residual tumor 24 (35.3) 24 (42.9) .390 Pathologic stage .183  I 51 (75.0) 34 (60.7)  II 13 (19.1) 13 (23.2)  III 4 (5.9) 9 (16.1) SLNB performed 44 (64.7) 45 (80.4) .054 Positive SLN 3 (4.4) 5 (8.9) .308 IQR, Interquartile range; SLN, sentinel lymph node; SLNB, sentinel lymph node biopsy. ∗ Indicates significance. During the COVID-19 pandemic, to reallocate clinical resources and control viral transmission, outpatient health care services were limited for patients from March to mid-June. We investigated whether absence of routine dermatologic evaluation during this time resulted in advanced tumor presentation status after clinical resurgence. There was no difference noted in median thickness or pT staging group in melanomas evaluated overall. Among surgical patients specifically, there was an increase in median tumor depth, the proportion of pT3/pT4 lesions, and lesions with satellitosis. This finding may reflect a goal among clinicians to remove thin melanomas at clinics locally, minimizing the need for patient travel. The increase in median thickness of melanomas and absolute number of pT3/pT4 lesions (>50% increase) referred for surgical evaluation raises concerns for delay in diagnosis. Although this study is limited as a single-institution study over a short period, further study is warranted to better define the impact of the pandemic on melanoma care nationally. Conflicts of interest None disclosed. The authors acknowledge support in part by the University of Pennsylvania Skin Disease Research Center (NIAMS P30-AR057217). Funding sources: None. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Richards M. Anderson M. Carter P. Ebert B.L. Mossialos E. The impact of the COVID-19 pandemic on cancer care Nat Cancer 1 2020 565 567 35121972 2 Maringe C. Spicer J. Morris M. The impact of the COVID-19 pandemic on cancer deaths due to delays in diagnosis in England, UK: a national, population-based, modelling study Lancet Oncol 21 8 2020 1023 1034 32702310 3 Bartlett E.K. Karakousis G.C. Current staging and prognostic factors in melanoma Surg Oncol Clin N Am 24 2 2015 215 227 25769707
PMC007xxxxxx/PMC7834715.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)31066-5 10.1016/j.jaad.2020.05.150 Research Letter The presence and distribution of novel coronavirus in a medical environment Jiang Qianli MD a Chen Yinghua PhD b Dai Yingchun PhD c Cai Shaoxi MD d Hu Guodong MD d∗ a Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China b Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Department of Histology and Embryology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China c Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China d Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China ∗ Correspondence to: Guodong Hu, MD, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, 1838, Guangzhou North Ave, Guangzhou, Guangdong 510515, China 6 6 2020 10 2020 6 6 2020 83 4 12181219 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: Coronavirus disease 2019 (COVID-19) has constituted a global pandemic,1 and infections of medical staff with severe acute respiratory syndrome-coronavirus-2 (SARS-Cov-2) are a major concern because the number of infected medical staff in Spain has exceeded 10,000.2 A significant undertaking is to explore possible routes of infection for medical staff to strengthen their protection, reduce the infection rate, and effectively control the epidemic.3 Because of daily disinfection and cleaning, the presence and distribution of SARS-COV-2 in a medical environment may differ from that in other environments. To detect COVID-19 in a medical environment, samples from surfaces of personal protective equipment, medical facilities, and the belongings of patients with confirmed disease were collected in Hankou Hospital, Wuhan. All samples were sent to the Wuhan Dean medical laboratory center for COVID-19 nucleic acid detection, which adopted real-time polymerase chain reaction technology to detect nucleic acid sequences at 3 targets, with a sensitivity of greater than 90%. After the medical staff removed their protective face shields and goggles and left the isolation ward, test swabs were daubed on the outer surfaces of the equipment 3 times. A total of 30 face shields and 30 sets of protective goggles were tested for SARS-Cov-2. In addition, the surfaces of a total of 20 nurse rolling carts and station tables were tested with the swabs in the same way. Surfaces of the belongings of 20 patients with confirmed disease, such as water cups and screens of mobile telephones, were also tested with swabs, and 30 samples were sent to the laboratory for nucleic acid testing for COVID-19 (Table I ).Table I Nucleic acid testing on the surface of personal protective equipment, medical facilities, and the belongings of patients Location No. of tests No. of positive results Face shields 30 0 Protective goggles 30 0 Nurse rolling carts 15 0 Nurse station tables 5 0 Patients' water cups 10 0 Patients' mobile telephones 20 1 All surfaces of the face shields and protective goggles were devoid of SARS-Cov-2. Additionally, the surface test results for nurse stations and rolling carts and the water cups were negative, except for 1 positive result from the surface of a mobile telephone of a patient with COVID-19 (Table I). It is well known that COVID-19 can be transmitted by an airborne route4; however, it was not clear whether the virus could float on surfaces in a medical environment and cause contact infection of medical staff. This study revealed that the probability that COVID-19 on surfaces can cause contact transmission is low; instead, more attention should be paid to personal isolation and protection from air transmisson. However, fomites such as patient belongings are a potential route of transmission, and therefore it is essential for hand washing and disinfection after contact with such items.5 We thank Inuk Zandvakili for revising the manuscript. Funding sources: Supported by the Technology Planning Project of Guangdong Province (2017A020215188). Conflicts of interest: None disclosed. ==== Refs References 1 Bedford J. Enria D. Giesecke J. COVID-19: towards controlling of a pandemic Lancet 395 10229 2020 1015 1018 32197103 2 Anelli F. Leoni G. Monaco R. Italian doctors call for protecting healthcare workers and boosting community surveillance during COVID-19 outbreak BMJ 368 2020 m1254 32217525 3 The Lancet. COVID-19: protecting health-care workers Lancet 395 10228 2020 922 4 Guan L. Zhou L. Zhang J. Peng W. Chen R. More awareness is needed for severe acute respiratory syndrome coronavirus 2019 transmission through exhaled air during non-invasive respiratory support: experience from China Eur Respir J 55 3 2020 2000352 32198275 5 Lotfinejad N. Peters A. Pittet D. Hand hygiene and the novel coronavirus pandemic: the role of healthcare workers J Hosp Infect 2020 10.1016/j.jhin.2020.03.017
PMC007xxxxxx/PMC7836213.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)33237-0 10.1016/j.jaad.2020.12.043 Research Letter Characteristics and outcomes of COVID-19 in patients with autoimmune bullous diseases: A retrospective cohort study Mahmoudi Hamidreza MD a Farid Ali Salehi PharmD a Nili Ali MD a Dayani Dorsa MD a Tavakolpour Soheil MSc ab Soori Tahereh MD a Teimourpour Amir PhD a Isazade Ahdie MD a Abedini Robabeh MD a Balighi Kamran MD a Daneshpazhooh Maryam MD a∗ on behalf of Autoimmune Bullous Diseases Research Group a Autoimmune Bullous Diseases Research Center, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran b Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA ∗ Correspondence and reprint requests to: Maryam Daneshpazhooh, MD, Razi Hospital, Vahdate-Eslami Square, 11996 Tehran, Iran 24 12 2020 4 2021 24 12 2020 84 4 10981100 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: Autoimmune bullous diseases (AIBDs) are a group of blistering conditions the management of which is mostly based on immunosuppressive drugs, and evidence on their outcomes is limited in the COVID-19 era.1 This retrospective cohort study on 704 AIBD patients was conducted in a dermatology referral hospital in Tehran, Iran, from April 17 to May 29, 2020. After ethics approval, history of COVID-19 and characteristics and history of AIBD treatments (ie, rituximab and prednisolone) were collected from 704 AIBD patients by an online survey, face-to-face visits, or phone calls. The diagnosis of COVID-19 was based on typical clinical findings and positive real time (RT) polymerase chain reaction (PCR) for SARS-CoV-2 or lung involvement compatible with COVID-19 on chest computed tomography (CT) scan, as suggested by World Health Organization guidelines.2 Patients with typical signs and symptoms of COVID-19 not confirmed by RT PCR or CT scan, were defined as highly suspicious. Results are expressed as relative risk (RR) with 95% confidence intervals (CI). After univariate log-binomial models, inverse probability weights (IPW) were calculated to minimize the effect of confounding factors. The individual predicted probabilities of rituximab (RTX) and prednisolone history were estimated with a multivariable logistic regression model, and weight was assigned for each subject. The effect of each variable was estimated using the multivariable log-binomial model. Among 704 patients, 21 (2.98%) had COVID-19; 15 of them had been hospitalized and 7 needed intensive care facilities (including high flow or mechanical ventilation), of which, 3 (14.28%) died. All had pulmonary involvement on CT. SARS-CoV-2 was detected in 13 (61.9%) patients by RT PCR and was negative in 2 (9.6%) patients. Fourteen (66.7%) had received RTX during the last 12 months. The median time from the last RTX infusion to COVID-19 diagnosis was 3.5 (interquartile range [IQR]:1.8-5.0) months. Ten (47.6%) patients were receiving prednisolone doses greater than 10 mg/d, 8 (38.1%) were on 10 mg/d or less, and 3 (14.3%) were off prednisolone. Additionally, 35 cases were highly suspicious of COVID-19 (Table I ).Table I Demographic and disease characteristics of patients with AIBDs Demographics and disease characteristics of AIBDs patients All AIBDs patients (n = 704) Total suspicious and diagnosed COVID-19 patients (n = 56) Highly suspicious COVID-19 (n = 35)∗ Diagnosed COVID-19 by PCR/chest CT (n = 21) Mean age ± SD, y 48.8 ± 13.4 46.2 ± 11.4 47.7 ± 11.6  <45 y 291 (41.3) 17 (48.6) 8 (38.1)  ≥45 y 413 (58.7) 18 (51.4) 13 (61.9) Male: Female 314: 390 15: 20 8: 13 Median body mass index [IQR], kg/m2 26.6 [24.1-29.8] 25.6 [24.5-30.1] 26.6 [25.0-27.7] Smoking- no. (%) 70 (9.9) 4 (11.4) 1 (4.8) Suspicious contact history,† n (%) 61 (8.7) 14 (40) 6 (28.6) Bullous disease type, n (%)  Pemphigus 620 (88.1) 32 (91.4) 20 (95.2)  Bullous pemphigoid 54 (7.7) 1 (2.9) 0 (0)  Mucous membrane pemphigoid 24 (3.4) 1 (2.9) 1 (4.8)  Linear IgA disease 3 (0.4) 0 (0) 0 (0)  Epidermolysis bullosa acquisita 2 (0.3) 1 (2.9) 0 (0)  Gestational pemphigoid 1 (0.1) 0 (0) 0 (0) Median duration bullous disease [IQR], y 4.0 [2.0-8.0] 4.0 [2.0-7.0] 3.0 [1.0-8.0] Comorbidities, n (%)  Hypothyroidism 81 (11.5) 6 (17.1) 2 (9.5)  Obesity (BMI>30) 172 (24.4) 9 (25.7) 1 (4.8)  Diabetes 105 (14.9) 5 (14.3) 2 (9.5)  Cardiovascular disease 150 (21.3) 6 (17.1) 7 (33.3)  Pulmonary disease 20 (2.8) 1 (2.9) 0 (0) Bullous disease status, n (%)  No relapse 380 (54) 13 (37.1) 11 (52.4)  Bullae ≤ 7 d 148 (21) 12 (34.3) 3 (14.3)  Bullae > 7 d 176 (25) 10 (28.6) 7 (33.3) History of rituximab use, n (%) 571 (81.1) 29 (82.9) 17 (81)  From April 2019, n (%) 337 (47.9) 15 (42.9) 14 (66.7)  From October 2019, n (%) 225 (32) 11 (31.4) 13 (61.9) Daily prednisolone dosage last 3 months, n (%)  ≤10 mg 578 (82.1) 27 (77.1) 11 (52.4)  >10 mg 126 (17.9) 8 (22.9) 10 (47.6) BMI, Body mass index. ∗ Highly suspicious cases: Typical clinical findings of COVID-19 without PCR or chest CT scan. † Using χ2 analysis, there was a significant relationship between suspicious contact history with total COVID-19 (P < .001) and confirmed COVID-19 (P = .002) after excluding highly suspicious cases. Multivariable analysis with IPW found an RR of 5.31 for subjects on greater than 10 mg/d prednisolone in cases diagnosed as COVID-19 (95% CI, 2.39-11.81) and 8.01 in the hospitalized group (95% CI, 3.32-19.68). Furthermore, the RR of getting COVID-19 and being hospitalized decreased by 38% (95% CI, 18%-57%) and 45% (95% CI, 15%-72%) with each passing month from the last RTX infusion, respectively. Including patients with highly suspicious COVID-19 in our analysis yielded similar results (Fig 1 ).Fig 1 Univariate and multivariate analysis with IPW. Association between prednisolone and rituximab infusion with COVID-19 in patients with autoimmune bullous diseases. Asterisk indicates all 704 patients were included in the total COVID-19 analysis. For the diagnosed COVID-19 analysis, highly suspicious cases were excluded from the cohort. Likewise, both highly suspicious and nonhospitalized COVID-19 cases were excluded from the cohort in the hospitalized COVID-19 analysis. Double asterisk indicates outcomes: Total COVID-19 including diagnosed and highly suspicious cases; diagnosed COVID-19 cases; hospitalized COVID-19 cases. Hashtag indicates RTX interval was analyzed for patients who received RTX after April 2019 and was defined as the interval from the last dose of RTX to either the date of contracting COVID-19 or May 2020. The blue line shows the relative risk of outcomes with each passing month from the last RTX infusion with a 95% CI. By reviewing the literature, prednisone dose greater than 10 mg was suggested as a risk factor for hospitalization and mortality of COVID-19,3 whereas a randomized, controlled trial in the United Kingdom found low-dose systemic dexamethasone decreased the mortality rate in patients on a ventilator or oxygen.4 Similarly, opinions regarding the safety of RTX in COVID-19 are contradictory partly due to the controversies about the role of B cells in defending against SARS-CoV-2.5 The retrospective design, patient admissions in different hospitals, and undetected mild cases were our limitations. We found a higher risk of COVID-19 and hospitalization with prednisolone doses of greater than 10 mg/d. In addition, we showed each passing month from the last dose of RTX decreased these risks. Therefore, patients on long-term prednisolone and recent RTX should be monitored closely. Moreover, physicians should be more vigilant when deciding for RTX administration. Conflicts of interest None disclosed. Drs Mahmoudi, Farid, and Nili contributed equally to this article. Funding sources: This research was supported by 10.13039/501100004484 Tehran University of Medical Sciences and Health Services grant number 99-1-161-47611. IRB approval status: IR.TUMS.VCR.REC.1399.189. ==== Refs References 1 Kasperkiewicz M. Schmidt E. Fairley J. Expert recommendations for the management of autoimmune bullous diseases during the COVID-19 pandemic J Eur Acad Dermatol Venereol 2020 2 Organization W.H. Use of chest imaging in COVID-19: a rapid advice guide, 11 June 2020 2020 World Health Organization 3 Gianfrancesco M. Hyrich K.L. Al-Adely S. Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry Ann Rheum Dis 79 7 2020 859 866 32471903 4 RECOVERY Collaborative GroupHorby P. Lim W.S. Dexamethasone in hospitalized patients with Covid-19 — preliminary report N Engl J Med Published online July 17, 2020 10.1056/NEJMoa2021436 5 Guilpain P. Le Bihan C. Foulongne V. Response to: ‘Severe COVID-19 associated pneumonia in 3 patients with systemic sclerosis treated with rituximab’ by Avouac et al Ann Rheum Dis 2020
PMC007xxxxxx/PMC7836520.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 Published by Elsevier on behalf of the American Academy of Dermatology, Inc. S0190-9622(20)33107-8 10.1016/j.jaad.2020.11.058 Research Letter Ultra-hypofractionated low-dose total skin electron beam followed by maintenance therapy: Preliminary findings from a prospective open-label study Rolf Daniel MD Elsayad Khaled MD ∗ Eich Hans Theodor PhD Prof. Department of Radiation Oncology, University Hospital of Muenster, Muenster, Germany ∗ Correspondence to: Khaled Elsayad, MD, Department of Radiation Oncology, University Hospital of Muenster, Building A1, 1 Albert Schweitzer Campus, Muenster D48149, Germany. 30 11 2020 12 2021 30 11 2020 85 6 16011603 © 2020 Published by Elsevier on behalf of the American Academy of Dermatology, Inc. 2020 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: low-dose total skin electron beam therapy (LD-TSEBT) with 12 Gy in 8 fractions is a reasonable approach for mycosis fungoides (MF) and Sezary syndrome (SS).1 Prior studies show that LD-TSEBT improves cutaneous manifestations and health-related quality of life (HRQL).2 , 3 Hypofractionated TSEBT regimens seem to be a feasible alternative to conventional fractionation.4 Accordingly, the International Lymphoma Radiation Oncology Group recommends ultra-hypofractionated LD-TSEBT as a compelling option during the COVID-19 pandemic to decrease therapy duration and any possible exposure to COVID-19.5 In this prospective study, we present the feasibility of ultra-hypofractionated LD-TSEBT. Seven radiation courses were administered to 7 patients with MF/SS at our radiation oncology department at the university hospital Münster during the initial phase of COVID-19 pandemic from April to July 2020 (Table I ). Patients underwent TSEBT with two 4 Gy fractions. Patients with thicker tumors or pathologically enlarged lymph nodes at the treatment time received additional focal radiotherapy. Treatment characteristics, modified skin-weighted severity (mSWAT), Skindex-29 questionnaire, and toxicity profiles were analyzed.Table I Patient characteristics Patient Gender/age (y) Type/stage TSEBT dose Additional focal radiotherapy Prior therapies Concurrent therapy Maintenance therapies Acute toxicities D1-W6 Subacute toxicities W8-W12 Response mSWAT D1/W8 PFS (W) Follow-up 1 M/69 SS 2 × 4 Gy None PUVA, INF, ECP, MTX, CST, 12 Gy TSEBT None Bexarotene Edema, erythema, and nail atrophy grade 2 Edema and alopecia grade 1 PR 112/13 36 ANEP 2 M/66 MF/IIB 2 × 4 Gy Tumors and lymph nodes brentuximab, 2 x 12 Gy TSEBT None Mogamulizumab Sepsis, alopecia grade 1, and nausea grade 1 Nail changes and alopecia grade 1 PR 31/4 26 Dead (due to COVID-19) 3 M/78 MF/IIB 2 × 4 Gy Tumors PUVA Bexarotene Bexarotene Edema, erythema grade, alopecia, and blistering grade 1 Alopecia grade 1 PR 59/16 26 ANEP 4 F/77 SS 2 × 4 Gy Lymph nodes MTX, acitretin, bexarotene, ECP None Bexarotene, ECP Erythema grade 2, edema grade 2, alopecia grade 1 Fatigue, nail changes, and alopecia grade 1 PR 100/37 31 ANEP 5 M/60 MF/IIB 2 × 4 Gy None PUVA, MTX, SCT, INF, brentuximab, bexarotene Bexarotene Bexarotene Erythema and fatigue grade 1 Fatigue, and edema grade 1 PR 46/5 28 ANEP 6 F/55 MF/IIB 2 × 4 Gy None IFN, bexarotene, PUVA, gemcitabin Acitretin Acitretin Fatigue, Erythema, and blistering grade 1 None CR 9/0 28 ANEP 7 M/57 MF/IIB 2 × 4 Gy Tumors MTX, 12 Gy TSEBT, PUVA None Methotrexate Erythema grade 2 Fatigue, alopecia, and blistering grade 1 PR 28/14 15 Progressed after 15 weeks ANEP, Alive with no evidence of progression; CR, complete response; CST, corticosteroids; D, day; ECP, extracorporeal photophoresis; INF, interferon; MF, mycosis fungoides; MTX, methotrexate; PFS, progression-free survival; PR, partial remission; PUVA, psoralen plus ultraviolet A; SCT, stem cell transplantation; SS, Sézary syndrome; TSEBT, total skin electron beam therapy; W, week. In this cohort study, the median mSWAT score before the LD-TSEBT was 46. Three patients received concomitant oral retinoid therapy. Moreover, all patients received maintenance treatment after irradiation. The median follow-up duration was 28 weeks. All patients experienced a clinical response with a median mSWAT reduction to 13. Among 5 patients with pruritus (median, 7), a substantial benefit was seen 8 weeks after LD-TSEBT, with a median score of 0. A marked decline in the global Skindex-29 score has been observed regarding patients' quality of life after 8 weeks of therapy with a clinically meaningful difference in the symptoms and emotional subscales. During ultra-hypofractionated LD-TSEBT, all of the patients encountered mild toxicities (Table I). Four patients had grade 1 toxicities, whereas three patients exhibited grade 2 toxicities. The most common adverse effects were erythema, followed by edema. One patient, who had a thick ulcerated lesion, had sepsis during the treatment course and was successfully treated with antibiotics. After 8 weeks, all grade 2 adverse events were resolved. No patients had grade 4 to 5 adverse events. In this research letter, we report the acute and subacute toxicities after LD-TSEBT with two 4-Gy fractions. Long-term outcome and toxicities need to be investigated in a subsequent report. Our preliminary results showed that ultra-hypofractionated LD-TSEBT is a safe and feasible alternative to conventionally fractionated TSEBT for patients with MF/SS to reduce the overall therapy duration and possible COVID-19 exposure. The mSWAT scores and the HRQL recovered after ultra-hypofractionated LD-TSEBT. A detailed HRQL analysis using several instruments and the possible role of oral retinoids as a maintenance treatment after TSEBT are under development by our cutaneous lymphoma group and is supposed to help clinicians find the suitable fractionation regimen and maintenance therapies for MF/SS patients. Conflict of interest None disclosed. Daniel Rolf and Khaled Elsayad contributed equally to this work. Funding sources: None. IRB approval status: Approved. Reprints not available from the authors. ==== Refs References 1 Hoppe R.T. Harrison C. Tavallaee M. Low-dose total skin electron beam therapy as an effective modality to reduce disease burden in patients with mycosis fungoides: results of a pooled analysis from 3 phase-II clinical trials J Am Acad Dermatol 72 2015 286 292 25476993 2 Elsayad K. Stadler R. Steinbrink K. Eich H.T. Combined total skin radiotherapy and immune checkpoint inhibitors: a promising potential treatment for mycosis fungoides and Sezary syndrome J Dtsch Dermatol Ges 18 2020 193 197 3 Song A. Gochoco A. Zhan T. A prospective cohort study of condensed low-dose total skin electron beam therapy for mycosis fungoides: reduction of disease burden and improvement in quality of life J Am Acad Dermatol 83 2020 78 85 32004646 4 Jeans E.B. Hu Y.-H. Stish B.J. Low-dose hypofractionated total skin electron beam therapy for adult cutaneous T-cell lymphoma Pract Radiat Oncol 10 6 2020 e529 e537 32781247 5 Yahalom J. Dabaja B.S. Ricardi U. ILROG Emergency guidelines for radiation therapy of hematological malignancies during the COVID-19 pandemic Blood 135 21 2020 1829 1832 32275740
PMC007xxxxxx/PMC7837130.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(20)33242-4 10.1016/j.jaad.2020.12.046 Original Article Eruptions and related clinical course among 296 hospitalized adults with confirmed COVID-19 Rekhtman Sergey MD, PharmD, MPH a Tannenbaum Rachel BS a Strunk Andrew MA a Birabaharan Morgan MD a Wright Shari BS a Grbic Nicole BA a Joseph Ashna BS a Lin Stephanie K. BA a Zhang Aaron C. BA a Lee Eric C. BA a Rivera Erika BA a Qiu Michael MD, PHD b Chelico John MD bc Garg Amit MD a∗ a Department of Dermatology, Donald and Barbara Zucker School of Medicine at Hofstra Northwell, Hempstead, New York b Center for Research Informatics and Innovation, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York c Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra Northwell, New Hyde Park, New York ∗ Correspondence to: Amit Garg, MD, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, 1991 Marcus Avenue, Suite 300, New Hyde Park, NY, 11042. 25 12 2020 4 2021 25 12 2020 84 4 946952 16 12 2020 © 2020 by the American Academy of Dermatology, Inc. 2020 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Background Limited information exists on mucocutaneous disease and its relation to course of COVID-19. Objective To estimate prevalence of mucocutaneous findings, characterize morphologic patterns, and describe relationship to course in hospitalized adults with COVID-19. Methods Prospective cohort study at 2 tertiary hospitals (Northwell Health) between May 11, 2020 and June 15, 2020. Results Among 296 hospitalized adults with COVID-19, 35 (11.8%) had at least 1 disease-related eruption. Patterns included ulcer (13/35, 37.1%), purpura (9/35, 25.7%), necrosis (5/35, 14.3%), nonspecific erythema (4/35, 11.4%), morbilliform eruption (4/35, 11.4%), pernio-like lesions (4/35, 11.4%), and vesicles (1/35, 2.9%). Patterns also showed anatomic site specificity. A greater proportion of patients with mucocutaneous findings used mechanical ventilation (61% vs 30%), used vasopressors (77% vs 33%), initiated dialysis (31% vs 9%), had thrombosis (17% vs 11%), and had in-hospital mortality (34% vs 12%) compared with those without mucocutaneous findings. Patients with mucocutaneous disease were more likely to use mechanical ventilation (adjusted prevalence ratio, 1.98; 95% confidence interval, 1.37-2.86); P < .001). Differences for other outcomes were attenuated after covariate adjustment and did not reach statistical significance. Limitations Skin biopsies were not performed. Conclusions Distinct mucocutaneous patterns were identified in hospitalized adults with COVID-19. Mucocutaneous disease may be linked to more severe clinical course. Key words adults COVID-19 eruption hospitalized morbilliform mucocutaneous necrosis Northwell purpura rash SarsCoV-2 ulcer Abbreviations used AKI acute kidney injury BMI body mass index CI confidence interval IQR interquartile range ==== Body pmc Capsule Summary • Little is understood about the morphologic spectrum of mucocutaneous disease and its relation to clinical course in hospitalized adults with COVID-19. • Eruptions are common among adults with COVID-19, and their presence may be linked to a more severe course of illness. Introduction Little is understood about the morphologic spectrum of eruptions and their relation to clinical course among acutely ill adults infected with SARS-CoV-2, the pathogen in COVID-19. Several knowledge gaps, including estimating prevalence of mucocutaneous disease, its detailed description, and its related outcomes were discussed in a call to action to develop high-quality prospective studies on mucocutaneous disease in COVID-19.1 In spring of 2020, the New York metropolitan area was an epicenter for the COVID-19 pandemic in the United States,2 and this provided an opportunity to characterize disease-related integumentary findings. The purpose of this study was to estimate prevalence of mucocutaneous findings in hospitalized adults with COVID-19, to characterize morphologic patterns, and to evaluate whether eruptions were related to more severe clinical course. Methods This study was performed at Long Island Jewish Medical Center and North Shore University Hospital, both of which are tertiary hospitals at Northwell Health located in Queens and Manhasset, New York, respectively. The study sample consisted of patients hospitalized between May 11, 2020 and June 15, 2020 who were 18 years of age and older and suspected of having COVID-19. Clinical characteristics for the cohort were monitored until August 11, 2020. The analysis sample was further limited to patients who had confirmed SARS-CoV-2 infection via positive polymerase chain reaction test or IgM/IgG antibody test. Consecutive prospective integumentary examinations were performed once by study personnel, which included trained medical students, for hospitalized patients suspected of having COVID-19 during the study period. Photographs of abnormal findings for each patient were captured as part of their care. These photographs were independently evaluated by 2 dermatologist raters (SR and AG) who classified morphologic patterns and locations of SARS-CoV-2–related findings. These raters also assessed whether each cutaneous observation was pre-existing or likely to be unrelated to SARS-CoV-2 infection. Examples of unrelated observations included xerosis cutis, nummular eczema, furunculosis, and prurigo nodularis. All patients who had eruptions without an otherwise known etiology were considered to have a COVID-19–related rash in the context of their acute clinical presentation. Clinical variables were selected a priori and included demographics, comorbidities, laboratory observations, imaging results, treatments, and other interventions. Clinical data were extracted from the enterprise electronic health record (Sunrise Clinical Manger; Allscripts). Clinical data were validated by the Northwell Health COVID-19 Research Consortium, and separately a sample of the dataset was verified against electronic medical records for accuracy. This study was approved by the Institutional Review Board at the Feinstein Institutes for Medical Research at Northwell Health. Statistical analysis Prevalence of mucocutaneous manifestations was estimated by the percentage of eligible patients with at least one COVID-19–related rash. Medians (interquartile range [IQR]) were reported for continuous variables, and frequencies (percentages) were reported for categorical variables. Summary statistics for laboratory values were calculated based on the maximum value during hospitalization. Hypothesis tests were 2 sided, and statistical significance was assessed at the .05 α level. Analysis was performed using R version 3.6.3. Acute kidney injury (AKI) was defined according to the KDIGO Clinical Practice Guideline for AKI (increase in serum creatinine by >0.3 mg/dL within 48 hours or increase in serum creatinine to >1.5 times baseline), or based on initiation of dialysis during hospitalization.3 Baseline serum creatinine was estimated using the most recent value in the year before the current admission, if available, otherwise, the median value during hospitalization. Patients with a history of chronic kidney disease were not included in calculations of AKI incidence. Prespecified primary outcomes for comparison between patients with rash and without rash included (1) requirement for invasive mechanical ventilation, (2) requirement for vasopressors, (3) initiation of dialysis during hospitalization, (4) thrombosis or venous thromboembolism diagnosed by duplex or computed tomography angiography, and (5) in-hospital mortality. Prevalence of each outcome during hospitalization was compared between groups using Poisson regression with robust variance estimates,4 adjusting for age, sex, race, body mass index (BMI), Charlson Comorbidity Index, and use of invasive mechanical ventilation (except when ventilation was itself the outcome). Multiple imputation was used to account for missing race and BMI data in the analysis of primary outcomes, with m = 10 imputations. Prespecified secondary outcomes of interest for comparison between those with and without rash included age, BMI, maximum neutrophil-to-lymphocyte ratio, and maximum D-dimer during hospitalization. Mann-Whitney U tests were used to compare variable distributions between groups, stratified by use of mechanical ventilation during hospitalization. In exploratory analyses, we also compared length of stay and presence of AKI in patients with and without rash, stratified by ventilation status. Hypothesis tests were not performed for exploratory analyses. Results Among 338 hospitalized patients identified as possibly having COVID-19 during the study period, 10 did not have laboratory confirmation of SARS-CoV-2 infection, and 32 others were not available for examination or declined examination. Demographic characteristics and comorbidities of patients with and without rash are summarized in Table I . Laboratory values representing markers of infection and inflammation for COVID-19 patients stratified by presence of rash and use of mechanical ventilation are described in the supplement (Supplementary Table I; available at: https://data.mendeley.com/datasets/hx5xfv9tpc/1).Table I Demographic and clinical characteristics of COVID-19 patients Characteristic Rash (n = 35) No rash (n = 261) Age, median (IQR), y 64 (57-77) 65 (55-74) Male sex, n (%)∗ 25 (71) 159 (61) Race, n (%)  White 13 (37) 98 (38)  Black 4 (11) 53 (21)  Asian 8 (23) 38 (15)  Native American/Alaskan 0 (0) 1 (0.4)  Other/Multiracial 10 (29) 65 (25)  Missing 0 6 (2) Hispanic or Latino ethnicity, n (%) 5 (14) 37 (14)  Missing ethnicity 1 (3) 25 (10) BMI, median (IQR), kg/m2 27.3 (23.7-31.0) 26.1 (22.7-31.1)  Missing, n (%) 4 (11) 60 (23) Comorbidities, n (%)  Coronary artery disease 8 (23) 48 (18)  Congestive heart failure 5 (14) 44 (17)  Asthma 3 (9) 24 (9)  Chronic obstructive pulmonary disorder 5 (14) 28 (11)  Diabetes mellitus 12 (34) 97 (37)  Hypertension 25 (71) 183 (70)  Chronic kidney disease 6 (17) 45 (17) Charlson comorbidity index, median (IQR) 4 (3-7.5) 6 (3-8) ∗ For categorical variables, percentages are for those with nonmissing data. Among the 296 included patients, 35 (11.8%) had at least 1 related eruption during the course of hospitalization. Type, locations, and frequencies of morphologic patterns observed in patients with COVID-19 are described in Table II . Morphologic patterns were varied and included ulcer (13/35, 37.1%) (Fig 1 ), purpura (9/35, 25.7%), necrosis (5/35, 14.3%) (Fig 2 ), red erythema (4/35, 11.4%), morbilliform pattern (4/35, 11.4%), pernio-like lesions (4/35, 11.4%), and vesicles (1/35, 2.9%). All 13 (100%) of the ulcers involved the face, lips, or tongue. All 9 (100%) of the purpuric lesions involved the extremities. All 5 (100%) of the necrotic lesions involved the toes. Red erythema most frequently involved the face, neck, and chest. The morbilliform pattern was most frequently observed on the trunk. All 4 (100%) of the pernio-like lesions involved the hands or feet. The vesicular eruption, noted in 1 patient, involved the abdomen.Table II Frequencies and morphologic types of rash among 296 COVID-19 patients‡ Location∗† Any rash, n = 35, n (%) Ulcer, n = 13 Purpura, n = 9 Necrosis, n = 5 Red erythema, n = 4 Morbilliform, n = 4 Pernio-like, n = 4 Vesicles, n = 1 Face 2 (5.7) — — — 2 — — — Cheeks 9 (25.7) 9 — — — — — — Chin 6 (17.1) 6 — — — — — — Ear 1 (2.9) 1 — — — — — — Nose 3 (8.6) 3 — — — — — — Lips 2 (5.7) 2 — — — — — — Tongue 1 (2.9) 1 — — — — — — Neck 2 (5.7) — — — 2 — — — Chest 5 (14.3) — — — 2 2 — — Abdomen 5 (14.3) — — — 1 2 — 1 Back 4 (11.4) — — — 1 2 — — Axilla 2 (5.7) — — — 2 0 — — Arms 5 (14.3) — 2 — — 3 — — Hands 5 (14.3) — 2 — 1 1 1 — Fingers 3 (8.6) — — — — — 3 — Legs 5 (14.3) — 2 — — 2 — — Groin 1 (2.9) — — — 1 — — — Feet 3 (8.6) — 1 — 1 — 1 — Toes 8 (22.9) — 4 5 — — 2 — ∗ Location counts within each rash may sum to more than the overall frequency of the rash because of patients having the same rash in multiple locations. Sum of patients with individual rashes exceeds the number with any rash because of patients who had multiple types of rash. † Percentages for morphology locations are not presented for each rash individually due to small numbers. ‡ In addition to the rashes presented in the table above, 1 patient had conjunctivitis, and 1 patient had desquamation, with both rashes considered COVID-19-related. Fig 1 Necrotic ulcer on the face at the placement of a medical device. Fig 2 Purpura and necrosis involving the foot and toes. All 13 (100%), 6 of 9 (66.7%), and 4 of 5 (80%) patients with ulcer, purpura, and necrosis, respectively, were mechanically ventilated. Clinical course for adult COVID-19 patients with and without mucocutaneous disease is described in Table III . A greater proportion of patients with rash required invasive mechanical ventilation compared with those without rash (61% vs 30%; adjusted PR, 1.98 [95% confidence interval (CI), 1.37-2.86]; P < .001). A greater proportion of patients with rash also had use of vasopressors (77% vs 33%; adjusted PR, 1.03 [95% CI, 0.94-1.13]; P = .52), initiation of dialysis during hospitalization (31% vs 9%; adjusted PR, 1.62 [95% CI, 0.91-2.90]; P = .10), and thrombosis or venous thromboembolism (17% vs 11%; adjusted PR, 0.84 [95% CI, 0.40-1.77]; P = .65), although these differences were attenuated after adjustment for covariates and did not reach statistical significance in adjusted analyses. In-hospital mortality was higher for patients with rash compared with those without rash, but this difference was not statistically significant in adjusted analysis (34% vs 12%; adjusted PR, 1.29 [95% CI, 0.78-2.13]; P = .32].Table III Clinical outcomes in COVID-19 patients with and without cutaneous manifestations Outcome No. cases/Total no. (%) Unadjusted PR (95% CI) Adjusted PR∗ (95% CI) P value (Adjusted PR) Rash No Rash Invasive mechanical ventilation† 14/23 (60.9) 79/261 (30.3) 2.01 (1.38-2.93) 1.98 (1.37-2.86) <.001 Use of vasopressors 27/35 (77.1) 86/261 (33.0) 2.34 (1.82-3.01) 1.03 (0.94-1.13) .52 Dialysis 11/35 (31.4) 24/261 (9.2) 3.42 (1.84-6.36) 1.62 (0.91-2.90) .10 Thrombosis or VTE 6/35 (17.1) 29/261 (11.1) 1.54 (0.69-3.45) 0.84 (0.40-1.77) .65 In-hospital mortality‡ 12/35 (34.3) 32/258 (12.4) 2.76 (1.58-4.85) 1.29 (0.78-2.13) .32 VTE, Venous thromboembolism. ∗ Based on multivariable Poisson regression models with robust (sandwich) standard errors. Covariates included age, sex, race, BMI, Charlson Comorbidity Index, and use of invasive mechanical ventilation (for the 4 other outcomes). † Twelve patients who had ulcers of the cheek or chin were excluded from the analysis of the ventilation outcome, as it was difficult to discern whether these cutaneous manifestations were directly related to COVID-19 infection, patients being ventilated for a prolonged period, or a combination of both. ‡ Three patients who were not discharged as of the date of data extraction were excluded from the analysis of in-hospital mortality. There were no clinically meaningful differences in age, BMI, neutrophil-to-lymphocyte ratio and D-dimer between COVID-19 patients with and without rash stratified by ventilation status (Supplementary Table II; available at: https://data.mendeley.com/datasets/hx5xfv9tpc/1). In exploratory analysis, AKI was present in nearly all ventilated patients with and without rash (95.7% vs 92.8%; adjusted PR, 1.02 [95% CI, 0.87-1.21]). In addition, among patients not requiring ventilation, those with rash were more likely to have AKI than those without rash (66.7% vs 25.5%; adjusted PR, 2.43 [95% CI, 1.37-4.31]) (Supplementary Table III; available at: https://data.mendeley.com/datasets/hx5xfv9tpc/1). Median time to discharge was 91 days for those with rash, compared with 73 days for those without rash, among patients requiring ventilation. Among patients not requiring ventilation, median time to discharge was 8 days in those with rash, compared with 9 days in those without rash (Supplementary Table III). A greater proportion of patients with COVID-19 and mucocutaneous eruptions received anti-inflammatory, anticoagulation, and vasopressor treatments (Supplementary Table IV; available at: https://data.mendeley.com/datasets/hx5xfv9tpc/1). Discussion In this study of consecutively examined patients with confirmed COVID-19, we estimate the prevalence of related mucocutaneous eruptions among a racially diversified cohort of hospitalized adults to be 11.8%. No distinct morphologic pattern emerged among hospitalized patients, rendering the appearance of mucocutaneous disease less pertinent to diagnosing COVID-19 among suspected cases. It is noteworthy that morphologic patterns demonstrated site specificity. For example, all ulcers appeared on the face, lips, and tongue. All patients who had these ulcers were also mechanically ventilated. Ulcer locations corresponded to areas of increased pressure from endotracheal tubes or medical devices used to hold tubes in place. This occurrence has also been described in case series of COVID-19 patients with ulcerated and/or necrotic lesions at sites in direct contact with medical devices.5 , 6 Whether this is simply a pressure phenomenon related to devices used to secure endotracheal tubes with or without prolonged intubation7 or whether microvascular injury with COVID-19 predisposed patients to ulceration warrants further investigation. Most patients in our study with purpura or necrosis were also mechanically ventilated, which raises the question of whether this presentation is the result of microvascular injury in critically ill patients or whether they are the result of iatrogenic (ie, vasopressor, anticoagulation) exposures or other unknown factors. An iatrogenic basis for pernio-like lesions and morbilliform eruptions also cannot be excluded. Although presence of mucocutaneous eruptions in patients with COVID-19 has been reported previously, prevalence estimates of mucocutaneous eruptions and morphologic characterization in a large cohort of hospitalized adults with COVID-19 is, to our knowledge, absent to date. Several reports, case series, and 1 cross-sectional study of patients from the international medical community have described chilblain-like lesions involving the fingers and toes, maculopapular eruptions, livedo, petechiae, purpura, necrosis, wheals, and vesicles.5 , 8, 9, 10, 11, 12, 13, 14, 15, 16 The series of 171 confirmed, predominantly ambulatory COVID-19 cases from the American Academy of Dermatology's registry is an important resource for description of the breadth of mucocutaneous findings.8 This registry also has limitations that impact the interpretation of observations. Prevalence of mucocutaneous disease could not be established in this case series. Patients in this series were predominantly white, whereas nonwhite adults have been disproportionately infected with COVID-19.17 Approximately 50% of cases were submitted by nondermatology physicians, midlevel practitioners, nurses, and other medical professionals, and it is possible that use of morphologic nomenclature was inconsistent among contributors, or that some eruptions may have been misclassified altogether. A series of 15 hospitalized adults with COVID-19 reported observations of acral ischemia, livedo racemosa, purpura, petechiae, and erythema multiforme-like lesions. However, these were selected cases for which a dermatology consult was requested.9 Here we also describe clinical course among hospitalized adults with COVID-19 and mucocutaneous disease. Patients with eruptions had nearly twice the prevalence of mechanical ventilation, suggesting that presence of rash in adults may be related to more severe course. Although values for laboratory markers of inflammation and severity of illness were increased among mechanically ventilated patients, we did not observe a pattern of differences between patients with and without mucocutaneous disease, after stratifying by ventilation status. Other clinical outcomes that may be associated with rash, including AKI, coagulopathy, length of stay, and mortality, may warrant further study. Impressions of disease course among adults hospitalized with COVID-19 appear to contrast with our observations in hospitalized children and adolescents with COVID-19 or multisystem inflammatory syndrome in children and rash, in whom presence of mucocutaneous disease may suggest a less severe clinical course.18 Prior studies reporting on clinical outcomes in relation to mucocutaneous manifestations in COVID-19 are limited to case series8 , 10 , 11 and one cross-sectional study12 including 53 hospitalized patients with rash from China and Italy. Study methods and clinical outcomes were not described in detail in the cross-sectional study; however, a link between mucocutaneous disease and COVID-19 severity was not established.12 The American Academy of Dermatology's series described worse prognosis among 11 patients with retiform purpura.8 In a Spanish series of 375 patients with cutaneous manifestations, those having livedo, necrosis, and maculopapular eruptions experienced pneumonia, hospital admission, intensive care unit admission, and mortality more frequently than with other patterns.10 However, maculopapular eruptions comprised approximately half of the cases, for which drug-induced eruptions could not be ruled out. More than one-third of cases in the series did not have confirmation of COVID-19, and there was limited follow-up time for data on disease course. There are limitations that warrant consideration when interpreting observations in this study. Our cohort may not be representative of those with milder disease or those who do not require hospitalization. We could not ascertain exact onset of rash from acutely ill patients and, as such, cannot describe the temporal relationship between rash and clinical course. Duration of illness before admission was not established for patients, and the variability between time from admission to mucocutaneous examination was also not captured. Accordingly, we could not describe the temporal relationship between rash onset and clinical course. It is also possible that some patients had integumentary findings after their examination. Oral mucosal examination was not possible for all patients, as a significant proportion were intubated, and some could not adequately cooperate in the context of their acute illness. The extent to which these limitations influence the prevalence estimate or spectrum of disease is unclear. We did not perform skin biopsy of the patterns observed; therefore, we cannot provide histopathologic correlations for the eruptions observed. It was not clear that biopsy, beyond clinical impression, would result in changes to management. Safety of study personnel was also an important consideration in deciding not to systematically pursue skin biopsies. Adults with COVID-19, unlike those with other acute viral infections, commonly have mucocutaneous eruptions, the presence of which may indicate a more severe course of illness. Although confirmatory studies may be required to assess the generalizability of these observations, this study provides insight into prevalence, morphologic characterization, distribution, and clinical course associated with eruptions in hospitalized adults with COVID-19. Conflicts of Interest Dr Garg has received honoraria from AbbVie, Amgen, Boehringer Ingelheim, Incyte, Janssen, Novartis, Pfizer, UCB, and Viela Bio. The rest of the authors have no conflicts to disclose. Funding Sources: None. IRB approval status: This investigation was approved by the Human Subjects Committee at the Feinstein Institute for Medical Research at the Northwell Health. Reprints not available from the authors. ==== Refs References 1 Shinkai K. Bruckner A.L. Dermatology and COVID-19 JAMA 324 12 2020 1133 1134 32960253 2 NYC Department of Health Coronavirus disease 2019 (COVID-19) Available at: https://www1.nyc.gov/site/doh/covid/covid-19-main.page 3 Khwaja A. KDIGO clinical practice guidelines for acute kidney injury Nephron Clin Pract 120 4 2012 c179 c184 22890468 4 Barros A.J. Hirakata V.N. Alternatives for logistic regression in cross-sectional studies: an empirical comparison of models that directly estimate the prevalence ratio BMC Med Res Methodol 3 2003 21 14567763 5 Karagounis T.K. Shaw K.S. Caplan A. Lo Sicco K. Femia A.N. Acrofacial purpura and necrotic ulcerations in COVID-19: a case series from New York City Int J Dermatol 2020 10.1111/ijd.15181 6 Sleiwah A. Nair G. Mughal M. Lancaster K. Ahmad I. Perioral pressure ulcers in patients with COVID-19 requiring invasive mechanical ventilation Eur J Plast Surg 2020 1 6 10.1007/s00238-020-01737-6 7 Kim C.H. Kim M.S. Kang M.J. Kim H.H. Park N.J. Jung H.K. Oral mucosa pressure ulcers in intensive care unit patients: a preliminary observational study of incidence and risk factors J Tissue Viability 28 1 2019 27 34 30551969 8 Freeman E.E. McMahon D.E. Lipoff J.B. The spectrum of COVID-19-associated dermatologic manifestations: an international registry of 716 patients from 31 countries J Am Acad Dermatol 83 4 2020 1118 1129 32622888 9 Strom M.A. Trager M.H. Timerman D. Cutaneous findings in hospitalized and critically-ill patients with COVID-19: a case series of 15 patients J Am Acad Dermatol 84 2 2021 510 511 33068643 10 Galván Casas C. Català A. Carretero Hernández G. Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases Br J Dermatol 183 1 2020 71 77 32348545 11 Recalcati S. Cutaneous manifestations in COVID-19: a first perspective J Eur Acad Dermatol Venereol 34 5 2020 e212 e213 32215952 12 De Giorgi V. Recalcati S. Jia Z. Cutaneous manifestations related to coronavirus disease 2019 (COVID-19): a prospective study from China and Italy J Am Acad Dermatol 83 2 2020 674 675 32442696 13 Tammaro A. Adebanjo G.A.R. Parisella F.R. Pezzuto A. Rello J. Cutaneous manifestations in COVID-19: the experiences of Barcelona and Rome J Eur Acad Dermatol Venereol 34 7 2020 e306 e307 32330340 14 Droesch C. Hoang M. DeSancho M. Lee E.J. Magro C. Harp J. Livedoid and purpuric skin eruptions associated with coagulopathy in severe COVID-19 JAMA Dermatol 156 9 2020 1022 1024 15 Fernandez-Nieto D. Jimenez-Cauhe J. Suarez-Valle A. Characterization of acute acral skin lesions in nonhospitalized patients: a case series of 132 patients during the COVID-19 outbreak J Am Acad Dermatol 83 1 2020 e61 e63 32339703 16 Freeman E.E. McMahon D.E. Lipoff J.B. Pernio-like skin lesions associated with COVID-19: a case series of 318 patients from 8 countries J Am Acad Dermatol 83 2 2020 486 492 32479979 17 Dyer O. Covid-19: black people and other minorities are hardest hit in US BMJ 369 2020 m1483 32291262 18 Rekhtman S. Tannenbaum T. Strunk A. Birabaharan M. Wright S. Garg A. Mucocutaneous disease and related clinical characteristics in hospitalized children and adolescents with COVID-19 and MIS-C J Am Acad Dermatol 84 2 2021 408 414 33323343
PMC007xxxxxx/PMC7868735.txt
==== Front Rev Fr Allergol (2009) Rev Fr Allergol (2009) Revue Francaise D'Allergologie (2009) 1877-0312 1877-0320 Published by Elsevier Masson SAS. S1877-0320(21)00015-4 10.1016/j.reval.2021.01.001 Éditorial Actualités et souvenirs. Du vaccin Covid-19 à la maladie des moules bronchiques idiopathiques… News and memories. From Covid-19 vaccine to plastic bronchitis…Dutau G. a⁎ a 9, rue Maurice-Alet, 31400 Toulouse, France Lavaud F. b b Service des maladies respiratoires, hôpital Maison-Blanche, CHU de Reims, 45, rue Cognacq-Jay, 51092 Reims, France Didier A. c c Pôle des voies respiratoires, hôpital Larrey, CHU de Toulouse, 24, chemin de Pouvourville–TSA, 30030–31059 Toulouse cedex 9, France ⁎ Auteur correspondant. 8 2 2021 2 2021 8 2 2021 61 1 14 © 2021 Published by Elsevier Masson SAS. 2021 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcLa tradition et les éléments du sommaire de chaque numéro de la Revue Française d’Allergologie — ou « RFA » si l’on veut sacrifier à la mode des acronymes — font que nous essayons, à chaque numéro, de proposer un éditorial. C’est donc une tradition et cela peut-être un exercice plutôt compliqué quand ni les modes, ni les actualités, ne nous inspirent… Il y aurait bien la COVID-19, mais, en si peu de temps, tellement de textes ont été produits que le mot saturation est le plus adapté à la situation. Saturation, certes, mais aussi incertitudes qui persistent sur les éventuels « risques de réactions dites allergiques au vaccin Pfizer BioNTech ». En effet, nous avons tous appris le 18 décembre 2020 que deux soignantes britanniques avaient développé une réaction dite « anaphylactique », débutant 10 min après avoir reçu l’injection du vaccin contre le coronavirus du laboratoire Pfizer. Par la suite 21 cas de réactions anaphylactiques sur 1 893 360 doses ont été rapportés aux États-Unis entre le 14 et le 23 décembre, à la date où ce texte est écrit [1]. Le risque d’anaphylaxie est donc estimé à 11,1 pour un million de doses injectées, très similaire à celui de toute vaccination. Tous les patients ont récupéré sans séquelles et l’accident s’était produit en moyenne 13 minutes après l’injection et dans 72 % des cas avant la quinzième minute. Dix-sept patients avaient un antécédent d’allergie dont 7 un antécédent d’anaphylaxie. Enfin, si 90 % des personnes concernées étaient des femmes il faut pondérer cela par le fait que 64 % des vaccinés étaient aussi des femmes. Bien évidemment, ces effets adverses ont alerté la communauté médicale et il a été recommandé de préciser l’anamnèse allergique des candidats à la vaccination et de les garder en surveillance comme, par exemple, après une injection sous cutanée d’allergènes lors d’une immunothérapie allergénique (ITA). À la date du 31 décembre 2020, une dizaine d’articles avaient déjà été publiés sur ce thème, et nul doute qu’au moment où ce texte paraîtra, il y en aura davantage. Un article de Klimek et al. [2], sous l’égide de ARIA (Allergic Rhinitis and its Impact on Asthma) assure, nous semble-t-il à juste raison, que le rapport bénéfices-risques est clairement en faveur du vaccin, même chez les 30 % (et davantage) de la population générale qui présentent des symptômes allergiques. Toutefois, ces réactions ne sont pas encore totalement documentées, ce qui a conduit, selon le « principe de précaution », à garder en observation pendant 15 min au minimum les personnes qui venaient d’être vaccinées, délai à rallonger à 30 min selon les éventuels antécédents d’anaphylaxie. Sensiblement au même moment, précisant que les mécanismes de ces réactions n’avaient pas actuellement d’explication physiopathologique précise, la FFAL (Fédération française d’allergologie) et la SFA (Société française d’allergologie) rappelaient que « les réactions adverses aux médicaments comme aux vaccins n’étaient pas toutes de nature allergique ». Les lecteurs intéressés consulteront le site les allergies.fr et y trouveront 3 textes récents :• vaccinations contre la Covid et antécédents allergiques ; • communiqué vaccin COVID-19 ; • réactions allergiques contre le SARS-CoV-21 . Les précautions et contre-indications retenues à ce jour figurent dans le Tableau 1 . Celles-ci sont bien sûr susceptibles de se modifier dans les semaines à venir selon le contexte. Ce tableau est accompagné du communiqué que nous reproduisons in extenso : « Récemment, le National Heart and Lung Institut, qui est l’agence de régulation en santé britannique, a suivi les recommandations de la British Society of Allergology and Clinical Immunology (BSACI). Ainsi, la contre-indication de l’administration du vaccin Pfizer/BioNTech pour les patients présentant des réactions allergiques graves vis-à-vis des médicaments et des aliments est modifiée. En effet, à la lumière des milliers de vaccinations qui ont eu lieu en Grande Bretagne, aux États-Unis et au Canada, on peut désormais vacciner avec le vaccin Pfizer/BioNTech les patients qui présentent une allergie médicamenteuse ou alimentaire grave. Cependant, le vaccin reste contre-indiqué chez les patients qui ont une histoire clinique d’allergie vis-à-vis des ingrédients contenus dans le vaccin Pfizer/BioNTech ou qui ont présenté une réaction anaphylactique lors de l’injection de la première dose. L’un des composés du vaccin qui pourrait être mis en cause en tant qu’allergène est le polyéthylène glycol (PEG). La Fédération française FFAL et la SFA sont en accord avec cette nouvelle recommandation. Elles conseillent aux patients allergiques au PEG ou à tout autre composé du vaccin de le signaler à leur médecin traitant » [3].Tableau 1 Vaccination contre la Covid-19 et antécédents allergiques. Résumé des recommandations françaises (SFA/FFAL/CNP allergologie) sur la conduite à tenir. Tableau 1Manifestations allergiques Conseil pour la vaccination Durée de surveillance après vaccination Conduite à tenir spéciale Antécédent d’allergie à un des composants du vaccin, en particulier aux polyéthylène-glycols et par risque d’allergie croisée aux polysorbates Contre indiqué Non vacciné Adresser en allergologie Antécédent de réaction immédiatea, b à une première injection d’un vaccin ARNm COVID 19 Contre indiqué Non vacciné Adresser en allergologie Antécédent de réaction immédiatea, b à un autre vaccin ou à un médicament non identifié Surseoir Vacciné après avis d’expert Adresser en allergologie Toute autre antécédent allergique Vaccination normale 15 à 30 min a Bronchospasme, urticaire généralisée, anaphylaxie. b Hors réaction locale qui autorise la vaccination avec 15 min de surveillance. Au chapitre des actualités, nous rappellerons, s’il en était besoin, que la fréquence de la dermatite atopique (DA), premier élément de l’histoire naturelle de l’atopie, est très élevée et toujours en augmentation. Plus fréquente chez le nourrisson et l’enfant que chez l’adulte, elle affecte au moins 10 % des enfants d’âge inférieur à 10 ans. Plus précisément, aux États-Unis, Silverberg [4] estime que sa prévalence était de 12,98 % en 2007–2009 (chez l’enfant) et de 7,2 % à 10,2 % en 2010–2012 (chez l’adulte) [5] 2 . La dermatite atopique persiste souvent chez l’adulte et, par conséquent, la notion de sa disparition fréquente avec l’âge est un mythe qui a toujours la vie dure ! Dans le présent numéro de la RFA, deux articles originaux sont consacrés, l’un aux soins primaires de la DA dans le cadre d’une enquête auprès de 200 médecins généralistes (MG) et, l’autre, aux dermatites des mains chez les marins de l’aire toulonnaise. Dans le premier, on apprend que 63 % des MG éprouvent des difficultés dans la prise en charge de la DA ce qui n’est pas très étonnant puisque 50 % des MG ont des difficultés vis-à-vis du diagnostic de DA, avec, de plus, un certain ostracisme vis-à-vis des dermocorticoïdes, réservés aux lésions sévères dans 50 % des cas, de durée de prescription très variable, et dont l’efficacité est grevée par l’inobservance fréquente des patients (79 % des cas). Dans le second, on n’est pas surpris d’apprendre que les causes des dermites des mains des marins de l’aire toulonnaise sont les eczémas allergiques (32 % des cas) et que les causes de ces derniers sont le caoutchouc et ses agents de vulcanisation ainsi que les dyshidroses. À cet égard, on se souviendra que la conférence de consensus sur la « Prise en charge de la dermatite atopique de l’enfant » [6], [7] date de 2005 — presque 20 ans déjà — et qu’elle fut organisée par les dermatologues quasi exclusifs. En 16 ans, nous avons enregistré beaucoup d’acquisitions théoriques et pratiques, de sorte qu’un nouveau point d’étape ne serait pas inutile, chez l’adulte et surtout chez les enfants, cela de façon pluridisciplinaire, ne serait-ce que pour insister sur le rôle joué par les pédiatres allergologues, avec l’exemple majeur de l’étude LEAP (Learning About Peanut Allergy) [8], [9]. Dans le domaine de la prévention primaire de la DA du nourrisson, deux grandes études récentes portant l’une sur 1394 enfants [10] et l’autre sur 2397 nouveau-nés [11], suivis respectivement pendant 2 ans et 1 an, montrent que l’application prolongée des émollients actuellement disponibles ne permet pas de prévenir l’apparition d’une dermatite/eczéma atopique. Même si elles ont été effectuées dans deux populations différentes (nourrissons à haut risque allergique et nourrissons issus de la population générale), ces études vont dans le même sens : les émollients actuels ne sont pas capables de prévenir la DA, aussi bien chez les nourrissons à haut risque allergique que chez les nourrissons tout venants, ni de diminuer la fréquence des allergies alimentaires qui, dans l’histoire naturelle de l’atopie, font très souvent suite à la dermatite atopique [10]. Toutefois, des études sont encore nécessaires pour mieux analyser les mécanismes de la fonction barrière de la peau ce qui, logiquement, devrait permettre de perfectionner la classe thérapeutique des émollients et, peut-être, d’obtenir des préparations plus efficaces. Il va de soi que ces résultats ne remettent pas en cause les émollients dans le traitement de la dermatite atopique installée dont ils représentent une option thérapeutique efficace permettant de contrôler la maladie, de lutter contre la xérose et d’assurer une épargne des corticoïdes topiques. Reste le souvenir ! Il y a longtemps, l’un d’entre nous a eu l’occasion d’observer une « maladie des moules bronchiques idiopathiques », maintenant dénommée bronchite plastique chez un enfant âgé de 6 ou 7 ans, sans pathologie apparemment associée, ni respiratoire, ni cardiaque ! Le mécanisme de cette affection reste hypothétique comme en témoigne la revue de Donato et Masilla [12] qui on répertorié une cinquantaine de ces observations curieuses. Dans leur expérience, l’affection s’était révélée par une atélectasie du poumon gauche chez un nourrisson de 17 mois [11], Pour notre part, nous nous souvenons de l’aspect endoscopique de notre patient qui, au premier abord, ressemblait à « l’inhalation d’un morceau de chewing-gum » dans la bronche principale gauche. Mais, devant la survenue de deux autres épisodes, avec expectoration spontanée de quelques moules bronchiques, cette éventualité n’était plus envisageable, si tant est qu’elle l’ait été… Dans un autre cas, chez un enfant plus âgé, l’affection de base était un asthme (Fig. 1, Fig. 2 ).Fig. 1 Moules bronchiques au cours d’une crise d’asthme aigu sévère (Collection Guy Dutau). Fig. 2 Moulage complet de l’arbre bronchique gauche dont ion reconnaît aisément la segmentation (Collection Lionel Donato). Il ne nous reste plus qu’à souhaiter à nos lecteurs et à nos futurs auteurs une très bonne année 2021 même si, dans les circonstances que nous avons vécu depuis un an et probablement allons vivre encore, il est assez « osé » de formuler ce souhait que veut la tradition. Cela va sans dire, le désormais « prenez soin de vous » — take care of yourself — est adressé à tous, sans oublier la formule aussi indispensable, sinon plus « prenez soin des autres » ! Et comme il faut penser aux dérivatifs, et ils sont nombreux, n’oubliez pas d’écrire pour votre « RFA » : des article originaux, des revues générales, des faits cliniques (vous en avez tous !) et aussi, car c’est une bonne formule, des « Lettres à la rédaction » : elles permettent de publier un cas rapide, d’entamer une discussion sur des textes parus antérieurement (ce n’est pas interdit !), et de prendre date pour la publication d’un article plus important. C’est ainsi que vous nous aiderez à faire vivre notre revue. Déclaration de liens d’intérêts Les auteurs déclarent ne pas avoir de liens d’intérêts. 2 Dans un article récent (Bawany et al, référence no 21), les auteurs indiquent des fourchettes de prévalence allant de 15% à 30% (chez l’enfant) et de 2% à 10% (chez l’adulte). 1 Premier communiqué de la Société française d’allergologie en date du 11 décembre 2020 : « La Société française d’allergologie (SFA) a pris connaissance de deux cas de réactions d’allure allergique survenus en Grande-Bretagne chez deux personnels de santé, après l’administration de la première dose du vaccin à ARNm de Pfizer-BioNTech. Ces manifestations ont concerné deux personnes ayant déjà eu des réactions allergiques sévères. Elles ont guéri sans séquelle. Le mécanisme de ces réactions et leur cause sont à l’heure actuelle non précisés et en cours d’analyse par les autorités de santé britanniques. Cette analyse devrait permettre de déterminer si ces réactions sont spécifiques ou pas au type de vaccin utilisé. La SFA tient à rappeler que les réactions allergiques vaccinales sont rares mais bien connues des allergologues et qu’il existe des procédures permettant l’administration en sécurité des vaccins chez les sujets à haut risque allergique ». Ibid. (consulté le 15 janvier 2021) ==== Refs Références 1 Allergic reactions including anaphylaxis after receipt pf the first dose ofPfizer-BioNtech Covid-19 vaccine-United States, December 14–23, 2020 MMWR 70 2021 46 51 33444297 2 Klimek L. Jutel M. Akdis C.A. Bousquet J. Akdis M. ARIA-EAACI statement on severe allergic reactions to COVID-19 vaccines - an EAACI-ARIA position paper Allergy 2020 10.1111/all.14726 [Online ahead of print] 3 Communiqué – Vaccin COVID-19 2021 https://sfa.lesallergies.fr/communique/ 4 Silverberg J.I. Public health burden and epidemiology of atopic dermatitis Dermatol Clin 35 3 2017 283 289 28577797 5 Bawany F. Beck L.A. Järvinen K.M. Halting the march: primary prevention of atopic dermatitis and food allergies J Allergy Clin Immunol 8 2020 860 875 10.1016/j.jaip.2019.12.005 6 Conférence de consensus. Prise en charge de la dermatite atopique de l’enfant Ann Dermatol Venereol 132 1 2005 81 91 15746619 7 Conférence de consensus. Prise en charge de la dermatite atopique de l’enfant Ann Dermatol Venereol 132 2005 1S9-18 http://www.cliderm.be/wp-content/uploads/9996-Dermatite-atopique.pdf (page S15) [Consulté le 15 janvier 2021]. 8 Lack G. Epidemiologic risks for food allergy J Allergy Clin Immunol 121 6 2008 1331 1336 18539191 9 Du Toit G. Roberts G. Sayre P.H. Bahson H.T. Radulovic S. Santos A.E. Randomized trial of peanut consumption in infants at risk for peanut allergy N Engl J Med 372 9 2015 803 813 25705822 10 Chalmers J.R. Haines R.H. Bradshaw L.E. Montgomery A.A. Daily emollient during infancy for prevention of eczema: the BEEP randomised controlled trial Lancet 395 10228 2020 962 972 32087126 11 Skjerven H.O. Rehbinder E.M. Vettukattil R. LeBlanc M. Granum B. Haugen G. Skin emollient and early complementary feeding to prevent infant atopic dermatitis (PreventADALL): a factorial, multicentre, cluster-randomised trial Lancet 395 10228 2020 951 961 32087121 12 Donato L. Mansilla M. Maladie des moules bonchiques chez lm’enfant Rev Fr Allergol 52 2 2012 90 96
PMC007xxxxxx/PMC7905375.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 Published by Elsevier on behalf of the American Academy of Dermatology, Inc. S0190-9622(21)00420-5 10.1016/j.jaad.2021.02.056 JAAD Online Response to: “Comment on ‘The spectrum of COVID-19-associated dermatologic manifestations: An international registry of 716 patients from 31 countries’” Freeman Esther E. MD, PhD ab∗ McMahon Devon E. BA a Desai Seemal R. MD cd Fox Lindy P. MD e a Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts b Medical Practice Evaluation Center, Mongan Institute, Massachusetts General Hospital, Boston, Massachusetts c The University of Texas Southwestern Medical Center, Dallas, Texas d Innovative Dermatology, Plano, Texas e Department of Dermatology, University of California San Francisco, San Francisco, California ∗ Correspondence and reprint requests to: Esther E. Freeman, MD, PhD, Department of Dermatology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114 25 2 2021 6 2021 25 2 2021 84 6 e293e294 © 2021 Published by Elsevier on behalf of the American Academy of Dermatology, Inc. 2021 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: We thank Baab et al1 for their commentary on our article “The spectrum of COVID-19-associated dermatologic manifestations: An international registry of 716 patients from 31 countries.” The authors bring up important concerns, which we note in our limitations, including the lack of photo/biopsy evidence of COVID-19 dermatologic manifestations and limited laboratory confirmation. These issues are a result of the nature of registry-based case entry and poor availability of laboratory COVID-19 testing early in the pandemic. The authors also note the lack of racial/ethnic diversity in our registry, which we agree is concerning and may be due in part to a deficiency in providers recognizing COVID-19 dermatologic manifestations in the skin of people of color.2 Efforts to educate the medical community to recognize dermatologic disease in people of color are key. One example is the educational curriculum created by the Skin of Color Society, developed to aid trainees and dermatologists to recognize inflammatory skin eruptions in darker skin tones. Training in earlier recognition/diagnosis will hopefully help bridge health disparities and improve outcomes in diverse populations. As a specialty, we must also advocate broader access to dermatologic care in tandem with these educational efforts.3 However, we disagree that case entry by non-dermatologists weakens our claims. During the early COVID-19 pandemic, many dermatology offices were closed and operations temporarily halted. It was therefore non-dermatology frontline workers who were evaluating patients with COVID-19, and their inclusion was essential in recognizing potentially associated cutaneous manifestations. We would like to point readers to Supplemental Table II of our article, where we showed that cutaneous manifestations reported by dermatologists alone are similar to morphologies reported by all healthcare workers. We are now almost a year out from launching the American Academy of Dermatology (AAD) and International League of Dermatological Societies COVID-19 Dermatology registry, which went live in April 2020. The pitfalls of registry-collected data remain, including the inability to estimate incidence/prevalence without a denominator and challenges of ensuring the representativeness of cases. However, the registry has significant strengths, such as rapid case collection, enhancing international collaboration, and the ability to form hypotheses through real-time data analysis.4 Our registry has grown significantly from the referenced publication of 716 patients. We have almost doubled this number to 1253 patients with dermatologic manifestations associated with COVID-19, many of whom now have undergone more robust laboratory testing, allowing us to explore nuances of test timing and test positivity/negativity in mild disease.5 The 7 publications from the registry to date must be viewed through the lens of the public health emergency, as the scientific community moved from no known skin findings associated with COVID-19 to characterizing the cutaneous manifestations and their potential implications within just a few months. We have recently expanded the AAD/International League of Dermatological Societies COVID-19 Dermatology Registry to collect cutaneous manifestations of the novel COVID-19 vaccines. This registry grows daily as COVID-19 vaccines roll out across the world. The role of dermatologists in understanding cutaneous reactions to the COVID-19 vaccines demonstrates our specialty's critical impact, not only to this specific public health effort, but also to the House of Medicine at large. Conflicts of interest Drs Freeman, Desai, and Fox are members of the AAD COVID-19 Ad Hoc Task Force. Author McMahon has no conflicts of interest to declare. Funding sources: None. IRB approval status: Not applicable. ==== Refs References 1 Baab K. Dunnick C. Dellavalle R.P. Comment on “The spectrum of COVID-19-associated dermatologic manifestations: an international registry of 716 patients from 31 countries.” J Am Acad Dermatol 84 6 2021 e291 e292 33640510 2 Lester J.C. Jia J.L. Zhang L. Okoye G.A. Linos E. Absence of images of skin of colour in publications of COVID-19 skin manifestations Br J Dermatol 183 3 2020 593 595 32471009 3 Buster K.J. Stevens E.I. Elmets C.A. Dermatologic health disparities Dermatol Clin 30 1 2012 53 59 viii 22117867 4 Freeman E.E. McMahon D.E. Hruza G.J. International collaboration and rapid harmonization across dermatologic COVID-19 registries J Am Acad Dermatol 83 3 2020 e261 e266 32562840 5 Freeman E.E. McMahon D.E. Hruza G.J. Timing of PCR and antibody testing in patients with COVID-19-associated dermatologic manifestations J Am Acad Dermatol 84 2 2021 505 507 32920037
PMC007xxxxxx/PMC7930730.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(21)00487-4 10.1016/j.jaad.2021.02.076 JAAD Online A response to “Mucocutaneous disease and related clinical characteristics in hospitalized children and adolescents with COVID-19 and multisystem inflammatory syndrome in children’’ Sert Ahmet MD ∗ Department of Pediatric Cardiology, Selçuk University Medical School, Konya, Turkey ∗ Correspondence and reprint requests to: Ahmet Sert, MD, Department of Pediatric Cardiology, Selçuk University Medical School, Konya 42130, Turkey 4 3 2021 6 2021 4 3 2021 84 6 e301e302 © 2021 by the American Academy of Dermatology, Inc. 2021 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: I read with great interest the article by Rekhtman et al1 which describes the association between mucocutaneous disease and clinical course among hospitalized children and adolescents with COVID-19 and multisystem inflammatory syndrome in children (MIS-C) in dermatology practice. First, I thank the authors for drawing attention to MIS-C findings. In addition, I have highlighted some important points on MIS-C from the perspective of pediatric cardiology. As the authors have indicated in Table II of their article, closely monitoring patients for cardiac involvement is important. MIS-C typically occurs a few weeks after acute infection, and the recognized etiology is a dysregulated inflammatory response to SARS-CoV-2 infection. Persistent fever and gastrointestinal symptoms are the most common symptoms. Cardiac manifestations, such as ventricular dysfunction, coronary artery dilation and aneurysms, arrhythmia, and conduction abnormalities, are also common.2 Further characterization of the relationship between mucocutaneous disease and coronary involvement in patients with MIS-C can provide important information regarding the course of the disease. Second, based on a small number of patients, the authors suggested some differences in outcomes when comparing the 2 groups of patients with MIS-C with and without rashes. As they have indicated, larger studies are necessary to confirm these observations. The authors have suggested that MIS-C patients with rashes were observed to have less frequent pediatric intensive care unit admission, shock, and the requirement for invasive mechanical ventilation than those without rashes. I believe that the main reason for a longer hospitalization period in MIS-C patients without rashes may be cardiac involvement, which is one of the most important prognostic factors. While evaluating these patients, the severity of cardiac involvement and mucocutaneous disease should also be considered. Third, based on their observations, Rekhtman et al1 have suggested that criteria for Kawasaki disease (KD) may not adequately apply to MIS-C and that MIS-C criteria should include an expansion of morphologic patterns of mucocutaneous disease. Although the authors' description of mucocutaneous findings may support the development of criteria for MIS-C, characterization of additional systemic features will also be required. Recent studies reveal more clearly the distinguishing features between MIS-C and KD. Although MIS-C shares several similarities with KD, they have several different clinical features. Gastrointestinal complications, shock, and coagulopathy are more common in patients with MIS-C, which are unusual in classic KD. Classic KD is common in North-East Asian countries, whereas MIS-C has been more commonly reported in African, Hispanic, or Latino children. KD is common in children below 5 years, whereas MIS-C is more common in older children.3 Yasuhara et al4 have noted that MIS-C manifests with a higher incidence of myocardial dysfunction and gastrointestinal symptoms than KD. Moreover, the extent of the elevation of inflammatory biomarkers and cardiac markers in MIS-C are significantly higher than that in KD. These marked differences suggest that MIS-C and KD are 2 distinct diseases with overlapping clinical characteristics. In my opinion, these patients should be managed with a multidisciplinary approach to improve prognosis. Conflicts of interest None disclosed. Funding sources: None. IRB approval status: Not applicable. ==== Refs References 1 Rekhtman S. Tannenbaum R. Strunk A. Birabaharan M. Wright S. Garg A. Mucocutaneous disease and related clinical characteristics in hospitalized children and adolescents with COVID-19 and multisystem inflammatory syndrome in children J Am Acad Dermatol 84 2 2021 408 414 33323343 2 Alsaied T. Tremoulet A.H. Burns J.C. Review of cardiac involvement in multisystem inflammatory syndrome in children Circulation 143 1 2021 78 88 33166178 3 Kabeerdoss J. Pilania R.K. Karkhele R. Kumar T.S. Danda D. Singh S. Severe COVID-19, multisystem inflammatory syndrome in children, and Kawasaki disease: immunological mechanisms, clinical manifestations and management Rheumatol Int 41 1 2021 19 32 33219837 4 Yasuhara J. Watanabe K. Takagi H. Sumitomo N. Kuno T. COVID-19 and multisystem inflammatory syndrome in children: a systematic review and meta-analysis Pediatr Pulmonol 2021 10.1002/ppul.25245
PMC007xxxxxx/PMC7955564.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(21)00571-5 10.1016/j.jaad.2021.02.085 Research Letter Dermatology applicant perspectives of a virtual visiting rotation in the era of COVID-19 Adusumilli Nagasai C. MBA Kalen Jessica MD Hausmann Kayleigh MPH Friedman Adam J. MD ∗ Department of Dermatology, The George Washington University School of Medicine and Health Sciences, Washington, District of Colombia ∗ Correspondence and reprint requests to: Adam J. Friedman, MD, Department of Dermatology, The George Washington University School of Medicine and Health Sciences, 2150 Pennsylvania Avenue, NW, 2nd Floor, Washington, DC 20037 13 3 2021 6 2021 13 3 2021 84 6 16991701 © 2021 by the American Academy of Dermatology, Inc. 2021 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: The COVID-19 pandemic has disrupted many aspects of undergraduate medical education, including clinical rotations and United States medical licensing examinations.1 The coalition for physician accountability has recommended the suspension of away (ie, visiting or external) rotations for the 2020-2021 residency application cycle, with exceptions of students without a home residency program and students needing them for graduation or accreditation requirements.2 Away rotations, completed at a medical school outside of their institution, are key for students applying to the field of dermatology for expanding opportunities for advanced clinical experiences, individualized mentorship, and an insight into resident life.3 Programs also benefit from evaluating candidates’ “fit” for their residency over an “audition” period. The visiting rotation freeze complicated this application cycle for both stakeholders but provided an opportunity to address the historical inaccessibility of away rotations for many.4 , 5 To tackle this limitation in hosting external students, our program organized a 4-week virtual visiting rotation allowing students to interact remotely with residents and faculty. Through videoconferencing platforms, learners actively participated in various academic activities, such as journal club, clinicopathologic conference, grand rounds, and resident didactics. Virtual “happy hours” and faculty mentoring sessions allowed for more personalized engagement. At the conclusion of the virtual rotations, the students were surveyed to evaluate their experience. The participants were asked about their priorities for an away rotation and the opportunity to meet those expectations, level of satisfaction on various facets of our offering, and whether they would have had the opportunity to visit our program if in-person away rotations were not canceled. With an overall response rate of 75% (n = 18), majority of the rotators reported “very satisfied” with the clinical curriculum, learning objectives, formal didactics, ability to assess program culture, opportunity to demonstrate interest, access to the residents, faculty advising, and diversity and inclusion initiatives (61%, 67%, 100%, 100%, 72%, 100%, 72%, and 83%, respectively; Fig 1 ). They viewed research opportunities and obtaining letters of recommendation as “not applicable” (Fig 1), but these aspects were also not the highest priorities reported (Fig 2 ). The students acknowledged that they received ample opportunity to meet their priorities for an away rotation (78%; Supplemental Fig 1, A, available via Mendeley at https://data.mendeley.com/datasets/6d9zg7m4h9/2), and 39% noted that they might not have had the traditional advantage to rotate with this program (Supplemental Fig 1, B).Fig 1 Self-reported level of satisfaction with various features of the virtual visiting program. Fig 2 Self-reported priorities for an away rotation. The nationwide discussion of adapting medical education and our sampling of applicant perspectives reflect the need for further data-driven exploration of virtual away rotations. The intrinsic selection and acquiescence biases in polling students interested in this specific program were addressed with informed consent emphasizing anonymity and no effect on evaluations, and recall bias was minimized by survey completion on a rolling basis immediately after a student's rotation ended. Academic faculty's views were not examined. Despite these limitations, our findings illustrated that the priorities of away rotations can be met through a virtual model and that remote alternatives can capture candidates unable to leverage a physical clinical rotation. Investing resources to establish or improve virtual visiting electives will not only mitigate challenges in this application cycle but also catalyze changes that address financial and scheduling inequities inherent to the traditional away rotation system. Conflicts of interest None disclosed. Funding Sources: None. IRB approval status: Designated as exempt (NCR203119). ==== Refs References 1 Rose S. Medical student education in the time of COVID-19 JAMA 323 21 2020 2131 2132 32232420 2 Coalition for Physician Accountability Final report and recommendations for medical education institutions of LCME-accredited, US osteopathic, and non-US medical school applicants Available at: https://www.aamc.org/system/files/2020-05/covid19_Final_Recommendations_05112020.pdf 3 Cao S.Z. Nambudiri V.E. A national cross-sectional analysis of dermatology away rotations using the visiting student application service database Dermatol Online J 23 12 2017 1 4 4 Griffith M. DeMasi S.C. McGrath A.J. Love J.N. Moll J. Santen S.A. Time to reevaluate the away rotation: improving return on investment for students and schools Acad Med 94 4 2019 496 500 30379660 5 Winterton M. Ahn J. Bernstein J. The prevalence and cost of medical student visiting rotations BMC Med Educ 16 1 2016 1 7 26727954
PMC007xxxxxx/PMC7965841.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(21)00580-6 10.1016/j.jaad.2021.03.034 JAAD Online Preliminary outcomes of 2020-2021 dermatology residency application cycle and adverse effects of COVID-19 Thatiparthi Akshitha BS a Martin Amylee BS b Liu Jeffrey BS c Wu Jashin J. MD d∗ a College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California b School of Medicine, University of California, Riverside, California c Keck School of Medicine, University of Southern California, Los Angeles, California d Dermatology Research and Education Foundation, Irvine, California ∗ Correspondence and reprint requests to: Jashin J. Wu, MD, Dermatology Research and Education Foundation, Irvine, CA 92620. 17 3 2021 6 2021 17 3 2021 84 6 e263e264 © 2021 by the American Academy of Dermatology, Inc. 2021 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: Due to the SARS-CoV-2 (COVID-19) pandemic, the dermatology residency application cycle was altered to mitigate adverse outcomes. The resulting actions necessitate governance processes to monitor outcomes and effects. In December 2020, the Association of American Medical Colleges (AAMC) indicated that there was a “maldistribution of residency interview invitations,” with increased invitations to the “highest tier applicants.”1 Programs and students were encouraged to increase the number of rankings, with a recommendation for programs to focus on diversification. The AAMC also recommended students with abundant interviews to release some interviews.1 Overall, there was an imbalance in the average number of interviews offered to applicants. Interestingly, preliminary 2021 application data showed a steady increase in the number of applicants over the last 6 years.2 Compared with 2016, the total number of applicants increased by 19.7%, the average applications submitted increased by 6.2%, and the average applications received by programs increased by 6.5% in 2021.2 However, the number of dermatology programs increased by 12.5% from the 2016-2017 to 2019-2020 academic years, with 527 open residency positions for the 2020 cycle.1 , 3 As discrepancy increases between dermatology applicants and positions, solutions must be sought. A potential solution is to limit the total applications submitted and interviews accepted (12-14, matching probability >95%) with the support of majority stakeholders.4 An applicant's accepted invites will be blinded to programs, allowing the prioritization of interviews. The difficulty lies in the feasibility of implementation because the AAMC is financially disincentivized to change the status quo. Residency applications provide 41.1% (94 million) of the AAMC's total revenue.5 The Electronic Residency Application Service revenue increased at 9.0% compounding annual growth rate (2009-2019) compared with the applications submitted, which increased by 6.2% (2016-2021), and a potential explanation is the increase in application fees to offset operational expenses.2 , 5 Additionally, we encourage programs to participate in coordinated releases with a sequential multi-step timeline, allowing 2 weeks to evaluate invites and prepare for the next steps, repeated in multiple rounds. The current coordinated release was a great first attempt; however, further modifications are required. Sequential processes allow participants and programs to better plan and coordinate interview logistics. However, interview maldistribution might persist with a preponderance for “highest tier applicants” through each release. This downfall could be alleviated when implemented in combination with preferential signaling, allowing holistic applicant review. With favorable outcomes for PhD candidates and in predictive models, the 2020-2021 otolaryngology match cycle uniquely implemented a 5-token preference signaling.4 The implementation of preference signaling in dermatology would allow the applicants to signal serious interest, which was previously indicated through rotations.4 Programs can holistically review select candidates.4 As 7%-21% of applicants receive over half of the interviews, the token system will allow for a comprehensive review.4 However, the students may be interested in more than the allotted token number and may not be able to change their choice if their interests change over the interview season. Rolling tokens are not recommended as the applicants could send preference signals to numerous programs. These combined steps might allow for the maximization of successful matching. The changes to the dermatology residency application cycle have resulted in increased barriers for the applicants and programs. We anticipate these challenges may affect the next match cycle as COVID-19 cases may still persist. Overall, we hope our recommendations will trigger positive system-wide changes allowing for greater transparency and support of applicants. Conflict of interest None disclosed. Funding sources: None. IRB approval status:Not applicable. ==== Refs References 1 Association of American Medical Colleges Open Letter on Residency Interviews AAMC 2020 Accessed December 18, 2020. Available at: https://www.aamc.org/media/50291/download 2 Association of American Medical Colleges MEDICAL EDUCATION: ERAS Statistics AAMC 2020 Accessed December 18, 2020 https://www.aamc.org/data-reports/interactive-data/eras-statistics-data 3 ACGME Data Resource Book Accreditation Council for Graduate Medical Education Available at: https://www.acgme.org/About-Us/Publications-and-Resources/Graduate-Medical-Education-Data-Resource-Book 4 Hammoud M.M. Standiford T. Carmody J.B. Potential implications of COVID-19 for the 2020-2021 residency application cycle JAMA 324 1 2020 29 30 32492097 5 Organizations N.E.R.T.-E. Association of American Medical Colleges Available at: https://projects.propublica.org/nonprofits/organizations/362169124
PMC007xxxxxx/PMC7968167.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(21)00589-2 10.1016/j.jaad.2021.02.087 Original Article The risk of COVID-19 in patients with bullous pemphigoid and pemphigus: A population-based cohort study Kridin Khalaf MD, PhD ab∗ Schonmann Yochai MD, MSc c Weinstein Orly MD, MPH cd Schmidt Enno MD, PhD a Ludwig Ralf J. MD a Cohen Arnon D. MD, PhD cd a Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany b Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel c Clalit Health Services, Tel-Aviv, Israel d Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel ∗ Correspondence and reprint requests to: Khalaf Kridin, MD, PhD, Lübeck Institute of Experimental Dermatology, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany. 17 3 2021 7 2021 17 3 2021 85 1 7987 14 2 2021 © 2021 by the American Academy of Dermatology, Inc. 2021 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Background The burden of COVID-19 in patients with bullous pemphigoid (BP) and pemphigus is yet to be evaluated. Objective To assess the risks of COVID-19 and COVID-19-associated hospitalization and mortality in patients with BP and pemphigus and to delineate determinants of severe COVID-19 illness among these patients. Methods A population-based cohort study compared COVID-19 and its complications in patients with BP (n = 1845) and pemphigus (n = 1236) with age-, sex-, and ethnicity-matched control subjects. Results The risks of COVID-19 (hazard rate [HR], 1.12; 95% confidence interval [CI], 0.72-1.73; P = .691) and COVID-19-associated hospitalization (HR, 1.58; 95% CI, 0.84-2.98; P = .160) was comparable between patients with BP and controls. The risk of COVID-19-associated mortality was higher among patients with BP (HR, 2.82; 95% CI, 1.15-6.92; P = .023). The risk of COVID-19 (HR, 0.81; 95% CI, 0.44-1.49; P = .496), COVID-19-associated hospitalization (HR, 1.41; 95% CI, 0.53-3.76; P = .499), and COVID-19-associated mortality (HR, 1.33; 95% CI, 0.15-11.92; P = .789) was similar in patients with pemphigus and their controls. Systemic corticosteroids and immunosuppressants did not predispose COVID-19-positive BP and pemphigus patients to a more severe illness. Limitations Retrospective data collection. Conclusions Patients with BP experience increased COVID-19-associated mortality and should be monitored closely. Maintaining systemic corticosteroids and immunosuppressive adjuvant agents during the pandemic is not associated with worse outcomes. Key words bullous pemphigoid coronavirus disease 2019 COVID-19 hospitalization mortality pemphigus Abbreviations used AIBD autoimmune bullous diseases BP bullous pemphigoid CHS Clalit Health Services CI confidence interval HR hazard ratios ==== Body pmc Capsule Summary • Patients with bullous pemphigoid and pemphigus do not have an increased risk of COVID-19 infection relative to control individuals but COVID-19-associated mortality may be elevated. • COVID-19-positive bullous pemphigoid patients should be followed and monitored closely. • The use of systemic corticosteroids and immunosuppressive adjuvants did not predict worse COVID-19 outcomes and should not be ceased during the pandemic. Introduction The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), started in China in late 2019 and has subsequently spread across the globe. Because severe COVID-19 is associated with a hyperinflammatory state,1 , 2 it is intriguing to investigate whether the presence of preexisting autoimmune diseases or past use of immunosuppressive agents affect the phenotype of COVID-19. Although certain studies demonstrated an increased risk and more aggressive course of SARS-CoV-2 infection in patients with autoimmune diseases,3, 4, 5 most others refuted this finding.6, 7, 8, 9, 10 Bullous pemphigoid (BP) and pemphigus are the most frequent autoimmune bullous diseases (AIBD) worldwide.11, 12, 13 Both diseases are associated with a life-threatening potential and impose an increased burden of mortality.13, 14, 15 The management of AIBD is challenging and often necessitates the administration of high-dose systemic corticosteroids and immunosuppressive agents.16 , 17 Treatment of these diseases represents an even greater challenge in light of the COVID-19 pandemic, given concerns about the vulnerability of pharmacologically immunosuppressed patients.18 The burden of COVID-19 and its complications for patients with AIBD has yet to be delineated, thus leaving the literature underpowered to formulate a treatment strategy for these patients during the pandemic. To optimize the treatment of AIBD, the predictors of worse outcomes in COVID-19-positive AIBD patients need to be identified and what influence AIBD-related medications may have on the prognosis of patients needs to be defined. The aims of the current study are to evaluate the risk that patients with BP and pemphigus have for acquiring COVID-19 infection and developing its complications and to identify determinants predicting a severe COVID-19 course among these patients. Methods Study design and dataset The current study was designed as a historical retrospective cohort study that followed patients with BP and pemphigus to estimate the incidence of COVID-19, COVID-associated hospitalization, and mortality. The current study received institutional review board approval before the start. The computerized data set of Clalit Health Services (CHS) was the origin of the current study. CHS is the main health maintenance organization in Israel and provides private and public health care services; as of October 2018, CMS had more than 4,540,768 enrollees. CHS is renowned for its inclusiveness because it retrieves data from a multitude of sources and covers a range of settings, including general community clinics, primary care and referral centers, and ambulatory care centers and hospitals. The loss to follow-up is negligible and access to CHS services is free, rendering this data set highly compatible with the performance of reliable epidemiologic studies.19 Study population and definition of main variables The computerized data set of CHS was systematically checked for incident cases with a diagnostic code of BP and pemphigus between the years 2002 and 2019. Patients were determined eligible if a documented diagnosis of BP or pemphigus was registered by a community-based board-certified dermatologist or if a diagnosis of BP or pemphigus was documented in discharge letters of patients admitted to dermatologic wards. A control group encompassing 5 individuals per case of BP and pemphigus was originally recruited, with controls being matched based on sex, age, and ethnicity. The index date of matching was defined at the diagnosis of BP and pemphigus. The current analysis, however, included only participants who were alive at the beginning of the pandemic (Supplemental Fig 1 available via Mendeley at https://data.mendeley.com/datasets/f3rcw5rfjz/1.) Dates of death were ascertained by linking the study cohort with the National Registry of Deaths Database. All study participants were followed up from the onset of the pandemic in Israel (defined as the date of the first confirmed case on February 27, 2020) until September 11, 2020, or their death. The diagnosis of COVID-19 relied on confirmation of cases by the molecular tests approved by the United States (US) Food and Drug Administration. COVID-19-associated hospitalization was defined as a COVID-19-confirmed patient who is admitted to an intensive care unit or an internal medicine or pulmonology inpatient ward. All hospitalized patients with COVID-19 were assigned 1 of the following severity degrees: mild (symptoms, such as cough, fever, fatigue, loss of smell, etc); moderate (clinical or radiologic diagnosis of COVID-19 pneumonia); severe (respiratory rate > 30, oxygen saturation <93% on room air, and PaO2/FiO2 < 300); and critical (severe systemic impairment, including septicemia or cardiac, hepatic, or renal insufficiency). The severity degree for non-hospitalized COVID-19-confirmed patients who were not managed in a health care facility was defined as subclinical. Outcome measures were adjusted for underlying comorbidities as assessed by the Charlson comorbidity index, a validated epidemiologic method of quantifying comorbidities. This index is reliable in predicting mortality and is widely used in large-scale epidemiologic studies.20 Among others, Charlson comorbidity index encompasses diabetes mellitus and respiratory and cardiovascular diseases, for which there is evidence that they have the worse COVID-19 prognostic outcomes.21 COVID-19-associated hospitalization and mortality were adjusted for smoking owing to the association of the latter with worse outcomes for COVID-19.21 , 22 COVID-19-associated hospitalization and mortality were adjusted for systemic corticosteroids and immunosuppressive adjuvant drugs (azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide, rituximab), given the accumulation of evidence suggesting the vulnerability of pharmacologically immunosuppressed COVID-19 patients.23 Statistical analysis Baseline characteristics were described by means and standard deviations (SD)s for continuous variables. Category values were indicated by percentages. Variables were compared using the chi-square test and t-test for category and continuous variables, respectively. Incidence rates of outcomes were calculated and expressed as the number of events per 1000 person-years. Hazard ratios (HRs) for the risk of incident outcomes were obtained using the Cox regression model. The cumulative survival of patients with COVID-19 was compared between the BP and pemphigus groups and their corresponding controls using a stratified log-rank test in the Kaplan-Meier method. Results Characteristics of the study population The study population included 1845 patients with BP and 1236 patients with pemphigus. In all, 11,117 and 6574 control subjects were matched for the eligible patients with BP and pemphigus, respectively. Although the sex and ethnic composition was comparable between cases and controls, patients with BP and pemphigus were older than their matched controls at the onset of the pandemic (Supplementary Table I). Both patients with BP and pemphigus had higher mean Charlson comorbidity index scores, whereas patients with pemphigus had lower frequency of smoking (Supplementary Table II). The demographic and clinical features of the study participants are detailed in Supplementary Table I. Descriptive data for COVID-19-positive BP and pemphigus patients Overall, 24 (1.3%) patients with BP tested positive for COVID-19. The disease was subclinical in 12 (50.0%), mild in 4 (16.7%), moderate in 2 (8.3%), and severe in 6 (25.0%). Although 12 (50.0%) patients were hospitalized, not the same that had a subclinical disease, due to COVID-19 complications, none of them underwent mechanical ventilation. Six (25.0%) patients died following COVID-19 infection (Fig 1 ).Fig 1 The different features of COVID-19 among patients with bullous pemphigoid and pemphigus. A, severity; B, hospitalization; C, mortality. Twelve (1.0%) patients with pemphigus had a COVID-19 infection. While 7 (58.3%) patients had a subclinical disease, 2 (16.7%) had a mild disease, 2 (16.7%) had moderate disease, and 1 (8.3%) had severe disease. Five (41.7%) patients were hospitalized, but none was mechanically ventilated. One patient (8.3%) died following COVID-19 infection (Fig 1). Matched controls of BP presented with 130 (1.2%) cases of COVID-19, of whom 84 (64.6%), 11 (8.5%), 13 (10.0%), and 22 (16.9%) were subclinical, mild, moderate, and severe, respectively. Matched controls of pemphigus had 79 (1.2%) COVID-19 positive cases, with 60 (75.9%), 2 (2.5%), 5 (6.3%), and 12 (15.2%) individuals presenting with subclinical, mild, moderate, and severe disease, respectively. The risk of COVID-19 among patients with bullous pemphigoid The incidence rate of COVID-19 among patients with BP was estimated to be 24.4 (95% CI, 16.0-35.7) per 1,000 person-years. The incidence rates of hospitalization and mortality due to COVID-19 complications were 12.2 (95% CI, 6.6-20.7) and 7.1 (95% CI, 3.1-14.0) per 1000 person-years, respectively. The unadjusted risk of acquiring the infection (HR, 1.12; 95% CI, 0.72-1.73; P = .691) and being hospitalized due to the infection (HR, 1.58; 95% CI, 0.84-2.98; P = .160) were comparable between patients with BP and their control subjects (Table I ). However, the risk of COVID-19-associated mortality was significantly higher among patients with BP as compared to their matched control subjects (HR, 2.82; 95% CI, 1.15-6.92; P = .023; Fig 2 , A). Increased mortality was more prominent among individuals older than 80.8 years of age (HR, 3.21; 95% CI, 1.21-8.56; P = .020) and persisted following adjustment for age, sex, ethnicity, comorbidities, exposure to systemic corticosteroids and immunosuppressants, and smoking (adjusted HR, 2.81; 95% CI, 1.14-6.94; P = .025).Table I The risk of COVID-19 and its complications among patients with bullous pemphigoid COVID-19 infection COVID-19-associated hospitalization COVID-19-associated mortality BP Controls BP Controls BP Controls Follow-up time, PY 984.9 5,947.6 986.4 5,958.0 987.8 5,964.3 Median follow-up time, years (range) 0.5 (0.1-0.5) 0.5 (0.1-0.5) 0.5 (0.1-0.5) 0.5 (0.1-0.5) 0.5 (0.1-0.5) 0.5 (0.1-0.5) Number of events 24 130 12 46 7 15 Incidence rate/1000 PY (95% CI) 24.4 (16.0-35.7) 21.9 (18.3-25.9) 12.2 (6.6-20.7) 7.7 (5.7-10.2) 7.1 (3.1-14.0) 2.5 (1.5-4.1) Unadjusted HR (95% CI) [P value] 1.12 (0.72-1.73) [.619] Reference 1.58 (0.84-2.98) [.160] Reference 2.82 (1.15-6.92) [.023]‡ Reference Adjusted HR (95% CI) [P value] 1.10 (0.71-1.71) [.665]∗ Reference 1.63 (0.86-3.09) [.133] † Reference 2.81 (1.14-6.94) [.025]†,‡ Reference Sex- and age-stratified analysis  Male-specific HR (95% CI) [P value] 0.91 (0.43-1.90) [.796] Reference 1.13 (0.39-3.29) [.819] Reference 3.13 (0.78-12.50) [0.107] Reference  Female-specific HR (95% CI) [P value] 1.26 (0.73-2.17) [.395] Reference 1.98 (0.89-4.40) [.096] Reference 2.63 (0.81-8.53) [.108] Reference  ≥80.8 year-specific HR (95% CI) [P value] 1.51 (0.88-2.61) [.135] Reference 1.93 (0.92-4.06) [.084] Reference 3.21 (1.21-8.56) [.020]‡ Reference  <80.8 year-specific HR (95% CI) [P value] 0.73 (0.35-1.53) [.403] Reference 1.07 (0.31-3.65) [.921] Reference 1.89 (0.20-18.18) [.581] Reference BP, Bullous pemphigoid; CI, confidence interval; HR, hazard ratio; N, Number; PY, person-year. ∗ Multivariate logistic regression model adjusting for age, sex, ethnicity, and comorbidities (as estimated by Charlson comorbidity index). † Multivariate logistic regression model adjusting for age, sex, ethnicity, comorbidities (as estimated by Charlson comorbidity index), intake of systemic corticosteroids and immunosuppressant, and smoking. ‡ denotes significant value. Fig 2 Survival of patients with bullous pemphigoid (A) and pemphigus (B) as compared to control subjects since the onset of the pandemic, as illustrated by Kaplan-Meier survival curves. The risk of COVID-19 among patients with pemphigus Among patients with pemphigus, the incidence rates of COVID-19 infection, COVID-19-associated hospitalization, and mortality were 18.1 (95% CI, 9.8-30.8), 7.5 (95% CI, 2.8-16.7), and 1.5 (95% CI, 0.1-7.4) per 1,000 person-years, respectively. Relative to control subjects, patients with pemphigus displayed a comparable risk of COVID-19 infection (HR, 0.81; 95% CI, 0.44-1.49; P = .496), COVID-19-associated hospitalization (HR, 1.41; 95% CI, 0.53-3.76; P = .499), and COVID-19-associated mortality (HR, 1.33; 95% CI, 0.15-11.92; P = .789; Fig 2, B). The comparable risk of the 3 outcomes persisted in age- and sex-stratified analyses as well as in multivariable analysis adjusting for putative confounders (Table II ).Table II The risk of COVID-19 and its complications among patients with bullous pemphigus COVID-19 infection COVID-19-associated hospitalization COVID-19-associated mortality Pemphigus Controls Pemphigus Controls Pemphigus Controls Follow-up time, PY 662.4 3528.4 663.2 3535.8 664.3 3,537.9 Median follow-up time, years (range) 0.5 (0.1-0.5) 0.5 (0.1-0.5) 0.5 (0.1-0.5) 0.5 (0.1-0.5) 0.5 (0.1-0.5) 0.5 (0.1-0.5) Number of events 12 79 5 19 1 4 Incidence rate/1000 PY (95% CI) 18.1 (9.8-30.8) 22.4 (17.9-27.8) 7.5 (2.8-16.7) 5.4 (3.3-8.2) 1.5 (0.1-7.4) 1.1 (0.4-2.7) Unadjusted HR (95% CI) [P value] 0.81 (0.44-1.49) [.496] Reference 1.41 (0.53-3.76) [.499] Reference 1.33 (0.15-11.92) [.789] Reference Adjusted HR (95% CI)∗ [P value] 0.79 (0.43-1.46) [.454]∗ Reference 1.36 (0.51-3.66) [.542] † Reference 1.15 (0.12-10.98) [.866] † Reference Sex- and age-stratified analysis  Male-specific HR (95% CI) [P value] 1.21 (0.59-2.94) [.605] Reference 1.47 (0.41-5.25) [.558] Reference 1.79 (0.19-17.16) [.616] Reference  Female-specific HR (95% CI) [P value] 0.41 (0.13-1.32) [.134] Reference 1.33 (0.28-6.25) [.720] Reference NA Reference  ≥66.6 year-specific HR (95% CI) [P value] 0.78 (0.31-1.99) [.603] Reference 0.80 (0.18-3.54) [.773] Reference 1.41 (0.16-12.59) [.760] Reference  <66.6 year-specific HR (95% CI) [P value] 0.82 (0.37-1.82) [.627] Reference 3.03 (0.72-12.67) [.129] Reference NA Reference CI, Confidence interval; HR, hazard ratio; n, number; PY, person-year. ∗ Multivariate logistic regression model adjusting for age, sex, ethnicity, and comorbidities (as estimated by Charlson comorbidity index). † Multivariate logistic regression model adjusting for age, sex, ethnicity, comorbidities (as estimated by Charlson comorbidity index), intake of systemic corticosteroids and immunosuppressant, and smoking. Determinants of moderate-to-severe COVID-19 infection among patients with BP and pemphigus Table III demonstrates the demographic and clinical features of patients with BP and pemphigus who tested positive for COVID-19 and stratified by the severity of the infectious disease. Although smoking was less frequent among pemphigus patients with moderate-to-severe COVID-19, the remaining variables (including the frequency of systemic corticosteroids and immunosuppressive agents at the onset of the pandemic) distributed equally between BP and pemphigus patients with moderate-to-severe and subclinical-to-mild COVID-19 (Table III). When COVID-19-positive control subjects were both BP and pemphigus, stratified by severity, those with moderate-to-severe infection were older and had higher burden of comorbidities (Supplementary Table II).Table III Determinants of COVID-19 severity among patients with bullous pemphigoid and pemphigus BP with subclinical-to-mild COVID-19 (n = 16) BP with moderate-to-severe COVID-19 (n = 8) P Value Pemphigus with subclinical-to-mild COVID-19 (n = 9) Pemphigus with moderate-to-severe COVID-19 (n = 3) P Value Age at the onset of pandemic; years, mean (SD) 73.2 (20.2) 83.2 (9.8) .119 56.1 (17.5) 73.9 (13.0) .139 Duration of the disease; years, mean (SD) 5.3 (3.9) 3.0 (2.3) .134 6.5 (4.5) 12.2 (2.6) .065 Female sex; n (%) 12 (75.0%) 4 (50.0%) .221 2 (22.2%) 1 (33.3%) .700 Jewish ethnicity; n (%) 11 (68.8%) 8 (100.0%) .076 8 (88.9%) 3 (100.0%) .546 BMI, mg/kg2; mean (SD) 30.2 (5.4) 26.6 (4.0) .118 27.7 (5.2) 25.5 (NA)∗ NA Smoking; n (%) 3 (18.8%) 2 (25.0%) .722 6 (66.7%) 0 (0.0%) .046 CCI; mean (SD) 2.5 (2.1) 2.9 (1.1) .643 0.7 (0.9) 1.0 (1.0) .588 Systemic corticosteroids at the onset of the pandemic; n (%) 3 (18.8%) 4 (50.0%) .112 6 (66.7%) 1 (33.3%) .310 Adjuvant agents at the onset of the pandemic∗; n (%) 0 (0.0%) 0 (0.0%) .999 1 (11.1%) 0 (0.0%) .546 Systemic corticosteroids anytime during the course of the diseases; n (%) 12 (75.0%) 8 (100.0%) .121 8 (88.9%) 2 (66.7%) .371 Adjuvant agents anytime during the course of the diseases∗; n (%) 0 (0.0%) 1 (12.5%) .149 2 (22.2%) 2 (66.7%) .157 BMI, Body mass index; BP, bullous pemphigoid; CCI, Charlson comorbidity index; n, number; SD, standard deviation. Bold denotes significant value. ∗ Patients managed by one of the following agents: azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide, dapsone, doxycycline, rituximab, plasmapheresis, intravenous immunoglobulins. Discussion The current population-based study revealed that although the risk of COVID-19 was comparable in patients with BP and pemphigus relative to their controls, COVID-19-associated mortality was significantly elevated among patients with BP. The duration of BP and pemphigus at the onset of the pandemic and exposure to systemic corticosteroids and immunosuppressive agents were not found to predict severe COVID-19 illness. BP and pemphigus are among the life-threatening dermatoses posing a real therapeutic challenge and conferring a high inpatient burden.24 , 25 Patients with both conditions were found to experience an increased risk for respiratory, cutaneous, multiorgan, and systemic infections, which were associated with considerable inpatient mortality and costs.26 The susceptibility to bacterial and viral infectious conditions in AIBD is consistent with that of other autoimmune diseases27 and may be attributed to immune dysregulation, higher prevalence of predisposing comorbidities (such as diabetes mellitus and cardiovascular conditions), and the chronic exposure to immunomodulatory medications.6 , 28 Therefore, estimating the risk of COVID-19 among patients with AIBD was an urgent unmet need. We did not find evidence for change in the overall risk of COVID-19 among patients with BP and pemphigus, compared to their controls, which is consistent with other autoimmune and rheumatic diseases.6, 7, 8, 9, 10 This increasing body of evidence indicates that the risk of catching the infection relies mainly on whether patients are exposed to the pathogen, adhere to social distancing, and follow safety instructions. The more interesting question is whether patients with AIBD follow a more severe course of COVID-19 and are more predisposed to the infection's complications. We found that patients with BP had an elevated COVID-19-associated mortality. Although the severity of COVID-19 is yet to be elucidated in AIBD, some studies that followed patients with other autoimmune diseases disclosed a more aggressive course of COVID-19 in patients with preexisting connective tissue diseases,3 and a higher frequency of mechanical ventilation among those with rheumatic diseases.5 Other studies found a similar course and comparable frequency of complications among those with various systemic autoimmune diseases6 and inflammatory bowel disease (IBD).10 In the current study, smoking was less frequent among patients with pemphigus. Because smoking is associated with the worse outcomes of COVID-19,22 its lower prevalence in patients with pemphigus may account, at least in part, for the comparable risk of COVID-19 complications in pemphigus. In the current study, exposure to systemic corticosteroids and immunosuppressive agents was not significantly associated with the severity of COVID-19. This finding may provide evidence-based advice on the importance of maintaining therapies during the pandemic. Discordant findings emerged from a global registry of patients with rheumatic diseases in which the use of systemic corticosteroids, but not other therapies, predicted an increased probability of COVID-19-associated hospitalization.4 Of note, exposure to tumor necrosis factor-α (TNF- α) antagonist was associated with a decreased risk of hospitalization in repository study.4 Systemic corticosteroids, but not biologic agents, were found to increase the risk of severe COVID-19 among patients with IBD.10 , 29 Solid organ transplant recipients, often placed on various immunosuppressive regimens, were found to be more susceptible to developing severe COVID-19.30 , 31 These conflicting findings may reflect the differential role exerted by immunosuppressive agents throughout different stages of the triphasic course of COVID-19.23 Although immunosuppressive drugs can be detrimental in the initial phase of the disease, when the host immune response is essential to constrain viral replication, these drugs may confer a protective role in the advanced severe phase of the diseases. In the latter, overshooting the host immune response (the “cytokine storm”), also referred to as secondary hemophagocytic lymphohistiocytosis, can result in acute respiratory distress syndrome, multi-organ failure, and mortality.23 Further research utilizing larger sample sizes is necessary to better delineate the precise role of immunosuppressive drugs in the course of COVID-19. The observations of the current study, once verified by other research groups, indicate that percussions should be practiced by the health care system for elderly patients with BP. Patients should be notified in advance that they are at increased risk for mortality and BP patients should avoid contagion, even more so than other people. The health care system should organize an outreach program to ensure the well-being of BP patients. During hospitalization, close monitoring is highly recommended. At discharge, the hospital should notify community health care personnel about the excess risk for mortality in BP patients. The current study throws light on an important and unexplored topic. The large sample size and the allocation of control groups enabled an assessment of the relative risk of COVID-19 in patients with BP and pemphigus. Given that the CHS data set facilitates comprehensive access to the whole array of health care services, it is highly compatible with detecting COVID-19 cases, even those occurring years following the initial diagnosis of BP and pemphigus. The latter cannot be fulfilled in hospital-based cohorts, where AIBD patients tend to be lost to follow-up as the time from the diagnosis increases. The study was performed in a country typified by a high incidence rate of COVID-19, thus allowing the detection and characterization of positive cases. The study has several limitations. Because it was based on a computerized data set, the current study did not follow the acceptable immunopathologic criteria to define BP and pemphigus. However, eligibility was grounded on the diagnosis distributed by board-certified dermatologists or after admission to a dermatologic ward. In both settings, immunopathologic diagnostics are widely utilized,32 thus arguing in favor of the validity of the diagnosis. Because the index date dictating age matching was defined at the diagnosis of BP and pemphigus, the case and control groups displayed slightly different ages at the onset of the pandemic. However, multivariable analysis adjusting for age did not alter any of the outcome measures. An additional drawback stems from the small sample size of the subgroups compared to define predictors of COVID-19 severity among patients with BP and pemphigus. To overcome some of these shortcomings a registry for all AIBD patients that had a confirmed case of COVID-19 has been initiated by the AIBD task force of the European Academy of Dermatology and Venereology (https://recovab.umcg.nl). The current population-based study provides a seminal report about the risk of COVID-19 in AIBD and defines the determinants of severe illness. Although the risk of acquiring COVID-19 infection was comparable in BP and pemphigus patients relative to their control subjects, patients with BP demonstrated an increased COVID-19-associated mortality. The administration of systemic corticosteroids and adjuvant immunosuppressive agents and the duration of BP and pemphigus did not seem to affect the severity of the infection or its complications. Consistent with current expert recommendations18 , 33 and using an evidence-based approach, the current study argues in favor of maintaining AIBD-related therapies during the pandemic. Given their greater vulnerability, patients with BP developing COVID-19 should be monitored closely. Conflicts of interest Dr. Cohen served as an advisor, investigator, or speaker for Abbvie, BI, Dexcel Pharma, Janssen, Novartis, Perrigo, Pfizer, and Rafa. Drs Kridin, Schonmann, Weinstein, Schmidt, and Ludwig have no conflicts of interest to declare. Funding sources: None. IRB approval status: The current study was approved by the Ben-Gurion University IRB in accordance with the declaration of Helsinki (approval code: 0212-17-COM). ==== Refs References 1 Shi Y. Wang Y. Shao C. COVID-19 infection: the perspectives on immune responses Cell Death Differ 27 5 2020 1451 1454 32205856 2 Vabret N. Britton G.J. Gruber C. Immunology of COVID-19: current state of the science Immunity 52 6 2020 910 941 32505227 3 Pablos J.L. Galindo M. Carmona L. Clinical outcomes of hospitalised patients with COVID-19 and chronic inflammatory and autoimmune rheumatic diseases: a multicentric matched cohort study Ann Rheum Dis 79 12 2020 1544 1549 32796045 4 Gianfrancesco M. Hyrich K.L. Al-Adely S. Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry Ann Rheum Dis 79 7 2020 859 866 32471903 5 D'Silva K.M. Serling-Boyd N. Wallwork R. Clinical characteristics and outcomes of patients with coronavirus disease 2019 (COVID-19) and rheumatic disease: a comparative cohort study from a US ‘hot spot’ Ann Rheum Dis 79 9 2020 1156 1162 32457048 6 Ansarin K. Taghizadieh A. Safiri S. COVID-19 outcomes in patients with systemic autoimmune diseases treated with immunomodulatory drugs Ann Rheum Dis 2020 10.1136/annrheumdis-2020-218737 annrheumdis-2020-218737 7 Emmi G. Bettiol A. Mattioli I. SARS-CoV-2 infection among patients with systemic autoimmune diseases Autoimmun Rev 19 7 2020 102575 32376395 8 Liu M. Gao Y. Zhang Y. Shi S. Chen Y. Tian J. The association between severe or dead COVID-19 and autoimmune diseases: a systematic review and meta-analysis J Infect 81 3 2020 e93 e95 9 Fredi M. Cavazzana I. Moschetti L. COVID-19 in patients with rheumatic diseases in northern Italy: a single-centre observational and case–control study Lancet Rheumatol 2 9 2020 e549 e556 32838307 10 Macaluso F.S. Orlando A. COVID-19 in patients with inflammatory bowel disease: a systematic review of clinical data Dig Liver Dis 52 11 2020 1222 1227 32928672 11 Kridin K. Pemphigus group: overview, epidemiology, mortality, and comorbidities Immunol Res 66 2 2018 255 270 29479654 12 Kridin K. Subepidermal autoimmune bullous diseases: overview, epidemiology, and associations Immunol Res 66 1 2018 6 17 29159697 13 Schmidt E. Kasperkiewicz M. Joly P. Pemphigus Lancet 394 10201 2019 882 894 31498102 14 Kridin K. Sagi S.Z. Bergman R. Mortality and cause of death in patients with pemphigus Acta Derm Venereol 97 5 2017 607 611 28093595 15 Kridin K. Shihade W. Bergman R. Mortality in patients with bullous pemphigoid: a retrospective cohort study, systematic review and meta-analysis Acta Derm Venereol 99 1 2018 72 77 16 Schmidt E. Zillikens D. Pemphigoid diseases Lancet 381 9863 2013 320 332 23237497 17 Kridin K. Ahn C. Huang W.C. Ansari A. Sami N. Treatment update of autoimmune blistering diseases Dermatol Clin 37 2 2019 215 228 30850044 18 Kasperkiewicz M. Schmidt E. Fairley J.A. Expert recommendations for the management of autoimmune bullous diseases during the COVID-19 pandemic J Eur Acad Dermatol Venereol 34 7 2020 e302 e303 32333823 19 Cohen A.D. Dreiher J. Regev-Rosenberg S. The quality indigators program in Clalit Health Services: the first decade Harefuah 149 4 2010 204 265 20812490 20 Charlson M.E. Pompei P. Ales K.L. MacKenzie C.R. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation J Chronic Dis 40 5 1987 373 383 3558716 21 Zheng Z. Peng F. Xu B. Risk factors of critical and mortal COVID-19 cases: a systematic literature review and meta-analysis J Infect 81 2 2020 e16 e25 22 Zhao Q. Meng M. Kumar R. The impact of COPD and smoking history on the severity of COVID-19: a systemic review and meta-analysis J Med Virol 92 10 2020 1915 1921 32293753 23 Schoot T.S. Kerckhoffs A.P.M. Hilbrands L.B. van Marum R.J. Immunosuppressive drugs and COVID-19: a review Front Pharmacol 11 2020 1333 32982743 24 Ren Z. Hsu D.Y. Brieva J. Silverberg N.B. Langan S.M. Silverberg J.I. Hospitalization, inpatient burden and comorbidities associated with bullous pemphigoid in the U.S.A Br J Dermatol 176 1 2017 87 99 27343837 25 Hsu D. Brieva J. Silverberg J.I. Costs of Care for hospitalization for pemphigus in the United States JAMA Dermatol 152 6 2016 645 654 26865293 26 Ren Z. Narla S. Hsu D.Y. Silverberg J.I. Association of serious infections with pemphigus and pemphigoid: analysis of the Nationwide Inpatient Sample J Eur Acad Dermatol Venereol 32 10 2018 1768 1776 29575160 27 Singh J.A. Cameron C. Noorbaloochi S. Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis Lancet 386 9990 2015 258 265 25975452 28 Jeong S.J. Choi H. Lee H.S. Incidence and risk factors of infection in a single cohort of 110 adults with systemic lupus erythematosus Scand J Infect Dis 41 4 2009 268 274 19172435 29 Brenner E.J. Ungaro R.C. Gearry R.B. Corticosteroids, but not TNF antagonists, are associated with adverse COVID-19 outcomes in patients with inflammatory bowel diseases: results from an international registry Gastroenterology 159 2 2020 481 491.e3 32425234 30 Fernández-Ruiz M. Andrés A. Loinaz C. COVID-19 in solid organ transplant recipients: a single-center case series from Spain Am J Transplant 20 7 2020 1849 1858 32301155 31 Travi G. Rossotti R. Merli M. Clinical outcome in solid organ transplant recipients with COVID-19: a single-center experience Am J Transplant 20 9 2020 2628 2629 32436646 32 Kridin K. Zelber-Sagi S. Khamaisi M. Cohen A.D. Bergman R. Remarkable differences in the epidemiology of pemphigus among two ethnic populations in the same geographic region J Am Acad Dermatol 75 5 2016 925 930 27614531 33 Shakshouk H. Daneshpazhooh M. Murrell D.F. Lehman J.S. Treatment considerations for patients with pemphigus during the COVID-19 pandemic J Am Acad Dermatol 82 6 2020 e235 e236 32283243
PMC007xxxxxx/PMC7979268.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 Published by Elsevier on behalf of the American Academy of Dermatology, Inc. S0190-9622(21)00602-2 10.1016/j.jaad.2021.03.051 Research Letter The significance of pressure injuries and purpura in COVID-19 patients hospitalized at a large urban academic medical center: A retrospective cohort study Rrapi Renajd BA a Chand Sidharth BA a Lo Jennifer A. MD, PhD ab Gabel Colleen K. BS a Song Sarah BS a Holcomb Zachary MD ab Iriarte Christopher MD ab Moore Kevin MD, MPH ab Shi Connie R. MD ab Song Hannah MD ab Di Xia Fan MD ab Yanes Daniel MD ab Gandhi Rajesh MD c Triant Virginia A. MD, MPH cd Kroshinsky Daniela MD, MPH a∗ a Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts b Harvard Combined Dermatology Residency, Harvard Medical School, Boston, Massachusetts c Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts d Division of General Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts ∗ Correspondence and reprint requests to: Daniela Kroshinsky, MD, MPH, Department of Dermatology, Massachusetts General Hospital, 50 Staniford Street, 2nd Floor, Boston, MA 02114 20 3 2021 8 2021 20 3 2021 85 2 462464 © 2021 Published by Elsevier on behalf of the American Academy of Dermatology, Inc. 2021 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo The Editor: Pressure injuries, a common skin finding that significantly impacts the quality of life in hospitalized patients, are associated with increased mortality and result in increased healthcare costs.1 In COVID-19 infection, pressure injury sites are associated with purpuric lesions.2 This study investigates the epidemiology and laboratory findings of these lesions to elucidate their etiology. From March 12, 2020, to May 31, 2020, at a single institution, 1216 adults hospitalized with laboratory-confirmed SARS-CoV-2 infection were retrospectively reviewed. A centralized clinical data registry with search functionality combined with a manual chart review identified patients with skin lesions. At least 2 dermatologists, with a third dermatologist for adjudication, evaluated patient records for pressure injury and identified the presence or absence of purpuric features. Altogether, 84 patients (6.9%) with 118 pressure injuries having onset concurrent with COVID-19 hospitalization were identified (Fig 1 ). The dermatologists were aided by photographs of 73.8% (n = 62/84) of the patients. The pressure injuries were associated with a prolonged length of stay (mean of 37.3 days) and high rates of endotracheal intubation (81.9%) (Table I ). A portion of the patients (32.5%; n = 27/83) had pressure injuries with purpuric features. Laboratory values related to coagulopathy at lesion onset did not differ between patients with and without purpura, with the exception of D-dimer values, which were higher (P = .016) for patients with purpuric features (Supplemental Table I; available at https://doi.org/10.17632/vkzxr32ffr.1).Fig 1 Flowchart of patient selection for constructing the study and control groups. Skin lesions were categorized as concurrent with COVID-19 hospitalization when onset occurred within 14 days prior to admission and up to discharge. Table I Comparison of patients with nonpurpuric and purpuric pressure injuries Characteristic Patients with nonpurpuric pressure injury∗ (n = 61) Patients with purpuric pressure injury∗ (n = 27) Total patients with pressure injury (n = 84) P value† Lesion evaluation  Day of injury onset since admission (mean ± SD) 11.2 ± 8.0 14.3 ± 10.0 12.0 ± 9.0 .25  Dermatology consultation obtained 4 (6.6%) 7 (25.9%) 10 (11.9%) .0070  Photographs obtained 40 (65.6%) 25 (92.6%) 62 (73.8%) .0075 Demographics  Age in years (mean ± SD) 60.9 ± 15.6 63.6 ± 14.8 61.9 ± 15.3 .49  Sex  Male 45 (73.7%) 21 (77.8%) 61 (73.5%) .54  Female 16 (26.2%) 6 (22.2%) 22 (26.5%) Patient past medical history  BMI (mean ± SD) 31.8 ± 7.9 33.6 ± 9.6 32.1 ± 8.3 .25  Hypertension 25 (40.9%) 15 (55.6%) 38 (45.9%) .21  Diabetes 25 (40.9%) 14 (51.9%) 36 (43.4%) .28  Chronic heart disease 5 (8.2%) 1 (3.7%) 6 (7.2%) .39  Chronic lung disease 7 (11.5%) 6 (22.2%) 12 (14.5%) .16  Stroke/cerebrovascular accident 3 (4.9%) 2 (7.4%) 5 (6.0%) .71  Smoking/cigarette use 24 (39.3%) 15 (55.6%) 36 (42.9%) .16 Hospitalization  Length of stay in days (mean ± SD) 36.5 ± 20.4 42.3 ± 25.1 37.3 ± 21.9 .15  Intensive care unit admission 52 (85.2%) 24 (88.9%) 71 (85.6%) .55  Death 13 (21.0%) 4 (14.8%) 17 (20.5%) .37  Treatment course  Endotracheal intubation 50 (81.9%) 23 (85.2%) 68 (81.9%) .59  Orogastric/nasogastric intubation 48 (78.6%) 21 (77.8%) 64 (77.1%) .92  Urinary catheterization 52 (85.2%) 24 (88.9%) 71 (85.5%) .55  Rectal intubation 49 (80.3%) 22 (81.5%) 66 (79.5%) .76  Parenteral nutrition 11 (18.0%) 3 (11.1%) 12 (14.5%) .55  Clinical course  Cerebrovascular accident - 1 (3.7%) 1 (1.2%) -  Deep vein thrombosis 5 (8.2%) 1 (3.7%) 6 (7.2%) .39  Pulmonary embolism 5 (8.2%) 3 (11.1%) 8 (9.6%) .76  Intracranial hemorrhage 2 (3.3%) - 2 (2.4%) -  On therapeutic anticoagulation at onset of first injury 12 (19.7%) 8 (29.6%) 18 (21.4%) .26 BMI, Body mass index; SD, standard deviation. ∗ 4 patients had multiple pressure injuries of which some had purpuric features and others had only nonpurpuric features. Values for these patients are tabulated in both columns. † Statistical testing is performed comparing patients having pressure injuries with purpuric features to patients having pressure injuries none of which had purpuric features. The incidence of pressure injury in this study (6.9%) is comparable to previous estimates of 5%-15% of hospitalized patients, depending on clinical context.1 With respect to COVID-19 hospitalization specifically, the especially tenuous respiratory status in these critically ill patients frequently interfered with standard preventative measures to turn patients for inspection and pressure offloading.1 , 3 Placing patients in a prone position has been demonstrated to reduce the development of pressure injuries and is associated with improved outcomes in the setting of a poor respiratory status.4 However, this study discovered 36 pressure ulcers (30.5%) occurring on the face, likely resulting from proning, emphasizing specific challenges affecting patients with COVID-19 and the importance of prophylactic measures to prevent these injuries in proned patients. This study only found elevated D-dimer levels in patients with purpuric pressure injuries, corroborating previous reports of elevation of fibrin and fibrinogen degradation products in COVID-19.5 Thromboembolic events and abnormalities in other markers of coagulation were not found to be more common in patients with purpuric pressure injuries within our cohort. Biopsies were obtained in 4 patients and previously reported as exhibiting epidermal and eccrine gland necrosis, supportive of pressure-induced injury, with fibrin thrombi in superficial dermal vessels only.2 These findings suggest that purpuric features of pressure injuries are less likely indicative of occult pathology resulting from COVID-19 infection and emphasize the usual prevalence of pressure injuries in critically ill patients, highlighting the importance of identifying risk factors, encouraging preventative measures, and reinforcing the known standard of care. Taking steps to address predisposing factors in hospitalized COVID-19 patients is essential in preventing these lesions and improving outcomes.1 , 3 The authors would like to thank the clinicians who cared for these patients during the COVID-19 pandemic and created the documentation necessary to make this study possible. Conflicts of interest None disclosed. Authors Rrapi and Chand contributed equally to this article. Funding Sources: None. IRB approval status: Not applicable. ==== Refs References 1 Mervis J.S. Phillips T.J. Pressure ulcers: pathophysiology, epidemiology, risk factors, and presentation J Am Acad Dermatol 81 4 2019 881 890 30664905 2 Chand S. Rrapi R. Lo J.A. Purpuric ulcers associated with COVID-19 infection: a case-series JAAD Case Rep 2021 10.1016/j.jdcr.2021.01.019 3 Tang J. Li B. Gong J. Li W. Yang J. Challenges in the management of critical ill COVID-19 patients with pressure ulcer Int Wound J 17 5 2020 1523 1524 32383319 4 Li L. Li R. Wu Z. Therapeutic strategies for critically ill patients with COVID-19 Ann Intensive Care 10 1 2020 1 9 31900667 5 Connors J.M. Levy J.H. COVID-19 and its implications for thrombosis and anticoagulation Blood 135 23 2020 2033 2040 32339221
PMC007xxxxxx/PMC7983002.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(21)00457-6 10.1016/j.jaad.2021.02.062 This month in JAAD This Month in JAAD: May 2021 Elston Dirk MD ∗ Department of Dermatology, MUSC, Charleston, South Carolina ∗ Correspondence to: Dirk Elston, MD, Department of Dermatology, MUSC, Charleston, SC. 22 3 2021 5 2021 22 3 2021 84 5 12491249 © 2021 by the American Academy of Dermatology, Inc. 2021 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcIn this month's JAAD, Gelfand et al (page 1254) present the National Psoriasis Foundation COVID-19 Task Force recommendations for psoriasis management in light of the current pandemic, including recommendations for vaccination and therapy continuation. They emphasize shared decision-making and note that the published recommendations are a living document, intended to be updated as data emerge. Most patients who are not infected with SARS-CoV-2 should continue their biologic or oral therapies for psoriasis and/or psoriatic arthritis. In most cases, those who are slated to receive mRNA-based COVID-19 vaccines should also continue their biologic or oral therapies for psoriasis and/or psoriatic arthritis. Pindado-Ortega et al (page 1285) present data on dutasteride for the treatment of frontal fibrosing alopecia. In a retrospective study of 224 patients with a median follow-up of 24 months, the stabilization rate in the frontal, right, and left temporal regions was 62%, 64%, and 62% in the dutasteride group; 60%, 35%, and 35% with other systemic therapies; and 30%, 41%, and 38% in those on no systemic treatment, respectively. A dose-dependent response was observed. Lohman et al (page 1385) discuss the impact of second-opinion consultation with a dermatopathologist for the surgical management of malignant neoplasms. They studied 358 cases and found that second-level review resulted in a change in treatment in 9% of cases. The highest rate of discordance was found among dermatologists without additional dermatopathology fellowship training. Ji et al (page 1378) report on the screening for hepatic hemangioma in patients with cutaneous infantile hemangiomas. They performed a prospective, multicenter study in patients younger than 9 months of age with multiple cutaneous infantile hemangiomas and compared them with patients with only focal hemangiomas. Their data suggest that the presence of 5 cutaneous hemangiomas may represent a reasonable threshold for screening. Hua et al (page 1371) describe congenital hemangiomas that initially exhibited proportional growth similar to that of NICH, but with tardive expansion of the lesion. The tumors were located in the head and neck region or abdominal wall, and expansion began between the ages of 12 and 61 months. They proposed the term “tardive expansion congenital hemangioma” for such lesions. Microscopic examination showed well-defined lobules, separated by bands of fibrous tissue containing large vessels. The lobules themselves consisted mostly of curved, small, proliferating capillaries with central thin-walled, often stellate channels, sometimes surrounded by fibrous tissue. Thromboses were frequently noted, but extramedullary hematopoiesis was not detected. Conflicts of interest None disclosed. Funding sources: None. IRB approval status: Not applicable.
PMC007xxxxxx/PMC7986311.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(21)00619-8 10.1016/j.jaad.2021.03.064 Research Letter Cutaneous manifestations of SARS-CoV-2: A 2-center, prospective, case-controlled study Unterluggauer Luisa MD a Pospischil Isabella MD b Krall Christoph PhD c Saluzzo Simona MD, PhD a Kimeswenger Susanne PhD b Karolyi Mario MD, MSc d Wenisch Christoph MD d Lamprecht Bernd MD, PhD e Guenova Emmanuella MD, PhD f Winkler Stefan MD g Viczenczova Csilla PhD h Bergthaler Andreas DVM h Weninger Wolfgang MD a Hoetzenecker Wolfram MD, PhD b∗ Stary Georg MD a∗ a Department of Dermatology, Medical University of Vienna, Vienna, Austria b Department of Dermatology, Kepler University Hospital, Johannes Kepler University, Linz, Austria c Centre for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria d Department for Infectious Diseases and Tropical Medicine, Klinik Favoriten, Vienna, Austria e Department of Pneumology, Kepler University Hospital, Johannes Kepler University, Linz, Austria f Department of Dermatology, University Hospital Lausanne, Lausanne, Switzerland g Division of Infectious Diseases and Tropical Medicine, Department of Medicine I, Medical University of Vienna, Vienna, Austria h CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria ∗ Correspondence and reprint requests to: Georg Stary, MD, Department of Dermatology, Medical University of Vienna, Vienna, Austria, Spitalgasse 23, 1090 Vienna, Austria ∗ Wolfram Hoetzenecker, MD, PhD, Department of Dermatology, Kepler University Hospital, Johannes Kepler University, Linz, Austria, Krankenhausstraße 9, 4021 Linz, Austria 23 3 2021 7 2021 23 3 2021 85 1 202204 © 2021 by the American Academy of Dermatology, Inc. 2021 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: A myriad of potential dermatologic manifestations of COVID-19, caused by SARS-CoV-2, has been reported.1, 2, 3, 4, 5 However, some of these previous reports had considerable limitations, including the lack of laboratory-confirmed COVID-19 diagnosis, suboptimal study designs, or the absence of case controls. Here, we report the results of a prospective and controlled cohort study with a 4-week follow-up period in which we investigated potential skin findings in 102 hospitalized SARS-CoV-2–positive patients and 41 age- and sex-matched SARS-CoV-2–negative controls with acute, nonprimary infectious diseases of the skin. In the control group, the most common infections were viral respiratory infections (26.8%), bacterial pneumonia (24.4%), and urinary tract infections (14.6%). We observed newly occurring skin symptoms, concomitant with the infection in 17 (16.6%) COVID-19 patients. Three major groups of cutaneous manifestations were discerned: livedo reticularis (n = 6, 5.8%), splinter hemorrhage-like lesions (n = 4, 3.9%), and subcutaneous nodules (n = 2 ,2%) (Fig 1 ). Five patients had various other skin symptoms (rashes containing macules and papules, papular exanthema, burning sensation of the oral cavity, and vitiligo). In the control group, 5 patients (n = 5, 12.2%) had an onset of skin symptoms, including livedo reticularis in 1 patient. Four patients had other skin manifestations (petechial enanthem, nail hemorrhage, as well as rashes containing macules and papules). In each group, 1 rash containing macules and papules was considered as drug-induced, whereas no other apparent cause was found in the rest of the patients. Statistical analyses did not reveal significant differences between COVID-19 patients and control group in terms of the occurrence of skin symptoms (Fisher's exact test; P value = .6130) (Fig 1).Fig 1 An overview of cutaneous manifestations in COVID-19 patients and the control group. Skin symptoms were examined in patients who tested positive (n = 102) and negative for SARS-CoV-2 (n = 41). We grouped the skin symptoms into 4 groups: livedo reticularis, splinter hemorrhage-like lesions, subcutaneous nodules, and others. We compared the number of cases in the COVID-19 patients and control group using the Fisher's exact test. Livedo reticularis occurred within the first week and splinter hemorrhage-like lesions occurred within the third week after disease onset (Fig 2 ). Asymptomatic subcutaneous nodules without systemic symptoms occurred in 2 patients 7 weeks after the occurrence of respiratory symptoms (Fig 2). Both patients suffered from a severe course of the disease, including intensive care unit admission. Subcutaneous drug application as a possible cause was excluded. The histopathologic workup result was consistent with reactive septal panniculitis, and both patients were negative for SARS-CoV-2, as determined using a quantitative polymerase chain reaction test. Five months after study inclusion, the patients reported spontaneous partial regression of the nodules.Fig 2 Appearance of cutaneous manifestation over time. Timeline of newly manifested skin symptoms in COVID-19 patients depicted as the number of patients with the respective skin symptom over 8 weeks measured from the onset of respiratory symptoms. The relatively small sample size must be considered as a limitation of our study. Therefore, we might have missed less frequent cutaneous manifestations and could not achieve statistical significance regarding the present skin findings. Although we observed skin symptoms in 16.6% of the patients, including signs of vasculopathy during the early course of the disease and subcutaneous nodules as a possible late manifestation, no statistically significant difference was detected when the COVID-19 patients were compared with the control group of patients with other acute infectious diseases. Therefore, our study suggests that skin manifestations in COVID-19 patients are less specific compared with those previously assumed and cannot be considered as reliable diagnostic tools. Physicians confronted with skin lesions in patients with confirmed or suspected COVID-19 need to carefully evaluate possible differential diagnoses before attributing the symptoms to COVID-19. Larger and well-planned controlled studies are required to further elucidate skin manifestations in COVID-19 patients. Conflicts of interest None disclosed. Drs Unterluggauer and Pospischil contributed equally to this article. Funding source: This work was supported by funds of the Department of Dermatology, Medical University of Vienna, Austria, and the MED-CALL from the Faculty of Medicine, Johannes Kepler University Linz, Austria. IRB approval status: Approved (#1392/2020). ==== Refs References 1 Bouaziz J.D. Duong T. Jachiet M. Vascular skin symptoms in COVID-19: a French observational study J Eur Acad Dermatol Venereol 34 9 2020 e451 e452 32339344 2 Fernandez-Nieto D. Jimenez-Cauhe J. Suarez-Valle A. Characterization of acute acral skin lesions in nonhospitalized patients: a case series of 132 patients during the COVID-19 outbreak J Am Acad Dermatol 83 1 2020 e61 e63 32339703 3 Freeman E.E. McMahon D.E. Lipoff J.B. The spectrum of COVID-19-associated dermatologic manifestations: an international registry of 716 patients from 31 countries J Am Acad Dermatol 83 4 2020 P1118 P1129 4 Galvan Casas C. Catala A. Carretero Hernandez G. Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases Br J Dermatol 183 1 2020 71 77 32348545 5 Recalcati S. Cutaneous manifestations in COVID-19: a first perspective J Eur Acad Dermatol Venereol 34 5 2020 e212 e213 32215952
PMC008xxxxxx/PMC8017917.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(21)00646-0 10.1016/j.jaad.2021.03.083 Original Article Mucocutaneous manifestations in children hospitalized with COVID-19 Andina-Martinez David MD a∗ Nieto-Moro Montserrat MD b Alonso-Cadenas Jose Antonio MD a Añon-Hidalgo Juan MD c Hernandez-Martin Angela MD d Perez-Suarez Esther MD a Colmenero-Blanco Isabel MD d Iglesias-Bouza Maria Isabel MD b Cano-Fernandez Julia MD c Mateos-Mayo Ana MD d Torrelo Antonio MD d a Emergency Department, Hospital Infantil Universitario Niño Jesús, Madrid, Spain b Paediatric Intensive Care Unit, Hospital Infantil Universitario Niño Jesús, Madrid, Spain c Paediatric Department, Hospital Infantil Universitario Niño Jesús, Madrid, Spain d Department of Dermatology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain ∗ Correspondence and reprint requests to: David Andina-Martinez, MD, Emergency Department, Hospital Infantil Universitario Niño Jesús, Avenida Menéndez Pelayo, 65, 28009 Madrid, Spain. 2 4 2021 7 2021 2 4 2021 85 1 8894 24 3 2021 © 2021 by the American Academy of Dermatology, Inc. 2021 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Background Cutaneous manifestations in hospitalized children with SARS-CoV-2 have not been studied systematically. Objective To describe the mucocutaneous involvement in pediatric patients with COVID-19 admitted to a pediatric institution in Madrid (Spain), located in a zone reporting among the highest prevalence of COVID-19 in Europe. Methods A descriptive, analytical study was conducted on a series of 50 children hospitalized with COVID-19 between March 1, 2020, and November 30, 2020. Results Twenty-one patients presented with mucocutaneous symptoms: 18 patients with macular and/or papular exanthem, 17 with conjunctival hyperemia, and 9 with red cracked lips or strawberry tongue. Eighteen patients fulfilled criteria for multisystem inflammatory syndrome in children. Patients with mucocutaneous involvement tended to be older and presented to the emergency department with poor general status and extreme tachycardia, higher C-reactive protein and D-dimer levels, and lower lymphocyte counts than patients without skin signs. Mucocutaneous manifestations pose a higher risk of admission to the pediatric intensive care unit (odds ratio, 10.24; 95% confidence interval, 2.23-46.88; P = .003). Conclusions Children hospitalized with COVID-19 frequently had mucocutaneous involvement, with most symptoms fulfilling criteria for multisystem inflammatory syndrome in children. Patients with an exanthem or conjunctival hyperemia at admission have a higher probability of pediatric intensive care admission than patients without mucocutaneous symptoms. Key words COVID-19 pediatric dermatology multisystem inflammatory syndrome SARS-CoV-2 Abbreviations used MIS-C multisystem inflammatory syndrome in children PICU pediatric intensive care unit RT-PCR reverse transcriptase polymerase chain reaction ==== Body pmc Capsule Summary • Macular and/or papular exanthems, conjunctival hyperemia, red cracked lips, or strawberry tongue appear in 42% of children admitted for COVID-19, mostly in the context of multisystem inflammatory syndrome. • Mucocutaneous manifestations are associated with a higher risk of admission to a pediatric intensive care unit and should warrant prompt attention. Introduction COVID-19 in previously healthy children is usually a mild or asymptomatic disease, practically without associated mortality.1 Fever and respiratory symptoms were the most frequent manifestations in early pediatric series from China and Italy2 , 3; however, the involvement of other organs and systems has been described.4 Gastrointestinal and mucocutaneous manifestations are frequent in multisystem inflammatory syndrome in children (MIS-C), the most serious condition associated with SARS-CoV-2 infection in the pediatric population.5 , 6 Based on findings in adult patients, skin manifestations of COVID-19 have been classified under 5 categories: acral pseudochilblain, vesicular eruptions, urticarial lesions, macular and/or papular eruptions, and livedo or necrosis.7 Chilblain lesions in healthy children and adolescents have received much attention; these lesions resolve without complications after a few weeks.8 , 9 The other cutaneous manifestations of COVID-19 in children have been the subject of case reports or small case series.10 The mucocutaneous manifestations in hospitalized children infected with SARS-CoV-2 and the implications on the clinical course have not yet been extensively described. The objective of this study was to describe mucocutaneous manifestations in children hospitalized for COVID-19. Methods Study design We conducted a descriptive, analytical study of pediatric patients with COVID-19 admitted from March 1 to November 30, 2020, to a single pediatric institution in Madrid (Spain). Approval was obtained from the institution's Ethics Committee and Board, and standard informed consent to record images was obtained. Inclusion criteria Patients from zero to 18 years of age admitted to the hospital with a COVID-19 diagnosis were eligible if they met at least 1 of the following criteria:• Positive reverse transcriptase polymerase chain reaction (RT-PCR) for SARS-CoV-2 collected from a nasopharyngeal and oropharyngeal swab; or • Clinical suspicion (symptoms compatible with MIS-C or symptoms compatible with COVID-19 with a close contact having tested positive for COVID-19) and a positive immunoglobulin-M enzyme-linked immunosorbent assay for SARS-CoV-2. Exclusion criteria Patients were not eligible if they had a positive RT-PCR result in the emergency department but infection with SARS-CoV-2 was not directly related to the cause of admission. Patients with cancer and undergoing chemotherapy were also excluded. Data collection Each patient received an identification code to blind investigators to individual patient data and to facilitate anonymous data collection. Epidemiologic, clinical, and testing data were retrieved from the electronic medical records of the admitted patients. Epidemiologic data included sex, age, length of hospital stay, pediatric intensive care unit (PICU) admission, and a record of close contact with suspected or confirmed cases of COVID-19. Clinical data included a history of chronic disease; previous treatment; signs (appearance, heart rate, oxygen saturation); and symptoms (fever, rhinorrhea, cough, respiratory distress, thoracic pain, sore throat, abdominal pain, vomiting, diarrhea, rash, conjunctival hyperemia without secretion, red cracked lips, strawberry tongue, headache, irritability, drowsiness, myalgia, anosmia, or ageusia). Reason for admission was classified into 6 categories: respiratory, gastrointestinal, neurologic, MIS-C, neonates with fever, and protracted fever. Analytical determination on admission included leukocyte, neutrophil, and lymphocyte counts; lactate dehydrogenase; D-dimer; C-reactive protein; and procalcitonin. Definitions We followed the case definition for MIS-C as described in the Health Advisory on MSS-C, published by the Centers for Disease Control.11 The case definition for MIS-C was as follows:• An individual younger than 21 years age, presenting with fever, laboratory evidence of inflammation, and clinical evidence of severe illness requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, or neurologic), and • No alternative plausible diagnoses, and • Positive for current or recent SARS-CoV-2 infection as determined by an RT-PCR, serology, or antigen test, or exposure to a suspected or confirmed COVID-19 case no more than 4 weeks prior to the onset of symptoms. Statistical analysis Data were analyzed using Stata version 15.0 (StataCorp). Variables with normal distribution were reported as mean and standard deviation. Variables that did not meet the normality requirements were reported as median and interquartile range. Variables within categories were expressed as percentages. Two-tailed t tests were used to compare means between groups. Chi-squared tests were used to compare proportions. A stepwise logistic regression analysis was used to calculate the risk of admission to a PICU. A P value < .05 was considered statistically significant. Results Fifty patients were included in the study (Fig 1 ). Forty-four (88%) had a positive RT-PCR for SARS-CoV-2 and 6 (12%) met the clinical criteria for suspicion and had a negative RT-PCR with a positive immunoglobulin serology. Thirty-four patients (68%) had a close contact with a suspected or confirmed case of COVID-19. In the remaining 16 (32%), the origin of the infection remained unknown.Fig 1 Flowchart of patients included in the study. ED, Emergency department. The main reasons for admission were respiratory illness (40%) and MIS-C (40%). The evolution of admitted COVID-19 patients during the pandemic is shown in Fig 2 .Fig 2 Evolution of children admitted to the authors' institution with COVID-19 throughout the pandemic. Respiratory disease consisted of pneumonia (9 cases), bronchiolitis (7 cases), and upper respiratory tract infection (4 cases). Gastrointestinal involvement consisted of prolonged diarrhea (1 case) and recurrent abdominal pain (1 case). Neurologic disease was due to multiple thrombosis in 1 patient. MIS-C, Multisystem inflammatory syndrome in children. A general description of the sample is shown in Table I . Twenty-one patients (42%) exhibited mucocutaneous symptoms, including 18 patients with exanthem, 17 with conjunctival hyperemia without secretion, and 9 with red cracked lips or strawberry tongue (Figs 3 and 4 ).Table I Characteristics of hospitalized children with COVID-19 Characteristics All cases (n = 50) Mucocutaneous involvement YES (n = 21) Mucocutaneous involvement NO (n = 29) P value Age median (interquartile range) 9.5 (4.7-12) 9.4 (5.1-11.7) 4 (0.1-12.2) <.001 Age group, n (%) .024  <2 years 15 (30) 2 (9.5) 13 (44.8)  2-10 years 16 (32) 11 (52.3) 5 (17.2)  >10 years 19 (38) 8 (38.1) 11 (37.9) Sex, n (%) .916  Male 29 (58) 12 (57.1) 17 (58.6)  Female 21 (42) 9 (42.8) 12 (41.4) Underlying medical condition, n (%) 5 (10) 1 (4.7) 4 (13.7) .293 Reason for admission, n (%) <.001  Respiratory 20 (40) 1 (4.7) 19 (65.5)  Digestive 2 (4) 0 2 (6.9)  Neurologic 1 (2) 0 1 (3.4)  Multisystem inflammatory syndrome 20 (40) 18 (85.7) 2 (6.9)  Fever in a neonate 3 (6) 1 (4.7) 2 (6.9)  Protracted fever 4 (8) 1 (4.7) 3 (10.3) PICU admission, n (%) 28 (56) 17 (80.9) 9 (31.3) <.001 Median days of stay (interquartile range) 8 (3-10) 10 (8-12) 4 (3-8) <.001 Symptoms at the ED, n (%)  Fever 45 (90) 21 (100) 24 (82.7) .044  Respiratory (rhinorrhea, cough, respiratory distress, thoracic pain, sore throat) 31 (62) 8 (38.1) 23 (79.3) .003  Gastrointestinal (abdominal pain, vomiting, diarrhea) 32 (64) 19 (90.4) 13 (44.8) <.001  Neurological (headache, irritability, drowsiness) 18 (36) 8 (38.1) 10 (34.5) .792  Myalgia 7 (14) 3 (14.2) 4 (13.8) .960  Anosmia, ageusia 3 (6) 1 (4.7) 2 (6.9) .753 Signs at the ED, n (%)  Altered appearance 16 (32) 12 (57) 4 (13.8) .001  Extreme tachycardia∗ 18 (36) 14 (66) 4 (13.8) .001  Oxygen saturation < 94% 7 (14) 0 7 (24.1) .003 Laboratory values median (interquartile range)  Leukocytes (cells/μL) 7940 (5510-12240) 7880 (7015-1197) 8510 (4910-13027) .659  Neutrophils (cells/μL) 6200 (3340-9400) 6875 (6252-10105) 4080 (1937-7747) .159  Lymphocytes (cells/μL) 870 (520-2130) 510 (362-772) 2415 (1005-3885) <.001  D-dimer (μg/mL) 2.22 (1.18-3.71) 4.04 (2.29-11.19) 1.39 (0.44-2.39) <.001  Lactate dehydrogenase (UI/L) 301 (268-351) 297 (253-1197) 303 (264-486) .419  C-reactive protein (mg/dL) 11.47 (0.77-20.68) 25.46 (12.36-34.12) 0.85 (0.20-8.69) <.001  Procalcitonin (ng/mL) 2.06 (0.63-6.46) 2.61 (1.39-4.64) 0.14 (0.06-1.84) <.001 ED, Emergency department; PICU, pediatric intensive care unit. ∗ Heart rate ≥ 99th percentile for age. Fig 3 Multisystem inflammatory syndrome. Confluent exanthem on thighs. Fig 4 Multisystem inflammatory syndrome. Macular and papular eruption on the neck and strawberry tongue. The exanthem was described as macular and/or papular in all 18 cases, with confluent erythematous macules and papules that might become diffuse or show a lacy or reticulated pattern. All patients had mucocutaneous symptoms at the time of diagnosis in the emergency department, with variable progression throughout hospital admission. The limbs (78%) and trunk (72%) were the most commonly involved areas, and palms and soles (55%), genitals/groins (50%), and face (33%) were affected less frequently. One patient had an isolated acral ischemic lesion with a diameter of 5 mm, which appeared on 1 finger after recovery. Patients with mucocutaneous symptoms tended to be older than those without skin signs and presented to the emergency department with a poor general status and extreme tachycardia. Fever and gastrointestinal symptoms were more frequent and respiratory symptoms were infrequent. Eighty-six percent of patients fulfilled the criteria for MIS-C (18 patients). An exanthem was also found in 1 patient admitted because of respiratory disease, 1 with protracted fever, and 1 febrile neonate. Of the 20 patients admitted because of MIS-C (40%), only 2 did not present mucocutaneous symptoms. Patients with mucocutaneous involvement also had higher C-reactive protein, procalcitonin, and D-dimer levels and lower lymphocyte counts in their first laboratory test on presentation to the emergency department. They were admitted to the PICU more frequently, and length of stay was longer than for patients without mucocutaneous involvement. All patients admitted to the PICU with mucocutaneous symptoms were classified as MIS-C. Adjusted for age and sex, patients with mucocutaneous involvement had a higher risk of PICU admission (odds ratio, 10.24; 95% confidence interval, 2.23-46.88; P = .003). The odds ratio for conjunctival hyperemia was 30.28 (3.25-281.69; P = .003), and the odds ratio for rash was 6.22 (1.42-27.26; P = .015). None of the patients died or experienced long-term sequelae apart from 1 patient with a coronary artery ectasia, who is currently being followed up by the Cardiology Department, and 1 patient who had myopathy that lasted for 6 months. Discussion The prevalence of COVID-19 within the 6.68 million people living in the community of Madrid is one of the highest in Europe.12 Our institution was designated as a pediatric referral center during the peak of the pandemic and attended the largest volume of COVID-19 and regular emergencies in the area.13 Between March and November 2020, only 0.14% of hospital admissions were because of COVID-19, but by November 30, 2020, hospital admissions grew to 52,449 patients, with 11,369 deaths in the Madrid region.14 Several mechanisms have been proposed to explain the difference in severity of SARS-CoV-2 infections between adult and pediatric patients.15 In our series of children admitted for COVID-19, mucocutaneous symptoms were fourth in frequency, after fever, respiratory symptoms, and gastrointestinal symptoms. The presence of mucocutaneous symptoms (42%) is much higher than in other series of admitted pediatric patients, which provide figures of the presence of rash (<15% patients) or conjunctivitis (<5% patients).4 As our investigation was entirely focused on the cutaneous manifestations of COVID-19, we made efforts to include data on these findings that other registries may have missed. In fact, the only previous study focused on hospitalized pediatric patients with mucocutaneous disease was by Rekhtman et al,16 who described the same proportion of mucocutaneous involvement (42%). In our institution during the first month of the outbreak, most admissions were due to respiratory diseases and skin manifestations were infrequent. Probably for that reason, in the early pediatric literature about COVID-19 manifestations in children there is either no mention of skin involvement in Chinese series or a reported rate as low as 3% in the Italian series.2 , 3 Mucocutaneous lesions have been seen more frequently since mid-April 2020, after the first cases of MIS-C were recognized, and studies have started to reflect the presence of skin lesions.5 , 6 , 17 Mucocutaneous symptoms appeared in 6 out of 10 patients who required admission to PICU. It is known that mucocutaneous symptoms are prominent in MIS-C. Up to 90% of patients diagnosed with MIS-C had some kind of mucocutaneous involvement. This is a higher rate than reported in other studies of patients with this condition, which described percentages from 47% to 83%.5 , 6 , 16 , 17 Because this syndrome usually requires PICU admission,16 the presence of exanthem or conjunctival hyperemia in our series is an independent predictor of PICU admission in hospitalized pediatric patients with COVID-19. A similar conclusion was reached regarding with gastrointestinal manifestations, probably due to the same underlying explanation.18 In the subgroup of patients with MIS-C, Trevor et al17 found no association between the presence of mucocutaneous changes and the risk of PICU admission. Due to the small percentage of MIS-C patients without mucocutaneous disease in our series, this finding cannot be evaluated. The presence of any mucocutaneous lesion in febrile children in the current epidemiologic context should prompt interrogation about close contacts with suspected or confirmed COVID-19 cases. The association of other symptoms, especially gastrointestinal complaints, should alert the pediatrician to the possibility of a severe COVID-19 case. The natural 4- to 5-week gap between SARS-CoV-2 infection and the development of MIS-C symptoms warrants monitoring of affected individuals.19 Attention to vital signs is key, because extreme tachycardia is a common early sign of shock. Initial blood tests should include full blood count, C-reactive protein, urea, creatinine, electrolytes, and liver function. If results from these tests support a diagnosis of MIS-C, additional investigation is recommended to determine the diagnosis and severity of the disease.20 The exanthem in admitted patients in our institution was described as macular and/or papular in all cases. Different from adult COVID-19 patients, in that no vesicular, livedoid, or necrotic lesions were found,7 except in 1 patient who had an isolated acral late ischemic lesion. At our institution, skin lesions in children with COVID-19 who did not require admission were usually located acrally,8 whereas lesions in hospitalized patients tended to appear on the trunk and limbs, with palms and soles less frequently involved. As in other series, pernio-like lesions are infrequent in hospitalized pediatric patients.16 , 17 Conjunctival hyperemia appeared in practically the same proportion as the exanthem in our series and was a better independent predictor of PICU admission than the exanthem itself. Although in adults, it has received little attention, it should be considered as an alarm sign in children with suspected or confirmed COVID-19, as it has been frequently described in patients with MIS-C.5 , 6 , 16 , 17 Our center is located in one of the regions most impacted during the pandemic in Europe. Although the fact of being a single-institution study is a limitation, we think the population is representative and offers a large cohort of hospitalized pediatric patients with COVID-19 and mucocutaneous involvement. Nevertheless, more data from other centers should be obtained in an effort to conduct a meta-analysis on patients admitted with COVID-19 and on the subgroup of MIS-C cases. As another limitation, although the study project started early in the course of the pandemic in Spain, most of the data were retrieved retrospectively. Conclusions Mucocutaneous involvement is frequent in COVID-19 pediatric patients admitted to the hospital. Most of the patients hospitalized with mucocutaneous symptoms fulfilled MIS-C criteria. As a result, patients with an exanthem or conjunctival hyperemia at admission have a higher probability of PICU admission and a longer length of stay than those without mucocutaneous symptoms. Conflicts of interest None disclosed. Funding sources: None. IRB approval status: Approval was provided by the Ethics Committee and Board of the Hospital Infantil Universitario Niño Jesús. Standard informed consent was obtained to record images. ==== Refs References 1 Munro A.P. Faust S.N. COVID-19 in children: current evidence and key questions Curr Opin Infect Dis 33 6 2020 540 547 33027185 2 Lu X. Zhang L. Du H. SARS-CoV-2 infection in children N Engl J Med 382 17 2020 1663 1665 32187458 3 Parri N. Lenge M. Buonsenso D. Children with COVID-19 in pediatric emergency departments in Italy N Engl J Med 383 2 2020 187 190 32356945 4 Swann O.V. Holden K.A. Turtle L. Clinical characteristics of children and young people admitted to hospital with COVID-19 in United Kingdom: prospective multicentre observational cohort study BMJ 370 2020 m3249 32960186 5 Feldstein L.R. Rose E.B. Horwitz S.M. Multisystem inflammatory syndrome in U.S. children and adolescents N Engl J Med 383 4 2020 334 346 32598831 6 Whittaker E. Bamford A. Kenny J. Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 JAMA 324 3 2020 259 269 32511692 7 Galván Casas C. Català A.C. Carretero Hernández G. Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases Br J Dermatol 183 1 2020 71 77 32348545 8 Colmenero I. Santonja C. Alonso-Riaño M. SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultrastructural study of seven paediatric cases Br J Dermatol 183 4 2020 729 737 32562567 9 Freeman E.E. McMahon D.E. Lipoff J.B. Pernio-like skin lesions associated with COVID-19: a case series of 318 patients from 8 countries J Am Acad Dermatol 83 2 2020 486 492 32479979 10 Andina D. Belloni-Fortina A. Bodemer C. Skin manifestations of COVID-19 in children: part 2 Clin Exp Dermatol 46 3 2021 451 461 33166429 11 Centers for Disease Control and Prevention Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19) Available at: https://emergency.cdc.gov/han/2020/han00432.asp 12 Pollán M. Pérez-Gómez B. Pastor-Barriuso Prevalence of SARS-CoV-2 in Spain (ENE-COVID): a nationwide, population-based seroepidemiological study Lancet 396 10250 2020 535 544 32645347 13 Alonso Cadenas J.A. Andina Martínez D. Martín Díaz M.J. In response to the article «Impact of the COVID-19 pandemic in the emergency room: first findings in a hospital in Madrid» An Pediatr (Barc) 94 4 2020 270 272 14 Actualización n° 262 Enfermedad por el coronavirus (COVID-19) Available at: https://www.mscbs.gob.es/profesionales/saludPublica/ccayes/alertasActual/nCov/documentos/Actualizacion_262_COVID-19.pdf 15 Zimmermann P. Curtis N. Why is COVID-19 less severe in children? A review of the proposed mechanisms underlying the age-related difference in severity of SARS-CoV-2 infections Arch Dis Child 2020 10.1136/archdischild-2020-320338 16 Rekhtman S. Tannenbaum R. Strunk A. Mucocutaneous disease and related clinical characteristics in hospitalized children and adolescents with COVID-19 and multisystem inflammatory syndrome in children J Am Acad Dermatol 84 2 2021 408 414 33323343 17 Young T.K. Shaw K.S. Shah J.K. Mucocutaneous manifestations of multisystem inflammatory syndrome in children during the COVID-19 pandemic JAMA Dermatol 157 2 2021 207 212 33295957 18 Jimenez D.G. Rodríguez-Belvís M.V. Gonzalez P.F. COVID-19 gastrointestinal manifestations are independent predictors of PICU admission in hospitalized pediatric patients Pediatr Infect Dis J 39 12 2020 e459 e462 33105340 19 Belot A. Antona D. Renolleau S. SARS-CoV-2-related paediatric inflammatory multisystem syndrome, an epidemiological study, France, 1 March to 17 May 2020 Euro Surveill 25 22 2020 2001010 32524957 20 Harwood R. Allin B. Jones C.E. PIMS-TS National Consensus Management Study Group. A national consensus management pathway for paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS): results of a national Delphi process Lancet Child Adolesc Health 5 2 2021 133 141 32956615
PMC008xxxxxx/PMC8052603.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(21)00827-6 10.1016/j.jaad.2021.04.026 JAAD Online Response to comment on “An evidence-based guide to SARS-Cov-2 vaccination of patients on immunotherapies in dermatology.” Gresham Louise M. MD a Marzario Barbara MD a Dutz Jan MD, FRCPC b Kirchhof Mark G. MD, PhD, FRCPC a∗ a Division of Dermatology, Department of Medicine, University of Ottawa and The Ottawa Hospital, Ontario, Canada b Department of Dermatology and Skin Sciences, University of British Columbia, Vancouver, Canada ∗ Correspondence to: Mark G. Kirchhof, MD, PhD, FRCPC, Division of Dermatology, Department of Medicine, University of Ottawa and The Ottawa Hospital, 737 Parkdale Ave, Ontario K1Y 4E9, Canada 17 4 2021 8 2021 17 4 2021 85 2 e91e91 © 2021 by the American Academy of Dermatology, Inc. 2021 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: We would like to thank Speeckaert et al for their thoughtful comments on our article. We appreciate the authors' attention to detail in noting that in the study by Cho et al,1 although rituximab exposure did not significantly affect the humoral response to seasonal influenza vaccination in patients with autoimmune blistering disease, the interpretation was limited as rituximab treatment had been discontinued for at least 5 months prior to the vaccination.1 Based on the study of ocrelizumab (a humanized anti-CD20 antibody),2 Waldman et al3 have suggested the timing of the vaccination to be at least 4 weeks prior to anti-CD20 administration, and/or vaccinating the patients 12-20 weeks after a treatment cycle. Until further data are available, we endorse this position. In our review, we discussed the temporary withholding of immunosuppressive medication prior to vaccination or following it to improve antibody responses and referred to current published guidelines. The safety and efficacy of this maneuver has only been demonstrated for methotrexate in the setting of influenza vaccination in rheumatoid arthritis. Although an extrapolation to the patients with skin disease and COVID-19 vaccination is reasonable, the specific data are missing. Patients with skin conditions treated with Janus kinase inhibitors may flare more rapidly upon drug cessation than those treated with methotrexate as has been demonstrated in preclinical models4; thus, we agree with the authors that withholding Janus kinase inhibitors cannot be routinely recommended at this time. The final decision to withhold immunotherapy to maximize vaccine efficacy will always be a risk/benefit discussion between the patient and the physician. Vaccine induced antibody response after the first dose of a SARS-CoV-2 messenger RNA vaccine was recently shown to be significantly reduced in solid organ transplant patients receiving maintenance immunosuppressive therapy.5 Patients who were not receiving antimetabolite maintenance immunosuppression were more likely to mount a satisfactory immune response.5 These findings are in line with our conclusion that dermatology patients treated with antimetabolite immunosuppressive therapies may demonstrate variable antibody levels against SARS-CoV-2. This study also supports the possibility that dermatology patients treated with mycophenolate may show decreased post-vaccination antibody titres. We look forward to reviewing further data regarding the real-world SARS-CoV-2 vaccine efficacy in dermatologic patient populations as they become available, following the more widespread SARS-CoV-2 vaccine distribution. Conflicts of interest None disclosed. Funding sources: None. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Cho A. Bradley B. Kauffman R. Robust memory responses against influenza vaccination in pemphigus patients previously treated with rituximab JCI Insight 2 12 2017 e93222 28614800 2 Bar-Or A. Calkwood J.C. Chognot C. Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis: the VELOCE study Neurology 95 14 2020 e1999 e2008 32727835 3 Waldman R.A. Creed M. Sharp K. Toward a COVID-19 vaccine strategy for patients with pemphigus on rituximab J Am Acad Dermatol 84 4 2021 e197 e198 33130180 4 Fukuyama T. Ganchingco J.R. Bäumer W. Demonstration of rebound phenomenon following abrupt withdrawal of the JAK1 inhibitor oclacitinib Eur J Pharmacol 794 2017 20 26 27847179 5 Boyarsky B.J. Werbel W.A. Avery R.K. Immunogenicity of a single dose of SARS-CoV-2 messenger RNA vaccine in solid organ transplant recipients JAMA 325 17 2021 1784 1786 33720292
PMC008xxxxxx/PMC8149466.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. Published by Elsevier Inc. S0190-9622(21)01005-7 10.1016/j.jaad.2021.05.020 Research Letter Mild-to-moderate COVID-19 is not associated with worsening of alopecia areata: A retrospective analysis of 32 patients Rudnicka Lidia MD, PhD ∗ Rakowska Adriana MD, PhD Waskiel-Burnat Anna MD, PhD Kurzeja Marta MD, PhD Olszewska Malgorzata MD, PhD Department of Dermatology, Medical University of Warsaw, Poland ∗ Correspondence to: Lidia Rudnicka, MD, PhD, Department of Dermatology, Medical University of Warsaw, Koszykowa 82A, 02-008 Warsaw, Poland 26 5 2021 9 2021 26 5 2021 85 3 723725 © 2021 by the American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved. 2021 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: COVID-19 is a viral, SARS-CoV-2–induced disease associated with systemic immune activation.1 Patients with COVID-19 have been reported to have substantially higher plasma concentrations of proinflammatory cytokines such as interferon gamma, tumor necrosis factor, interleukin (IL) 6, IL-1β, IL-2, and IL-17A.2 This has raised concerns about the possible effect of COVID-19 on the course of alopecia areata. The aim of our study was to determine whether COVID-19 infection is associated with worsening disease in patients with pre-existing alopecia areata. The study included 32 consecutive patients with alopecia areata. All the patients had confirmed, mild-to-moderate COVID-19. The patients' characteristics are presented in Table I and Supplemental Table I, available via Mendeley at https://doi.org/10.17632/8v3s224grh.1. In all the patients, the severity of alopecia tool (SALT) score was assessed during regular check-up visits 1-6 weeks before COVID-19 and 3 months after disease onset. In 5 patients, an additional evaluation was performed 6 months after the onset of COVID-19. A post-COVID-19 trichoscopy checkup was performed in 17 patients. The study was conducted according to the principles outlined in the Declaration of Helsinki. The patients were receiving the following treatment when COVID-19 developed: intralesional triamcinolone (12 patients), oral glucocorticosteroids (10 patients), cyclosporine (10 patients), methotrexate (6 patients), azathioprine (1 patient), and none (4 patients). Their dermatologic comorbidities were as follows: lichen planopilaris with oral lichen planus, pemphigus, and psoriasis. In 10 (31.3%) of the 32 patients, the treatment was discontinued for 7-28 days because of COVID-19.Table I Characteristics of 32 patients with alopecia areata and COVID-19 Characteristic Data Women/men, n (%) 20/12 (62.5%/37.5%) Age in years, mean (range) 33.6 (14-59) Patchy alopecia/AT and AU, n (%) 29/3 (90.6.5%/9.4.%) SALT score before COVID-19,mean ± SD 40.8 ± 28.6 SALT score after COVID-19, mean ± SD 36.3 ± 27.3 Patients in whom treatment was discontinued during COVID-19, n (%) 10 (31.3%) Time of treatment discontinuation during COVID-19 in days, mean (range) 11 (7-28) AT, Alopecia totalis; AU, alopecia universalis; SALT, severity of alopecia tool. The SALT scores were as follows: 40.8 ± 28.6 (mean ± SD) before COVID-19 and 36.3 ± 27.3 after COVID-19. The difference was not statistically significant. In trichoscopy, only 3 (17.6%) of 17 patients were found to have the features of disease activity (exclamation-mark hairs and black dots). Patient history reviews revealed that there were no unexpected changes in the extent of alopecia areata from the moment of acquiring the SARS-CoV-2 infection to the first dermatologic appointment after recovery. No deterioration was observed in patients who were evaluated 6 months after the onset of COVID-19. In our patients, COVID-19 was not associated with the worsening of the dermatologic comorbidities. However, mild-to-moderate diffuse hair loss developed in 10 patients, consistent with telogen effluvium (confirmed using a trichogram). Progression from patchy alopecia to alopecia totalis/universalis occurred in none of the patients. A limitation of the study was the small group of patients included in the analysis and the fact that majority of the patients were on active treatment, which might have suppressed an inflammatory response. The literature presents conflicting data on the statistics regarding new-onset alopecia areata in the context of COVID-19. Cases of new-onset patchy alopecia areata and alopecia universalis developing in association with COVID-19 have been described.3 An increase in the incidence of alopecia areata during the pandemic was observed and was attributed to increased psychologic stress or the inflammatory storm associated with COVID-19.4 , 5 The pandemic and the stress related to the pandemic may have caused an increase in the incidence of alopecia areata. In this study, we evaluated the association between COVID-19 and the severity of pre-existing alopecia areata. Our analysis shows that mild-to-moderate COVID-19 is not associated with the worsening of the disease. Conflicts of interest Dr Rudnicka is a member of advisory boards in Eli Lilly, Janssen Pharmaceutical Companies, L'Oreal, Leo Pharma, Pfizer, Sanofi, Novartis, and UCB; a speaker for Abbvie, Eli Lilly, Leo Pharma, L'Oreal, and Pierre Fabre. Dr Olszewska is a speaker for Axxon, Leo Pharma, and medac. Dr Rakowska is a speaker for Pierre Fabre and Axon. Drs Waskiel-Burnat and Kurzeja have no conflicts of interest to declare. Funding sources: None. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Rudnicka L. Glowacka P. Goldust M. Cyclosporine therapy during the COVID-19 pandemic J Am Acad Dermatol 83 2 2020 e151 e152 32376422 2 Zhong J. Tang J. Ye C. Dong L. The immunology of COVID-19: is immune modulation an option for treatment? Lancet Rheumatol 2 7 2020 e428 e436 32835246 3 Ferreira S.B. Dias M.G. Ferreira R.B. Neto A.N. Trueb R.M. Lupi O. Rapidly progressive alopecia areata totalis in a COVID-19 patient, unresponsive to tofacitinib J Eur Acad Dermatol Venereol 35 7 2021 e411 e412 33587766 4 Kutlu O. Aktas H. Imren I.G. Metin A. Short-term stress-related increasing cases of alopecia areata during the COVID-19 pandemic J Dermatolog Treat 2020 5 Rinaldi F. Trink A. Giuliani G. Pinto D. Italian survey for the evaluation of the effects of coronavirus disease 2019 (COVID-19) pandemic on alopecia areata recurrence Dermatol Ther (Heidelb) 11 2 2021 339 345 33580408
PMC008xxxxxx/PMC8184255.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 Mosby S0190-9622(21)00917-8 10.1016/j.jaad.2021.04.073 This month in JAAD case reports July 2021: Lisinopril for delayed inflammatory responses to hyaluronic acid fillers after COVID-19 vaccinations Sloan Brett MD ∗ University of Connecticut School of Medicine, Farmington, Connecticut ∗ Correspondence to: Steven Brett Sloan, MD, University of Connecticut School of Medicine, Newington, CT, 06032. 8 6 2021 7 2021 8 6 2021 85 1 3434 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcIn the April 2021 edition of JAAD Case Reports, Munavalli et al1 reported a case series of 4 patients in whom delayed inflammatory responses to dermal hyaluronic acid filler developed following COVID-19 vaccination. All the patients had the facial filler placed for >8 months prior to the vaccination and significant edema developed at the sites of the filler 24-48 hours after receiving the COVID-19 messenger RNA vaccination. Through a proposed novel mechanism of action, the authors reported a rapid improvement with lisinopril via the inhibition of angiotensin-converting enzyme. The SAR-CoV-2 spike protein produced from the currently available messenger RNA vaccines interacts with its target ligand, the angiotensin-converting enzyme receptor 2. Alijotas-Reig et al2 postulated that quiescent filler granulomas can be activated via specific stimulation of the CD8+ helper T cell type 1 immune response by various triggers, including a viral infection or vaccine, resulting in the clinical findings of a delayed inflammatory response. Through the use of clinical images taken before and after the response as well as a detailed schematic, Munavalli et al1 demonstrated an impressive response after the use of lisinopril. They illustrated the potential mechanism of delayed inflammatory responses following the accumulation of proinflammatory angiotensin II and certain metabolites occurring downstream in the cutaneous renin-angiotensin system due to the inactivation of angiotensin-converting enzyme receptor 2 by the viral spike protein. Although the authors acknowledged that further studies are needed, they provided a promising treatment option for this unique vaccine-related phenomenon. Conflicts of interest None disclosed. Funding sources: None. IRB approval status: Not applicable. Reprints not available from the author. ==== Refs References 1 Munavalli G.G. Knutsen-Larson S. Lupo M.P. Geronemus R.G. Oral angiotensin-converting enzyme inhibitors for treatment of delayed inflammatory reaction to dermal hyaluronic acid fillers following COVID-19 vaccination-a model for inhibition of angiotensin II-induced cutaneous inflammation JAAD Case Rep 10 2021 63 68 33681439 2 Alijotas-Reig J. Fernández-Figueras M.T. Puig L. Late-onset inflammatory adverse reactions related to soft tissue filler injections Clin Rev Allergy Immunol 45 1 2013 97 108 23361999
PMC008xxxxxx/PMC8200325.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(21)01130-0 10.1016/j.jaad.2021.06.026 Research Letter Clinical manifestations and patch test results for facial dermatitis associated with disposable face mask use during the COVID-19 outbreak: A case-control study Kang Seok Young MD Chung Bo Young MD, PhD Kim Jin Cheol MD Park Chun Wook MD, PhD Kim Hye One MD, PhD ∗ Department of Dermatology, Kangnam Sacred Heart Hospital, Hallym University, Seoul, Korea ∗ Correspondence to: Hye One Kim, MD, PhD, Department of Dermatology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, 1 Singil-ro, Yeongdeungpo-gu, Seoul 07441, Korea 14 6 2021 9 2021 14 6 2021 85 3 719721 © 2021 by the American Academy of Dermatology, Inc. 2021 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: Due to the recent COVID-19 pandemic, people are wearing disposable masks more often than ever. The prolonged use of disposable masks has markedly increased cases of facial dermatitis, including irritant contact dermatitis, allergic contact dermatitis, and exacerbations of preexisting atopic dermatitis.1 Patch tests help differentiate possible etiologies and exclude allergic contact dermatitis; however, objective data are lacking to help determine the validity of positive allergens.2 Here, we undertook an observational study to investigate the clinical manifestation and patch test results of patients with facial dermatitis induced by wearing disposable masks. Korean patients older than 18 years of age with facial dermatitis diagnosed by dermatologists from the Department of Dermatology at Kangnam Sacred Heart Hospital after the outbreak of COVID-19 between January 2020 and July 2020 were included in the study. Clinically, 27 patients whose lesions and symptoms worsened after wearing a mask wereestablished as the mask group and 70 patients who developed facial dermatitis due to other causes were established as the control group. Both groups were recruited and distinguished using a questionnaire.2 Demographic features, clinical manifestations, objective bioengineering measurements (transepidermal water loss and stratum corneum hydration), and patch test (Korean standard series)3 results were analyzed in this study. The mean duration of disease was 6.24 months among the patients in the mask group and 22.87 months in the control group (Table I ). The distribution of skin lesions was similar in both groups except for the chin area, where skin lesions were more frequently observed in the mask group (14.81%; 4 of 27 patients). Erythema and papules were the most common characteristics of the skin lesions in both groups; however, hyperkeratosis (22.22%; 6 of 27) and xerosis (11.11%; 3 of 27) were significantly more frequent in the mask group.Table I Comparison between mask group and group induced by other causes with clinical manifestation Clinical manifestation Induced by mask (n = 27) Induced by other causes (n = 70) Disease duration, mean (SD), month∗ 6.24 ± 6.00 22.78 ± 30.37 Mean stratum corneum hydration (SD), A.U. 61.93 ± 21.03 58.94 ± 19.33 Mean TEWL (SD), g/m2/hr 16.98 ± 6.53 21.11 ± 20.88 Patients, Number (%)  Distribution∗  Centrofacial 18 (66.66) 9 (33.33)  Peripheral 45 (64.28) 25 (35.71) Location of eczematous skin lesions  Forehead 8 (29.62) 23 (32.85)  Nose 3 (11.11) 7 (10)  Perioral 6 (22.22) 17 (24.28)  Chin∗ 4 (14.81) 4 (5.71)  Ears 4 (14.81) 10 (14.28)  Cheek 13 (48.14) 38 (54.28)  Others 3 (11.11) 8 (11.42) Cutaneous signs  Erythema 19 (70.37) 46 (65.71)  Hyperkeratosis∗ 6 (22.22) 3 (4.28)  Pustule 3 (11.11) 18 (25.71)  Papule 6 (22.22) 22 (31.42)  Excoriation 0 2 (2.85)  Vesicle 2 (7.40) 10 (14.28)  Xerosis∗ 3 (11.11) 1 (1.42)  Hyperpigmentation 1 (3.70) 10 (14.28)  Edema∗ 2 (7.40) 0 Cutaneous symptoms  Itching 15 (55.55) 51 (72.85)  Flushing∗ 6 (22.22) 4 (5.71)  Stinging/heating sensation 4 (14.81) 11 (15.71) Each patient has 1 or more skin lesions, cutaneous signs, or symptoms. A.U., Arbitrary unit; SD, standard deviation; TEWL, transepidermal water loss. ∗ P value < .05. In patch test results (Table II ), the mask patch tested positive more frequently to potassium dichromate (25.92%; 7 of 27) and 4-tert-butylphenol-formaldehyde resin (14.81%; 4 of 27). Positive reactions to N-isopropyl-N-phenyl-4-phenylenediamine (7.40%; 2 of 27), formaldehyde (11.11%; 3 of 27), and thimerosal (14.81%; 4 of 27) were more common in the mask group, but the difference was not statistically significant. Interestingly, these substances are known components of disposable facial masks. In addition, 11 patients in the control group (15.71%; 11 of 70) had negative reactions to all the items in the patch tests, while only 1 patient in the mask group did (3.70%; 1 of 27).Table II Comparison between the mask group and control group in the patch test results Patch test items Induced by mask (n = 27) Induced by other causes (n = 70) 1. Nickel (II) sulfate hexahydrate 15 (55.55%) 31 (44.28%) 2. Lanolin alcohol (wool alcohol) 1 (3.70%) 2 (2.85%) 3. Neomycin sulfate 0 2 (2.85%) 4. Potassium dichromate∗ 7 (25.92%) 7 (10%) 5. Mercury ammonium chloride 0 5 (7.14%) 6. Fragrance mix I 1 (3.70%) 6 (8.57%) 7. Colophonium 1 (3.70%) 2 (2.85%) 8. Imidazolidinyl urea 0 1 (1.42%) 9. Clinquinol 0 1 (1.42%) 10. Myroxylon pereirae resin (Balsam Peru) 2 (7.40%) 4 (5.71%) 11. IPPD 2 (7.40%) 0 12. Cobalt (II) chloride hexahydrate 3 (11.11%) 2 (2.85%) 13. PTBP∗ 4 (14.81%) 0 14. Paraben mix 1 (3.70%) 0 15. Captan 2 (7.40%) 3 (4.28%) 16. Budesonide 0 2 (2.85%) 17. Methylisothizolinone + methylcholoroisothizolinone 0 1 (1.42%) 18. Quaternium-15 1 (3.70%) 0 19. MBT 0 1 (1.42%) 20. PPD 0 7 (10%) 21. Formaldehyde 3 (11.11%) 2 (2.85%) 22. Mercapto mix 1 (3.70%) 1 (1.42%) 23. Thimerosal 4 (14.81%) 5 (7.14%) 24. Thiuram mix 1 (3.70%) 1 (1.42%) 25. Tixocortol-21-pivalate 0 1 (1.42%) IPPD, N-Isopropyl-N-pheynyl-4-phenylenediamine; MBT, 2-Mercaptobenzothiazole; PPD, p-phenylenediamine; PTBP, 4-tert-butylphenol-formaldehyde resin. ∗ P value < .05. These results would infer that the chemical components of disposable masks and residues of disinfectants or cosmetics can cause allergic and irritant reactions. Further, given the occlusive, humid environment within a facial mask, it can be assumed that these substances could more easily penetrate the skin and cause facial dermatitis. Since the COVID-19 pandemic started, our living and medical environments have significantly changed, as have the frequency and types of exposure to allergens.4 , 5 Consequently, patch tests are essential for determining the correct diagnosis in patients with facial dermatitis. Our study could be a useful index for determining the causative allergens in patients with facial dermatitis induced by disposable masks. Conflicts of interest None disclosed. Drs Kang and Chung contributed equally to this work. Funding sources: This study was supported by grants from the 10.13039/501100003725 National Research Foundation of Korea (2017R1A2B4006252, 2018R1C1B6007998) and the 10.13039/501100003669 Korea Centers for Disease Control and Prevention (2020-ER6714-00). IRB approval status: This study was approved by the Institutional Review Board of Hallym University Kangnam Sacred Heart Hospital (IRB No. 2020-10-016). Reprints not available from the authors. ==== Refs References 1 Aerts O. Dendooven E. Foubert K. Stappers S. Ulicki M. Lambert J. Surgical mask dermatitis caused by formaldehyde (releasers) during the COVID-19 pandemic Contact Dermatitis 83 2 2020 172 173 32468589 2 Choi S.Y. Hong J.Y. Kim H.J. Mask induced dermatoses during COVID-19 pandemic: a questionnaire-based study in 12 hospitals of Korea Clin Exp Dermatol 2021 3 Yu D.S. Kim H.J. Park Y.G. Bae J.M. Kim J.W. Lee Y.B. Patch-test results using Korean standard series: a 5-year retrospective review J Dermatolog Treat 28 3 2017 258 262 27469077 4 Warshaw E.M. Schlarbaum J.P. Maibach H.I. Facial dermatitis in male patients referred for patch testing: retrospective analysis of North American Contact Dermatitis Group data, 1994 to 2016 JAMA Dermatol 156 1 2020 79 84 31774459 5 Xie Z. Yang Y.X. Zhang H. Mask-induced contact dermatitis in handling COVID-19 outbreak Contact Dermatitis 83 2 2020 166 167 32390190
PMC008xxxxxx/PMC8282438.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(21)02109-5 10.1016/j.jaad.2021.07.015 Research Letter An increase in respiratory protection device injuries associated with the COVID-19 pandemic McGwin Gerald Jr. MS, PhD ∗ McGwin Madeleine BS Griffin Russell L. MPH, PhD Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama ∗ Correspondence to: Gerald McGwin, Jr. MS, PhD, Department of Epidemiology, University of Alabama at Birmingham, 1720 University Boulevard, Suite 609, Birmingham, AL 35223 16 7 2021 10 2021 16 7 2021 85 4 973975 © 2021 by the American Academy of Dermatology, Inc. 2021 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: The COVID-19 pandemic abruptly changed many people's lives. While social distancing, quarantining, and personal protective equipment (PPE) have positively impacted the pandemic's progression, ancillary consequences have occurred.1 , 2 Prior to the COVID-19 pandemic, the use of respiratory protection equipment was largely limited to health care and industrial settings. However, as PPE use by the general population increased, reports of dermatologic reactions have also increased.3 This study reports on the epidemiology of respiratory protection equipment-related injuries in the United States associated with the COVID-19 pandemic. The data for this study was obtained from the National Electronic Injury Surveillance System (NEISS) for the period 2016 through 2020.4 The NEISS is a probability sample of approximately 100 hospitals and emergency rooms in the United States and is used to produce national estimates for emergency department treated consumer-product related injuries. Patient demographic and injury characteristics are abstracted from hospital medical record systems using standardized protocols. The injuries of interest in this study involved “Respiratory Protection Devices” (ie, NEISS Product Code 1618). Using this information, each injury was classified as due to rashes and/or allergic reactions, obscured vision, mask manufacturing, improper fit, or application issues. From 2016 through 2019, approximately 200 face mask-related injuries were treated in the US emergency departments annually; 4976 persons were treated for such injuries in 2020, a 2400% increase. The injuries occurred across the lifespan, and most of those injured were women; White and Black patients were equally represented (Table I ). The most common injury diagnoses were dermatitis (28.3%) and laceration (10.1%), with the face (72.5%), head (8.2%) and finger (8.1%) representing the most commonly injured body parts among patients with such diagnoses. The majority of injuries were attributable to rashes and/or allergic reactions (38%), followed by poorly fitting masks (19%), obscured vision (14%) and application issues (10%). Injuries related to obscured vision included falls and motor vehicle collisions. In addition, there was a small (5%) but a meaningful number of injuries, all among children, attributable to consuming pieces of a mask or inserting dismantled pieces of a mask into body orifices (eg, nose, ear). Finally, injuries attributable to falls secondary to bending over to pick up a dropped mask (all elderly patients) and injuries associated with mask manufacturing were uncommon (3% and 2%, respectively).Table I Demographic characteristics of persons sustaining emergency department treated face mask-related injuries in the United States, 2020 Number (N = 4976) Percent Age  <10 327 6.6  10-19 524 10.5  20-29 517 10.4  30-39 480 9.7  40-49 239 4.8  50-59 791 15.9  60-69 655 13.2  70-79 734 14.8  ≥80 708 14.3 Sex  Male 1772 35.6  Female 3203 64.4 Race  White 2064 41.5  Black 2091 42.0  Other 821 16.5 There has been a dramatic increase in face mask-related injuries during the COVID-19 pandemic. This increase is mostly attributable to increased PPE utilization rather than changes in their inherent danger. The majority of injuries were due to contact dermatitis or skin abrasions. The latter was likely due to prolonged use; poorly fitting masks, leading to pain or shortness of breath, were also common. Of particular interest was the number of injuries attributable to obscured vision. The Centers for Disease Control and Prevention has published recommendations and resources to aid in the choice and proper fit of face masks.3 The current study results underscore the need for increased awareness of these resources to minimize the future occurrence of mask-related injuries. Conflicts of interest None disclosed. Funding sources: None. IRB approval status: Exempt. Reprints not available from the authors. ==== Refs References 1 Li L. Neuroth L.M. Valachovic E. Schwebel D.C. Zhu M. Association between changes in social distancing policies in Ohio and traffic volume and injuries, January through July 2020 JAMA 325 10 2021 1003 1006 10.1001/jama.2020.25770 33687457 2 Phillips T. Schulte J.M. Smith E.A. Roth B. Kleinschmidt K.C. COVID-19 and contamination: impact on exposures to alcohol-based hand sanitizers reported to Texas Poison Control Centers, 2020 Clin Toxicol (Phila) 2021 1 11 10.1080/15563650.2021.1887491 3 Centers for Disease Control and Prevention Guidance for wearing masks https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/cloth-face-cover-guidance.html 4 United States Consumer Product Safety Commission National Electronic Injury Surveillance System https://www.cpsc.gov/Research–Statistics/NEISS-Injury-Data
PMC008xxxxxx/PMC8282440.txt
==== Front Neurologia Neurologia Neurologia (Barcelona, Spain) 0213-4853 1578-1968 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. S0213-4853(21)00120-1 10.1016/j.nrl.2021.06.005 Original Article The miRNA neuroinflammatory biomarkers in COVID-19 patients with different severity of illness Los biomarcadores neuroinflamatorios miARN en pacientes con COVID-19 con diferente gravedad de la enfermedadKeikha R. ab Hashemi-Shahri S.M. a Jebali A. c⁎ a Infectious Diseases and Tropical Medicine Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran b Department of Pathology, Faculty of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran c Department of Medical Nanotechnology, Faculty of Advanced Sciences and Technology, Tehran Medical Science, Islamic Azad University, Tehran, Iran ⁎ Corresponding author. 16 7 2021 July-August 2023 16 7 2021 38 6 e41e51 7 5 2021 27 6 2021 © 2021 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. 2021 Sociedad Española de Neurología Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Introduction The expression of specific miRNAs and their mRNA targets are changed in infectious disease. The aim of this study was to analyze the expression of pro-neuroinflammatory miRNAs, anti-neuroinflammatory miRNAs, and their mRNA targets in the serum of COVID-19 patients with different grades. Methods COVID-19 patients with different grades were enrolled in this study and the expression of pro-neuroinflammatory miRNAs, anti-neuroinflammatory miRNAs, and their target mRNAs was analyzed by q-PCR. Results The relative expression of anti- neuroinflammatory miRNAs (mir-21, mir-124, and mir-146a) was decreased and the relative expression of their target mRNAs (IL-12p53, Stat3, and TRAF6) was increased. Also, the relative expression of pro-neuroinflammatory miRNAs (mir-326, mir-155, and mir-27b) was increased and the relative expression of their target mRNA (PPARS, SOCS1, and CEBPA) was decreased in COVID-19 patients with increase of disease grade. A negative significant correlation was seen between mir-21 and IL-12p53 mRNA, mir-124 and Stat3 mRNA, mir-146a and TRAF6 mRNA, mir-27b and PPARS mRNA, mir-155 and SOCS1 mRNA, and between mir-326 and CEBPA mRNA in COVID-19 patients (P < 0.05). Conclusions This study showed that the relative expression of anti- neuroinflammatory miRNAs was decreased and the relative expression of their targeted mRNAs was increased in COVID-19 patients from asymptomatic to critical illness. Also, this study showed that the relative expression of pro-neuroinflammatory miRNAs was increased and the relative expression of their targeted mRNA was decreased in COVID-19 patients from asymptomatic to critical illness. Introducción La expresión de miARN específicos y sus dianas de ARNm se modifican en las enfermedades infecciosas. El objetivo de este estudio fue analizar la expresión de miARN pro-neuroinflamatorios, miARN anti-neuroinflamatorios y sus ARNm dianas en el suero de pacientes con COVID-19 de diferentes grados. Métodos Se incluyeron en este estudio pacientes con COVID-19 de diferentes grados y se analizó la expresión de miARN pro-neuroinflamatorios, miARN anti-neuroinflamatorios y sus ARNm diana mediante q-PCR. Resultados La expresión relativa de miARN anti-neuroinflamatorios (mir-21, mir-124 y mir-146a) disminuyó y la expresión relativa de sus ARNm diana (IL-12p53, Stat3 y TRAF6) aumentó. Además, la expresión relativa de miARN pro-neuroinflamatorios (mir-326, mir-155 y mir-27b) aumentó y la expresión relativa de su ARNm diana (PPARS, SOCS1 y CEBPA) disminuyó en pacientes con COVID-19 con aumento del grado de enfermedad. Se observó una correlación negativa significativa entre ARNm de mir-21 e IL-12p53, ARNm de mir-124 y Stat3, ARNm de mir-146a y TRAF6, ARNm de mir-27b y PPARS, ARNm de mir-155 y SOCS1, y entre mir-326 y ARNm de CEBPA en pacientes con COVID-19 (p < 0,05). Conclusiones Este estudio mostró que la expresión relativa de miARN anti-neuroinflamatorios disminuyó y la expresión relativa de sus ARNm diana se incrementó en pacientes con COVID-19 de enfermedad asintomática a crítica. Además, este estudio mostró que la expresión relativa de miARN pro-neuroinflamatorios aumentó y la expresión relativa de su ARNm diana disminuyó en pacientes con COVID-19 de enfermedad asintomática a crítica. Keywords miRNAs COVID-19 Pro-neuroinflammatory Anti-neuroinflammatory Palabras clave miARN COVID-19 Pro-neuroinflamatorio Anti-neuroinflamatorio ==== Body pmcIntroduction Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), known as COVID-19, is a new infectious disease first seen in late December 2019 in Wuhan, China, and similar outbreaks occurred in the hospital in neighboring countries. Major clinical symptoms include fever, dry cough, diarrhea, muscle aches, pneumonia, and in severe cases death.1, 2 COVID-19 also is associated with neurological manifestations such as encephalopathy and encephalomyelitis, ischemic stroke and intracerebral hemorrhage, anosmia, neuromuscular diseases, and neuroinflammation diseases.3 Since COVID-19 is a new disease, complete information on its etiology, cellular mechanisms, and possible risk factors is not available. COVID-19 may be similar to recent acute respiratory syndromes, such as SARS and MERS.4 Theoretically, after the SARS-CoV-2 enters the human body, different types of immune cells are stimulated. These cells trigger the proper immune response by producing different cytokines, chemokines, antibodies, etc. SARS-CoV-2 can infect the CNS following the entry of the virus into the nose or the eye. The viral particles are transmitted to the olfactory bulb and then to the brainstem, and then all parts of the brain.5 In addition to the direct attack of nerve cells, the SARS-CoV-2 can systematically cross the BBB through the blood vessels and reach the CNS. The main feature of systemic infection in COVID-19 is the massive increase in pro-inflammatory factors in the blood, which is described as a “cytokine stor”.6 This leads to BBB permeability and transmission of SARS-CoV-2 and peripheral immune cells. Once the coronavirus enters the CNS, it is the turn of the astrocytes and microglia to fight it. The immune response of astrocytes and microglia is regulated by different microRNAs (miRNAs). Previous studies showed inflammatory processes in CNS are guided by pro-neuroinflammatory miRNAs (such as mir-155, mir-27b, mir-326) and anti- neuroinflammatory miRNAs (such as mir-146a, mir-124, and mir-21).7, 8 This study aimed to analyze the expression of pro-neuroinflammatory miRNAs, anti-neuroinflammatory miRNAs, and their mRNA targets in the serum of COVID-19 patients with different grades. Materials and methods Materials All primers were provided from Bioneer, South Korea. MirPremier microRNA isolation kit was sourced from Sigma-Aldrich, USA. Mir-X miRNA First-Strand Synthesis kit and cDNA matermix were purchased from Takara bio inc, USA. SYBR® Green Real-Time Master Mix was from Invitrogen, UK. Bioinformatics In this study, to determine the miRNAs associated with the COVID-19, we used online bioinformatics Softwares.9 In the first step, mirTarP (https://mcube.nju.edu.cn/jwang/mirTar/docs/mirTar/) was used to the list of appropriate miRNAs.10, 11 In the second step, to reduce the number of selected miRNAs, we selected some limited pro-neuroinflammatory and anti-neuroinflammatory miRNAs that were previously reported in other studies. In the third step, the miRDB online database (http://mirdb.org/) was used to find the target of selected miRNAs.12 Target genes of the differentially regulated miRNAs were predicted using the mirPath tool (version 3.0).13 KEGG molecular pathways were also retrieved using the same tool.14 Pathways and processes regulated with P values lower than 0.05 were considered significant. Study groups Table 1 shows the full characteristics of 6 study groups enrolled in this study. The licensing committee that approved the experiments, including any relevant details was Zahedan University of Medical Sciences, Zahedan, Iran. All experiments were under the guidelines of the National Institute of Health, and the ethics committee of Zahedan University of Medical Sciences, Zahedan, Iran. (Ethical code: IR.ZAUMS.REC.1399.317). Also, informed consent was obtained from all participants. Five ml of whole blood was collected from each person and their serum was separated by centrifugation at 3000 rpm/min for 10 min at 4 °C. In this study, only COVID-19 patients with English variant of SARS-COV-2 (Lineage B.1.1.7; GISAID accession number: EPI-ISL-2227268) were included.Table 1 The characteristics of study groups. Table 1 Study group 1 Study group 2 Study group 3 Study group 4 Study group 5 Control Number (n) 21 20 20 21 21 20 Age distribution ± SD 50 ± 10 50 ± 10 50 ± 10 50 ± 10 50 ± 12 50 ± 12 Sex percentage ± SD Female (52% ± 2%) Male (48% ± 1%) Female (51% ± 2%) Male (49% ± 2%) Female (50% ± 3%) Male (50% ± 1%) Female (53% ± 1%) Male (47% ± 2%) Female (52% ± 1%) Male (48% ± 2%) Female (50% ± 3%) Male (50% ± 1%) Severity of illnessa Grade 5 Critical illness: Individuals who have respiratory failure, septic shock, and/or multiple organ dysfunction. Grade 4 Severe illness: Individuals who have SpO2 < 94% on room air at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) < 300 mm Hg, respiratory frequency > 30 breaths/min, or lung infiltrates > 50%. Grade 3 Moderate illness: Individuals who show evidence of lower respiratory disease during clinical assessment or imaging and who have saturation of oxygen (SpO2) ≥94% on room air at sea level. Grade 2 Mild illness: Individuals who have any of the various signs and symptoms of COVID-19 (e.g., fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of taste and smell) but who do not have shortness of breath, dyspnea, or abnormal chest imaging. Grade 1 Asymptomatic: Individuals who test positive for SARS-CoV-2 using a virologic test (i.e., a nucleic acid amplification test or an antigen test) but who have no symptoms that are consistent with COVID-19. Healthy people Comorbidities No No No No No No Inflammatory autoimmune diseases No No No No No No Drug treatment No No No No No No a The severity of COVID-19 was categorized according to NIH guidelines, https://www.covid19treatmentguidelines.nih.gov/overview/clinical-spectrum. Small RNA isolation, first-strand cDNA synthesis, and quantification of miRNAs and mRNAs by qPCR Here, Small RNA was isolated from blood samples using mirPremier microRNA isolation kit. Briefly, 1000 μL of the lysis buffer was added to 100 μL of serum samples, vortexed for 2 min, and incubated at 55 °C for 5 min. The samples were then centrifuged for 5 min at 14,000 ×  g to remove cellular debris, genomic DNA, and large RNA. The lysate supernatant was filtered through the filtration column and binding column. After binding, the column was first washed with 700 μL of 100% ethanol and centrifuged at 14,000 ×  g for 30 s and again the flow-through was discarded. The second wash was done by adding 500 μl of binding solution into the column and centrifuged at maximum speed (14,000 ×  g) for 1 min. Subsequently, 500 ml of the ethanol-diluted wash solution 2 was added to the column for a third wash. After centrifugation at maximum speed (14,000 ×  g) for 30 s, the flow-through was discarded. Next, the column was dried by centrifuging at maximum speed (14,000 ×  g) for 1 min. The column-tube assembly was carefully removed from the centrifuge to avoid splashing of the residual flow-through liquid to the dried column. Small RNA was eluted from the column using 50 ml elution solution and by centrifugation at 16,000 ×  g and the process was repeated to improve small RNA yield. The purity of the RNA samples was analyzed by NanoDrop ND-1000 UV-VIS spectrophotometer. The A260 nm/A280 nm ratio of all samples was between 1.8 and 2.1. The quantity of RNA samples was analyzed by agarose gel electrophoretic separation. For first-strand cDNA synthesis, small RNAs were polyadenylated and reverse transcribed using the Mir-X miRNA First-Strand Synthesis kit. Briefly, 5 μl mRQ buffer (2×), 5 μg RNA and 1.25 μl mRQ enzyme was mixed in a reaction volume of 10 μl and incubated in a thermocycler for 1 h at 37 °C, then terminate at 85 °C for 5 min to inactivate the enzymes. After reverse transcription, the cDNA was diluted. For quantification of miRNA by qPCR, Mir-X miRNA qPCR SYBR Kit was used. Briefly, 10 μl PCR reaction mixture was prepared to comprise of 1× SYBR advantage premix, 0.2 mM of both forward and reverse primers, and 50 ng of the first-strand cDNA. qPCR reactions were incubated in a 96 well plate at 95 °C for 2 min, followed by 40 cycles of 95 °C for 10 s and 60 °C for 20 s. Amplification cycles were followed by a melting curve analysis ranging from 56 to 95 °C. Finally, the threshold cycle (Ct) values were recorded. For mRNA, total RNA was extracted using an RNA extraction kit. Then, the cDNA was synthesized in the presence of the superscript enzyme and hexamers. For real-time PCR, 2 μL of cDNA, 2 μL of forward primer, and 2 μL of reverse primer of each gene were added to 10 μL of SYBR® Green Real-Time Master Mix. In this study, the relative expression of mir-155, mir-27b, mir-326, mir-124, mir-146a, mir-21, IL-12p53, Stat3, TRAF6, PPARS, SOCS1, and CEBPA was analyzed. The expression of microRNA and mRNA was normalized to RNU 48 and GAPDH, respectively. Statistical analysis All data were reported as the mean ± standard deviation. To find significant differences between groups, a one-way ANOVA method was applied. A P-value of less than 0.05 was considered statistically significant. Also, Spearman's correlation coefficient was used to correlate the expression of miRNAs and their mRNA targets. Results Bioinformatics analysis Five-top human mRNA targets for pro-neuroinflammatory miRNAs (mir-155, mir-27b, and mir-326) and anti- neuroinflammatory miRNAs (mir-124, mir-146a, and mir-21) are shown in Table 2 . It should be noted that each miRNA has many targets, but here we have listed only 5 important mRNA targets with the highest target score. Theoretically, all of them can be affected by pro-neuroinflammatory and anti-neuroinflammatory miRNAs.Table 2 The human gene targets of pro-neuroinflammatory miRNAs and anti- neuroinflammatory miRNAs, obtained from miRDB online database. Table 2Target score miRNA Name Gene Symbol Gene description 98 miR-155 SOCS1 Suppressor Of Cytokine Signaling 1 99 miR-155 ZNF629 Zinc finger protein 629 99 miR-155 CREBRF CREB3 regulatory factor 99 miR-155 DENND1B DENN domain containing 1B 98 miR-155 PTPN21 Protein tyrosine phosphatase, non-receptor type 21 98 miR-27b PPARs Peroxisome Proliferator Activated Receptor Gamma 97 miR-27b AFF4 AF4/FMR2 family member 4 97 miR-27b GXYLT1 Glucoside xylosyltransferase 1 97 miR-27b ARFGEF1 ADP ribosylation factor guanine nucleotide exchange factor 1 96 miR-27b GCC2 GRIP and coiled-coil domain containing 2 99 miR-326 CEBPA CCAAT Enhancer Binding Protein Alpha 99 miR-326 ETS1 ETS proto-oncogene 1, transcription factor 99 miR-326 CEP85 Centrosomal protein 85 98 miR-326 FGF11 Fibroblast growth factor 11 98 miR-326 GPD2 Glycerol-3-phosphate dehydrogenase 2 98 miR-124 Stat3 Signal Transducer And Activator Of Transcription 3 98 miR-124 OSBPL3 Oxysterol binding protein like 3 98 miR-124 SLC50A1 Solute carrier family 50 member 1 98 miR-124 ITGB1 Integrin subunit beta 1 98 miR-124 SIX4 SIX homeobox 4 100 miR-146a TRAF6 TNF Receptor Associated Factor 6 100 miR-146a FOXC1 Forkhead box C1 100 miR-146a CPLX2 Complexin 2 100 miR-146a STXBP6 Syntaxin binding protein 6 100 miR-146a ZFX Zinc finger protein X-linked 99 miR-21 IL-12p53 Interleukin 12 p53 protein 99 miR-21 STK38L Serine/threonine kinase 38 like 99 miR-21 PCDH19 Protocadherin 19 99 miR-21 LAMP1 Lysosomal associated membrane protein 1 99 miR-21 GRIA2 Glutamate ionotropic receptor AMPA type subunit 2 Based on KEGG database (Table 3 ), we found that both pro-neuroinflammatory miRNAs and anti-neuroinflammatory miRNAs are significantly enriched in important cellular pathways, such as PI3K-Akt signaling pathway, mRNA surveillance pathway, mTOR signaling pathway, MAPK signaling pathway, Wnt signaling pathway, and AMPK signaling pathway.Table 3 Important pathways of pro-neuroinflammatory miRNAs and anti- neuroinflammatory miRNAs, extracted from KEGG molecular pathway. Table 3KEGG pathway P-value Genes miRNAs Adherens junction 0.0001 30 6 Endometrial cancer 0.0001 24 6 Small cell lung cancer 0.0001 36 6 Regulation of actin cytoskeleton 0.0001 67 56 Bladder cancer 0.0002 21 4 PI3K-Akt signaling pathway 0.0002 105 5 Shigellosis 0.0002 26 4 Thyroid hormone signaling pathway 0.0003 44 4 Lysine degradation 0.001 15 3 Non-small cell lung cancer 0.001 23 4 mRNA surveillance pathway 0.001 34 4 mTOR signaling pathway 0.002 25 4 Oocyte meiosis 0.003 38 4 Prolactin signaling pathway 0.003 28 4 Melanoma 0.003 25 5 Ubiquitin mediated proteolysis 0.004 48 5 Fatty acid metabolism 0.004 11 3 Fatty acid elongation 0.004 6 3 Arrhythmogenic right ventricular 0.006 16 3 Estrogen signaling pathway 0.006 31 5 Signaling pathways regulating of stem cells 0.007 42 5 Gap junction 0.008 27 5 Sphingolipid signaling pathway 0.009 38 5 Amoebiasis 0.01 30 4 Pantothenate and CoA biosynthesis 0.01 6 3 MAPK signaling pathway 0.01 72 5 Insulin signaling pathway 0.02 45 5 Wnt signaling pathway 0.02 41 4 Axon guidance 0.02 37 4 Pathogenic Escherichia coli infection 0.02 21 5 AMPK signaling pathway 0.02 41 5 Hepatitis C 0.03 20 5 Vibrio cholerae infection 0.03 23 4 Epithelial cell signaling in Helicobacter pylori infection 0.04 54 4 Platelet activation 0.04 39 5 Steroid biosynthesis 0.04 5 3 Salmonella infection 0.04 27 5 The expression of anti-neuroinflammatory miRNAs and their mRNA targets We found that the relative expression of anti-neuroinflammatory miRNAs, including mir-21, mir-124, and mir-146a, was significantly decreased with increase of COVID-19 grade (P  < 0.05) (Fig. 1 (a–c)). Interestingly, the relative expression of human mRNA targets, including IL-12p53, Stat3, and TRAF6, of anti-neuroinflammatory miRNAs was significantly increased with increase of COVID-19 grade (P  < 0.05) (Fig. 2 (a–c)). A negative significant correlation was seen between the expression of (mir-21 and IL-12p53 mRNA), (mir-124 and Stat3 mRNA), and (mir-146a and TRAF6 mRNA) in COVID-19 patients at all grades (P  < 0.05) (Fig. 3 (a–c)).Figure 1 The relative expression of mir-21 (a), mir-124 (b), and mir-146a (c) in COVID-19 patients with different grades. *P < 0.05 compared with Mild Illness and Asymptomatic by one-way ANOVA. Figure 2 The relative expression of IL-12p53 (a), Stat3 (b), and TRAF6 (c) mRNAs in COVID-19 patients with different grades. *P < 0.05 compared with Mild Illness and Asymptomatic by one-way ANOVA. Figure 3 The correlation between the relative expression of mir-21 and IL-12p53 mRNA (a), mir-124 and Stat3 mRNA (b), and mir-146a and TRAF6 mRNA (c) in COVID-19 patients with different grades. Spearman's correlation coefficient was used to correlate these parameters. The expression of pro-neuroinflammatory miRNAs and their mRNA targets The relative expression of pro-neuroinflammatory miRNAs, including mir-326, mir-155, and mir-27b, was significantly increased with increase of COVID-19 grade (P  < 0.05) (Fig. 4 (a–c)). Interestingly, the relative expression of human mRNA targets, including PPARS, SOCS1, and CEBPA, of pro-neuroinflammatory miRNAs was significantly decreased with increase of COVID-19 grade (P  < 0.05) (Fig. 5 (a–c)). A negative significant correlation was also seen between the expression of (mir-27b and PPARS mRNA), (mir-155 and SOCS1 mRNA), and (mir-326 and CEBPA mRNA) in COVID-19 patients at all grades (P  < 0.05) (Fig. 6 (a–c)).Figure 4 The relative expression of mir-27b (a), mir-155 (b), and mir-326 (c) in COVID-19 patients with different grades. *P < 0.05 compared with Mild Illness and Asymptomatic by one-way ANOVA. Figure 5 The relative expression of PPARS (a), SOCS1 (b), and CEBPA (c) mRNAs in COVID-19 patients with different grades. *P < 0.05 compared with Mild Illness and Asymptomatic by one-way ANOVA. Figure 6 The correlation between the relative expression of mir-27b and PPARS mRNAs (a), mir-155 and SOCS1 mRNAs (b), and mir-326 and CEBPA mRNA (c) in COVID-19 patients with different grades. Spearman's correlation coefficient was used to correlate these parameters. Discussion This study showed that the relative expression of anti-neuroinflammatory miRNAs (mir-21, mir-124, and mir-146a) was decreased and the relative expression of their target mRNAs (IL-12p53, Stat3, and TRAF6) was increased in COVID-19 patients with increase of disease grade from asymptomatic to critical illness. Also, this study showed that the relative expression of pro-neuroinflammatory miRNAs (mir-326, mir-155, and mir-27b) was increased and the relative expression of their target mRNA (PPARS, SOCS1, and CEBPA) was decreased in COVID-19 patients with increase of disease grade. A negative significant correlation was seen between each miRNA and its target mRNA. Based on bioinformatics analysis, some important pathways are affected by these pro-neuroinflammatory and anti-neuroinflammatory miRNAs, including PI3K-Akt, mRNA surveillance, mTOR, MAPK, Wnt, and AMPK signaling pathways. What we have found is that in patients with high severity of illness, the expression of pro-inflammatory miRNAs is increased, and conversely, the expression of anti-inflammatory miRNAs is decreased. Of course, it is clear that this situation follows a cytokine storm. Unfortunately, we have to say that this special condition not only causes serious damage to the brain but also causes damage to several organs and leads to multiple organ failure. We think that when immune cells are highly stimulated, cytokines and miRNAs can travel through the bloodstream to the whole body. This phenomenon has been mentioned by some researchers.15, 16 Mir-155 is a central pro-inflammatory mediator in CNS by NF-κB dependent TLR signaling. It is synthesized inside macrophages and microglia.17, 18, 19 mir-155 targets anti-inflammatory regulators such as SOCS1,17, 19 SHIP1,20 C/EBP-β 21 and IL13Rα1.22 mir-155 inhibits the suppression of anti-inflammatory signaling and induces neuroinflammation. When mir-155 is expressed, it stimulates the transcription factor p53, and it targets the c-Maf transcription factor, which induces differentiation and inflammatory responses.23 Mir-146a is an anti-inflammatory regulator in nerve cells, microglia, and astrocytes. It activates by NF-κB dependent TLR signaling.24, 25 The Mir-146a targets MyD88 signaling complex, including IRAK1 and TRAF6, and acts as an NF-κB signaling regulator. In addition, Mir-146a targets other pro-inflammatory mediators including STAT-1,26, 27 IRF-5 27 and CFH.28, 29 The polarization of macrophages and microglia are also altered by mir-146a.30 mir-124 is also an anti-inflammatory miRNA and has a major role in neuronal differentiation31 and is highly expressed in microglia under normal conditions, but is not expressed in peripheral macrophages.32 Expression of mir-124 in microglia leads to anti-inflammatory effects33 by M2 phenotype.34 It is clear that mir-124 has anti-inflammatory activity by reducing inflammatory mediators and limiting microglia to activity. The role of mir-21 is very prominent in different types of CNS cells such as microglia35 and astrocytes,36 neurons,37 and oligodendrocytes.38 Mir-21 is an anti-inflammatory regulator activated by TLR signaling. This induces the expression of the anti-inflammatory cytokine such as IL-10.39 In addition, mir-21 decreases TNF-α secretion in macrophages and microglia.40 mir-27b targets an anti-inflammatory transcriptional activator, PPAR-γ; in human macrophages, this interaction blocks the induction of an anti-inflammatory phenotype. Inhibiting mir-27b also limits inflammatory signaling. It leads to produce inflammatory cytokines including IL-6 and TNF-α.41 mir-326 is another pro-inflammatory miRNAs and can affect on differentiation of IL-17-producing Th17 cells. It was found that silencing mir-326 reduced EAE pathology.42 miRNAs have a cumulative effect on neuronal signaling and act together in inflammatory or anti-inflammatory pathways. For example, both mir-146a and mir-21 target different components of the TLR/MyD88/NF-κB and JAK-STAT pathways.26, 28 In contrast, mir-155, mir-27b, and mir-326 activate the JAK-STAT pathway by targeting SOCS1 and SHIP1.19 It is interesting to note that miRNAs are also present in extracellular exosomes and can participate in intercellular communication.43 For example, mir-124, mir-21, and let-7 are found in exosomes and stimulate and regulate adjacent cells such as microglia and contribute to inflammatory signaling.44 One of main limitations of this study was to find and to collect COVID-19 patients with no comorbidities, no inflammatory autoimmune diseases, and no drug treatments. Theoretically, these factors can affect the expression of mRNAs and miRNAs. Second limitation was that we did not include COVID-19 patients caused by different variants of SARS-COV-2. Here, only COVID-19 patients with English variant (Lineage B.1.1.7) were included. We think that the expression of mRNAs and miRNAs may also be affected by virus variants. The third limitation was that we evaluated only 6 neuroinflammatory miRNAs in COVID-19 patients and it is suggested that other neuroinflammatory miRNAs could be studied in future studies. Conclusions This study showed that the relative expression of anti-neuroinflammatory miRNAs (mir-21, mir-124, and mir-146a) was decreased and the relative expression of their mRNAs (IL-12p53, Stat3, and TRAF6) was increased in COVID-19 patients from asymptomatic to critical illness. Also, this study showed that the relative expression of pro-neuroinflammatory miRNAs (mir-326, mir-155, and mir-27b) was increased and the relative expression of their mRNA (PPARS, SOCS1, and CEBPA) was decreased in COVID-19 patients from asymptomatic to critical illness. A negative significant correlation was seen between mir-21 and IL-12p53 mRNA, mir-124 and Stat3, between mir-146a and TRAF6, between mir-27b and PPARS, between mir-155 and SOCS1, and between mir-326 and CEBPA mRNA in COVID-19 patients (P  < 0.05). Authors’ contributions (I) Conception and design: R.K. and A.J., (II) Administrative support: R.K. and A.J., (III) Provision of study materials or patients: R.K., (IV) Collection and assembly of data: A.J., (V) Data analysis and interpretation: R.K. and A.J., (VI) Manuscript writing: All authors, (VII) Final approval of manuscript: All authors. Ethics approval and consent to participate “The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.” All experiments were under the guidelines of the National Institute of Health, the provisions of the Declaration of Helsinki,and the ethics committee of Zahedan University of Medical Sciences, Zahedan, Iran. (Ethical code: IR.ZAUMS.REC.1399.317). Consent for publication Not. Availability of data and material Not. Funding This article was financially supported by 10.13039/501100004847 Zahedan University of Medical Sciences , Zahedan, Iran (grant number: 9937). Conflict of interest There is no conflict of interest. Acknowledgements We thank the Reference Laboratory of Zahedan University of Medical Sciences. ==== Refs References 1 Rothan H.A. Byrareddy S.N. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak J Autoimmun 2020 102433 32113704 2 Zu Z.Y. Jiang M.D. Xu P.P. Chen W. Ni Q.Q. Lu G.M. Coronavirus disease 2019 (COVID-19): a perspective from China Radiology 200490 2020 3 Berlit P. Bösel J. Gahn G. Isenmann S. Meuth S.G. Nolte C.H. “Neurological manifestations of COVID-19”-guideline of the German society of neurology Neurol Res Pract 2 2020 1 14 33324907 4 Peeri N.C. Shrestha N. Rahman M.S. Zaki R. Tan Z. Bibi S. The SARS MERS and novel coronavirus (COVID-19) epidemics, the newest and biggest global health threats: what lessons have we learned? Int J Epidemiol 2020 5 Li K. Wohlford-Lenane C. Perlman S. Zhao J. Jewell A.K. Reznikov L.R. Middle East respiratory syndrome coronavirus causes multiple organ damage and lethal disease in mice transgenic for human dipeptidyl peptidase 4 J Infect Dis 213 2016 712 722 26486634 6 Coperchini F. Chiovato L. Croce L. Magri F. Rotondi M. The cytokine storm in COVID-19: an overview of the involvement of the chemokine/chemokine-receptor system Cytokine Growth Factor Rev 53 2020 25 32 32446778 7 Gaudet A.D. Fonken L.K. Watkins L.R. Nelson R.J. Popovich P.G. MicroRNAs: roles in regulating neuroinflammation Neuroscientist 24 2018 221 245 28737113 8 Slota J.A. Booth S.A. MicroRNAs in neuroinflammation: implications in disease pathogenesis, biomarker discovery and therapeutic applications Non-coding RNA 5 2019 35 31022830 9 Ekimler S. Sahin K. Computational methods for microRNA target prediction Genes 5 2014 671 683 25153283 10 Shu X. Zang X. Liu X. Yang J. Wang J. Predicting microRNA mediated gene regulation between human and viruses Cells 7 2018 100 30096814 11 Sardar R. Satish D. Gupta D. Identification of novel SARS-CoV-2 drug targets by host microRNAs and transcription factors co-regulatory interaction network analysis Front Genet 11 2020 1105 12 Wong N. Wang X. miRDB: an online resource for microRNA target prediction and functional annotations Nucleic Acids Res 43 2015 D146 D152 25378301 13 Vlachos I.S. Zagganas K. Paraskevopoulou M.D. Georgakilas G. Karagkouni D. Vergoulis T. DIANA-miRPath v3.0 deciphering microRNA function with experimental support Nucleic Acids Res 43 2015 W460 W466 25977294 14 Kanehisa M. Goto S. Kawashima S. Nakaya A. The KEGG databases at GenomeNet Nucleic Acids Res 30 2002 42 46 11752249 15 Latimer G. Corriveau C. DeBiasi R.L. Jantausch B. Delaney M. Jacquot C. Cardiac dysfunction and thrombocytopenia-associated multiple organ failure inflammation phenotype in a severe paediatric case of COVID-19 Lancet Child Adolescent Health 4 2020 552 554 32437638 16 Wang T. Du Z. Zhu F. Cao Z. An Y. Gao Y. Comorbidities and multi-organ injuries in the treatment of COVID-19 Lancet 395 2020 e52 32171074 17 Wang P. Hou J. Lin L. Wang C. Liu X. Li D. Inducible microRNA-155 feedback promotes type I IFN signaling in antiviral innate immunity by targeting suppressor of cytokine signaling 1 J Immunol 185 2010 6226 6233 20937844 18 Bala S. Marcos M. Kodys K. Csak T. Catalano D. Mandrekar P. Up-regulation of microRNA-155 in macrophages contributes to increased tumor necrosis factor α (TNFα) production via increased mRNA half-life in alcoholic liver disease J Biol Chem 286 2011 1436 1444 21062749 19 Cardoso A.L. Guedes J.R. Pereira de Almeida L. Pedroso de Lima M.C. miR-155 modulates microglia-mediated immune response by down-regulating SOCS-1 and promoting cytokine and nitric oxide production Immunology 135 2012 73 88 22043967 20 O’Connell R.M. Chaudhuri A.A. Rao D.S. Baltimore D. Inositol phosphatase SHIP1 is a primary target of miR-155 Proc Natl Acad Sci USA 106 2009 7113 7118 19359473 21 Worm J. Stenvang J. Petri A. Frederiksen K.S. Obad S. Elmen J. Silencing of microRNA-155 in mice during acute inflammatory response leads to derepression of c/ebp Beta and down-regulation of G-CSF Nucleic Acids Res 37 2009 5784 5792 19596814 22 Martinez-Nunez R.T. Louafi F. Sanchez-Elsner T. The interleukin 13 (IL-13) pathway in human macrophages is modulated by microRNA-155 via direct targeting of interleukin 13 receptor α1 (IL13Rα1) J Biol Chem 286 2011 1786 1794 21097505 23 Su W. Hopkins S. Nesser N.K. Sopher B. Silvestroni A. Ammanuel S. The p53 transcription factor modulates microglia behavior through microRNA-dependent regulation of c-Maf J Immunol 192 2014 358 366 24319262 24 Taganov K.D. Boldin M.P. Chang K-J. Baltimore D. NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses Proc Natl Acad Sci USA 103 2006 12481 12486 16885212 25 Cui J.G. Li Y.Y. Zhao Y. Bhattacharjee S. Lukiw W.J. Differential regulation of interleukin-1 receptor-associated kinase-1 (IRAK-1) and IRAK-2 by microRNA-146a and NF-κB in stressed human astroglial cells and in Alzheimer disease J Biol Chem 285 2010 38951 38960 20937840 26 He X. Tang R. Sun Y. Wang Y-G. Zhen K-Y. Zhang D-M. MicroR-146 blocks the activation of M1 macrophage by targeting signal transducer and activator of transcription 1 in hepatic schistosomiasis EBioMedicine 13 2016 339 347 27780686 27 Tang Y. Luo X. Cui H. Ni X. Yuan M. Guo Y. MicroRNA-146a contributes to abnormal activation of the type I interferon pathway in human lupus by targeting the key signaling proteins Arthritis Rheumat 60 2009 1065 1075 19333922 28 Li Y.Y. Cui J.G. Dua P. Pogue A.I. Bhattacharjee S. Lukiw W.J. Differential expression of miRNA-146a-regulated inflammatory genes in human primary neural, astroglial and microglial cells Neurosci Lett 499 2011 109 113 21640790 29 Lukiw W.J. Zhao Y. Cui J.G. An NF-κB-sensitive micro RNA-146a-mediated inflammatory circuit in Alzheimer disease and in stressed human brain cells J Biol Chem 283 2008 31315 31322 18801740 30 Huang C. Liu X-j. Xie J. Ma T-t. Meng X-m. Li J. MiR-146a modulates macrophage polarization by inhibiting Notch1 pathway in RAW264 7 macrophages Int Immunopharmacol 32 2016 46 54 26800097 31 Makeyev E.V. Zhang J. Carrasco M.A. Maniatis T. The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing Mol Cell 27 2007 435 448 17679093 32 Ponomarev E.D. Veremeyko T. Barteneva N. Krichevsky A.M. Weiner H.L. MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-α-PU. 1 pathway Nat Med 17 2011 64 70 21131957 33 Ma C. Li Y. Li M. Deng G. Wu X. Zeng J. microRNA-124 negatively regulates TLR signaling in alveolar macrophages in response to mycobacterial infection Mol Immunol 62 2014 150 158 24995397 34 Veremeyko T. Siddiqui S. Sotnikov I. Yung A. Ponomarev E.D. IL-4/IL-13-dependent and independent expression of miR-124 and its contribution to M2 phenotype of monocytic cells in normal conditions and during allergic inflammation PLoS ONE 8 2013 e81774 24358127 35 Zhang L. Dong L.Y. Li Y.J. Hong Z. Wei W.S. miR-21 represses FasL in microglia and protects against microglia-mediated neuronal cell death following hypoxia/ischemia Glia 60 2012 1888 1895 22907769 36 Li H.-J. Pan Y.-B. Sun Z.-L. Sun Y.-Y. Yang X.-T. Feng D.-F. Inhibition of miR-21 ameliorates excessive astrocyte activation and promotes axon regeneration following optic nerve crush Neuropharmacology 137 2018 33 49 29709341 37 Han Z. Chen F. Ge X. Tan J. Lei P. Zhang J. miR-21 alleviated apoptosis of cortical neurons through promoting PTEN-Akt signaling pathway in vitro after experimental traumatic brain injury Brain Res 1582 2014 12 20 25108037 38 Miguel-Hidalgo J.J. Hall K.O. Bonner H. Roller A.M. Syed M. Park C.J. MicroRNA-21: expression in oligodendrocytes and correlation with low myelin mRNAs in depression and alcoholism Prog Neuropsychopharmacol Biol Psychiatry 79 2017 503 514 28802862 39 Sheedy F.J. Palsson-McDermott E. Hennessy E.J. Martin C. O’leary J.J. Ruan Q. Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21 Nat Immunol 11 2010 141 147 19946272 40 Barnett R.E. Conklin D.J. Ryan L. Keskey R.C. Ramjee V. Sepulveda E.A. Anti-inflammatory effects of miR-21 in the macrophage response to peritonitis J Leukoc Biol 99 2016 361 371 26382295 41 Jennewein C. von Knethen A. Schmid T. Brüne B. MicroRNA-27b contributes to lipopolysaccharide-mediated peroxisome proliferator-activated receptor γ (PPARγ) mRNA destabilization J Biol Chem 285 2010 11846 11853 20164187 42 Du C. Liu C. Kang J. Zhao G. Ye Z. Huang S. MicroRNA miR-326 regulates T H-17 differentiation and is associated with the pathogenesis of multiple sclerosis Nat Immunol 10 2009 1252 19838199 43 Bayraktar R. Van Roosbroeck K. Calin G.A Cell-to-cell communication: microRNAs as hormones Mol Oncol 11 2017 1673 1686 29024380 44 Pinto S. Cunha C. Barbosa M. Vaz A.R. Brites D. Exosomes from NSC-34 cells transfected with hSOD1-G93A are enriched in miR-124 and drive alterations in microglia phenotype Front Neurosci 11 2017 273 28567000
PMC008xxxxxx/PMC8302886.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(21)02182-4 10.1016/j.jaad.2021.06.895 JAAD Online Expanding teledermatology educational opportunities after the COVID-19 pandemic Hassan Shahzeb BA a Safadi Mohannad G. BS b Mohammed Taha O. BS a Lipoff Jules B. MD cd∗ a Northwestern University Feinberg School of Medicine, Chicago, Illinois b University of Illinois College of Medicine, Chicago, Illinois c Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania d Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, Pennsylvania ∗ Correspondence to: Jules B. Lipoff, MD, Department of Dermatology, University of Pennsylvania, Penn Medicine University City, 3737 Market Street, Suite 1100, Philadelphia, PA 19104 24 7 2021 10 2021 24 7 2021 85 4 e253e254 © 2021 by the American Academy of Dermatology, Inc. 2021 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: According to a recent survey by the American Academy of Dermatology, dermatologists believe that the increased use of teledermatology will persist even after COVID-19.1 Moreover, teledermatology has been successfully implemented not only in outpatient settings but also for inpatient services.2 We read with interest the study by Gabel et al2 and support the implementation of teledermatology in inpatient settings for making decisions about the diagnosis, evaluation, and management of dermatologic conditions. These findings build upon previous work that demonstrated both agreement and improvement in the time to response and average handling of inpatient dermatology cases using telemedicine.3 According to a survey, 34 of 72 dermatology residency respondents indicated that they used telemedicine as a part of their curriculum. Only 12 of 57 programs offered telemedicine education to medical students. Importantly, 39 of the 57 programs said that they would be interested in incorporating more telemedicine into their curriculum.4 Moreover, the increased use of teledermatology may continue post-pandemic, given its resource efficiency and improvement in enabling access to care in underserved areas.1 Given teledermatology's expanding role in clinical care, we believe that it is important to include telemedicine in medical school and residency curricula to ensure that its increase in use is appropriate and high-quality. What would an expanded teledermatology curriculum look like? First, teledermatology in practice can be directly incorporated into medical student and resident patient care as well as workflows. For instance, using store-and-forward teledermatology, medical students and residents can review clinical images and propose differential diagnoses and treatment suggestions, which can then be screened and adjusted as necessary by a faculty preceptor.5 In this way, trainees would learn not only proper patient care but also the appropriate adaptations, triage, and workflow of dermatology care using telemedicine. Second, medical school curricula can leverage teledermatology to facilitate existing didactic programs into teaching medical knowledge. In fact, the long standing tradition of Kodachrome review sessions, in which an attending physician presents unknown clinical images to trainees, is itself a respresentation of an established technique that harnesses telemedicine diagnostic skills for general dermatology education. In the residency survey regarding teledermatology, only 5 of the 57 programs reported that residents have knowledge of health policy effects and the legal landscape of teledermatology. Ten of the 57 programs felt that residents lack any knowledge of telemedicine.4 Given this gap in education, the designated time during residency and medical training should prepare trainees, through both practice cases and teaching sessions, for telemedicine visits. Although store-and-forward teledermatology was previously the most-used modality in both care and education before the pandemic,5 given the expansion of video visits during the COVID-19 pandemic, synchronous telemedicine practices must also be included. Besides using teledermatology for practice and medical knowledge, given the rapidly changing environment, it will remain important to engage trainees on the legal and financial aspects of telemedicine. Given the potential for teledermatology in education, we hope that in the future, medical schools and residency programs will expand their telemedicine curricula to provide the most comprehensive training for our future dermatologists. Conflicts of interest Dr Lipoff has served as a paid consultant on telemedicine for Havas Life Medicom and is an advisor for AcneAway, a direct-to-consumer telemedicine start-up. Authors Hassan, Safadi, and Mohammed have no conflicts of interest to declare. Funding sources: None. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Kennedy J. Arey S. Hopkins Z. Dermatologist perceptions of teledermatology implementation and future use after COVID-19: demographics, barriers, and insights JAMA Dermatol 157 5 2021 595 597 33787839 2 Gabel C.K. Nguyen E. Karmouta R. Use of teledermatology by dermatology hospitalists is effective in the diagnosis and management of inpatient disease J Am Acad Dermatol 84 6 2021 1547 1553 32389716 3 Sharma P. Kovarik C.L. Lipoff J.B. Teledermatology as a means to improve access to inpatient dermatology care J Telemed Telecare 22 5 2016 304 310 26377123 4 Wanat K.A. Newman S. Finney K.M. Kovarik C.L. Lee I. Teledermatology education: current use of teledermatology in US residency programs J Grad Med Educ 8 2 2016 286 287 27168912 5 Boyers L.N. Schultz A. Baceviciene R. Teledermatology as an educational tool for teaching dermatology to residents and medical students Telemed J E Health 21 4 2015 312 314 25635528
PMC008xxxxxx/PMC8381623.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 Published by Elsevier on behalf of the American Academy of Dermatology, Inc. S0190-9622(21)02370-7 10.1016/j.jaad.2021.08.031 A Clinician's Perspective Dermatology patients on biologics and certain other systemic therapies should receive a “booster” messenger RNA COVID-19 vaccine dose: A critical appraisal of recent Food and Drug Administration and Advisory Committee on Immunization Practices recommendations Waldman Reid Alexander MD a∗ Grant-Kels Jane M. MD b a Dermatology Associates of Glastonbury, Glastonbury, Connecticut b Department of Dermatology, University of Connecticut Health Center, Farmington, Connecticut ∗ Correspondence and reprint requests to: Reid Alexander Waldman, MD, Dermatology Associates of Glastonbury, 210 New London Turnpike, Glastonbury, CT 06132. 23 8 2021 11 2021 23 8 2021 85 5 11131116 © 2021 Published by Elsevier on behalf of the American Academy of Dermatology, Inc. 2021 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Key words adalimumab brodalumab certolizumab COVID-19 COVID-19 vaccine dermatology etanercept glucocorticoid golimumab guselkumab infliximab ixekizumab janus kinase inhibitor methotrexate mRNA vaccine mycophenolate prednisone risankizumab rituximab SARS-CoV-2 secukinumab tildrakizumab vaccine Abbreviations used ACIP Advisory Committee on Immunization Practices mRNA messenger RNA ==== Body pmcOn August 12, 2021, the US Food and Drug Administration expanded the emergency use authorization of both messenger RNA (mRNA) COVID-19 vaccines “to allow for the use of an additional dose in certain immunocompromised individuals.”1 This announcement may leave dermatologists wondering whether certain patients should receive the third dose of the mRNA COVID-19 vaccine. Herein, we have summarized the data supporting the Food and Drug Administration/Advisory Committee on Immunization Practices (ACIP) expansion of vaccine authorization and subsequently applied these data to dermatology practice.1 Who is “immunocompromised?” Patient groups that may be primarily managed by a dermatologist that are categorized as “immunocompromised” by the Centers for Disease Control and Prevention have been listed here.1 Under the mRNA COVID-19 vaccines’ expanded authorization, immunocompromised individuals who are immunocompromised to a degree that is similar to the solid organ transplant recipients include patients receiving the following2:1. Active treatment for solid malignancy 2. Prednisone at the dosage of ≥20 mg or equivalent daily (chronic use) 3. Transplant-related immunosuppressive drugs 4. Tumor necrosis factor blockers 5. Biologic agents that are immunosuppressive or immunomodulatory 6. Methotrexate (not specifically mentioned in ACIP definition; however, evidence of impaired response to COVID-19 vaccine has been demonstrated in references discussed in the later sections, which were presented at the ACIP meeting) This definition is according to the “CDC Yellow Book” and has not been specifically modified for application to the mRNA COVID-19 vaccine. Are there studies supporting this definition? Many dermatologists may question this broad definition based on consensus from the National Psoriasis Foundation COVID-19 Task Force that “Existing data generally suggest that treatments for psoriasis and/or psoriatic arthritis do not meaningfully alter the risk of acquiring SARS-CoV-2 infection or having worse COVID-19 outcomes.”2 Similarly, biologic therapies have been associated with a decreased risk of hospitalization in cohorts with psoriasis.3 Although publications support consensus statements regarding the safety of certain medications during the pandemic, ACIP's recommendations were made based on emerging data that individuals receiving certain medications are “less likely” to mount an adequate immune response to the mRNA COVID-19 vaccine 2-dose series.1 Specifically, studies have demonstrated reduced seroconversion in individuals with chronic inflammatory diseases such as psoriasis and psoriatic arthritis receiving glucocorticoids, mycophenolate mofetil, methotrexate, and anti-CD20 monoclonal antibodies, including rituximab.1 One study evaluated vaccine response in 24 individuals with psoriasis, 9 of whom were receiving methotrexate and found that the rate of adequate response to the vaccine was 20% lower in individuals receiving methotrexate.4 They also observed a slight decrease in vaccine response among individuals receiving Janus kinase inhibitors.4 However, although lower titers have been observed in patients receiving anti–tumor necrosis factor and anti–interleukin 17 biologics than those in controls, no difference in the rate of seroconversion has been observed in these patients.1 When should “immunocompromised individuals” receive an additional dose of the mRNA COVID-19 vaccine? ACIP has recommended that individuals categorized as “immunocompromised” receive the third dose >28 days after the completion of their 2-dose mRNA COVID-19 vaccine series.1 Patients should receive the same vaccine that they initially received. Specific recommendations have not been made for patients who received the Johnson & Johnson vaccine. There is no recommendation to use serologies to determine whether a patient should receive the third vaccine dose. Are there data supporting the safety and efficacy of an additional dose of the mRNA COVID-19 vaccine? Data supporting the safety and efficacy of the third vaccine dose were derived from 3 prospective studies.1 Two studies evaluated the third dose in individuals receiving hemodialysis and 1 evaluated the third dose in transplant recipients. These studies demonstrated that “Among those who had no detectable antibody response to an initial mRNA vaccine series, 33% to 50% developed an antibody response to an additional dose.”1 No serious adverse events were identified in these studies. How should dermatologists adjust their practice in response to the expanded authorization of the mRNA COVID-19 vaccine? Our recommendations based on these data are summarized in Table I .5 Table I Author recommendations regarding administration of an additional dose of the messenger RNA COVID-19 vaccine to certain dermatology patient populations Patient population Evidence-based risk Recommendation Receiving systemic glucocorticoids Patients receiving >20 mg prednisone or equivalent daily are at risk of inadequate response to the standard 2-dose mRNA COVID-19 vaccine series (1) Patients receiving systemic glucocorticoids should receive an additional dose of the mRNA COVID-19 vaccine (2) Conscious efforts should be made to taper patients on prednisone below 20 mg daily Receiving oral immunosuppressants, including methotrexate, mycophenolate mofetil, cyclosporine, and JAKis Patients receiving oral immunosuppressants are at risk of inadequate response to the standard 2-dose mRNA COVID-19 vaccine series (1) Patients receiving oral immunosuppressants should receive an additional dose of the mRNA COVID-19 vaccine (2) Patients who have not yet been vaccinated who are receiving these medications or who are considering initiation of these medications should be preferentially offered a less immunosuppressing biologic, if indicated clinically Receiving B-cell depletion (ie, anti-CD20 monoclonal antibodies) Patients receiving B-cell depletion are more likely than not to mount an inadequate response to the standard 2-dose mRNA COVID-19 vaccine series (1) Patients undergoing B-cell depletion should receive an additional dose of the mRNA COVID-19 vaccine. The ideal timing of this additional dose is discussed in the referenced article5 (2) Patients with conditions that can be adequately treated with therapeutics other than B-cell depletion (eg, bullous pemphigoid) should be preferentially offered a less immunosuppressing biologic, if indicated clinically Receiving TNF blockers and IL-17 inhibitors Patients receiving TNF blockers and IL-17 inhibitors may mount lower absolute titers to the standard 2-dose mRNA COVID-19 vaccine series; however, there is insufficient evidence to suggest that these patients are at increased risk of mounting an inadequate immune response to the 2-dose series (1) As an aggregate, patients receiving TNF blocker and IL-17 inhibitor monotherapy do not appear to need the third dose of the mRNA COVID-19 vaccine based on existing data; however, the third dose may be indicated for patients with comorbidities that predispose the patient to severe COVID-19 infection. Shared decision making with all patients on these medications is recommended. (2) There are no specific data regarding the ideal timing of vaccination; however, like other nonlive vaccinations, the mRNA COVID-19 vaccine can likely be administered without interruption in biologic therapy Receiving IL-12/23, IL-23, and IL-4/13 inhibitors There are inadequate real-world data to assess the effect of IL-12/23, IL-23, and IL-4/13 inhibitors on mRNA COVID-19 vaccine response (1) Based on the mechanism of action of these medications, it is unlikely that these medications predispose patients to an increased risk of mounting an inadequate response to the standard 2-dose mRNA COVID-19 vaccine series. Additional prospective data are needed to confirm the presumed immunogenicity of the mRNA COVID-19 vaccine in patients receiving these medications. At this time, shared decision making is recommended given the paucity of available data Patients with metastatic melanoma, squamous cell carcinoma, or other internal malignancy undergoing active treatment Patients undergoing treatment for metastatic melanoma, squamous cell carcinoma, and other malignancies are at risk of inadequate response to the standard 2-dose mRNA COVID-19 vaccine series (1) Patients undergoing treatment for metastatic skin cancer should be encouraged to urgently contact their oncologist about whether they should receive an additional dose of the mRNA COVID-19 vaccine IL, Interleukin; JAKi, Janus kinase inhibitor; mRNA, messenger RNA; TNF, tumor necrosis factor. Conflicts of interest Dr Waldman has served as a subinvestigator on clinical trials sponsored by 10.13039/100006483 AbbVie , Eli Lilly, Janssen, 10.13039/100009857 Regeneron /10.13039/100004339 Sanofi , and 10.13039/501100009754 Galderma . He has also served as a subinvestigator on the CorEvitas Registry. He received no direct compensation for participation in these trials/registries. He has received direct compensation for participation on an advisory board for a drug aimed at the treatment of myasthenia gravis sponsored by Argenx. Dr Grant-Kels has no conflicts of interest to declare. Funding sources: None. IRB approval status: Not applicable. ==== Refs References 1 Advisory Committee on Immunization Practices (ACIP) ACIP Presentation Slides: August 13, 2021 Meeting. Centers for Disease Control and Prevention https://www.cdc.gov/vaccines/acip/meetings/slides-2021-08-13.html 2021 2 Gelfand J.M. Armstrong A.W. Bell S. National Psoriasis Foundation COVID-19 Task Force guidance for management of psoriatic disease during the pandemic: version 2—advances in psoriatic disease management, COVID-19 vaccines, and COVID-19 treatments J Am Acad Dermatol 84 5 2021 1254 1268 10.1016/j.jaad.2020.12.058 33422626 3 Attauabi M. Seidelin J.B. Felding O.K. Coronavirus disease 2019, immune-mediated inflammatory diseases and immunosuppressive therapies—a Danish population-based cohort study J Autoimmun 118 2021 102613 10.1016/j.jaut.2021.102613 33592545 4 Haberman R.H. Herati R. Simon D. Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease Ann Rheum Dis 2021 10.1136/annrheumdis-2021-220597 5 Waldman R.A. Creed M. Sharp K. Toward a COVID-19 vaccine strategy for patients with pemphigus on rituximab J Am Acad Dermatol 84 4 2021 e197 e198 10.1016/j.jaad.2020.10.075 33130180
PMC008xxxxxx/PMC8403003.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(21)02383-5 10.1016/j.jaad.2021.08.039 JAAD Online Comment on “The impact of the COVID-19 pandemic on the presentation status of newly diagnosed melanoma: A single institution experience” McFeely Orla BA, MRCPI ∗ Hollywood Aoife BA, MRCPI Stanciu Maria BA O'Connell Michael BA, MRCP Paul Lyndsey BA, MRCP Dermatology Department, University Hospital Waterford, Waterford, Ireland ∗ Correspondence to: Orla McFeely, BA, MRCPI, Dermatology Department, University Hospital Waterford, Ardkeen, Waterford, Ireland X91 ER8E 28 8 2021 12 2021 28 8 2021 85 6 e419e420 © 2021 by the American Academy of Dermatology, Inc. 2021 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Key words COVID-19 melanoma pandemic skin cancer ==== Body pmcTo the Editor: We read with interest the article by Shannon et al1 regarding the impact of the COVID-19 pandemic on the presentation status of newly diagnosed malignant melanomas (MMs). We noted a recent Italian study,2 which demonstrated a similar finding of increased tumor depth. We conducted this study to assess and compare melanoma diagnosis before and during the COVID-19 pandemic at our tertiary referral center. Our aim was to assess whether the rates, clinical characteristics, and thicknesses of MMs differed between 2019 and 2020 and then between the 2 halves of 2020. In 2020, Ireland was under lockdown for more than 6 months, from March to July and then again from August to November. This retrospective review examined all patients discussed at the melanoma multidisciplinary team (MDT) meeting at a single tertiary referral center from 2019 and 2020. We compared the number of MMs diagnosed, along with characteristics from all periods. We also compared the period from January to June 2020 with that from July to December 2020 to assess whether multiple outbreaks and subsequent lockdowns affected MM diagnosis. In 2019, 78 patients were diagnosed with MM and 54 with melanoma in situ (Table I ). The average Breslow thickness was 2.13 mm. In 2020, 84 patients were diagnosed with MM and 44 with melanoma in situ. The average Breslow thickness was 2.79 mm. From January to June 2020, 40 patients were diagnosed with MM, with an average Breslow thickness of 2.13 mm. From July to December 2020, 44 patients were diagnosed with MM, with an average Breslow thickness of 3.23 mm.Table I Patient and tumor characteristics of all melanomas discussed at MDT Patient and tumor characteristics 2019 2020 n = 78 n = 84 Age (median), y 68.5 75.5  <50 16 (20.5%) 18 (21.4%)  50-59 7 (9%) 18 (21.4%)  60-69 19 (24.35%) 16 (19%)  70-79 19 (24.35%) 14 (16.67%)  >80 17 (21.8%) 18 (21.4%) Sex  Male 34 (44%) 39 (46.4%)  Female 44 (56%) 45 (53.4%) Breslow thickness  Median (average) 1.15 (2.13) 1.9 (2.79) PT staging group  1/2 53 (68%) 52 (61.9%)  3/4 25 (32%) 32 (38.1%) Clarke level  II 30 (38.4%) 20 (23.8%)  III 11 (14.1%) 19 (22.6%)  IV 29 (37.1%) 37 (44%)  V 4 (5.1%) 5 (5.95%)  Unknown 4 (5.1%) 3 (3.6%) Mitotic count  None 28 (35.9%) 26 (31%)  <1 20 (25.6%) 16 (19%)  >1 25 (38.5%) 39 (46%)  Unknown 5 (6.4%) 3 (3.6%) Ulceration 20 (25.6%) 18 (21.4%) Place of diagnosis  Dermatology 53 (68%) 53 (63%)  Surgery 20 (26%) 21 (25%)  GP 5 (6%) 10 (12%) GP, General practitioner; MDT, multidisciplinary team; PT, primary tumor. We compared the Breslow thickness measured in the period from January to June 2020 inclusive with that measured in the period from July to December 2020. We found that the median Breslow thickness was greater in the second half of the year (2.45 mm) than in the first half of the year (1.15 mm) (Fig 1 ). A statistically significant difference was noted between median figures (2.45 mm − 1.15 mm = 1.3 mm) upon applying the 1-tailed Mann-Whitney U test (P = .0304).Fig 1 Box-plot of Breslow thickness for half-year. Our data support the theory that the COVID-19 pandemic may have led to a delay in the diagnosis of MM, supporting research published by Shannon et al.1 Our data showed a progression in the Breslow thickness over the 2 halves of 2020. This strengthens the theory that repeated lockdowns and the closure of health care services might have resulted in delayed presentations. As the COVID-19 pandemic continues, we must ensure that time-sensitive diagnoses are referred and seen promptly. Conflicts of interest None disclosed. Funding sources: None. IRB approval status: Not applicable. ==== Refs References 1 Shannon A.B. Sharon C.E. Straker R.J. III The impact of the COVID-19 pandemic on the presentation status of newly diagnosed melanoma: a single institution experience J Am Acad Dermatol 84 4 2021 1096 1098 10.1016/j.jaad.2020.12.034 33352269 2 Ricci F. Fania L. Paradisi A. Delayed melanoma diagnosis in the COVID-19 era: increased Breslow thickness in primary melanomas seen after the COVID-19 lockdown J Eur Acad Dermatol Venereol 34 12 2020 e778 e779 32780876
PMC008xxxxxx/PMC8415736.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(21)00895-1 10.1016/j.jaad.2021.04.057 Health Policy & Practice Beyond burnout: Talking about physician suicide in dermatology Lee Michelle S. BA Nambudiri Vinod E. MD, MBA ∗ Harvard Medical School and Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts ∗ Correspondence to: Vinod E. Nambudiri, MD, MBA, Department of Dermatology, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, MA 02115. 22 4 2021 10 2021 22 4 2021 85 4 10551056 15 4 2021 © 2021 by the American Academy of Dermatology, Inc. 2021 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Key words burnout dermatology mental health public policy stigma suicide wellness ==== Body pmcPhysician suicide made headlines during the COVID-19 pandemic when emergency medicine physician Dr Lorna Breen committed suicide in April 2020. While this prompted discussions about burnout and physician suicide, especially among frontline workers, the conversation has remained limited in the dermatology community.1 Although burnout rates in dermatology have traditionally been lower compared with other specialties, the rates have been rising more quickly.2 With the increasing rates of physician burnout and suicide, we believe that it is time for the dermatology community to raise awareness and support efforts around physician suicide. Multiple factors that influence physician suicide have been impacted by higher levels of stress, burnout, and depression during the COVID-19 pandemic. Over 50% of physicians currently experience burnout, contributing to reduced productivity, worse patient outcomes, and poor physician mental health and suicidality.2 Nearly 400 physicians die by suicide each year in the United States, with the rates especially high among female physicians, who die by suicide at rates 2-4 times higher than women in the general population.3 Physicians with histories of mental illness or substance use may also be at an increased risk. Within dermatology, it is imperative to encourage discourse around physician suicide for several reasons. First, burnout rates are rising among dermatologists; a recent survey found that nearly 50% of dermatologists reported burnout, similar to the national average across the specialties.2 The contributors to burnout among dermatologists include excessive documentation and time spent on the electronic medical record, which have increased during the pandemic due to the transition to virtual care. Given the link between burnout, depression, and suicide, future studies must investigate the implications of these workplace shifts in dermatology. While suicide rates among dermatologists are unknown, an estimated 19% have experienced suicidal ideation—already a significant cause for concern.4 Second, an increasing majority of the dermatologist workforce is female, a population at higher risk of suicide given stressors that may include increased household responsibilities, sex- or gender-based workplace harassment, and navigating through a historically male-dominated profession.5 Third, the perceptions of high job satisfaction and low burnout rates may construct barriers to normalizing discussion around suicide in dermatology, leading to a stifling culture of silence and hesitancy to seek help. Therefore, we must increase the collective efforts to support each other as peers and dismantle the stigma around suicide in our specialty. Dermatologists can act against physician suicide in several meaningful ways (Table I ). Organizations such as the American Academy of Dermatology can join and support nationwide efforts including National Physician Suicide Awareness Day. Individually and collectively, we can support policies including the Dr Lorna Breen Healthcare Provider Protection Act, which spearheads research and awareness around provider mental health. Perhaps most importantly, we must destigmatize physician suicide within dermatology by starting conversations about this difficult topic, encouraging support groups, increasing our vigilance of the signs of burnout and depression, and not hesitating to act when we recognize the suffering in our colleagues or ourselves.Table I Resources for addressing physician suicide Category Resources Wellness and burnout resources Accreditation Council for Graduate Medical Education physician well-being resources: https://www.acgme.org/What-We-Do/Initiatives/Physician-Well-Being/Resources American Psychiatric Association: wellness education, self-assessment, and physician resources for burnout and depression: https://www.psychiatry.org/psychiatrists/practice/well-being-and-burnout Suicide prevention National Suicide Prevention Lifeline: 1-800-273-8255 Crisis Text Line: Text TALK to 741-741 American Foundation for Suicide Prevention suicide prevention resources: https://afsp.org/suicide-prevention-resources Suicide Prevention Resource Center: https://sprc.org American Hospital Association: Be well: preventing physician suicide: https://www.aha.org/advancing-health-podcast/be-well-preventing-physician-suicide Taking action Dr Lorna Breen Heroes' Foundation: https://drlornabreen.org Dr Lorna Breen Health Care Provider Protection Act: https://drlornabreen.org/about-the-legislation/ Association of American Medical Colleges: “Time to talk about it: physician depression and suicide” video/discussion session for interns, residents, and fellows https://www.mededportal.org/doi/10.15766/mep_2374-8265.10508 National Academies of Medicine: “Breaking the culture of silence of physician suicide” https://nam.edu/breaking-the-culture-of-silence-on-physician-suicide/ American Medical Association: “Now's the time to have a difficult talk about physician suicide” https://www.ama-assn.org/about/leadership/now-s-time-have-difficult-talk-about-physician-suicide Coping with physician suicide American Foundation for Suicide Prevention: After a suicide: a toolkit for physician residency/fellowship programs https://www.acgme.org/Portals/0/PDFs/13287_AFSP_After_Suicide_Clinician_Toolkit_Final_2.pdf It is time for us, as a specialty, to raise awareness, encourage dialogue, and support efforts around physician suicide to promote openness around the topic and ensure the well-being of all the dermatologists. Conflicts of interest None disclosed. Funding sources: None. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 American Medical Association Now's the time to have a difficult talk about physician suicide Available at: www.ama-assn.org/about/leadership/now-s-time-have-difficult-talk-about-physician-suicide 2020 2 Nagler A.R. Shinkai K. Kimball A.B. Burnout among all groups of physicians-mitigation strategies for dermatologists JAMA Dermatol 156 10 2020 1049 1050 32756892 3 Schernhammer E.S. Colditz G.A. Suicide rates among physicians: a quantitative and gender assessment (meta-analysis) Am J Psychiatry 161 12 2004 2295 2302 15569903 4 Colon A. Gillihan R. Motaparthi K. Factors contributing to burnout in dermatologists Clin Dermatol 38 3 2020 321 327 32563344 5 Sharp K.L. Whitaker-Worth D. Burnout of the female dermatologist: how traditional burnout reduction strategies have failed women Int J Womens Dermatol 6 1 2019 32 33 32025558
PMC008xxxxxx/PMC8455235.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(21)02514-7 10.1016/j.jaad.2021.09.032 Research Letter Impact of the COVID-19 pandemic on hospitalizations of patients with moderate-to-severe skin diseases: A retrospective cohort analysis from a Central European Center Schauer Franziska MD a∗ Behrens Max b Mueller Sabine MD a Meiss Frank MD a Kiritsi Dimitra MD a a Department of Dermatology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany b Institute of Medical Biometry and Statistics, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany ∗ Correspondence to: Franziska Schauer, MD, Department of Dermatology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Hauptstrasse 7, 79104 Freiburg, Germany 22 9 2021 1 2022 22 9 2021 86 1 245248 © 2021 by the American Academy of Dermatology, Inc. 2021 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Key words dermatology health services utilization rare diseases SARS-CoV-2 skin cancer ==== Body pmcTo the Editor: The COVID-19 pandemic created a global health emergency, forcing infection prevention measures into the clinical routines of patients with skin disorders. Our location in southwest Germany, near Italy, led to COVID-19 cases starting in February 2020. Evidence shows that the elderly and those with comorbidities are more vulnerable for severe SARS-CoV-2 disease, with higher mortality rates. We evaluated the impact of the pandemic on dermatologic patients, including both inpatients and day hospital outpatients, throughout 2020 compared with 2019. We analyzed a total of 6206 patients from January 1, 2019, to December 31, 2020 (Tables I and II ). Diagnoses were recorded with ICD-10 codes for each hospital visit individually, visits referring to both admissions and day hospital visits. Nonmelanoma skin cancer, including Merkel cell carcinoma and malignant melanoma, followed by eczema, leg ulcers, desensitization to allergens, and psoriasis, were the most frequent reasons for admission at our department in 2019, consistent with previous years.1 Pan-German data showed a 13% decrease in inpatients in 2020 compared with 2019.2 Similarly, we noticed an 8% (P < .001) decline in patient admissions (Table I). Proportionally, admissions below the age of 65 years decreased, whereas those above the age of 65 years increased to 58% of all hospitalizations (P > .99, Table I). We had fewer admissions of patients with inflammatory skin diseases (eg, eczema/psoriasis) and patients with lower leg ulcers (P < .001). Interestingly, patients admitted with herpes zoster as main diagnosis and receiving intravenous treatment as per German guidelines increased by 52% (P < .05) and were recorded throughout the year, possibly induced by stress-associated immunosuppression.3 We specifically aimed at not postponing admissions for oncologic patients, but reduced outpatient assessments could have led to delays.4 Although there were no differences in mean T stages in melanoma patients, we observed a higher proportion of sentinel lymph node extirpations in 2020 (2019: 45.6%, 2020: 47.4%; P = .462) (Table I). The increased number of immune-related adverse events (P = .001, Table I) likely mirrors the growing patient numbers treated with combined immunotherapy in stage IV melanoma.Table I Hospital admissions in 2019 compared with those in 2020 Variable 2019 2020 P values Treatment days per year 17.520 15.608 .140 Total, N 2.411 2.231 <.001∗  Male, n (%) 1.302 (54) 1.206 (54) >.99  Female, n (%) 1.109 (46) 1.025 (45.9) >.99 Age, mean (SD) in years 64.78 (19.14) 64.76 (19.07) >.99 Stratified by age (years), n in years (%)  0-17 30 (1.2) 25 (1.1)  18-35 208 (8.6) 202 (9.1)  36-49 251 (10.4) 232 (10.4)  50-64 552 (22.9) 478 (21.4)  65-74 422 (17.5) 431 (19.3)  75-84 625 (27) 617 (28)  85-94 635 (26.3) 583 (26.1)  95+ 23 (1) 24 (1.1)  <65 vs ≥65 1370 (56.8) 1294 (58) >.99 Hospital stay, median in days 6.02 5.88 Disease classification (ICD-10), n (%)  NMSC (C44) 684 (28.4) 615 (27.6) >.99  Malignant Melanoma (C43) 265 (10.9) 253 (11.3) >.99  Sentinel lymph node extirpation (OPS 05-401) 120 (5) 140 (6) >.99  Radical lymphadenectomy (OPS 05-404) 17 (<1) 17 (<1) >.99  Secondary and unspecified malignant neoplasm of lymph nodes (C77) 29 (1.2) 41 (1.8) >.99  Immunotherapy associated adverse events (K52.1, K71.6, K75.4, E23.1, R50.6) 6 (0.2) 29 (1.3) .001∗  Hidradenitis suppurativa (L73.2) 56 (2.3) 59 (2.6) >.99  Eczema, dermatitis, prurigo (L20, L28, L30) 185 (7.7) 156 (7.0) >.99  Psoriasis (L40) 158 (6.6) 115 (5.2) .798  Herpes zoster (B02) 59 (2.4) 93 (4.2) <.05∗  Erysipelas (A46) 44 (1.8) 43 (1.9) >.99  Ulceration of the lower leg (I83, I89, L97, I70) 182 (7.5) 93 (4.2) <.001∗  Pyoderma gangraenosum (L88) 23 (1.0) 19 (0.9) >.99  Pemphigus foliaceus/vulgaris (L10) 8 (0.3) 6 (0.3) >.99  Bullous pemphigoid (L12) 60 (2.5) 55 (2.5) >.99  Desensitization to allergens (Z51.6) 176 (7.3) 138 (6.2) >.99 Statistical analysis was performed with R (version 4.0.4). Categorical variables were tested with the chi-square test, and continuous variables with a t test. The Holm method was used for the P value adjustment. NMSC, Nonmelanoma skin cancer. ∗ Level of significance is P < .05. Table II Day hospital treatments in 2019 compared with those in 2020 Variable 2019 2020 P values Treatment days 5.100 4.782 <.05∗ Total, N 876 688 <.001∗  Male, n (%) 427 (48.7) 324 (47.1) >.99  Female, n (%) 449 (51.3) 362 (52.6) >.99 Age, mean (SD), in years 46.85 (22.75) 48.71 (22.68) .975 Stratified by age (years), n (%)  0-17 115 (13.1) 73 (10.6)  18-35 157 (17.9) 140 (20.3)  36-49 142 (16.2) 104 (15.1)  50-64 243 (27.7) 172 (25.0)  65-74 122 (13.9) 108 (15.7)  75-84 84 (9.6) 76 (11.0)  85-94 9 (1.0) 13 (1.9)  95+ 4 (0.5) 2 (0.3)  <65 vs ≥65 219 (25.0) 199 (28.9) .923 Disease classification (ICD-10), n (%)  Eczema, dermatitis, prurigo (L20, L28, L30) 194 (22.1) 170 (24.7) >.99  Psoriasis (L40) 140 (16.0) 104 (15.1) >.99  Epidermolysis bullosa (Q81) 126 (14.4) 86 (12.5) >.99  Lichen planus (L43) 5 (0.6) 8 (1.2) >.99  Cutaneous T-cell lymphoma (C84) 6 (0.7) 8 (1.2) >.99  Pemphigus foliaceus (L10) 1 (<1) 1 (<1) >.99  Bullous pemphigoid (L12) 6 (0.7) 9 (1.3) >.99 Statistical analysis was performed with R (version 4.0.4). Categorical variables were tested with the chi-square test, continuous variables with a t test. The Holm method was used for the P value adjustment. ∗ Level of significance P < .05 Our day hospital allows patient treatment over several hours for skin disorders of moderate intensity. We had a 6% decline in day hospital visits (P < .05) and reduced patient numbers (P < .001) in almost all diagnosis groups (Table II). We also noticed around 30% (P > .99) fewer day hospital visits for patients with epidermolysis bullosa, a rare, inherited skin fragility disease treated at our Skin Fragility Center, a specialized day hospital (Table II). Our data suggest that the pandemic primarily affected treatment options for patients with inflammatory and rare skin disorders, whereas patients with infectious and oncologic indications were still sufficiently treated. Limitations of this study are its monocentric character and the fact that mildly affected patients were actively short-term postponed in the early phase of the pandemic. Overall, adopting security measures (questionnaires, polymerase chain reaction testing, and visitor restrictions) prevented a significant negative impact for geriatric admissions. Nonetheless, enabling easy access and emphasizing high-quality medical and telemedical care for patients, especially those with inflammatory skin diseases, could reduce long-term complications and prevent irreversible damage.5 Conflicts of interest None disclosed. We thank Oliver Pfeiffer, Medical Documentary of the Skin Cancer Cente—Comprehensive Cancer Center Freiburg, and Sarah Riechert of the Department of Medical Controlling, both from the Medical Center, University of Freiburg, for providing the anonymized data on patient diagnoses. Language editing was performed by Gillian Marsden, Australia, and Maysa Sarhan, MD, PhD, MBChB, Department of Dermatology, University of Freiburg. Funding sources: FS and DK are supported by the Berta-Ottenstein Advanced Clinician Scientist Programme of the University of Freiburg. DK is supported by theGerman Research Foundation (DFG) through SFB1160 project B03 and KI1795/2-1, as well as the Fritz Thyssen Foundation. IRB approval status: No 21-147 of Freiburg Ethics Committee Board and study registration on the German Clinical Trials Register (http://www.drks.de, DRKS-ID DRKS000244633). Reprints not available from the authors. ==== Refs References 1 Ansorge C. Miocic J.M. Schauer F. Skin diseases in hospitalized geriatrics: a 9-year analysis from a University Dermatology Center in Germany Arch Dermatol Res June 2, 2021 10.1007/s00403-021-02244-9 2 Busse R. Nimptsch U. COVID-19 pandemic: historically low bed occupance rate Dtsch Arztebl Int 118 10 2021 A-504 Article in German 3 Schmidt S.A.J. Sørensen H.T. Langan S.M. Vestergaard M. Perceived psychological stress and risk of herpes zoster: a nationwide population-based cohort study Br J Dermatol 185 1 2021 130 138 33511645 4 Marson J.W. Maner B.S. Harding T.P. The magnitude of COVID-19's effect on the timely management of melanoma and nonmelanoma skin cancers J Am Acad Dermatol 84 4 2021 1100 1103 33482258 5 Miller R.C. Stewart C.R. Lipner S.R. Retrospective study of trends in dermatology telemedicine and in-person visits at an academic center during COVID-19 J Am Acad Dermatol 84 3 2021 777 779 33221466
PMC008xxxxxx/PMC8483165.txt
==== Front Curr Stem Cell Rep Curr Stem Cell Rep Current Stem Cell Reports 2198-7866 Springer International Publishing Cham 34608428 196 10.1007/s40778-021-00196-4 Stem Cells: Policies from the Bench to the Clinic (G Moll and N Drzeniek, Section Editors) Regulatory Framework for Academic Investigator-Sponsored Investigational New Drug Development of Cell and Gene Therapies in the USA http://orcid.org/0000-0002-8736-0011 Dasgupta Anindya adasgupta@expressiontherapeutics.com 1 Herzegh Kristen 2 Spencer H. Trent 3 Doering Christopher 3 Day Eric 1 Swaney William P. 1 1 Expression Manufacturing LLC, West Chester, OH USA 2 grid.428158.2 0000 0004 0371 6071 Marcus Center for Pediatric Cellular Therapies, Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta and Emory University, Atlanta, GA USA 3 grid.428158.2 0000 0004 0371 6071 Cell and Gene Therapy Program, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta and Emory University, Atlanta, GA USA 30 9 2021 2021 7 4 129139 27 7 2021 © The Author(s), under exclusive licence to Springer Nature Switzerland AG 2021. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. Purpose of Review The promise of cell and gene therapy (CGT) products for a multitude of diseases has revitalized investigators to advance novel CGT product candidates to first-in-human trials by pursuing the investigational new drug (IND) mechanism administered by the United States (US) Food and Drug Administration (FDA). This review is intended to familiarize academic investigators with the IND governing regulations set forth by the FDA. Recent Findings CGT products are extraordinarily complex biologics and, therefore, early-stage evaluation programs must be customized to satisfactorily address their unique developmental challenges. The US FDA continues to foster the development of transformational technology that will facilitate the broad application of safe and effective gene therapy products that have the potential to alleviate many conditions previously out of reach of therapeutic intervention. FDA is committed to working with the scientific community and industry to facilitate the availability of these treatments to patients. Summary The pathway to meet regulatory compliance during early stage IND programs can be daunting to academic investigators interested in CGT product development that typically don’t progress beyond phase 1/2. However, by keeping abreast of current regulatory framework and building upon FDA’s supportive infrastructure, an investigator can be well-positioned to advance innovative scientific discoveries towards early stage clinical assessments. Keywords FDA Regulatory IND Cell and gene therapy Noneissue-copyright-statement© Springer Nature Switzerland AG 2021 ==== Body pmcIntroduction Under US federal law, chemical or biological articles that are intended to diagnose, cure, treat, mitigate, or prevent disease, or are intended to affect the structure or function of the body, are defined as drugs. Biologics, such as cell and gene therapy (CGT) products that share such attributes as described above are therefore drugs. Drugs and biological products intended for use in humans in the USA are regulated by the Food and Drug Administration (FDA), an agency under the US Department of Health and Human Services (HHS). A set of federal laws and codifications of regulations, Code of Federal Regulations (CFR), as described under the Federal Food, Drug, and Cosmetic Act (FD&C Act) and the Public Health Service Act (PHS Act) bestow such authority to FDA [1]. The FDA is composed of nine center level organizations. Of these, the Center for Drug Evaluation and Research (CDER), Center for Devices and Radiological Health (CDRH), and the Center for Biologics Evaluation and Research (CBER) are primarily tasked with regulatory oversight of clinical trials involving investigational drugs and biological products. Each center has several offices to oversee various aspects of the regulatory framework. CBER’s mission is to protect and enhance the public health through the regulation of biological products including blood, vaccines, allergenics, human cells or tissue, and CGTs. The office of Tissues and Advanced Therapies (OTAT) within CBER is currently charged to oversee cellular therapies. CGT products encompass cellular products that include stem cells and their derivatives, cellular immunotherapeutic, and gene therapy products that include viral and nonviral-based vectors and ex vivo manipulated bioengineered immune cells. The field of CGT products has overcome early periods of great uncertainty which saw serious adverse events leading to skepticism towards the durability of such treatments and has now entered an era of exciting and promising growth [2–5]. It must be noted that clinical trials with experimental treatment modalities, including CGT-based approaches, can lead to unforeseen adverse events and deaths which must be promptly reported to the FDA using established reporting mechanisms. These reports may also be disseminated to key stakeholders via presentation at prominent meetings, publications in scientific and media outlets to inform clinicians and the interested public on the current state on the usage of such therapeutic interventions [6, 7]. In 2019, the majority of CGT-based IND submissions were geared towards the development of therapies against hematological and solid cancers while the investigational agents to combat infectious diseases, autoimmune disorders and other diseases constitute the remaining pool of applications (Fig. 1) [8]. Both technological advancement and growing experience in conducting clinical trials have contributed to an increase in benefit to risk ratio of such therapeutics. Such refinements have drawn renewed interest within the biotechnological companies to capitalize on this market alongside traditional academic investigators restricted primarily to early stage developments. Consequently, the number of IND submissions have risen exponentially over the last 5 years with more than 900 applications last year (2020) alone compared to about 150 submissions in the year earlier [9]. Keeping up with such a meteoric growth is FDA’s prediction that from year 2025 onwards the agency may approve between 10 to 20 CGT based therapeutics every year [10•]. Investigators in academic centers will continue to be valuable players in this space which benefited from the early-stage developments of a majority of approved products with genetic modifications that were initiated in academia [9]. Currently, there are nineteen FDA-approved cellular and gene therapy products of which the included eight blood products are regulated in a different manner than the majority of the CGT products. [11]. With the intent to benefit patients with significant unmet clinical needs comes the risk of introducing potential serious adverse events. Such effects may include the potential for inappropriate cell proliferation, risks of insertional mutagenesis and onset of cytokine storm after adoptive transfer, all of which continue to direct drug development programs. Towards this end, the FDA’s modern regulatory framework supports risk mitigation strategies to increase efficiency in the much-needed exploration of these therapy approaches.Fig. 1 Distribution of product indications for all cell and gene immunotherapy IND submissions to the FDA in 2019. Reproduced with permission: Copyright © 2020 Galaro AK & Saeui C. Published by Cell and Gene Therapy Insights under Creative Commons License Deed CC BY NC ND 4.0: https://www.insights.bio/cell-and-gene-therapy-insights/journal/article/1787/FDA-perspective-on-the-preclinical-development-of-cell-based-immunotherapies Stakeholders engaged in developing CGT-based drug products that are intended to be evaluated for investigational use only are exempted under FD&C Act 505(i) from filing a New Drug Application (NDA). The route to apply for such exemption is called an Investigational New Drug Application (IND) which is codified in Title 21 of the Code of Federal Regulations, Part 312 (21 CFR 312). It is assumed that such investigational drugs would require interstate shipping for evaluation and testing purposes. The exemption from the federal law, 21 CFR 312.1, that authorizes movement for drugs requiring an approved marketing application such as NDA or Biologics License Application (BLA), allows for such free movement of the investigational drugs across the country [1]. A distinguishing feature of the IND is that it is neither approved nor disapproved. The sponsor applies for an IND designation, receives a receipt from FDA acknowledging the filing and waits for a mandatory period of 30 days from the receipt of such a letter before commencing the clinical trial. However, the FDA has the authority to ask for clarifications, place a partial or a full hold on the proposed clinical trial under 21 CFR 312.42. The sponsor must produce enough evidence to clarify any concern from FDA before proceeding with the trial. If a partial hold is in place, then the sponsor can start the trial with the components not under hold. However, no portion of the trial can be initiated if the full hold is in place and the trial can commence only after the underlying cause of such an action is resolved [12]. Besides the FDA, the investigator or sponsor must also adhere to procedures set forth by the host institute to enable studies with biological materials. Such policies are enacted upon the guidelines provided by the federal authority such as National Institute of Health (NIH) and regulations on public health and environment protection from state and local communities. The key governing bodies that are charged to enforce such directives are listed in Table 1.Table 1 Examples of host institution research oversite Host institutions research oversite (examples) Oversite responsibilities Institutional Review Board (IRB) Tasked to review any investigation comprising of human subjects Data Safety and Monitoring Board/Committee (DSMB/C) Ensure that study protocols provide provisions to ensure the safety of trial participants and monitors all aspects related to data integrity such as its accuracy and validation Institutional Biosafety Committee (IBC) Entrusted to oversee all safety assessments and contingency plans to manage exposure to engineered genetic material and other biohazardous agents Investigational Drug Service (IDS) Management and dispensing of investigational drugs Research Health and Safety Committee (RHSC) Review research conducted with, but not limited to, biological toxins, samples of human origin including human cell lines, tissues, arthropods, nanoparticles, and microorganisms Institutional Animal Care and Use Committee IACUC Oversite of animal care (applicable to pre-clinical IND studies) CGT-based IND studies are typically approved by the IRB pursuant to a satisfactory review by both IBC and DSMB/C as well as the receipt of a “Study may Proceed” letter from the FDA upon request from the sponsor The primary objective of the FDA is patient safety while creating a supportive and encouraging environment by affording freedom, at the early stages of innovative drug development, to the investigator for selecting proper study designs and rationale for a clinical trial. Towards this end, the FDA issues guidance documents at appropriate intervals [13, 14]. At any time the FDA sees appropriate, such as to clarify and/or update an existing document, it publishes draft guidance documents in the Federal Register which is governed by the National Archives and Records Administration, and provides a time period for comments from the stakeholders prior to the issuance of the final document. After taking into accounts of such responses, the FDA publishes the “final guidance document.” Stakeholders should adhere to the recommendations as set forth in these documents. However, considering the unique diversity and biology of the CGT products, tailor made developmental pathways are often crafted in consultations with the FDA. The latest guidance document to impact CGT-based product developments acknowledges that the materials for pre-clinical testing may differ from the final therapeutic products for early-stage clinical trials. In such circumstances, it is recommended that an early stage IND submission describes such differences with regard to product safety, especially for their proposed use in first in human (FIH) trials and activity [15••]. The guidances are nonbinding and legally nonenforceable recommendations unless specific regulatory or statutory requirements are cited. The FDA relies upon the user-dependent understanding and interpretations to align them to its current thinking. If the FDA feels that such user-reliance leads to occasions where the user is not taking full advantage afforded by an existing guidance, then a new guidance document is issued. An IND can originate from (i) commercial enterprise such as pharmaceutical/biotechnological/governmental/nonacademic entities or (ii) an individual academic investigator. In contrast to a commercial venture that typically has access to resource and logistics for preparation of an IND document and partake multi-site clinical trial, an academic investigator can find it challenging to navigate the complex network of regulatory requirements towards an IND submission and to conduct single site trials. The FDA considers phase 2 and 3 submissions commercial. Investigators may submit a waiver should the sole focus of the studies be for research purposes only. This review describes the IND mechanism as it relates to such an investigator engaged primarily in early-stage evaluations of investigational CGT products. Roadmap for an Early-Stage CGT Product-Based IND Program The IND mechanism provides a springboard for investigators to carry their preliminary evaluations to advanced clinical stages. The critical attributes to navigate an early-stage IND pathway are as follows: (i) identification of the drug candidate and its evaluation in a nonclinical setting, (ii) implementation of scientific and regulatory strategies to transition the potential therapeutic benefits derived from pre-clinical animal models towards FIH trial as required for IND filing, and (iii) conduct the clinical trial pursuant to the regulatory oversights of the host institution and the FDA. Key steps that are typically encountered during such a journey are described below. Exploratory Studies to Evaluate the Suitability of the Investigational Drug for IND Designation As described below, an investigational drug development scheme is initiated by undertaking preliminary evaluation which intensifies to studies suitable for IND filling, assuming the product shows therapeutic benefit and is deemed potentially safe for human trial. Discovery Phase with Pre-clinical POC Studies. Basic research on a conceptual idea takes shape during this time. In this phase, initial identification and evaluation of the innovative drug candidate and its disease modifying action is evaluated. Towards this end, decisions are drawn on existing literature or new ideas on the selection of several components such as (i) adoptive cell product, either naïve or gene-modified, (ii) cell source such as established or primary cell lines with the desired properties or discovery/development of a new cell line, (iii) viral vectors for either ex-vivo cell manipulation or in vivo vector delivery, and (iv) potential phase compliant GMP manufacturing procedures. The proof-of-concept (POC) studies, in the initial stage, typically involve both in vitro and in vivo animal (nonclinical) studies. Outcomes from animal model-based evaluations of the investigational product are important determinants for its potential progression to a clinical trial. Therefore, the selection criteria of an animal model are crucial and are based on various factors such as (i) recapitulation and pathophysiology of the targeted disorder and (ii) permissiveness to the therapeutic modality [16]. The investigator must be aware of limitations posed by the employment of in vivo models in their abilities to closely mimic human response to the administered test product. Immunocompromised hosts, such as NOD SCID mice are often employed when the product candidate is a human cell-based therapy. However, their use is limited, and evaluation of drug-induced immune responses is not possible, as these mice are immunocompromised. During the designing of animal studies, the investigator is encouraged, in principle, to (i) follow the recommendation from National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) to reduce animal use by adhering to the three ‘R’ principles of replace, reduce, or refine their usage without compromising on safety and toxicity data [17], (ii) plan for study durations with scheduled evaluations at several time points to adequately capture biological response, (iii) incorporate sufficient number of animals to derive targeted biological response with statistically meaningful outcomes, and (iv) incorporated a strategy of blinded studies where the research staff do not know the controls from the drug product candidate. Pre-clinical IND Enabling Studies. The main objective of such studies is to evaluate if the investigational product has the appropriate risk to benefit profile for the intended indication. Towards this end intensification and refinements to the pre-clinical studies are designed to include pharmacological and toxicological profile of the investigational drug along with its efficacy, biodistribution, starting dose, and dosing regimen as described later [17]. Evaluation of pre-clinical toxicological studies are typically required to be performed at a testing facility compliant to Good Laboratory Practice (GLP) as per 21 CFR part 58 [18, 19]. However, toxicological studies with CGT-derived products frequently require (i) unique on-site animal care, and (ii) in-house expertise for end point analysis from animals exposed to bioengineered products. Such studies can be undertaken non-GLP provided those aspects of GLP not performed are identified and the studies performed in-house in facilities that are subjected to oversight by an independent quality assurance unit/person to fulfill the requirements set forth in 21 CFR 58.35. In anticipation for progression to the clinical stage, the investigator is encouraged to (i) use the exact clinical test material or material that closely matches the characteristics of the presumed clinical product, (ii) identify avenues to generate sufficient cGMP product to support an early-stage clinical assessment, and (iii) develop robust assays that are specific, sensitive and reproducible. Key Sections of an IND Application The content and format of an IND submission to the FDA should adhere to 21CFR 312.23 and the application must contain information on three components: (i) Chemistry Manufacturing and Control (CMC), which describes the critical components such as the choice of cells and vector types along with the design and conduct of pre-clinical studies with those components in a manner that is amenable to clinical setting, (ii) pharmacology and toxicological profile of the investigational drug, and (iii) the design of the proposed clinical study such as dosage, administration routes and the manner it will be conducted. Investigators may provide a Letter of Authorization (LoA) for nonclinical sections, which allows the FDA to cross-reference the stated sections of other active INDs or Drug Master Files. CMC. The contents of this section are to be addressed with respect to the phase of the IND developmental program and the scope of the proposed trial as per 21 CFR 312.23(a)(7)) [15••]. However, the primary focus at every IND stage is geared towards safety consideration and manufacturing controls associated with the drug. For initial IND submissions, the following key aspects of the investigational drug development are generally expected to be addressed: (i) history, and derivations of starting materials such as cells, tissues and viral banks, (ii) detailed description including the mode of action with intended clinical use and characterizations of (i) the drug substance (DS) which is defined as the active pharmacological ingredient, as per 21 CFR 312.23(a)(7)(iv)(a), such as the vector for ex vivo cell manipulation, that gets incorporated into the final drug product, and (ii) drug product (DP), defined as “the finished dosage form” as per 21 CFR 312.23(a)(7)(iv)(b), such as the bioengineered cell product that contains the DS; (iii) manufacturing procedure and controls with respect to phase specific regulatory requirements such as GMP compliance; (iv) analytical tests to assess quality attributes of DS and DP and if needed; (iv) compliance to donor eligibility criteria that depends upon the cell source, whether autologous or allogeneic, as described in 21 CFR 1271 [15••]. It must be noted that the FDA acknowledges that a clear distinction between DS and DP may not be possible for some CGT products and that an explanation of how DS and DP are defined in the IND submission would suffice. The latest guidance document includes FDA’s expectations while describing certain aspects of DS and DP such as their manufacturing and analytical test procedures in the IND application [15••]. CGT products are inherently complex and are rife with inherent variables such as (i) homing of the adoptively transferred cells to target sites, (ii) off-target effects, (iii) aberrant proliferation of cells that may lead to tumorigenesis, (iv) interaction with immunodepleting and immunosuppressive agents used prior to adoptive transfer or to counteract overt immune stimulation that may occur after adoptive transfer, respectively, (v) lack of consistent control of ex vivo cell expansion strategies to achieve a clinical starting dose, (vi) inflammatory response to transplanted cells, vii) duration of in vivo persistence of the vector, (viii) potential for vector-borne insertional mutagenesis; and (ix) uneven biodistribution of administered vectors and cells. Therefore, the acquisition of complete CMC data on CGT products are challenging during pre-clinical studies and thereby necessitates an extensive follow up of enrollees in early stages of clinical trials to capture meaningful safety, PK, and efficacy data. Thus, compared to small molecule or antibody-based studies, CGT-based drug development programs are inherently different especially in the context of measuring safety, feasibility, and tolerability [20]. In recognition of the burden on the investigator to gather complete CMC information to qualify the investigational product for phase 1 or 1/2 trial that employs only small number of participants thereby requiring limited amounts of products while the manufacturing and analytical procedures are still being refined, FDA has waived the requirement to furnish comprehensive CMC data during early-stage IND filing [15••] but does require long-term follow-up of patients to ensure safety. The manufacturing attributes of an investigational drug is governed by the stage of drug development (Fig. 2). Production of GCT materials are typically performed under, GLP during the pre-clinical development stages and advances to GMP manufacturing procedures for products fit for clinical trials as proposed in the IND application. During such progression in the manufacture of the investigational product, an investigator can encounter changes in product quality that can affect the level of the proposed clinical utility. This finding is not surprising given the changes associated between making stage-specific components in terms of equipment, materials, purification methods, or processes performed differently between the manufacturing grades. The cGMP manufacturing process must adhere to regulatory compliance which is driven by three key aspects. Raw material practices. FDA defines components as any ingredient used in manufacturing including those that do not appear in the final product. For clinical products, including viral vector products, additional considerations for components are needed. For example, the cell substrate used to manufacture the viral vector must originate from qualified sources (such as Master Cell Bank and Master Working Cell Bank) which has been extensively tested and characterized and shown to be suitable for manufacturing as directed under 21 CFR 210.3(b). To lower or eliminate the risk of zoonotic transmission of adventitious agents, reagents should be free of animal derived components wherever possible and if needed, serum, such as Fetal Bovine Serum, need to be appropriately sourced to avoid the occurrence of bovine spongiform encephalopathy (BSE). These requirements are in addition to normal expectations for control of raw materials (RMs) such as use of appropriate grade (GMP, USP), establishment of RM specifications and unique identifiers of all components used in the batch, qualification of RM suppliers, and the implementation of procedures for the receipt, quarantine, testing, and subsequent release for use or rejection of RM based on testing results. The FDA, in its recognition to the sky-rocketing manufacturing needs of CGT products, has released its latest guidance to reduce the burden of clinical bridging studies when small changes in the manufacturing are made that do not result in transformation of the manufactured product [14]. To safeguard the manufacture of CGT products while the world is being upended by COVID-19 infections, the FDA has published suggestions to prevent product contaminations with the disease causative SARS-CoV-2 virus. Broadly, those recommendations are to (i) review cGMP manufacturing practice to prevent unintended amplification of the viral loads in cellular therapeutic products and (ii) incorporate additional risk assessments to mitigate viral propagation [21]. To date, there is no evidence of such a disease transmission through a pharmaceutical product.Fig. 2 Manufacturing characteristics of a CGT product from development through market approval Quality practices. Quality systems (QS) establish confidence in the quality of manufactured products which are predictable and reproducible by operating under pre-determined manufacturing procedures with quality assurance (QA) oversight while the process parameters are continually being evaluated and improved through a controlled and documented process [22]. Such systems can be (i) paper based which is frequently employed in academic core facilities and/or early startups, or (ii) validated software driven operations more commonly employed in larger pharmaceutical manufacturers. Quality systems are implemented to ensure strict control of all GMP sub-systems used in manufacturing and analytical testing. The QS covers various pre-, in-process, and post-manufacturing operations to ensure quality by design manufacturing and includes, but are not limited to, production and process controls, deviation/corrective action and preventive action (CAPA) management, document control, change control, risk management and facility/equipment controls. As mentioned, modern manufacturing facilities typically integrate and automate their QS using specialized software commonly referred to as a Quality Management System (QMS) that aids with all quality aspects of 21CFR 210 and 211 compliance. These regulations may also apply to suppliers of raw materials procured for cGMP production. The tenants of the QS are instilled by a quality control unit that comprises of QA and quality control (QC) teams. Coordinated efforts between QA and QC impart efficiency in the manufacturing procedures that lead to the production of reliable and safe CGT products. QA is deemed independent and is not subordinate to any groups/units within the organization. Major functions that QA is entrusted to oversee include (i) documentation practices, such as review of batch records (BR), product release certificates and assay reports from qualified quality control laboratories, (ii) review and approval of raw materials used in cGMP manufacturing, and (iii) audits, both internal and external, and analysis of trends to track and uphold the strict performance driven factors essential to produce materials with high quality. The key aspects of QC involve release of raw materials, in-process, and final product release testing and ensure that the manufacture is performed under pre-determined acceptance and specification criteria. Pre-established QC testing procedures fit for the evaluation of traditional pharmaceuticals are difficult to practice with cell and gene therapy products due to their built-in complexities such as limited availability and short life spans of the samples. Therefore, the FDA encourages investigators for mutual engagements to identify and develop novel and/or flexible methods that are conducive for quality determinations of CGT-based IND candidates. Facilities and Equipment. Manufacturing unit and associated apparatuses must be validated to be compliant with FDA requirements. Such units typically comprise of dedicated areas specific for the type of production such as viral vector production and cell processing. Generally, the logistical and operational requirements for clinical production is beyond the purview of the investigator and is typically assigned to an in-house facility or outsourced to external manufacturers such as contract development and manufacturing organizations (CDMOs) and contract manufacturing organizations (CMOs) that are specialized in this field. However, a general knowledge of the manufacturing process can benefit an investigator to package such information adequately under the CMC section as required. Final product testing must occur on materials, such as viral vectors and cellular products, manufactured under cGMP. The primary testing goals are to provide investigational drug-specific information such as (i) safety by providing evidence for sterility, absence of adventitious agents that includes replication competent virus and mycoplasma; (ii) identity by testing for suitable biological features such as cell surface markers; (iii) purity of the composition by detecting for extraneous materials that may have been introduced during the manufacturing process such as endotoxin, protein, growth factors or other factors that may influence final product characteristics; and (iv) potency/product characterization to demonstrate (a) lot-to-lot consistency, (b) comparability if changes are introduced during manufacturing procedures, and (c) clinical suitability for pivotal trials that require drug stability assessments [15••, 23]. Stability studies, required under 21 CFR 312.23, are integral to an IND program and are applicable for all IND phases to build quality into products. The goal of such studies is to determine if the CGT product retains pre-established quality limits that are sustained during the proposed clinical trial duration although the intrinsic variabilities in these products can pose a challenge to accurately assess their shelf life and storage conditions. These studies are performed on (i) in-process materials to measure product integrity during the cryopreservation period, and (ii) final product to establish expiration dates. A stability study protocol generally incorporates (i) procedures to (a) capitulate maximum stress conditions and (b) understand degradation via accelerated studies; (ii) testing schedules, that includes evaluation at time zero, and intervening periods followed by a suitable end point; and (iii) justification of assay design, such as the number of lots to test and the suitability of their application. Due to the inherently complex nature of the CGT products, the collection of comprehensive stability data to support the entire period of the proposed human trial may be incomplete or unavailable in some circumstances, such as during pre-clinical stages. Therefore, the inclusion of a proposed plan to determine stability will fulfill the requirements for initial an IND submission with the provision that the FDA be notified of timely updates on such data as they become available. As per 21 CFR 312.23(a)(7), the amount of information to be furnished on the IND application is dependent on (i) the phase of the study, (ii) proposed duration and dose, and (iii) available information. For early-phase IND submissions, data reporting with nonvalidated testing methods are allowed provided they incorporate scientifically sound quality attributes, such as specification and acceptance criteria. Pharmacology and Toxicology (P/T). As set forth in 21CFR 312.23(a)(8), P/T data is a mandatory requirement in an IND application. The primary goal of these studies is to gather safety data of the investigational drug to make informed decision on whether the investigational drug can safely advance to clinical testing [24]. Such data are sourced mainly from appropriate animal models (and cell lines) that are integrated into the pre-clinical studies which must be designed and conducted to support the establishment of a safe starting dose and dose escalation studies with due cognizance of potential toxicities to reduce unwarranted exposure of trial participants to suboptimal dose. Pharmacological evaluation of an investigational drug consists of measurement of its pharmacokinetic (PK) and pharmacodynamic (PD) profile. PK for a traditional pharmaceutic consists of its absorption, distribution, metabolism, and excretion (ADME) profile, whereas PD is defined as the mechanistic pathways by which the drug exerts its action. Due to the inherent variability and novelty in biological features and characteristics of CGT products, it is necessary to customize strategies to determine such pharmacological determinants. Measurements of PK of an investigational CGT product starts with the adoptive transfer of the drug into the appropriate animal model identified during the pre-clinical studies. At suitable time points gathered from the previous studies, the expression, persistence, and tissue biodistribution profile of the vector and the transgene are determined. Any adverse effects that may arise during such study period must be reported and assays are to be developed to relate such events to the viral vector type, transgene expression level and size of the animal cohort. The PD profile is evaluated by measuring the in vivo efficacy of the investigational drug. The aim of toxicity studies is to determine the characteristic (identity and quantity) of the investigational drug in an in vivo setting with respect to potential local and systemic toxicities that may be acute and/or chronic in nature. Evaluation of such studies is helpful to prepare patient monitoring plan. Clinical Study Design. Design of clinical trials to evaluate CGT investigational products differs from those employed to test traditional pharmaceutical agents. Towards this end, FDA has provided specific regulatory guidance documents to facilitate the preparation of early stage CGT-based IND application [25]. The portfolio of nonclinical studies formulated and performed to identify and capture information, such as P/T profile of the investigational drug, critical for its clinical stage advancement, form the basis to develop early phase human trial. Several features of a CGT product such as its characteristics, preclinical considerations, and manufacturing needs drive the design rationale. Such a design takes into account the (i) goals of early-phase trials which are primarily geared to access safety; (ii) evaluation of minimum tolerable dose and dose regimen; (iii) considerations on the characteristics of the clinical trial population such as qualifications and the vetting process to recruit eligible trial participants based on their disease stages and severities, adequacy of response to existing therapies if available, lack of treatment options, physiological and biological considerations amenable to the proposed treatment; (iv) heightened risk associated with a CGT product for a delayed adverse clinical outcome that warrants the formulation of a long term follow-up (LTFU) protocol as exemplified by the FDA mandated time intervals to detect replication competent lentivirus (RCL) in patients administered with retrovirus-based genetically engineered products, and (v) mitigation plan for potential toxicities with established treatment options [26, 27]. Participation of healthy volunteers are discouraged for most CGT-based trials since such therapies are directed to induce permanent or semi-permanent genetic changes while children can only be enrolled if additional safeguards as described in 21 CFR Part 50 are incorporated in the pre-clinical study designs. IND Application Stage Satisfactory completion the IND-enabling studies leads to the preparation of the dossier to apply for IND designation. To streamline the process of writing and submitting documents required for an IND application, electronic common technical document (eCTD) compliant templates that are updated with the current regulatory requirements are commercially available. It is important to recognize that products not intended to be distributed commercially, such as investigator-sponsored INDs, are excluded from the eCTD requirement. Investigators may submit a hardcopy IND submission by mailing their application in triplicate. Alternatively, investigators may pursue DocuSign’s Part 11 Module, which is compliant with 21 CFR Part 11. Host institutions may provide regulatory support, including IND compilation and review, through a Regulatory Affairs Office. Investigators working on investigational drugs that address unmet medical needs are encouraged to seek advantage of special regulatory provisions. FDA has designed four programs to promote and accelerate the development of such drugs to allow their prompt use in patients provided the therapeutic efficacy justify potential risk [28]. The programs that qualify for submission along with the IND application are as follows: (i) “Fast Track” designation which can be based solely upon pre-clinical data. Such a status is bestowed under Sect. 506(b) of the FD&C Act if the following conditions applicable to the investigational drug are met: (a) it is to treat serious and life-threatening conditions, and (b) it has demonstrated evidence to address unmet medical needs. It is expected that either theoretic/mechanistic rationale, or satisfactory therapeutic outcomes from pre-clinical animal models, or both, would suffice for an academic investigator to request such designation during the early stage IND application. Upon approval of such a request, a window of various interactive opportunities with the FDA opens to the investigator-sponsor to prepare and conduct studies appropriate for such designation, and ii) “Breakthrough Therapy” designation status which is provided under Sect. 506(a) of the FD&C Act to the investigational drug if it (a) is to treat a serious disorder and (b) has been demonstrated to afford significant improvement over existing drugs in a clinical setting. Therefore, an investigator-sponsor is expected to request for such a designation no earlier than the end of phase 1 but no later than end of phase 2. The other two programs, “Accelerated approval” and “Priority Review” are reserved for FDA’s evaluation during product approval stages based on either meeting a well-controlled clinical surrogate end point during late stage human trials or demonstrated findings, submitted with the BLA, that show compared to existing therapies, the investigation product affords significant improvement in critical quality attributes such as safety and efficacy profiles, respectively. Following the initial submission, any changes to an existing IND application, such as identification of new safety concerns, and manufacturing procedures that can affect product purity and composition, with the potential to influence the core nature of the study proposals must be declared by filling amendments as per 21 CFR 312.31. Annual reports are also due, as per 21 CFR 312.33 to summarize any major manufacturing or microbiological changes. Meeting Opportunities with CBER/OTAT The FDA provides and encourages opportunities to discuss various aspects of the study sections, such as re-evaluation of study design, drug safety data, concern for response to drug and any critical/urgent issues for interactions with the stakeholder during early-stage IND development studies as summarized below [29]. Initial Targeted Engagement for Regulatory Advice on CBER Products (INTERACT) This is an Informal, early-stage meeting to review features in preliminary studies, CMC, or P/T studies [30]. Pre-IND Meeting This is a nonbinding meeting which is typically scheduled at least after the satisfactory completion of preliminary evaluations. The objectives of such a meeting is to obtain input from the FDA on regulatory, and scientific aspects such as advice on the plans for preliminary studies, design of animal studies to support the rationale to advance to clinical testing, and the format for the IND. Questions regarding the clinical protocol can also be discussed. Meeting Type A. This is a formal meeting to resolve any stalled drug developmental program such as a clinical hold. Meeting Type B. This is an informal meeting such as in pre-IND stage and formal meeting at the later stage such as at the end of phase 1 (for products with Fast Track designation) and phase 2. Meeting Type C. This meeting if for discussion of issues that are beyond the scope of either type A or B such as seeking recommendations to improve upon ongoing issues. In addition to the established avenues of engagements, it is the FDA’s desire to open additional interactive opportunities to improve upon the manufacturing processes and enhance the understanding of critical quality attributes of cell and gene therapy products [31]. Refinements in these categories are critical to bring reproducible clinical outcomes with interventions based on such products. Clinical Trials The IND dossier is designed to support the rationale and justification to advance the investigational drug for human trials. The CGT product typically must meet trial-phase specific endpoints, which are either clinical or exploratory such as a surrogate marker of the disease, to progress between phases. It is only upon the satisfactory completion of the last testing phase that the drug can qualify for the review of commercial licensure, unless the drug meets specifications for expedited approval mechanisms that exist in the early stages. Below is a brief discussion of clinical phases that are within the scope of early stage drug development by an investigator-sponsor. Phase 1. The primary goal at this stage is to evaluate the safety and tolerance of the CGT product in recruited trial participants. The drug product is administered at the proposed starting dose and may include dosing escalations. The best practice in the selection of a dosing strategy is built upon the product characteristics and the intervention strategy such as the safety profile of the IND product and its route of administration. A cohort of very few (around 10 or less) to 80 participants, selected based on factors such as disease prevalence, funding, and existing clinical data, are enrolled and their pharmacological and toxicological evaluations are closely monitored for unwarranted adverse outcomes. Besides drug safety assessments, a secondary objective is the preliminary monitoring of indications for drug efficacy and such a data can influence the design of later stages of a clinical trial. Due to the uniqueness in CGT products such as their persistence, biodistribution and durability of action, the probability of success in early clinical phases often times relies on the outcomes from well-defined pre-clinical studies such as the derivation of a starting dose with minimal risk from the organ toxicity profiles of pre-clinical animal models. Amount of CGT products required to conduct this phase are within the production capacities of academic CGT manufacturing units. In addition, phase 1 testing should identify drug dosing to be used in phase 2 testing. Phase 2. The primary goals of this trial is to continue (i) phase 1 safety assessments and evaluation of the effectiveness of the CGT product on a larger cohort size that can range up to a few hundreds. To accommodate the scale of materials required for this phase such as viral vectors and cell products, third-party manufacturers rather than academic core facilities, may be more suitable. The investigator-sponsor should be aware of escalation in operational requirements and pre-plan for budgetary and logistical resources in order to successfully navigate such a phase. (ii) In addition, phase 2 studies should identify the drug dose to be used in pivotal phase 3 testing. Phase 3. The main goals at this stage are to continue to collect data on the safety and efficacy profile of the investigational drug. The scope and magnitude of the trial parameters at this phase are wide such that it (i) is designed to be tested in various formats such as controlled, uncontrolled, and expanded; (ii) recruits hundreds to thousands of participants; and (iii) is conducted across multiple centers and sites. Activities necessary to conduct phase 3 studies are beyond the scope of this article as are phase 4 post-licensure studies after market approval and requires extensive operational resources that are usually managed outside of the host institution of the investigator-sponsor. Conclusion CGT-based therapeutics are transformative medicines with life-altering prospects. Innovators engaged in bringing such disruptive medical technologies must have a well-chartered path to navigate their investigational products for FIH assessment via the IND mechanism (which is summarized in Fig. 3). Due to the uniqueness of CGT products, a well-planned IND program must address the technical and logistical hurdles that are intrinsic to their developmental processes. Advancements in vector design and selection, delivery mechanisms of CGT products, and their manufacturing strategies are potential avenues to increase efficiency in evaluating such innovative products. An investigator well versed in scientific skills must also be proficient on the knowledge of regulatory oversight mechanisms set forth by the FDA, which is committed to safeguarding the health of the nation while promoting exploration of innovative therapies. Towards this end, fostering a robust investigator-FDA partnership early during the preliminary evaluation stages of drug development is a mission critical to fulfill the tenets set forth in the IND application.Fig. 3 Representation of the processes and agencies working together for the successful clinical testing of a drug product candidate Declarations Conflict of Interest Dr. Doering reports other from Expression Therapeutics, Inc., during the conduct of the study. The other authors declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors. This article is part of the Topical Collection on Stem Cells: Policies from the Bench to the Clinic Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ==== Refs References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1. Bailey AM Arcidiacono J Benton KA Taraporewala Z Steve WS United States Food and Drug Administration regulation of gene and cell therapies Adv Exp Med Biol 2015 871 1 29 10.1007/978-3-319-18618-4_1 26374210 2. Verma IM A Tumultuous year for gene therapy Mol Ther 2000 2 5 415 416 10.1006/mthe.2000.0213 11082313 3. Marwick CBMJ FDA halts gene therapy trials after leukemia case in France 2003 326 7382 181 4. Cole A Child in gene therapy programme develops leukaemia BMJ 2008 336 7634 13 10.1136/bmj.39436.582292.DB 18174583 5. Dunbar CE, High KA, Joung JK, Kohn DB, Ozawa K, Sadelain M. Gene therapy comes of age. Science. 2018;359(6372):eaan4672. 6. News in Brief High-dose AAV gene therapy deaths Nat Biotechnol 2020 38 910 10.1038/s41587-020-0642-9 32760031 7. Philippidis A “Profoundly saddened” Lysogene discloses child’s death in phase II/III trial Hum Gene Ther 2020 31 21–22 1141 1143 10.1089/hum.2020.29139.bfs 33200963 8. Galaro AK Christopher SC FDA perspective on the preclinical development of cell-based immunotherapies Cell & Gene Therapy Insights 2020 6 9 1381 1390 10.18609/cgti.2020.148 9. Lapteva L Purohit-Sheth T Serabian M Puri RK Clinical development of gene therapies: the first three decades and counting Mol Ther Methods Clin Dev 2020 10 19 387 397 10.1016/j.omtm.2020.10.004 10. • S. Gottlieb. Statement from FDA Commissioner Scott Gottlieb, MD and Peter Marks, MD, PhD, Director of the Center for Biologics Evaluation and Research on New Policies to Advance Development of Safe and Effective Cell and Gene Therapies. 2019. https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-and-peter-marks-md-phd-director-center-biologics. Accessed 7 Feb 2021. Given the surge in the exploration of cell and gene therapy-based modalities FDA has issued this forward-looking statement on its mission to modernize the regulatory framework and to reiterate its commitment to assist the stakeholders as they develop their INDs. 11. U.S. Food and Drug Administration. Approved cellular and gene therapy products. 2021. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products. Accessed 7 Feb 2021. 12. Holbein BME Understanding FDA regulatory requirements for investigational new drug applications for sponsor-investigators J Investig Med 2009 57 6 688 694 10.2310/JIM.0b013e3181afdb26 19602987 13. U.S. Food and Drug Administration, Guidance. https://www.fda.gov/industry/fda-basics-industry/guidances. Accessed 7 Feb 2021. 14. U.S. Food and Drug Administration. FDA continues strong support of innovation in development of gene therapy products. 2020. https://www.fda.gov/news-events/press-announcements/fda-continues-strong-support-innovation-development-gene-therapy-products. Accessed 7 Feb 2021. 15. •• U.S. Department of Health and Human Services Food and Drug Administration Center for Biologics Evaluation and Research. Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs), Guidance for Industry. 2020. https://www.fda.gov/media/113760/download. Accessed 7 Febr 2021. With the overarching goal being to streamline the review and approval process to enhance promising treatment entry into the clinic, this is FDA’s latest guidance for recommendations on the CMC section of a gene therapy IND application. 16. Huang W, Percie du Sert N, Vollert J, Rice ASC. General principles of preclinical study design. Handb Exp Pharmacol. 2020;25755–69. 17. U.S. Department of Health and Human Services Food and Drug Administration Center for Biologics Evaluation and Research. Preclinical assessment of investigational cellular and gene therapy products, Guidance for Industry. 2013. https://www.fda.gov/media/87564/download. Accessed 7 Feb 2021. 18. U.S. Department of Health and Human Services Food and Drug administration, Office of Regulatory affairs. Good laboratory practices questions and answers, Guidance for Industry 1981; June (Minor editorial and formatting changes made December1999 & 2007; July). https://www.fda.gov/media/75866/download. Accessed 7 Feb 2021. 19. United Sates Department of Health and Human Services, Food and Drug Administration. Good laboratory practice for nonclinical laboratory studies; Proposed Rule. 2016. https://www.fda.gov/media/99828/download. Accessed 7 Feb 2021. 20. Husain SR, J Han J, Au P, Shannon K, Puri RK. Gene therapy for cancer: regulatory considerations for approval. Cancer Gene Therapy. 2015;22:554–63. 21. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research. Manufacturing considerations for licensed and investigational cellular and gene therapy products during COVID-19 public health emergency, Guidance for Industry. 2021. https://www.fda.gov/media/145301/download. Accessed 7 Feb 2021. 22. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Center for Veterinary Medicine (CVM). Quality systems approach to pharmaceutical current good manufacturing practice regulations, Guidance for Industry. 2006. https://www.fda.gov/media/71023/download. Accessed 7 Feb 2021. 23. U.S. Department of Health and Human Services Food and Drug Administration Center for Biologics Evaluation and Research. Potency tests for cellular and gene therapy products, guidance for industry. 2011. https://www.fda.gov/media/79856/download .Accessed 7 Feb 2021. 24. National gene vector Biorepository. Approach to preclinical evaluation for gene therapy (GT) products, FDA Regulations and Guidance’s. https://www.ngvbcc.org/pdf/NGVB_Pharm_Tox.PreClin_doc2.17.11.pdf. Accessed 7 Feb 2021. 25. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research. Guidance for industry: considerations for the design of early-phase clinical trials of cellular and gene therapy products, Guidance for Industry. 2015. https://www.fda.gov/media/106369/download. Accessed 7 Feb 2021. 26. U.S. Department of Health and Human Services Food and Drug Administration Center for Biologics Evaluation and Research. Long term follow-up after administration of human gene therapy products, guidance for industry. 2020. https://www.fda.gov/media/113768/download. Accessed 7 Feb 2021. 27. U.S. Department of Health and Human Services Food and Drug Administration Center for Biologics Evaluation and Research. Testing of retroviral vector-based human gene therapy products for replication competent retrovirus during product manufacture and patient follow-up, Guidance for Industry. 2020. https://www.fda.gov/media/113790/download. Accessed 7 Feb 2021. 28. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER). Expedited programs for serious conditions – drugs and biologics, Guidance for Industry. 2014. https://www.fda.gov/media/86377/download. Accessed 7 Feb 2021. 29. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). IND Meetings for Human Drugs and Biologics, Chemistry, Manufacturing, and Controls Information, Guidance for Industry. 2001. https://www.fda.gov/media/70827/download. Accessed 7 Feb 2021. 30. U.S. Food and Drug Administration, Center for Biologics Evaluation and Research. SOPP 8214: INTERACT Meetings with Sponsors for Drugs and Biological Products. 2020. https://www.fda.gov/media/124044/download. Accessed 7 Feb 2021. 31. Marks Peter. A year like no other: reflecting on the challenges of 2020, and looking to regain momentum for cell and gene therapy in 2021. Cell and Gene Therapy Insights. 2021. https://www.insights.bio/cell-and-gene-therapy-insights/journal/article/1892/A-year-like-no-other-reflecting-on-the-challenges-of-2020-and-looking-to-regain-momentum-for-cell-and-gene-therapy-in-2021. Accessed 7 Feb 2021.
PMC008xxxxxx/PMC8492899.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(21)02578-0 10.1016/j.jaad.2021.09.061 Research Letter The risk of COVID-19 infection in patients with atopic dermatitis: A retrospective cohort study Wu Jashin J. MD a∗ Martin Amylee BS b Liu Jeffrey BS c Thatiparthi Akshitha BS d Ge Shaokui PhD b Egeberg Alexander MD, PhD e Thyssen Jacob P. MD, PhD, DmSci e a Dermatology Research and Education Foundation, Irvine, California b School of Medicine, University of California, Riverside, California c Keck School of Medicine, University of Southern California, Los Angeles, California d Western University of Health Sciences, Pomona, California e Department of Dermatology, Bispebjerg University Hospital, University of Copenhagen, Copenhagen, Denmark ∗ Reprint requests: Jashin J. Wu, MD, Dermatology Research and Education Foundation, Irvine, CA 6 10 2021 1 2022 6 10 2021 86 1 243245 © 2021 by the American Academy of Dermatology, Inc. 2021 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Key words atopic dermatitis COVID-19 dupilumab epidemiology infection ==== Body pmcTo the Editor: The dermatology community remains concerned about the risk of COVID-19 in individuals with atopic dermatitis (AD). Using Symphony Health-derived data from the COVID-19 Research Database,1 we aimed to assess the risk of contracting COVID-19 in adults with AD while controlling for demographic factors and comorbidities known or speculated to be COVID-19 risk factors and assess the risk of contracting COVID-19 in adults with AD treated with dupilumab. Subjects aged ≥20 years were eligible for inclusion. All subjects with at least 2 diagnoses of AD prior to January 1, 2020, were included in the AD cohort. Subjects with no record of AD diagnosis prior to January 1, 2020, were randomly placed in the control group in a 10:1 size ratio compared with the AD group. Individuals without known ethnicity or race, type of payment, and/or sex were then excluded. Laboratory-confirmed cases of COVID-19 between January 1, 2020, and April 17, 2021, were identified (Supplemental Fig I available via Mendeley at https://data.mendeley.com/datasets/j95wfcyy3j/1). A description of the methodology for this retrospective study is provided in Supplemental Methods (available via Mendeley at https://data.mendeley.com/datasets/t26gnt3pss/1), Supplemental Table I (available via Mendely at https://data.mendeley.com/datasets/ww6b5n327m/1), and Supplemental Table II (available via Mendeley at https://data.mendeley.com/datasets/tbh86d3z8r/1). The AD and non-AD cohorts included 39,417 and 397,293 subjects, respectively (Table I ). Poisson regression revealed a crude COVID-19 incidence rate ratio (IRR) of 1.41 (95% CI 1.34-1.48) for adults with AD compared with adults without AD (Table II ). After adjusting for demographic factors and baseline comorbidities, the IRR remained statistically significant but was reduced to 1.18 (95% CI 1.12-1.24).Table I Patient characteristics stratified by atopic dermatitis status Characteristics Atopic Dermatitis (n = 39,417) No Atopic Dermatitis (n = 397,293) P Value Age, mean (SD) 54.9 (17.0) 57.3 (16.0) <.0001 Sex, n (%) <.0001  Female 23,555 (59.8) 223,412 (56.2)  Male 15,862 (40.2) 173,881 (43.8) Race/ethnicity, n (%)  Caucasian 25,187 (63.9) 295,823 (74.5) <.0001  Hispanic 4468 (11.3) 36,035 (9.1)  African American 6969 (17.7) 52,415 (13.2)  Asian 1822 (4.6) 6670 (1.7)  Other 971 (2.5) 6350 (1.6) Payment type, n (%)  Assistance program∗ 24,065 (61.1) 209,202 (52.7) <.0001  Medicare, private, cash 15,352 (39.0) 188,091 (47.3) Confirmed COVID-19, n (%) 1807 (4.6) 12,910 (3.3) <.0001 Comorbidities, n (%)  Asthma 3428 (8.7) 5024 (1.3) <.0001  Rhinitis† 5317 (13.5) 3927 (1.0) <.0001  COPD 1519 (3.9) 9667 (2.4) <.0001  CHF 896 (2.3) 6598 (1.7) <.0001  Chronic ischemic heart disease 1464 (3.7) 12,097 (3.0) <.0001  DM2 4185 (10.6) 29,258 (7.4) <.0001  DM1 192 (0.5) 1631 (0.4) .025  Overweight or obese 2580 (6.6) 10,906 (2.8) <.0001  CKD 1442 (3.7) 10,831 (2.7) <.0001  Hypertension 8880 (22.5) 56,510 (14.2) <.0001  HIV 155 (0.4) 623 (0.2) <.0001 COPD, Chronic obstructive pulmonary disease; CHF, congestive heart failure; CKD, chronic kidney disease; DM2, type 2 diabetes mellitus; DM1, type 1 diabetes mellitus. ∗ Includes Medicaid. † Allergic and/or vasomotor. Table II Poisson regression for risk of contracting COVID-19 in patients with atopic dermatitis Factor Crude IRR (95% CI) P Value Adjusted IRR (95% CI)∗ P Value AD vs no AD—main analysis 1.41 (1.34-1.48) <.0001 1.18 (1.12-1.24) <.0001 AD vs no AD—sensitivity analysis 1† 1.51 (1.45-1.56) <.0001 1.18 (1.12-1.24) <.0001 AD vs no AD—sensitivity analysis 2‡ 1.33 (1.14-1.56) <.0001 1.31 (1.11-1.53)§ .001 AD vs no AD—age subgroup analysis  Age 20-40 y 1.32 (1.18-1.47) <.0001 1.18 (1.05-1.33) .007  Age ≥41 y 1.44 (1.37-1.53) <.0001 1.18 (1.12-1.25) <.0001 AD vs no AD—sex subgroup analysis  Men 1.36 (1.26-1.47) <.0001 1.16 (1.07-1.25) <.0001  Women 1.45 (1.36-1.54) <.0001 1.20 (1.12-1.28) <.0001 Dupilumab vs no systemic medication 0.62 (0.49-0.78) <.0001 0.66 (0.52-0.83) <.0001 Methotrexate vs no systemic medication 0.80 (0.54-1.17) .25 0.82 (0.56-1.21) .32 Prednisone vs no systemic medication 1.16 (1.04-1.30) .007 1.13 (1.01-1.26) .03 Cyclosporine vs no systemic medication 1.37 (0.96-1.94) .08 1.20 (0.84-1.71) .32 Azathioprine vs no systemic medication 1.68 (0.87-3.24) .12 1.61 (0.83-3.10) .16 Dupilumab vs methotrexate 0.78 (0.50-1.21) .26 0.80 (0.51-1.27) .35 Dupilumab vs prednisone 0.53 (0.42-0.68) <.0001 0.58 (0.45-0.74) <.0001 Dupilumab vs cyclosporine 0.45 (0.30-0.68) <.0001 0.57 (0.36-0.90) .02 Dupilumab vs azathioprine 0.37 (0.18-0.73) .004 0.40 (0.20-0.82) .01 AD, Atopic dermatitis; IRR, incidence rate ratio. ∗ Adjusted for sex, age, race/ethnicity, payment type, and comorbidities (eg, asthma, rhinitis, overweight/obese, congestive heart failure, chronic ischemic heart disease, chronic kidney disease, chronic obstructive pulmonary disease, essential hypertension, human immunodeficiency virus, type 2 diabetes mellitus, and type 1 diabetes mellitus). † Sensitivity analysis 1 includes subjects with missing race or ethnicity, type of payment, and/or sex. ‡ Sensitivity analysis 2 includes subjects aged 20-59 years with zip code in California or New York and excludes subjects with a history of asthma, rhinitis, overweight or obese, congestive heart failure, chronic ischemic heart disease, chronic kidney disease, chronic obstructive pulmonary disease, essential hypertension, human immunodeficiency virus, type 2 diabetes mellitus, and/or type 1 diabetes mellitus. § Adjusted for sex, age, race/ethnicity, payment type. In a sensitivity analysis including subjects with missing race or ethnicity, sex, and/or type of payment (to account for selection bias), the risk of COVID-19 associated with AD remained unchanged (adjusted IRR 1.18). In another sensitivity analysis (to address potential type I error) including subjects aged 20-65 years with zip codes in California or New York and excluding subjects with comorbidities associated with COVID-19 (n = 32,857), the adjusted IRR point estimate was higher (1.31, 95% CI 1.11-1.53) than that in the main analysis. Dupilumab was associated with lower risk of contracting COVID-19 (adjusted IRR 0.66, 95% CI 0.52-0.83) compared with no systemic medication. Additionally, AD subjects on dupilumab showed significantly lower associated risk of contracting COVID-19 infection compared with AD subjects exposed to prednisone, cyclosporine, and/or azathioprine (Table II). The limitations include the inability to account for treatment duration and establish a strong causal relationship. Moreover, assessment of disease burden according to diagnostic codes might have missed individuals who never underwent COVID-19 laboratory testing. A prospective study with scheduled COVID-19 testing would address this limitation. In this large population-based study, we found small increased risk of contracting COVID-19 to be associated with AD in adults. However, adult AD subjects had a higher prevalence of baseline comorbidities, previously identified as COVID-19 risk factors,2 , 3 compared with adults without AD. Our results were attenuated after adjusting for baseline comorbidities, suggesting that residual confounding may explain the remaining association. Studies are needed to identify which demographic characteristics or comorbidities are the strongest COVID-19 risk factors for adults with AD. Dupilumab was associated with lower risk of contracting COVID-19 infection compared with other systemic medications. Interestingly, interleukin 4 activity (blocked by dupilumab)4 has been known to be associated with severe COVID-19 infections.5 Based on the current evidence, dupilumab does not appear to increase COVID-19 risk in patients with AD. Conflicts of interest Dr Wu is or has been an investigator, consultant, or speaker for AbbVie, Almirall, Amgen, Arcutis, Aristea Therapeutics, Boehringer Ingelheim, Bristol–Myers Squibb, Dermavant, Dr Reddy's Laboratories, Eli Lilly, Galderma, Janssen, LEO Pharma, Mindera, Novartis, Regeneron, Sanofi Genzyme, Solius, Sun Pharmaceutical, UCB, Valeant Pharmaceuticals North America LLC, and Zerigo Health. Dr Egeberg has received research funding from 10.13039/100004319 Pfizer , Eli Lilly, 10.13039/100004336 Novartis , 10.13039/100002491 Bristol-Myers Squibb , 10.13039/100006483 AbbVie , 10.13039/100008897 Janssen Pharmaceuticals , the Danish National Psoriasis Foundation, the 10.13039/501100014553 Simon Spies Foundation , and the 10.13039/501100006286 Aage Bang's Foundation , and honoraria as consultant and/or speaker from AbbVie, Almirall, Leo Pharma, Galápagos NV, Sun Pharmaceuticals, Samsung Bioepis Co, Ltd, Pfizer, Eli Lilly, Novartis, Galderma, Dermavant, UCB, Mylan, Bristol–Myers Squibb, and Janssen Pharmaceuticals. Dr Thyssen has been an advisor, speaker, or investigator for AbbVie, LEO Pharma, Regeneron, Pfizer, Sanofi Genzyme, Almirall, and Eli Lilly. Dr Ge and Authors Martin, Liu, and Thatiparthi have no conflicts of interest to declare. The data, technology, and services used in the generation of these research findings were generously supplied pro bono by the COVID-19 Research Database partners, who are acknowledged at https://covid19researchdatabase.org/. Funding sources: None. IRB approval status: Exempt - de-identified data. ==== Refs References 1 COVID-19 Research Database COVID-19 Research Database Consortium https://covid19researchdatabase.org 2 Sanyaolu A. Okorie C. Marinkovic A. Comorbidity and its impact on patients with COVID-19 SN Compr Clin Med 2 8 2020 1069 1076 10.1007/s42399-020-00363-4 32838147 3 Yang J.M. Koh H.Y. Moon S.Y. Allergic disorders and susceptibility to and severity of COVID-19: a nationwide cohort study J Allergy Clin Immunol 146 4 2020 790 798 10.1016/J.JACI.2020.08.008 32810517 4 Thibodeaux Q. Smith M.P. Ly K. Beck K. Liao W. Bhutani T. A review of dupilumab in the treatment of atopic diseases Hum Vaccin Immunother 15 9 2019 2129 2139 10.1080/21645515.2019.1582403 30785362 5 de Paula C.B. de Azevedo M.L. Nagashima S. IL-4/IL-13 remodeling pathway of COVID-19 lung injury Sci Rep 10 1 2020 1 8 10.1038/s41598-020-75659-5 31913322
PMC008xxxxxx/PMC8557108.txt
==== Front Vis Comput Vis Comput The Visual Computer 0178-2789 1432-2315 Springer Berlin Heidelberg Berlin/Heidelberg 34744231 2322 10.1007/s00371-021-02322-z Survey A systematic review on application of deep learning in digestive system image processing Zhuang Huangming Huangming Zhuang currently pursues his Master degree in clinical medicine at Wuhan University in China. He not only studies medical knowledge earnestly, but also has great interest in cutting-edge science and technology. His research focuses on new strategies for diagnosis and treatment of digestive system diseases, especially gastrointestinal tumors, under the cross-discipline. Zhang Jixiang Jixiang Zhang is a PhD jointly trained by Wuhan University and Texas A&M University (2013–2017). He is currently an attending physician in the Department of Gastroenterology, Renmin Hospital of Wuhan University. His research interests: basic research including utilization of artificial intelligence of digestive system disease. http://orcid.org/0000-0002-6026-7976 Liao Fei feiliao@whu.edu.cn Fei Liao is a Medicine Doctor of Wuhan University and Visiting Scholar of University of Michigan, USA (2016–2017). Presently, he is a Deputy chief physician of Gastroenterology Department, Renmin Hospital of Wuhan University. His research interests: basic research including utilization of artificial intelligence of digestive system disease. grid.412632.0 0000 0004 1758 2270 Gastroenterology Department, Renmin Hospital of Wuhan University, Wuhan, 430060 Hubei China 31 10 2021 2023 39 6 22072222 30 9 2021 © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. With the advent of the big data era, the application of artificial intelligence represented by deep learning in medicine has become a hot topic. In gastroenterology, deep learning has accomplished remarkable accomplishments in endoscopy, imageology, and pathology. Artificial intelligence has been applied to benign gastrointestinal tract lesions, early cancer, tumors, inflammatory bowel diseases, livers, pancreas, and other diseases. Computer-aided diagnosis significantly improve diagnostic accuracy and reduce physicians’ workload and provide a shred of evidence for clinical diagnosis and treatment. In the near future, artificial intelligence will have high application value in the field of medicine. This paper mainly summarizes the latest research on artificial intelligence in diagnosing and treating digestive system diseases and discussing artificial intelligence's future in digestive system diseases. We sincerely hope that our work can become a stepping stone for gastroenterologists and computer experts in artificial intelligence research and facilitate the application and development of computer-aided image processing technology in gastroenterology. Keywords Deep learning Artificial intelligence Digestive system Endoscopic Imaging Pathology Diagnosis issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2023 ==== Body pmcIntroduction The diagnosis of digestive tract diseases depends on gastrointestinal endoscopy, imaging, and pathology. Deep learning (DL) has been widely applied in these fields. It can automatically establish an image recognition system without manipulating image features and achieve high diagnostic efficiency. In recent years, various advanced algorithms and models of computer-aided diagnosis (CAD) have been proposed, which is expected to reduce doctors’ workload and misdiagnosis rates (Fig. 1).Fig. 1 Mind map Artificial intelligence (AI) can be defined as the intelligence displayed by machines that mimic human cognitive functions [1, 2]. Machine learning (ML), a subdomain of AI, is an algorithm trained from data to perform a task rather than directly executing an explicit program. Representation Learning (RL) is a sub-category of ML, which can master core features and implement algorithms through the autonomous classification of data [3]. DL is a kind of RL. DL acquires feature combinations that reflect the hierarchical structure of data structures to provide detailed image classification output. At present, DL represented by convolutional neural networks (CNN) is the most widely used AI in medicine [4]. DL technology can extract pathological features through active learning of massive clinical data without providing features in advance and make a CAD through these pathological features. CAD can significantly reduce clinicians’ workload and assist doctors in making more accurate and rapid diagnoses. Besides, advanced diagnosis and treatment technologies can be shared across a wider region, and medical resources can be rebalanced through CAD. Application of DL in gastrointestinal endoscopy Digestive endoscopy is an essential method for diagnosing and treating digestive tract diseases and plays a vital role in screening precancerous lesions and early cancers. The detection rate of early precancerous lesions under endoscopy is relatively low, so it is of great significance to improve the endoscopic detection rate of early tumors for improving the prognosis of patients with digestive tract tumors. AI-assisted endoscopic diagnosis is expected to strengthen gastrointestinal lesions’ detection rate by endoscopic physicians and reduce misdiagnosis or missed diagnosis [5]. With the continuous iteration of computer technology and the arrival of the big data era, the research on the diagnosis of endoscopic diseases assisted by AI technology is flourishing. DL has been applied in the endoscope-assisted diagnosis of tumors and precancerous lesions of the esophagus [6, 7], stomach [8], small intestine [9], and colorectum [10, 11]. The vast majority of scholars use endoscopic photographs or videos to carry out DL. The number and size of training sets adopted by different studies vary greatly, but most CAD systems’ accuracy in diagnosing tumors or precancerous lesions can exceed 80%. Due to the lack of large-scale public authoritative data sets, studies often used single-center endoscopic data. The number of patients is usually less than 100, limiting DL’s accuracy and universality, leading to selection bias. Therefore, a study enhances data utilization and improves Barrett’s esophagus diagnostic accuracy by establishing an adversarial network [12]. Multi-center randomized controlled trials are the most compelling studies. However, there have been few multi-center prospective studies of AI in gastrointestinal endoscopy so far. Wu and Xu et al. Conducted two randomized controlled trials to verify the effectiveness of ENDOANGEL, a CAD system, in white-light imaging (WLI) and image-enhanced endoscopy (IEE) examination of early gastric cancer [13, 14]. CNN in fully supervised is challenging for endoscopes because it is challenging to obtain depth maps directly corresponding to authentic endoscope images. Weakly annotated images may be a cost-effective approach in future. Weakly supervised convolutional neural network (WCNN) can identify abnormal video frames and detect specific pathological points from video frames [15]. In this way, images can be marked only by image-level annotations instead of detailed pixel-level annotations. The system can automatically analyze detailed lesion areas by roughly dividing, thus achieving favorable detection and localization performance. Mahmood et al. put forward an unsupervised reverse domain adaptation framework to avoid excessive comments [16]. Their system worked by using confrontational training to remove patient-specific details from real endoscopic images while preserving diagnostic details. It is a pity that their research was limited to static image recognition, unable to adapt to endoscope videoed in poor light or unknown depth scenes. Ozyoruk et al. proposed an unsupervised monocular visual odometry and estimated depth to solve the problem of frequently changing lighting conditions and scale inconsistency between consecutive frames [17]. The algorithm was optimized by mixed loss functions, using spatial attention modules to instruct the network to focus on tissue areas. Besides, the system detected photometric loss to improve the robustness of fast inter-frame illumination changes in endoscope videos. Itoh et al. performed unsupervised DL by introducing the lambert reflection model as an auxiliary task for domain conversion between real and virtual colonoscopy images. The system can accurately extract 3D information, reducing the impact of specular reflection and colon wall texture on depth estimation [18]. Hwang et al. proposed a self-supervised monocular depth estimation method to assess Spatio-temporal consistency in the colonic environment by detecting depth differences between adjacent frames [19]. They used loss function and depth feedback network to estimate depth information in the next frame from previous frames’ data. The diagnostic accuracy of esophageal disease by narrow-band imaging (NBI) is higher than WLI, but there are few DL studies on NBI at present. Compared with traditional WLI, NBI images have no significant difference in AI diagnostic efficiency because NBI improves lesion detection sensitivity and increases the possibility of overdiagnosis, leading to reduced diagnostic specificity. However, NBI is beneficial to enhance histological diagnostic grading accuracy [6]. Moreover, NBI can enhance the ability to differentiate squamous cell carcinoma microvessels [20]. A multi-center study shows that magnifying endoscopy narrow-band imaging (ME-NBI) reached senior endoscopic physicians’ predictive performance in early gastric cancer. Nevertheless, the system, which used images rather than videos for the study, requires an endoscopic magnification of the suspected lesion site before the CAD system can be used. Moreover, the system cannot distinguish the depth of tumor invasion [21]. Colorectal cancer is the third most common cancer in the world [22]. Colorectal adenomas have a 50% chance of malignant transformation, so early detection plays a crucial role in reducing mortality. About a quarter of adenomas are missed during standard colonoscopy [23]. DL’s study identifies and classifies colorectal polyps with excellent application value. Bora et al. collected WLI and NBI images of the colorectum to settle the complex problem of systematic visualization [24]. He used Generic Fourier Descriptors (GFD) to quantify shapes, Nonsubsampled Contourlet Transform (NSCT) to extract texture and color features and performed variance analysis to confirm that the GFD and NSCT features of tumors and non-neoplastic polyps were significantly different. After constructing the CNN model, Lai et al. found that both full-color NBI and red-green dual-channel NBI had better sensitivity than WLI in detecting polyps under colonoscopy [25]. Endoscopic ultrasonography (EUS) can improve imaging function and provide various methods for treating biliary tract diseases. Its steep learning curve and over-reliance on operators limit its clinical application in remote areas. Seven et al. predicted the mitotic index of gastrointestinal stromal tumors (GISTs) in EUS by DL. The system was able to automatically determine the prognosis of patients by EUS images [26]. The DL model designed by Yao’s research team can accurately identify the bile duct in EUS and automatically calibrate the anatomical position to measure the bile duct’s diameter, thus significantly improving the accuracy of the operator. The ability to identify lesions needs to be further developed in future [27]. The practical application of AI in gastrointestinal endoscopy is strongly time-sensitive, so it is necessary to integrate CAD into the working process of gastrointestinal endoscopy. The uneven light, gas, liquid, and surgical scars are the critical factors affecting the real-time application of AI in the endoscope. Manually filtered or standardized images for DL may reduce the system’s robustness. Gutierrez et al. collected clinical endoscopic videos of patients with ulcerative colitis from hundreds of different sites using different equipments, significantly increasing the area under the receiver operating characteristic curve (AUROC). Besides, these videos do not need to be marked by professional endoscopic physicians. The system automatically preprocesses and screens the original endoscopic videos and automatically carries out CNN system training, significantly reducing clinicians’ workload and reducing the deviation caused by artificial selection [28]. Confocal laser endoscopy (CLE) can detect various focal lesions with accuracy even close to pathological detection. CLE can also dynamically observe lesions under a microscope, so it has great application value in diagnosing and treating inflammatory bowel disease(IBD). However, CLE requires accurate image interpretation, which only experienced endoscopic physicians can do. Udristoiu’s team designed the DL system can distinguish between ulcerated and healed Crohn’s disease patients in CLE pictures [29]. Still, the algorithm was unable to determine active ulcers from inactive ulcers. Wireless capsule endoscopy (WCE) can move along the entire digestive tract to identify gastrointestinal polyps and other lesions and allow patients to avoid the discomfort of traditional endoscopes. At present, there are two research hotspots: one is how to use the DL models to accurately find the lesion site from thousands of pictures taken by WCE; the other is how to control the active recognition of capsule endoscopy, the arrival of the lesion, and the administration of drugs or biopsy. Up to now, DL has been able to identify intestinal vascular dilatation [30], hemorrhage [31], polyps [32], colorectal tumors [33], and ulcers caused by Crohn’s disease [34] from tens of thousands of photographs taken during each WCE. However, current researches are mainly retrospective studies, and most of the data sets are composed of still images. Therefore, multi-center prospective studies with large samples are required to verify CNN’s effectiveness in WCE image recognition. IncetanK et at. introduced VR technology into WCE. His group used computed tomography (CT) images to create a 3D organ model and then remove interference such as bone, fat, and skin [35]. The system can precisely generate the same organ as the patient’s real organ, with mucosal texture and vascular network images, to locate the capsule accurately through DL technology. Furthermore, the capsule containing magnets is controlled by an external robotic arm, making it possible for physicians to observe and perform relevant tasks with the help of WCE (Table 1).Table 1 Application of DL in gastrointestinal endoscopy Author year Organ Imaging modality Study design Best results: Sens/Spec/Acc% Iakovidis [15] GI WLI Retrospective AUC 0.96 De Souza [12] Esophagus WLI Retrospective NA, NA, 85 Zhang [8] Stomach WLI Retrospective 94.5, 94.0, 94.2 Hu [21] Stomach ME-NBI Prospective 79.2, 74.5, 77.0 Saito [9] Small intestine WCE Retrospective 90.7, 79.8, NA Tsuboi [30] Small intestine WCE Retrospective 98.8,98.4,NA Klang [34] Small intestine WCE Retrospective 96.8, 96.6, 96.7 Yamada [33] Colon CCE Retrospective 79.0,87.0,83.9 Laiz [32] Colorectum WCE Retrospective 51.2, 99.5, 99.4 Zhou [10] Colorectum WLI Retrospective 99.0, NA, NA Lee [11] Colorectum WLI Retrospective 96.7, NA, NA Wang [6] Esophagus WLI NBI Pilot 96.2, 70.4, 90.9 Struyvenberg [7] Esophagus NBI Retrospective 88, 78,84 Wang [6] Esophagus WLI NBI Pilot 96.2,70.4,90.9 Uema [20] Esophagus NBI Retrospective 86.2, 97.8, 86.3 Wu [13] Stomach WLI Prospective 100, 84.3, 84.7 Xu [14] Stomach IEE Prospective 96.7, 73.0, 87.8 Bora [24] Colon WLI NBI Retrospective 95.3, 95.0, 95.7 Udristoiu [29] Colon CLE Retrospective 94.6, 92.8, 95.3 Lai [25] Colorectum WLI NBI Retrospective 93, 100, 95 Gutierrez [28] UC WLI Retrospective AUC 0.85 Seven [26] GIST EUS Retrospective 99.7, 99.7, 99.6 Yao [27] Bile duct EUS Retrospective 89.5, 82.3, 93.3 Caroppo [31] GI WCE Retrospective 98.7, 97.3, 98.2 Sens, sensitive; Spec, specificity; Acc, accuracy; WLI, white-light imaging; NA, not available; NBI, narrow-band imaging; ME-NBI, magnifying endoscopy narrow-band imaging; WCE, wireless capsule endoscope; IEE, image-enhanced endoscopy; CLE, Confocal laser endoscopy; GIST, gastrointestinal stromal tumor; EUS, Endoscopic ultrasonography; UC, ulcerative colitis; AUC, area under curve; GI, gastrointestinal tract Application of DL in digestive system imaging Computed tomography Patients with cirrhosis were proposed for screening esophageal and gastric varices by gastroscopy. The invasive procedure may bring bleeding and other risks. Therefore, some studies suggested that platelet count, spleen length, and platelet count ratio to spleen length should be used to determine the shunt degree of esophageal varices to evaluate the risk of varices in patients as a non-invasive examination [36]. Ma’s team used DL to assess the CT volume of the liver and spleen in patients with hepatitis B virus-related cirrhosis, combined with patients’ platelet ratio, to perform a computer-intelligent assessment of patients’ varicose veins risk [37]. Zhang et al. established a 3D learning network to evaluate models from a data set of CT images collected from three medical centers, achieving promising performance in gastric tumor edge segmentation and lymph node classification [38]. Another study established a dual-energy computed tomography (DECT) radiology DL model [39]. The predictive value of its response to chemotherapy was analyzed to predict patients’ treatment response during chemotherapy, which may help adjust treatment strategies in time through semi-automatic segmentation of advanced gastric cancer. Due to the small sample size, performing a performance analysis for each chemotherapy regimen was impossible. The DL system developed by Jiang’s research team can predict occult peritoneal metastasis of gastric cancer preoperatively by analyzing CT images, thus reducing the risk of blindly performing extensive total gastrectomy [40]. The next research direction may be the judgment of peritoneal metastasis after neoadjuvant chemotherapy and the DL of 3D images of other tumors. DL also plays a role in the interpretation of CT in patients with cystic pancreatic lesions [41], pancreatic neuroendocrine tumors [42], and pancreatic cancer [43]. It can also achieve automatic localization and boundary segmentation of the pancreas in CT [44]. Due to the high degree of malignancy, patients with pancreatic cancer present irregular contours and unclear periphery in CT, leading to difficulties in demarcation with surrounding tissues. Besides, it is challenging to label CT images manually because of the complex anatomy around the pancreas. Liu et al. artificially labeled CT images of pancreatic cancer enhanced the data exploitation degree by moving and flip images and reduced the number of convolutional layers to reduce the model’s complexity [43]. Besides, he limited the pixel size to 50 × 50 to avoid too small plaques to contain sufficient information about the relationship between the tumor and adjacent tissue or too large to increase the unrelated image interference. As a result, the diagnosis of pancreatic cancer in patients of different races has a high AUROC. Magnetic resonance imaging Compared with CT, there are few DL studies on magnetic resonance imaging (MRI). Most current research has focused on the diagnosis of liver, pancreatic, and rectal diseases, such as liver cancer [45], liver fibrosis [46], liver fat segmentation [47], pancreatic tumors [48], rectal cancer [49], etc. Abdominal organ segmentation and fat segmentation are the advantages of MRI. Automatic segmentation of high-risk organs has important application value in MRI-guided radiotherapy. The robotic abdominal multi-organ segmentation technology developed by Chen’s team can accurately segment the nine abdominal organs with fewer parameters, and the duodenum segmentation should be further improved [50]. The quantification of human adipose tissue depots can help doctors understand a patient’s health. Belly fat has been linked to high blood pressure, inflammation, and type 2 diabetes [51]. Langner’s multi-center study demonstrated the robustness of their DL model in fat quantification [52]. In recent years, studies have found interactions and pathological similarities between IBD and metabolic disorders, including metabolic tissue disorders, inadequate immune response, and inflammatory response [53]. Patients with non-alcoholic fatty liver diseases (NAFLD) or a high body fat percentage are at higher risk for IBD [54, 55]. Combined with the patient’s clinical symptoms, MRI fat quantification could be applied to CAD of IBD and diabetes in future. Positron emission tomography Positron emission tomography (PET) imaging is commonly used in clinical oncology for diagnosis, staging, restaging, and monitoring of treatment response [56]. Image quality is crucial for visual interpretation and quantitative analysis [57]. Outside the receiving energy window, Scattered photons can be ignored and cause attenuation. In the receiving energy window, the path variation of photon scattering needs to be corrected. Attenuation or scattering events result in local decrease or increase of detection count, which leads to underestimation or overestimation of tracer uptake, respectively. Resulting in decreased image contrast and quantization error. Thus, image contrast is reduced, and quantization error is caused. In PET imaging analysis, CNN has been applied to image reconstruction [58] and image denoising [59]. These technologies will help radiologists produce more accurate PET images without obtaining CT images. While earlier studies were limited to the brain, current studies tend to look at whole-body scans. Shiri and Mostafapour's DL model can automatically correct attenuation and scatter in PET images [60, 61]. The most conspicuous advantage of their systems is that they did not require pre-entry of anatomical information. Nevertheless, they were susceptible to artifacts, leading to misjudgment of organ boundaries, especially between lungs and livers, abdomen, and pelvis. To avoid misjudgment in whole-body dynamic PET, appropriate function and kinetic models are required, along with whole-body motion correction. In digestive system, PET images are used to help detect lesions in liver CT scans. Using a combination of the generative adversarial network (GAN) and whole convolutional network (FCN) to generate PET images from CT scans, a research team reduced the false positive rate by 28% [62]. Wang et al. introduced a Gan-based method for generating high-quality PET images in low-dose tracers, thereby reducing the risk of radioactive isotopes [63]. They introduced a progressive refinement scheme based on 3D to improve the quality of image display. Ultrasound Although MRI is accurate and non-invasive, the cost of using MRI to assess liver fat is high, so some research teams want to quantify liver fat by ultrasound. For example, Byra et al. used MRI to obtain the proton density fat fraction (PDFF) of patients and then matched the ultrasound images for the training model, achieving qualified diagnostic accuracy [64]. Ultrasound is the front line of screening for abdominal diseases. At present, the research on the application of DL in ultrasound is gradually increasing. Yang’s team created a mouse model of intestinal inflammation to collect micro-ultrasound (μ US) images of the cecum, small intestine, and colon. Three DL networks were trained to distinguish between healthy tissue and early inflammation tissue [65]. A prospective five-center study using DL from ultrasound videos of biliary atresia achieved higher diagnostic accuracy than human experts. The research team has also developed a mobile APP by DL of ultrasound pictures, enabling rural doctors in remote areas to perform CAD by taking and uploading photographs of suspected biliary atresia [66]. Hepatic cystic echinococcosis is still endemic in some areas. Hepatic cystic echinococcosis has five subtypes [67]. The ultrasonic appearance may change naturally over time or in response to treatment, making diagnosis difficult [68]. Although microscopic examination after surgical treatment is the gold standard for diagnosing subtypes and stages of hepatic cystic echinococcosis, accurate ultrasound diagnosis is of great value for patients who can be cured with medical treatment [69]. Wu et al. used three types of CNNs for DL, and because the architecture and features extraction was different, the final result was not wholly consistent. The three systems complement each other further to improve the accuracy of the model’s accuracy and ultimately enable the exact classification of hepatic cystic echinococcosis under ultrasound [70]. Ultrasonography(US) has crucial diagnostic value for benign and malignant lesions of the liver. Due to the low contrast between lesions and normal liver tissue, the diagnosis of solid lesions is a challenge. Ryu et al. used 4309 US images with focal liver disease, including liver cysts, hemangioma, metastasis, and hepatocellular carcinomas, for DL and precise segmentation and classification of focal liver lesions [71]. Contrast-Enhanced Ultrasound (CEUS) can allow real-time scanning and provide dynamic perfusion information, so it has the potential to surpass CT and MRI in liver and gallbladder diseases [72, 73]. Hu’s CEUS system can assist young ultrasound physicians to achieve higher diagnostic sensitivity for liver tumors diagnosis [74]. Imaging is an essential method for the diagnosis of liver diseases. With CT, MRI, and ultrasound, clinicians can accurately determine whether a patient has liver fibrosis, cirrhosis, non-alcoholic fatty liver disease (NAFLD), benign tumors, or hepatocellular carcinoma (HCC). With the development of next-generation sequencing and multi-omics tools, precision medicine can help doctors more comprehensively understand the health status of patients [75, 76]. In future, omics information can be integrated into imaging data to facilitate the development of precision medicine, provide professional health care strategies for patients with sub-health, and design the best diagnosis and treatment plan for patients [77] (Table 2).Table 2 Application of AI in digestive system imaging Author year Organ Imaging modality Study design Best results: Sens/Spec/Acc% Roth [44] Pancreas CT Retrospective DSC 81.3 Corral [48] Pancreas MRI Retrospective 92, 52, NA Langner [52] Abdomen MRI Retrospective DSC 0.99 Tan [39] Stomach DECT Retrospective AUC 0.828 Zhang [49] Rectum MRI Retrospective AUC 0.99 Hectors [46] Liver MRE Retrospective AUC 0.99 Liu [43] Pancreas CT Retrospective 97.3, 100, 98.6 Watson [41] Pancreas CT Pilot NA, NA, 88.9 Lee [37] Spleen CT Retrospective 69.4, 78.5, NA Chen [50] Abdomen MRI Retrospective DSC 0.96 Zhang [38] Liver Enhanced CT Retrospective NA, 61.6, 80.5 Zhang [45] Liver MRI Retrospective 55, 81, 71 Jimenez [47] Liver MRI Retrospective DSC 0.93 Byra [64] Liver US Retrospective 83, 88, 85 Ryu [71] Liver US Retrospective 95.0, 86.0, 89.8 Hu [74] Liver CEUS Retrospective 92.7, 85.1, 91.0 Zhou [66] Gallbladder US Retrospective 88.2, 89.8, 89.4 Huang [42] Pancreas CT Retrospective 86, 100, 91 Jiang [40] Abdomen CT Retrospective 87.5, 98.2, NA Sens, sensitive; Spec, specificity; Acc, accuracy; CT, computed tomography; NA, not available; DECT, dual-energy computed tomography; DSC, dice similarity coefficient; MRI, magnetic resonance imaging; MRE, magnetic resonance elastography; AUC, area under curve; US, ultrasound; CEUS, contrast-enhanced ultrasound Application of AI in digestive pathology Pathology biopsy is the golden standard for diagnosing benign or malignant diseases of the digestive tract, but the number of pathologists is relatively small, so DL can effectively reduce pathologists’ workload. In recent studies, images at different amplification ratios were extracted from standardized HE staining specimens, and affine transformations were used to make up for deficiencies in data sets. Then, whole slide image (WSI) learning could be done by using these pictures. Standardized images have the advantage of removing stained samples, but retrospective studies can also lead to selective bias, and different staining conditions can affect CAD diagnoses. There have been retrospective studies on DL in the pathological diagnosis and prognosis analysis of Helicobacter pylori gastritis [78], rectal cancer [79], pancreatic tumors [80], gastrointestinal, and endocrine tumors [81]. Prospective, multi-center, and large-scale trials have also begun to verify these algorithms’ usability [82]. However, these studies generally have the problem of low interpretative ability for the results of CAD. The DL system developed by Ma et al. can distinguish between normal gastric mucosa, chronic gastritis, and gastric cancer. They used visualization techniques to display the DL model’s content and revealed how the AI program extracted gastric mucosal lesions’ morphological characteristics at different stages. Eventually, gastric cancer progression was revealed, and the effects of the CAD black box were attenuated [83]. The number of metastatic lymph nodes is an essential determinant of the TNM staging of gastrointestinal malignant tumors and is also one of the most critical factors in evaluating gastric cancer prognosis. The clinical-pathological diagnosis of lymph nodes is influenced by subjective factors and requires much time and effort [84]. Pan’s and Ding’s DL system can quickly detect the number of esophageal and rectal lymph node metastases in a large field of vision. However, as their system only supports rectangular annotation, its robustness is deficient in small detection objects or complex contours [85]. Hu’s model was improved on this basis, achieved excellent contour segmentation of a single lymph node, thus effectively improved the lymph node’s quantification accuracy [86]. Wang et al. have come up with a DL framework to analyze patients’ gastric carcinoma lymph node WSI. The system can accurately identify and divide the area of lymph nodes, then reveal the tumor area’s ratio and mesenteric lymph nodes area to predict patients’ prognosis. The system even found several poorly differentiated tumor cells missed by pathologists [87]. Kwak’s team also used WSI for the DL of lymph node metastasis in patients with colorectal cancer. They found that the peri-tumoral stroma (PTS) score was a reference for predicting the number of lymph node metastases [88]. A large sample of prospective studies recently investigated the DL system’s application in the pathological diagnosis of gastric cancer. The algorithm achieved 100% sensitivity and 97% specificity for gastric epithelial-derived tumors, and the vast majority of false positives were due to ulcers or inflammation [89]. However, the system often mistakenly identified GIST as atypical hyperplasia because there was no targeted dataset for non-epithelial tumors. Therefore, it is still worthwhile to establish a new learning model for mesenchymal tumors. The evaluation of surgical margins is inseparable from the prognostic analysis. However, due to the excessively large resolution of WSI images, prognostic analysis based on WSI is often costly [90]. It is promising to divide the whole WSI into small pieces and then automatically analyze the prognosis of patients through DL. While the edge between tumors and normal tissues can be delineated artificially, labeled tumor areas can also contain normal tissues. Pixel-level annotation can alleviate this problem, but it is a drain on the pathologist's energy. Saillard et al. extracted regions randomly for manual marking to patch the DL system. They found that vascular spaces, the macrotrabecular architectural pattern, and a lack of immune infiltration suggested a poor prognosis of HCC. Although highlighting these areas can increase the accuracy of their system, it still does not utilize all pathological information [91]. Weakly supervised learning (WSL) utilizes easily available image-level annotations to infer pixel-level information automatically. Pathologists label WSI as cancer as long as a small portion of the image contains the cancerous area without specifying its exact location, greatly reducing pathologists' annotation burden and particularly applicable to the field of histopathology. Pathologists only need to mark WSI lesion types, but do not need to specify the exact location of cancer cells [92]. Shao et al. divided WSI into about 1000 patches with the size of 512*512 pixels and then used WSL to conduct DL recognition on all images. So as to fully obtain background information of pathological images. The effectiveness of the WSI level inpatient prognosis assessment was validated in three cancer datasets from the Cancer Genome Atlas (TCGA) [93]. Due to the large size of WSI images and the small proportion of lesions in some cases, image-level labels make automatic diagnosis difficult. Recalibrated multi-instance deep learning method (RMDL) can automatically find the key instances. The high-precision positioning network and recalibrated multi-instance learning were optimized, and the accuracy reached 86.5% [94]. Hyperspectral imaging (HSI) is a non-contact, non-contrast, non-invasive optical imaging technique that provides the analyzed region's pixel spectral and spatial information. It has been applied to both gastric and colorectal cancer. Jansen-Winkeln combined HSI with AI technology to intelligently distinguish colorectal cancer or adenomas from healthy mucosa on specimens. Besides, they used visualization techniques to help clinicians understand the mind of computers [95]. In future, with increased time efficiency, the technology may be used in the operating room on freshly removed specimens or even integrated into the laparoscope to help surgeons determine the extent of lymph node dissection in real-time. In one study, 12 specimens of GIST were irradiated with near-infrared (NIR). NIR irradiation transparency distinguished the specific HSI information of GIST, and the lesion range of GIST was predicted by ML [96]. This technique may be utilized in the prediction of all submucosal tumors in future. However, light is often affected by the specimen’s thickness, and the training set is sometimes too small. (Table 3).Table 3 Application of AI in digestive pathology Author year Organ Imaging modality Study design Best results: Sens/Spec/Acc% Pan 2020 [85] Esophagus HE WSI Retrospective 99.2, 93.0, 94.0 Martin 2020 [78] Stomach HE WSI Retrospective 100, 98.3, 98.9 Ma 2020 [83] Stomach HE WSI Retrospective 98.0, 98.9, 98.4 Klimov 2020 [80] Pancreas HE WSI Retrospective 94, 100, 100 Sato 2020 [96] GIST NIR-HSI Retrospective 91.3, 73.0, 86.1 Govind 2020 [81] GI DS WSI Retrospective NA, NA, 98.4 Hu 2021 [86] Stomach HE WSI Retrospective PPV: 93.5, NPV: 98.0 Wang 2021 [87] Stomach HE WSI Retrospective 98.5, 96.1, 96.9 Park 2021 [89] Stomach HE WSI Prospective 100, 97.5, 96.0 Wang 2021 [82] Colorectum HE WSI Retrospective 97.0, 99.2, 96.1 Jansen 2021 [95] Colorectum HSI Retrospective 86, 95, NA Liu 2021 [79] Rectum HE WSI Retrospective AUC 0.88 Sens, sensitive; Spec, specificity; Acc, accuracy; HE, hematoxylin ered; WSI, whole slide images; GIST, gastrointestinal stromal tumor; GI, gastrointestinal tract; DS, double-immunostained; NA, not available; PPV, positive predictive value; NPV, negative predictive value; HIS, Hyperspectral imaging; NIR-HIS, near-infrared hyperspectral imaging; AUC, area under curve Major techniques and Issues DL is a kind of ML technique that can recognize highly complex patterns in large data sets. As mentioned above, DL can be broadly divided into supervised learning and unsupervised learning. The most popular architectures in supervised learning are CNN and recurrent neural network(RNN) (Fig. 2). In addition, there are also spatial convolutional network (SCN), temporal convolutional network (TCN), and Spatio-temporal attention convolutional network (STACN), which are, respectively, used to extract the appearance information of RGB images, capture the motion information of flow fields and learn the appearance information of areas with significant attention to motion [97]. The latter three methods are used relatively infrequently in medicine.Fig. 2 Node graphs of architectures commonly used in medical imaging. a convolutional neural network, b recurrent neural network, c Auto-encoder, d multi-stream convolutional neural network.( Adapted from Litjens’ survey) CNN is mainly composed of alternating convolutional layer and pooling layer, and each layer contains trainable filter banks [98]. CNN can continuously learn abstract features and integrate them into the full connection layer to calculate local weights and generate output values, thus completing tasks [99]. In this paper, many studies described above designed and optimized systems by modifying the number of cores, channels, or filter sizes. A typical chief underlying mathematical implementation expressions of CNN [98]:1 yn=xn∗ωn=∑m=-∞∞xmωn-m, 2 Yi,j=Xi,j∗ωi,j=∑m∑nXm,nωi-m,j-n. RNN are designed for discrete sequence analysis. Each point in the sequence generates an internal signal fed through the neural network to the next layer. Hidden layers preserve information in the observed sequence and updates it in real-time [100]. Medical reports are typically processed by RNN. To integrate information from medical reports, it is often necessary to include a hybrid network combining. A typical chief underlying mathematical implementation expressions of RNN [100]:3 alt=flnlt; 4 n1t=IW1,1pt;pt-1;…pt-TDLin+LW1,1a1t-1;…a1t-TDLint+LW1,2a2t-1;…a2t-TDLint+LW1,3a3t-1;…a3t-TDLout+b_1; 5 n2t=LW2,1a1t+LW2,2a2t-1;…a2t-TDLint+LW2,3a3t-1;…a3t-TDLint+b_2; 6 n3t=LW2,2a2t+LW3,3a3t-1;…a3t-TDLint+c_. Although most studies are based on supervised learning with per-pixel annotation, WSL with image-level labels and even unsupervised learning has high application value. WSL uses labeled data to train the entire network and unlabeled data to train encoders and decoders [101]. Original data for unsupervised learning come in the form of images without any expert-annotated labels. A common technique in unsupervised learning is converting input data into low-dimensional subspaces and then grouping. The most common method of unsupervised learning is GAN. GAN has been widely used in medical imaging, such as denoising, modal transfer, anomaly detection, and image synthesis [102]. In addition, unsupervised learning also includes Auto-Encoders (AEs), stacked auto-encoders (SAEs), restricted Boltzmann machines (RBMs), deep belief networks (DBNs), and variational auto-encoders (VAE) [103]. AEs can reduce nonlinear dimensionality reduction, find compressed raw information in the network and reenter the low-dimensional space [104]. These techniques have rarely been used in medicine, but because unsupervised learning allows for network training using large amounts of unlabeled data and the best use of information, it may have broad applications in future. A typical chief underlying mathematical implementation expressions of GAN [12]:7 minGmaxDφD,G=ExlogDx+Ezlog1-DGz, 8 FBiφj,ϕ=argkminGφj,ϕk, 9 SBi=1|Bi|∑j=1BiFBiφj,ϕ. A typical chief underlying mathematical implementation expressions of AEs [103]:10 h=σwx,hx+bx,h. A typical chief underlying mathematical implementation expressions of RBM [103]:11 Ex,h=hTWx-cTx-bTh, 12 px,h=1Zexp-Ex,h. 13 Phj|x=11+exp-bj-Wjx. Transfer learning(TL) can fine-tune or retrain the original DL model by using new annotations. Tajbakhsh demonstrated that pre-trained CNN with fine-tuning is superior to CNN trained from scratch CNN [105]. Fine-tuning can significantly reduce costs than retraining. When ideal training sets are small, TL can bring greater performance improvement. So far, most approaches have started pre-training with natural image data. It may be possible to design cross-domain data sets in future, for example, using TL between CT, MRI, ultrasound, and PET. Active learning (AL) can be learned in an interactive environment by selecting learning strategies through trial and error. The system tries to achieve its goals based on feedback from its own behavior and experience. At present, no application of AL in the digestive system has been found, which may be due to the high inherent coupling between AL selection strategies and the model being trained. These results in later data sets that may not be conducive to model training [106]. Overview Applications of DL in medicine AI is becoming increasingly valuable in the early diagnosis of digestive tract diseases. DL systems can significantly reduce the workload of clinicians and maintain high diagnostic accuracy and systematic robustness. As the public dataset expands, more and more high-quality algorithms will be discovered. However, Large sample prospective studies are needed to verify the effectiveness of the algorithm. Although DL has been extensively studied in the image processing of endoscopy, imaging, and pathology of gastrointestinal tract diseases, each auxiliary diagnostic method has its limitations. At present, there is still a lack of a CAD system that can comprehensively recognize the image data of different auxiliary examinations. This review lists progresses of DL in different auxiliary examinations, hoping that the data of different auxiliary examinations can be integrated to improve diagnosis accuracy one day. What AI can bring us better identifying endoscopic images or pathological data from a single angle, but perhaps its most outstanding value is that it can help us break through the traditional thinking patterns, transcend the fixed diagnosis ideas, and give us a broader explorative space. Shortly, AI may help us implement diagnosis and treatment methods more flexibly, achieve disciplines integration more thoroughly, and evaluate conditions more comprehensively. AI can create infinite possibilities for our future. Aslam studied the characteristics of exhaled gas compounds in patients with gastric cancer through CNN analysis, and the diagnostic accuracy of early and advanced gastric cancer reached 97.3% and 98.7, respectively [107]. With the development of computer technology and the iteration of CNN, we will use computers to find more non-invasive examination items in future. Xiao led a prospective multi-center study using a slit lamp to conduct DL on the fundus and iris of patients with several common liver diseases and finally achieved excellent results in identifying liver cancer and chronic cirrhosis. In future, ophthalmology imaging may be used as a tool for the early screening of liver and biliary diseases [108]. This project is innovative because linking two seemingly distant organs together, allows this kind of interdisciplinary computer-aided research to discover biological phenomena that have not been discovered before. COVID-19 has become a serious public problem, and companies are racing to develop drugs. Recently, Li's research team used DL models to predict drug-induced liver injury, thereby reducing the cost of clinical drug development and testing [109]. In future, when facing unacquainted sudden diseases, we can also adopt DL technology to input disease information and let the computer judge the patient's condition, treatment, and prognosis. AI has shown its superiority in the early diagnosis of gastrointestinal diseases. However, if clinicians rely too much on AI, the images under a specific condition may be repeatedly missed due to the algorithm’s limitations or data set. AI will help clinicians discover the potential links between diseases and comprehensively assess the patient's condition and prognosis, but it also requires clinicians to continuously accept, learn, and improve this new technology. Besides, Wong comprehensively evaluated non-alcoholic fatty liver disease severity based on clinical information, including electronic health records, liver biopsies, and liver images [110]. In future, AI health assessment of patients may not be limited to cross-sectional studies. Still, it can collect patients’ dynamic data in more detail to conduct intelligent analysis to obtain professional suggestions with solid persuasion. Characteristics and Challenges of DL in medicine Medical image analysis has three main tasks: disease diagnosis, lesions detection, and lesions and organs segmentation. It also includes other related tasks, such as image reconstruction, image retrieval, and report generation. The digestive field emphasizes the ability to recognize abnormalities, such as polyps and early cancer. Since medicine is a human-facing science, DL has its own characteristics and challenges in medical image processing compared with other CV scenarios. Characteristics Physiological structures are often irregular and disordered, making it difficult to conceptualize them as matrices. There are multiple stages, such as precancerous lesions, between the tumor and normal tissue. Medical judgment is subjective and may vary from doctor to doctor, requiring extensive expert annotations to reach a consensus. Image recognition is obviously interfered with by viewpoint, noise, background motion, and illumination changes [111]. In medicine, diagnosis often needs reference background information to achieve higher accuracy. The use of implicit information in biological systems has attracted great attention. The compatibility of the DL system between hospitals needs special attention. Different light sources, resolutions, doctors' skills, and examination habits may affect judgment accuracy. Medicine values the prediction of causal effects in order to evaluate the curative effects in time. Genomics will be more widely used in future, and DL will become a daily tool for analysis [112]. Medical images require high resolution, which makes image analysis costly and time-consuming. DL models can be trained using cloud computing in future, with instances deployed on different sites and trained on local data while sharing standard parameters, enabling the use of multiple GPUs at a reasonable cost and promoting respect for medical data privacy. Challenges:Most DL applications are considered to be a "black box". Users are tough in explaining, understanding, or correcting how the model makes predictions. The system needs to explain prediction conclusions further to gain the trust of doctors and patients. Where is the application boundary of AI? The abuse of DL may infringe personal privacy, disturb natural law, and violate ethic. For example, what should a doctor do when the AI decides that abandoning treatment is the best option? In health security, minor errors can lead to catastrophic results. How to further improve the accuracy is always the challenge and pursuit of engineers. In the classification training of rare diseases, overfitting will occur if the sample number of one class is much larger than another class. Computer vision techniques can solve the overfitting problem. However, model complexity reduction and data enhancement techniques focus only on the target task on a given data set without introducing new information into the DL model. Today, introducing more information beyond a given medical data set has become a promising approach to solving the problem of small medical data sets. In addition to broader collaboration, enhanced data extraction using unsupervised learning and integration using different DL techniques are likely to mitigate this problem. Restriction on AI’s clinical application Currently, restriction on AI’s clinical application has three key factors: first, the compatibility of each system; second, daily maintenance and fault handling of the DL system; third, the legal liability. When the test is false, these errors involving computer knowledge are often difficult to be explained by doctors’ experience alone, so who should be responsible for this during the clinical process? Therefore, more multi-center prospective studies should be conducted in future. Relevant laws and regulations should be improved to translate scientific and technological achievements into practical applications. The current limitation of AI in the digestive system image has its particularity: 1. Digestive endoscopy plays a significant role in clinical diagnosis and treatment. Inadequate intestinal preparation will affect image recognition and misdiagnose debris as the tumor. 2. While AI can serve as a second set of eyes for endoscopic physicians. There are still misdiagnosis rates to overcome. 3. The determination of tumor invasion depth depends on EUS, but the accuracy is limited. It is difficult to accurately distinguish the origin of tumors, which challenges the selection of surgical methods. 4. Blind spot is a vital factor leading to a missed diagnosis. It is necessary to develop further DL systems that can automatically prompt blind spots. 5. Digestive system covers a large number of organs and has high requirements for lesion localization in imaging. Currently, some systems can accurately achieve organ segmentation, but the localization inside organs is not accurate enough. 6. In the endoscopy process, rapid determination of polyp or tumor properties has high application value, but there is still a long way to go. Conclusion DL will be widely used in the medical field in the near future, especially for image recognition. CAD can significantly narrow the technical gap between physicians, reduce work pressure, and improve patients’ experience. However, there are many technical, ethical, and legal hurdles to overcome before AI is finally used in clinical practice. Authors’ contribution JXZ and HMZ analyzed the data, prepared the tables, and drafted the manuscript. HMZ and FL designed the project and finalized the manuscript. All authors assisted with reference collection and the reorganization and partial data analysis. All authors read and approved the final manuscript. Funding No. Declarations Conflict of interest The authors declare no competing interest. Availability of data and material Available. Consent for publication Yes. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Huangming Zhuang and Jixiang Zhang authors contributed equally to this work. ==== Refs References 1. Min JK Kwak MS Cha JM Overview of deep learning in gastrointestinal endoscopy Gut Liver. 2019 13 4 388 393 10.5009/gnl18384 30630221 2. Tizhoosh HR Pantanowitz L Artificial intelligence and digital pathology: challenges and opportunities J. Pathol. Inform. 2018 10.4103/jpi.jpi_53_18 3. Pannala R Krishnan K Melson J Parsi MA Schulman AR Sullivan S Artificial intelligence in gastrointestinal endoscopy VideoGIE. 2020 5 12 598 613 10.1016/j.vgie.2020.08.013 33319126 4. Jisu, H., Bo-Yong, P., Hyunjin, P.: Convolutional neural network classifier for distinguishing Barrett's esophagus and neoplasia endomicroscopy images. Annu Int Conf IEEE Eng Med Biol Soc. 2892–2895 (2017) 10.1109/EMBC.2017.8037461 5. Le Berre C Sandborn WJ Aridhi S Devignes M Fournier L Smaïl-Tabbone M Application of artificial intelligence to gastroenterology and hepatology Gastroenterology 2020 158 1 76 94 10.1053/j.gastro.2019.08.058 31593701 6. Wang YK Syu HY Chen YH Chung CS Tseng YS Ho SY Endoscopic images by a Single-Shot multibox detector for the identification of early cancerous lesions in the esophagus: a pilot study Cancers (Basel) 2021 10.3390/cancers13020321 7. Struyvenberg MR de Groof AJ van der Putten J van der Sommen F Baldaque-Silva F Omae M A computer-assisted algorithm for narrow-band imaging-based tissue characterization in Barrett's esophagus Gastrointest. Endosc. 2021 93 1 89 98 10.1016/j.gie.2020.05.050 32504696 8. Zhang Y Li F Yuan F Zhang K Huo L Dong Z Diagnosing chronic atrophic gastritis by gastroscopy using artificial intelligence Dig. Liver Dis. 2020 52 5 566 572 10.1016/j.dld.2019.12.146 32061504 9. Saito H Aoki T Aoyama K Kato Y Tsuboi A Yamada A Automatic detection and classification of protruding lesions in wireless capsule endoscopy images based on a deep convolutional neural network Gastrointest. Endosc. 2020 92 1 144 151 10.1016/j.gie.2020.01.054 32084410 10. Zhou G Xiao X Tu M Liu P Yang D Liu X Computer aided detection for laterally spreading tumors and sessile serrated adenomas during colonoscopy PLoS ONE 2020 15 4 e231880 10.1371/journal.pone.0231880 11. Lee JY Jeong J Song EM Ha C Lee HJ Koo JE Real-time detection of colon polyps during colonoscopy using deep learning: systematic validation with four independent datasets Sci. Rep. 2020 10 1 8379 10.1038/s41598-020-65387-1 32433506 12. de Souza LJ Passos LA Mendel R Ebigbo A Probst A Messmann H Assisting barrett's esophagus identification using endoscopic data augmentation based on generative adversarial networks Comput. Biol. Med. 2020 10.1016/j.compbiomed.2020.104029 13. Wu L He X Liu M Xie H An P Zhang J Evaluation of the effects of an artificial intelligence system on endoscopy quality and preliminary testing of its performance in detecting early gastric cancer: a randomized controlled trial Endoscopy 2021 10.1055/a-1350-5583 14. Xu M Zhou W Wu L Zhang J Wang J Mu G Artificial intelligence in diagnosis of gastric precancerous conditions by image-enhanced endoscopy: a multi-center, diagnostic study (with video) Gastrointest. Endosc. 2021 10.1016/j.gie.2021.03.013 15. Iakovidis DK Georgakopoulos SV Vasilakakis M Koulaouzidis A Plagianakos VP Detecting and locating gastrointestinal anomalies using deep learning and iterative cluster unification IEEE Trans. Med. Imaging. 2018 37 10 2196 2210 10.1109/TMI.2018.2837002 29994763 16. Mahmood F Chen R Durr NJ Unsupervised reverse domain adaptation for synthetic medical images via adversarial training IEEE Trans. Med. Imaging. 2018 37 12 2572 2581 10.1109/TMI.2018.2842767 29993538 17. Ozyoruk KB Gokceler GI Bobrow TL EndoSLAM dataset and an unsupervised monocular visual odometry and depth estimation approach for endoscopic videos Med. Image Anal. 2021 71 102058 10.1016/j.media.2021.102058 33930829 18. Itoh H Oda M Mori Y Unsupervised colonoscopic depth estimation by domain translations with a Lambertian-reflection keeping auxiliary task Int. J. Comput. Assist. Radiol. Surg. 2021 16 6 989 1001 10.1007/s11548-021-02398-x 34002340 19. Hwang SJ Park SJ Kim GM Baek JH Unsupervised monocular depth estimation for colonoscope system using feedback network Sensors (Basel). 2021 21 8 2691 10.3390/s21082691 33920357 20. Uema R Hayashi Y Tashiro T Saiki H Kato M Amano T Use of a convolutional neural network for classifying microvessels of superficial esophageal squamous cell carcinomas J. Gastroenterol. Hepatol. 2021 10.1111/jgh.15479 21. Hu H Gong L Dong D Zhu L Wang M He J Identifying early gastric cancer under magnifying narrow-band images with deep learning: a multi-center study Gastrointest. Endosc. 2021 93 6 1333 1341.e3 10.1016/j.gie.2020.11.014 33248070 22. Bray F Ferlay J Soerjomataram I Siegel RL Torre LA Jemal A Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J. Clin. 2018 68 6 394 424 10.3322/caac.21492 30207593 23. le Clercq CM Bouwens MW Rondagh EJ Bakker CM Keulen ET de Ridder RJ Postcolonoscopy colorectal cancers are preventable: a population-based study Gut 2014 63 6 957 963 10.1136/gutjnl-2013-304880 23744612 24. Bora K Bhuyan MK Kasugai K Mallik S Zhao Z Computational learning of features for automated colonic polyp classification Sci. Rep. 2021 11 1 4347 10.1038/s41598-021-83788-8 33623086 25. Lai LL Blakely A Invernizzi M Lin J Kidambi T Melstrom KA Separation of color channels from conventional colonoscopy images improves deep neural network detection of polyps J. Biomed. Opt. 2021 10.1117/1.JBO.26.1.015001 26. Seven G Silahtaroglu G Kochan K Ince AT Arici DS Senturk H Use of artificial intelligence in the prediction of malignant potential of gastric gastrointestinal stromal tumors Dig. Dis. Sci. 2021 10.1007/s10620-021-06830-9 27. Yao L Zhang J Liu J Zhu L Ding X Chen D A deep learning-based system for bile duct annotation and station recognition in linear endoscopic ultrasound EBioMedicine 2021 10.1016/j.ebiom.2021.103238 28. Gutierrez BB Arcadu F Thalhammer A Gamez SC Feehan O Drawnel F Training and deploying a deep learning model for endoscopic severity grading in ulcerative colitis using multicenter clinical trial data Ther. Adv. Gastrointest. Endosc. 2021 10.1177/2631774521990623 29. Udristoiu AL Stefanescu D Gruionu G Gruionu LG Iacob AV Karstensen JG Deep learning algorithm for the confirmation of mucosal healing in crohn's disease, based on confocal laser endomicroscopy images J. Gastrointestin. Liver Dis. 2021 30 1 59 65 10.15403/jgld-3212 33723558 30. Tsuboi A Oka S Aoyama K Saito H Aoki T Yamada A Artificial intelligence using a convolutional neural network for automatic detection of small-bowel angioectasia in capsule endoscopy images Dig. Endosc. 2020 32 3 382 390 10.1111/den.13507 31392767 31. Caroppo A Leone A Siciliano P Deep transfer learning approaches for bleeding detection in endoscopy images Comput. Med. Imaging Graph 2021 10.1016/j.compmedimag.2020.101852 32. Laiz P Vitria J Wenzek H Malagelada C Azpiroz F Segui S WCE polyp detection with triplet based embeddings Comput. Med. Imaging Graph 2020 10.1016/j.compmedimag.2020.101794 33. Yamada A Niikura R Otani K Aoki T Koike K Automatic detection of colorectal neoplasia in wireless colon capsule endoscopic images using a deep convolutional neural network Endoscopy 2020 10.1055/a-1266-1066 34. Klang E Barash Y Margalit RY Soffer S Shimon O Albshesh A Deep learning algorithms for automated detection of Crohn's disease ulcers by video capsule endoscopy Gastrointest. Endosc. 2020 91 3 606 613 10.1016/j.gie.2019.11.012 31743689 35. Incetan K Celik IO Obeid A Gokceler GI Ozyoruk KB Almalioglu Y VR-Caps: a virtual environment for capsule endoscopy Med. Image Anal. 2021 10.1016/j.media.2021.101990 36. Colli A Gana JC Yap J Adams-Webber T Rashkovan N Ling SC Platelet count, spleen length, and platelet count-to-spleen length ratio for the diagnosis of oesophageal varices in people with chronic liver disease or portal vein thrombosis Cochrane Database Syst. Rev. 2017 10.1002/14651858.CD008759.pub2 37. Lee CM Lee SS Choi WM Kim KM Sung YS Lee S An index based on deep learning-measured spleen volume on CT for the assessment of high-risk varix in B-viral compensated cirrhosis Eur. Radiol. 2021 31 5 3355 3365 10.1007/s00330-020-07430-3 33128186 38. Zhang Y Li H Du J Qin J Wang T Chen Y 3D multi-attention guided multi-task learning network for automatic gastric tumor segmentation and lymph node classification IEEE Trans. Med. Imaging. 2021 40 6 1618 1631 10.1109/TMI.2021.3062902 33646948 39. Tan JW Wang L Chen Y Xi W Ji J Wang L Predicting chemotherapeutic response for far-advanced gastric cancer by radiomics with deep learning semi-automatic segmentation J Cancer. 2020 11 24 7224 7236 10.7150/jca.46704 33193886 40. Jiang Y Liang X Wang W Chen C Yuan Q Zhang X Non-invasive prediction of occult peritoneal metastasis in gastric cancer using deep learning JAMA Netw. Open. 2021 4 1 e2032269 10.1001/jamanetworkopen.2020.32269 33399858 41. Watson MD Lyman WB Passeri MJ Murphy KJ Sarantou JP Iannitti DA Use of artificial intelligence deep learning to determine the malignant potential of pancreatic cystic neoplasms with preoperative computed tomography imaging Am. Surg. 2021 87 4 602 607 10.1177/0003134820953779 33131302 42. Huang B Lin X Shen J Chen X Chen J Li Z Accurate and feasible deep learning based semi-automatic segmentation in CT for radiomics analysis in pancreatic neuroendocrine neoplasms IEEE J. Biomed. Health Inform. 2021 10.1109/JBHI.2021.3070708 43. Liu KL Wu T Chen PT Tsai YM Roth H Wu MS Deep learning to distinguish pancreatic cancer tissue from non-cancerous pancreatic tissue: a retrospective study with cross-racial external validation Lancet Digit. Health. 2020 2 6 e303 e313 10.1016/S2589-7500(20)30078-9 33328124 44. Roth HR Lu L Lay N Harrison AP Farag A Sohn A Spatial aggregation of holistically-nested convolutional neural networks for automated pancreas localization and segmentation Med. Image Anal. 2018 10.1016/j.media.2018.01.006 45. Zhang Y Lv X Qiu J Zhang B Zhang L Fang J Deep learning with 3D convolutional neural network for non-invasive prediction of microvascular invasion in hepatocellular carcinoma J. Magn. Reson. Imaging. 2021 54 1 134 143 10.1002/jmri.27538 33559293 46. Hectors SJ Kennedy P Huang KH Stocker D Carbonell G Greenspan H Fully automated prediction of liver fibrosis using deep learning analysis of gadoxetic acid-enhanced MRI Eur. Radiol. 2021 31 6 3805 3814 10.1007/s00330-020-07475-4 33201285 47. Jimenez-Pastor A Alberich-Bayarri A Lopez-Gonzalez R Marti-Aguado D Franca M Bachmann R Precise whole liver automatic segmentation and quantification of PDFF and R2* on MR images Eur. Radiol. 2021 10.1007/s00330-021-07838-5 48. Corral JE Hussein S Kandel P Bolan CW Bagci U Wallace MB Deep learning to classify intraductal papillary mucinous neoplasms using magnetic resonance imaging Pancreas 2019 48 6 805 810 10.1097/MPA.0000000000001327 31210661 49. Zhang XY Wang L Zhu HT Li ZW Ye M Li XT Predicting rectal cancer response to neoadjuvant chemoradiotherapy using deep learning of diffusion kurtosis MRI Radiol. 2020 296 1 56 64 10.1148/radiol.2020190936 50. Chen Y Ruan D Xiao J Wang L Sun B Saouaf R Fully automated multiorgan segmentation in abdominal magnetic resonance imaging with deep neural networks Med. Phys. 2020 47 10 4971 4982 10.1002/mp.14429 32748401 51. Despres JP Lemieux I Abdominal obesity and metabolic syndrome Nature 2006 444 7121 881 887 10.1038/nature05488 17167477 52. Langner T Hedstrom A Morwald K Weghuber D Forslund A Bergsten P Fully convolutional networks for automated segmentation of abdominal adipose tissue depots in multi-center water-fat MRI Magn. Reson. Med. 2019 81 4 2736 2745 10.1002/mrm.27550 30311704 53. Michalak A Mosinska P Fichna J Common links between metabolic syndrome and inflammatory bowel disease: current overview and future perspectives Pharmacol. Rep. 2016 68 4 837 846 10.1016/j.pharep.2016.04.016 27238750 54. Kwon J Lee C Heo S Kim B Hyun CK DSS-induced colitis is associated with adipose tissue dysfunction and disrupted hepatic lipid metabolism leading to hepatosteatosis and dyslipidemia in mice Sci. Rep. 2021 11 1 5283 10.1038/s41598-021-84761-1 33674694 55. Carreras-Torres R Ibanez-Sanz G Obon-Santacana M Duell EJ Moreno V Identifying environmental risk factors for inflammatory bowel diseases: a Mendelian randomization study Sci. Rep. 2020 10 1 19273 10.1038/s41598-020-76361-2 33159156 56. Ben-Haim S Ell P 18F-FDG PET and PET/CT in the evaluation of cancer treatment response J. Nucl. Med. 2009 50 1 88 99 10.2967/jnumed.108.054205 19139187 57. Boellaard R Standards for PET image acquisition and quantitative data analysis J. Nucl. Med. 2009 50 Suppl 1 11S 20S 10.2967/jnumed.108.057182 19380405 58. Häggström I Schmidtlein CR Campanella G Fuchs TJ DeepPET: a deep encoder-decoder network for directly solving the PET image reconstruction inverse problem Med. Image Anal. 2019 54 253 262 10.1016/j.media.2019.03.013 30954852 59. Sanaat A Arabi H Mainta I Garibotto V Zaidi H Projection space implementation of deep learning-guided low-dose brain PET imaging improves performance over implementation in image space J. Nucl. Med. 2020 61 9 1388 1396 10.2967/jnumed.119.239327 31924718 60. Shiri I Arabi H Geramifar P Deep-JASC: joint attenuation and scatter correction in whole-body 18F-FDG PET using a deep residual network Eur. J. Nucl. Med. Mol. Imaging. 2020 47 11 2533 2548 10.1007/s00259-020-04852-5 32415552 61. Mostafapour S Gholamiankhah F Dadgar H Arabi H Zaidi H Feasibility of deep learning-guided attenuation and scatter correction of whole-body 68Ga-PSMA PET studies in the image domain Clin. Nucl. Med. 2021 46 8 609 615 10.1097/RLU.0000000000003585 33661195 62. Ben-Cohen A Klang E Raskin SP Soffer S Ben-Haim S Konen E Amitai MM Greenspan H Cross-modality synthesis from ct to pet using fcn and gan networks for improved automated lesion detection Eng. Appl. Artif. Intell. 2019 78 186–94 186 194 10.1016/j.engappai.2018.11.013 63. Wang Y Yu B Wang L 3D conditional generative adversarial networks for high-quality PET image estimation at low dose Neuroimage 2018 174 550 562 10.1016/j.neuroimage.2018.03.045 29571715 64. Byra M Han A Boehringer AS Zhang YN O'Brien WJ Erdman JJ Liver fat assessment in multiview sonography using transfer learning with convolutional neural networks J. Ultrasound Med. 2021 10.1002/jum.15693 65. Yang S Lemke C Cox BF Newton IP Nathke I Cochran S A learning-based microultrasound system for the detection of inflammation of the gastrointestinal tract IEEE Trans. Med. Imaging. 2021 40 1 38 47 10.1109/TMI.2020.3021560 32881684 66. Zhou W Yang Y Yu C Liu J Duan X Weng Z Ensembled deep learning model outperforms human experts in diagnosing biliary atresia from sonographic gallbladder images Nat. Commun. 2021 12 1 1259 10.1038/s41467-021-21466-z 33627641 67. Feng X Qi X Yang L Duan X Fang B Gongsang Q Human cystic and alveolar echinococcosis in the Tibet autonomous region (TAR), China J. Helminthol. 2015 89 6 671 679 10.1017/S0022149X15000656 26271332 68. Golemanov B Grigorov N Mitova R Genov J Vuchev D Tamarozzi F Efficacy and safety of PAIR for cystic echinococcosis: experience on a large series of patients from Bulgaria Am. J. Trop. Med. Hyg. 2011 84 1 48 51 10.4269/ajtmh.2011.10-0312 21212200 69. Dehkordi AB Sanei B Yousefi M Sharafi SM Safarnezhad F Jafari R albendazole and treatment of hydatid cyst: review of the literature Infect. Disord. Drug. Targets. 2019 19 2 101 104 10.2174/1871526518666180629134511 29956639 70. Wu M Yan C Wang X Liu Q Liu Z Song T Automatic classification of hepatic cystic echinococcosis using ultrasound images and deep learning J. Ultrasound. Med. 2021 10.1002/jum.15691 71. Ryu H Shin SY Lee JY Lee KM Kang HJ Yi J Joint segmentation and classification of hepatic lesions in ultrasound images using deep learning Eur. Radiol. 2021 10.1007/s00330-021-07850-9 72. Wang W Chen LD Lu MD Liu GJ Shen SL Xu ZF Contrast-enhanced ultrasound features of histologically proven focal nodular hyperplasia: diagnostic performance compared with contrast-enhanced CT Eur. Radiol. 2013 23 9 2546 2554 10.1007/s00330-013-2849-3 23624595 73. Xie XH Xu HX Xie XY Lu MD Kuang M Xu ZF Differential diagnosis between benign and malignant gallbladder diseases with real-time contrast-enhanced ultrasound Eur. Radiol. 2010 20 1 239 248 10.1007/s00330-009-1538-8 19657645 74. Hu HT Wang W Chen LD Ruan SM Chen SL Li X Artificial intelligence assists identifying malignant versus benign liver lesions using contrast-enhanced ultrasound J. Gastroenterol. Hepatol. 2021 10.1111/jgh.15522 75. Wu X Li J Gassa A Buchner D Alakus H Dong Q Circulating tumor DNA as an emerging liquid biopsy biomarker for early diagnosis and therapeutic monitoring in hepatocellular carcinoma Int. J. Biol. Sci. 2020 16 9 1551 1562 10.7150/ijbs.44024 32226301 76. Hakim A Zhang X DeLisle A Oral EA Dykas D Drzewiecki K Clinical utility of genomic analysis in adults with idiopathic liver disease J. Hepatol. 2019 70 6 1214 1221 10.1016/j.jhep.2019.01.036 31000363 77. Su TH Wu CH Kao JH Artificial intelligence in precision medicine in hepatology J. Gastroenterol. Hepatol. 2021 36 3 569 580 10.1111/jgh.15415 33709606 78. Martin DR Hanson JA Gullapalli RR Schultz FA Sethi A Clark DP A deep learning convolutional neural network can recognize common patterns of injury in gastric pathology Arch. Pathol. Lab. Med. 2020 144 3 370 378 10.5858/arpa.2019-0004-OA 31246112 79. Liu S Zhang Y Ju Y Li Y Kang X Yang X Establishment and clinical application of an artificial intelligence diagnostic platform for identifying rectal cancer tumor budding Front Oncol. 2021 11 626626 10.3389/fonc.2021.626626 33763362 80. Klimov S Xue Y Gertych A Graham RP Jiang Y Bhattarai S Predicting metastasis risk in pancreatic neuroendocrine tumors using deep learning image analysis Front Oncol. 2020 10.3389/fonc.2020.593211 81. Govind D Jen KY Matsukuma K Gao G Olson KA Gui D Improving the accuracy of gastrointestinal neuroendocrine tumor grading with deep learning Sci. Rep. 2020 10 1 11064 10.1038/s41598-020-67880-z 32632119 82. Wang KS Yu G Xu C Meng XH Zhou J Zheng C Accurate diagnosis of colorectal cancer based on histopathology images using artificial intelligence BMC Med. 2021 19 1 76 10.1186/s12916-021-01942-5 33752648 83. Ma B Guo Y Hu W Yuan F Zhu Z Yu Y Artificial intelligence-based multiclass classification of benign or malignant mucosal lesions of the stomach Front Pharmacol. 2020 10.3389/fphar.2020.572372 84. Zhao B Huang R Lu H Mei D Bao S Xu H Risk of lymph node metastasis and prognostic outcome in early gastric cancer patients with mixed histologic type Curr. Probl. Cancer. 2020 44 6 100579 10.1016/j.currproblcancer.2020.100579 32451068 85. Pan Y Sun Z Wang W Yang Z Jia J Feng X Automatic detection of squamous cell carcinoma metastasis in esophageal lymph nodes using semantic segmentation Clin. Transl. Med. 2020 10 3 e129 10.1002/ctm2.129 32722861 86. Hu Y Su F Dong K Wang X Zhao X Jiang Y Deep learning system for lymph node quantification and metastatic cancer identification from whole-slide pathology images Gastric Cancer 2021 10.1007/s10120-021-01158-9 87. Wang X Chen Y Gao Y Zhang H Guan Z Dong Z Predicting gastric cancer outcome from resected lymph node histopathology images using deep learning Nat. Commun. 2021 12 1 1637 10.1038/s41467-021-21674-7 33712598 88. Kwak MS Lee HH Yang JM Cha JM Jeon JW Yoon JY Deep convolutional neural Network-Based lymph node metastasis prediction for colon cancer using histopathological images Front. Oncol. 2020 10.3389/fonc.2020.619803 89. Park J Jang BG Kim YW Park H Kim BH Kim MJ A prospective validation and observer performance study of a deep learning algorithm for pathologic diagnosis of gastric tumors in endoscopic biopsies Clin. Cancer Res. 2021 27 3 719 728 10.1158/1078-0432.CCR-20-3159 33172897 90. Shao W Han Z Cheng J Integrative analysis of pathological images and multi-dimensional genomic data for early-stage cancer prognosis IEEE Trans. Med. Imaging. 2020 39 1 99 110 10.1109/TMI.2019.2920608 31170067 91. Saillard C Schmauch B Laifa O Predicting survival after hepatocellular carcinoma resection using deep learning on histological slides Hepatology 2020 72 6 2000 2013 10.1002/hep.31207 32108950 92. Srinidhi CL Ciga O Martel AL Deep neural network models for computational histopathology: a survey Med. Image Anal. 2021 67 101813 10.1016/j.media.2020.101813 33049577 93. Shao W Wang T Huang Z Han Z Zhang J Huang K Weakly supervised deep ordinal cox model for survival prediction from whole-slide pathological images IEEE Trans. Med. Imaging 2021 10.1109/TMI.2021.3097319 94. Wang S Zhu Y Yu L RMDL: recalibrated multi-instance deep learning for whole slide gastric image classification Med. Image Anal. 2019 58 101549 10.1016/j.media.2019.101549 31499320 95. Jansen-Winkeln B Barberio M Chalopin C Schierle K Diana M Kohler H Feedforward artificial neural network-based colorectal cancer detection using hyperspectral imaging: a step towards automatic optical biopsy Cancers (Basel) 2021 10.3390/cancers13050967 96. Sato D Takamatsu T Umezawa M Kitagawa Y Maeda K Hosokawa N Distinction of surgically resected gastrointestinal stromal tumor by near-infrared hyperspectral imaging Sci. Rep. 2020 10 1 21852 10.1038/s41598-020-79021-7 33318595 97. Tu Z Li H Zhang D Dauwels J Li B Yuan J Action-stage emphasized spatiotemporal VLAD for video action recognition IEEE Trans. Image Process. 2019 28 6 2799 2812 10.1109/TIP.2018.2890749 98. Chen W Sun Q Chen X Xie G Wu H Xu C Deep learning methods for heart sounds classification: a systematic review Entropy (Basel). 2021 23 6 667 10.3390/e23060667 34073201 99. Xie X Niu J Liu X Chen Z Tang S Yu S A survey on incorporating domain knowledge into deep learning for medical image analysis Med. Image Anal. 2021 69 101985 10.1016/j.media.2021.101985 33588117 100. Curreri F Patanè L Xibilia MG RNN- and LSTM-based soft sensors transferability for an industrial process Sensors (Basel) 2021 21 3 823 10.3390/s21030823 33530476 101. Chen, Y., Tu, Z., Ge, L., Zhang, D., Chen, R., and Yuan, J.: SO-HandNet: Self-Organizing Network for 3D Hand Pose Estimation with Semi-supervised Learning. In Proc. ICCV, pp.6961–6970, (2019) 102. Yi X Walia E Babyn P Generative adversarial network in medical imaging: a review Med. Image Anal. 2019 58 101552 10.1016/j.media.2019.101552 31521965 103. Litjens G Kooi T Bejnordi BE A survey on deep learning in medical image analysis Med. Image Anal. 2017 42 60 88 10.1016/j.media.2017.07.005 28778026 104. Zou J Huss M Abid A Mohammadi P Torkamani A Telenti A A primer on deep learning in genomics Nat. Genet. 2019 51 1 12 18 10.1038/s41588-018-0295-5 30478442 105. Tajbakhsh N Shin JY Gurudu SR Convolutional neural networks for medical image analysis: full training or fine tuning? IEEE Trans. Med. Imaging. 2016 35 5 1299 1312 10.1109/TMI.2016.2535302 26978662 106. Budd S Robinson EC Kainz B A survey on active learning and human-in-the-loop deep learning for medical image analysis Med. Image Anal. 2021 71 102062 10.1016/j.media.2021.102062 33901992 107. Aslam MA Xue C Chen Y Zhang A Liu M Wang K Breath analysis based early gastric cancer classification from deep stacked sparse autoencoder neural network Sci. Rep. 2021 11 1 4014 10.1038/s41598-021-83184-2 33597551 108. Xiao W Huang X Wang JH Lin DR Zhu Y Chen C Screening and identifying hepatobiliary diseases through deep learning using ocular images: a prospective, multicentre study Lancet Digit. Health. 2021 3 2 e88 97 10.1016/S2589-7500(20)30288-0 33509389 109. Li T Tong W Roberts R Liu Z Thakkar S DeepDILI: deep learning-powered drug-induced liver injury prediction using model-level representation Chem. Res. Toxicol. 2021 34 2 550 565 10.1021/acs.chemrestox.0c00374 33356151 110. Wong GL Yuen PC Ma AJ Chan AW Leung HH Wong VW Artificial intelligence in prediction of non-alcoholic fatty liver disease and fibrosis J. Gastroenterol Hepatol. 2021 36 3 543 550 10.1111/jgh.15385 33709607 111. Tu Z Xie W Qin Q Poppe R Veltkamp RC Li B Multi-stream CNN: Learning representations based on human-related regions for action recognition Pattern Recognit. 2018 10.1016/j.patcog.2018.01.020 112. Eraslan G Avsec Ž Gagneur J Theis FJ Deep learning: new computational modelling techniques for genomics Nat. Rev. Genet. 2019 20 7 389 403 10.1038/s41576-019-0122-6 30971806
PMC008xxxxxx/PMC8642832.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(21)02924-8 10.1016/j.jaad.2021.11.052 Research Letter Impact of COVID-19 delays on skin cancer worry and Mohs micrographic surgery for keratinocytic carcinoma Ruiz Emily Stamell MD, MPH a∗ Veldhuizen Inge J. MD b Abdullah Aleisa MD b Rossi Anthony MD b Nehal Kishwer S. MD b Schmults Chrysalyne MD, MSCE a Waldman Abigail MD a Lee Erica H. MD b a Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts b Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, New York ∗ Reprint requests: Emily Stamell Ruiz, MD, MPH, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, 1153 Centre Street Suite 4J, Boston, MA 02130 4 12 2021 10 2022 4 12 2021 87 4 878880 © 2021 by the American Academy of Dermatology, Inc. 2021 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Key words basal cell carcinoma COVID-19 cutaneous squamous cell carcinoma Mohs micrographic surgery ==== Body pmcTo the Editor: In March 2020, the National Comprehensive Cancer Network recommended delaying treatment during the COVID-19 pandemic for keratinocyte carcinoma (KC), except for tumors determined to pose a risk of “metastasis or debilitating progression within 3 months.”1 This study sought to evaluate the impact of the COVID-19 pandemic on cancer worry in patients undergoing Mohs micrographic surgery (MMS) for KCs. The study was approved by the institutional review boards of Brigham and Women's Micrographic Surgery Center and Memorial Sloan Kettering Cancer Center. KCs treated with MMS at both the institutions were included in the study if they met the following criteria: (1) MMS was cancelled because of the stay-at-home recommendations and rescheduled from April to August 2020 (“COVID-delay patients”) and (2) MMS was performed between May and August 2019 (“control patients”). Electronic medical records were reviewed for patient demographics, tumor characteristics, and MMS outcomes (Supplementary Table I, available via Mendeley at https://10.1016/j.jaad.2021.11.052). The cancer worry scale, from the FACE-Q skin cancer module, was completed by all patients prior to surgery.2, 3, 4 The COVID-delay patients were asked 4 additional COVID-19–related questions (Table I ). The patient and tumor characteristics as well as MMS outcomes were analyzed using descriptive statistics and frequency tabulation. Analysis of variance was used to evaluate whether certain factors influenced the cancer worry scores, and significant risk factors were analyzed using multivariate analysis of variance. All reported P values were 2 sided, and P values < .05 were considered statistically significant. The statistical analyses were performed using Stata, version 14.0 (StataCorp).Table I Results of the COVID-19–related questions Combined (n = 143) BWH (n = 64) MSKCC (n = 79) What would you say your skin cancer worry compared with COVID-19 worry is: n (%)  Less 64 (45) 35 (54) 29 (37)  The same 40 (28) 14 (22) 28 (35)  More 31 (22) 10 (15) 21 (27) How did you feel when your treatment was delayed (select all): n (%)  Understood the reason (COVID-19) 119 (84) 49 (75) 72 (91)  Understood the rationale (skin cancer treatment was not urgent) 38 (27) 18 (28) 20 (25)  Was upset about the delay 14 (10) 4 (6) 10 (13) Did you develop any of the following symptoms after March 1, 2020? n (%)  Cough 5 (4) 3 (3) 2 (3)  Fever 0 (0) 0 (0) 0 (0)  Sore throat 0 (0) 0 (0) 0 (0)  Nasal congestion or runny nose 1 (1) 2 (2) 0 (0)  Shortness of breath 1 (1) 0 (0) 1 (1)  Muscle aches 0 (0) 1 (1) 0 (0)  Anosmia 1 (1) 0 (0) 1 (1) History of COVID-19, n (%) 3 (2) 0 (0) 3 (4) BWH, Brigham and Women's Hospital; MSKCC, Memorial Sloan Kettering Cancer Center. Supplementary Table I (available via Mendeley). summarizes the details of 191 COVID-delay and 381 control patients (response rate, 75%). The mean time from biopsy to treatment was approximately 3 months longer for the COVID-delay group (COVID-delay patients: 129.0 days [SD, 97.9 days] vs controls: 41.0 days [SD, 44.3 days], P ≤ .0001). For MMS variables, there was no significant difference in pre- or postoperative defect size, the mean number of MMS stages, or the complexity of reconstruction. The mean cancer worry scale score was similar in all the patients (COVID-delay patients: 45.0 [SD, 17.9] vs controls: 44.7 [SD, 44.7], P = .9). The multivariate analysis of variance found higher equivalent cancer worry scores in patients with tumors ≥20 mm (+7.9), patients less than 65 years of age (+7.1), and female patients (+4.4). Table I summarizes the results of the COVID-19–related questions. About one-quarter of the COVID-delay patients were more worried about their skin cancer (31/143 [22%]), and only 10% (14/143) were upset about the delay. A prior history of cutaneous squamous cell carcinoma and tumor diameter of ≥20 mm were associated with being more worried about skin cancer, as determined using a univariate analysis, but neither were significant in the multivariate analysis (prior cutaneous squamous cell carcinoma: odds ratio, 1.9; 95% CI, 0.82-4.2; tumor diameter ≥20 mm: odds ratio, 2.5; 95% CI, 0.73-8.7). Surgical delays occur for many reasons, but the first wave of the pandemic created an opportunity to examine the impact of delays on emotional well-being and surgical outcomes. Surprisingly, a quarter of the COVID-delay patients were more worried about their KC than about a novel, life-threatening viral illness despite surgical outcomes not being affected. These data could be used to enhance patient-centered communication at the time of surgical delays, given the indolent nature of most KCs, which could alleviate cancer worry and improve the overall patient experience. Conflict of interest None disclosed. Funding sources: This research was funded, in part, by the 10.13039/100000002 National Institutes of Health /National Cancer Institute Cancer Center Support Grant P30 CA008748. The funder had no role in the design and conduct of the study: collection, management, analysis, and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication. IRB approval status: Reviewed and approved by the Partners (2020P001143) and Memorial Sloan Kettering (18-168) Cancer Center Human Research Office. ==== Refs References 1 National Comprehensive Cancer Network COVID-19 Resources: advisory statement for Non Melanoma Skin Cancer Care during the COVID-19 Pandemic https://merkelcell.org/wp-content/uploads/2020/05/NCCN-NMSC.pdf April 22, 2020 2 Lee E.H. Klassen A.F. Cano S.J. Nehal K.S. Pusic A.L. FACE-Q skin cancer module for measuring patient-reported outcomes following facial skin cancer surgery Br J Dermatol 179 1 2018 88 94 29654700 3 Lee E.H. Klassen A.F. Lawson J.L. Cano S.J. Scott A.M. Pusic A.L. Patient experiences and outcomes following facial skin cancer surgery: a qualitative study Australas J Dermatol 57 3 2016 e100 e104 25833383 4 Lee E.H. Klassen A.F. Nehal K.S. Cano S.J. Waters J. Pusic A.L. A systematic review of patient-reported outcome instruments of nonmelanoma skin cancer in the dermatologic population J Am Acad Dermatol 69 2 2013 e59 e67 23102770
PMC008xxxxxx/PMC8647520.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(21)02949-2 10.1016/j.jaad.2021.12.001 This month in JAAD International This month in JAAD International: March 2022: Photography, skin cancer, and the limits of teledermatology during the COVID-19 pandemic Kantor Jonathan MD, MSCE ∗ Department of Dermatology, Center for Global Health, and Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania Florida Center for Dermatology, St. Augustine, Florida ∗ Correspondence to: Jonathan Kantor, MD, MSCE, Department of Dermatology, University of Pennsylvania School of Medicine, 1301 Plantation Island Dr S, St. Augustine, FL 32080. 6 12 2021 2 2022 6 12 2021 86 2 300300 © 2021 by the American Academy of Dermatology, Inc. 2021 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcThis month in JAAD International, Cheng and Schurr1 describe their New Zealand experience in using teledermatology to diagnose suspected skin cancers in the context of the COVID-19 pandemic. They note that although teledermatology has played an important role, it also has critical limitations in terms of managing putative skin cancers. Indeed, with more than a quarter of patients seen using teledermatology requiring an in-person follow-up visit, their findings suggest that teledermatology is a valuable adjunct, rather than a replacement for, in-person skin examinations in patients with a high baseline skin cancer burden. Although much has been written extolling the potential benefits of teledermatology both before and during the pandemic, it also behooves us to appreciate the inherent limitations of this technology.2, 3, 4 For example, the quality of teledermatology-produced diagnoses is limited by the quality of images received: in teledermatology, as in many other fields, the adage of “garbage in, garbage out” holds true because even the most brilliant dermatologist can only render a diagnosis if the image quality—and image choice—is adequate. Unfortunately, the ubiquity of powerful smartphone cameras does not guarantee that an image sent by a patient will be of high quality, representative, or use adequate lighting—or even be in focus. Standardizing photography for teledermatology may help mitigate these concerns; therefore, a range of options has been considered in the past, including relying on a dedicated teledermatology image capture team for patients being assessed in the context of primary care clinics, although further work in this important area is needed.5 Conflicts of interest None disclosed. Funding sources: None. IRB approval status: Not applicable. Reprints not available from the author. ==== Refs References 1 Cheng HS, Schurr L. Teledermatology for suspected skin cancer in New Zealand during the COVID-19 pandemic required in-person follow-up in 28% of cases. Preprint. Posted online November 29, 2021. JAAD Int. https://doi.org/10.1016/j.jdin.2021.11.003 2 Loh C.H. Tam Y.C. Oh C.C. Teledermatology in the COVID-19 pandemic: a systematic review JAAD Int 5 2021 54 64 34368789 3 Puri P. Yiannias J.A. Mangold A.R. Swanson D.L. Pittelkow M.R. The policy dimensions, regulatory landscape, and market characteristics of teledermatology in the United States JAAD Int 1 2 2020 202 207 34409341 4 Giavina-Bianchi M. Giavina-Bianchi P. Santos A.P. Rizzo L.V. Cordioli E. Accuracy and efficiency of telemedicine in atopic dermatitis JAAD Int 1 2 2020 175 181 34409337 5 Barros-Tornay R. Ferrándiz L. Martín-Gutiérrez F.J. Feasibility and cost of a telemedicine-based short-term plan for initial access in general dermatology in Andalusia, Spain JAAD Int 4 2021 52 57 34409393
PMC008xxxxxx/PMC8664718.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(21)02915-7 10.1016/j.jaad.2021.11.043 JAAD Online Reply to early-onset effluvium secondary to COVID-19 and body hair effluvium Wambier Carlos Gustavo MD, PhD a∗ Tosti Antonella MD b a Department of Dermatology Alpert Medical School of Brown University, Providence, Rhode Island b Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Florida ∗ Correspondence to: Carlos Gustavo Wambier, MD, PhD, Rhode Island Hospital, 593 Eddy Street, APC, 10th Floor, Providence, RI 02903 11 12 2021 5 2022 11 12 2021 86 5 e209e210 © 2021 by the American Academy of Dermatology, Inc. 2021 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Key words alopecia alopecia areata anagen effluvium body hair effluvium COVID-19 hair loss IL-6 JAK SARS-CoV-2 telogen effluvium ==== Body pmcTo the Editor: We agree with the points made by Miola et al1 about the possibility of dystrophic anagen effluvium in cases assumed to be diagnosed with acute telogen effluvium, particularly in more severe hospitalized cases, when associated with early onset. Additionally, our previous article showed a wide range of duration of shedding, from 12 to 100 days. Theoretically, a different duration of shedding could have an association with hair cycle phase shedding (anagen vs telogen) and the presence or absence of chronic inflammation. To add to the list of differential diagnoses, for cases with later onset and a longer duration, clinically manifesting as alopecia (without expected regrowth of the hair shafts), alopecia areata has been reported after COVID-19 infection as a straightforward diagnosis of patchy areas of alopecia.2 , 3 However, diffuse alopecia areata can be difficult to diagnose clinically and can be initially misdiagnosed as chronic telogen effluvium. Dermatologists play a pivotal role in such patients' care by providing the correct diagnosis and therapy for hair involvement. For cases with alopecia areata, dermatology therapeutics have greatly expanded over the past years with the use of Janus Kinase inhibitors. Many of these have been tested for the treatment of hospitalized COVID-19 patients. Tofacitinib at 10 mg twice daily and baricitinib at 4 mg daily for up to 14 days showed benefits in patients hospitalized for COVID-19 pneumonia, whereas ruxolitinib at 5 mg twice daily showed no benefit (NCT04362137).4 , 5 It is still unknown whether initiation of anti-inflammatory therapy, such as that using anti-interleukin 6, corticosteroids, Janus kinase inhibitors, or even antiandrogens, can have any effect on post-COVID–19 hair loss. As pointed out, some scalp biopsies showed no evidence of inflammation.1 Thus, in the context of therapeutic initiation for COVID-19, therapy could have a benefit by halting respiratory involvement progression, improving oxygenation and physical stress, thus preserving the homeostasis of multiple organs, including the skin. As Miola et al1 pointed out, much is still unknown about postinfectious acute telogen effluvium, including areas with more involvement and the expected progression. One of the clinically striking and still rarely reported characteristics of effluvium was observed in our patients, namely, body hair effluvium. Fig 1 , A depicts the first patient, seen by Dr Wambier, who complained of severe body hair effluvium after COVID-19 infection. Dr Tosti recently evaluated 25 patients with post-COVID–19 telogen effluvium and found 8 patients with body hair effluvium, which was often patchy (Fig 1, B) even if the scalp had no signs of patchy alopecia. We hope that more studies are conducted on the involvement of body hair in post-COVID–19 effluvium and telogen effluvium from other etiologies.Fig 1 Body hair effluvium after COVID-19. A, A 74-year-old man with scalp acute telogen effluvium 2 months after COVID-19 presented with the progression of patchy alopecia from the scalp to the neck and upper portion of the back at 4 months. Later, his upper limbs, axillae, pubic area, buttocks, and lower limbs also became involved, whereas the beard, eyebrows, and eyelashes were spared. Spontaneous body hair regrowth was noticed at 8 months. B, A 56-year-old woman presented with severe telogen effluvium 45 days after COVID-19 pneumonia. An examination showed diffuse scalp thinning most pronounced on the temporal aspect of the scalp and patchy alopecia of the forearms. According to recent data, up to 20% of patients with COVID-19 have cutaneous manifestations. Dermatologists should be aware of the different types of hair loss that can be observed after COVID-19 infection. Conflicts of interest None disclosed. Funding sources: None. IRB status: Not applicable. Key words: alopecia; alopecia areata; anagen effluvium; body hair effluvium; COVID-19; hair loss; IL-6; JAK; SARS-CoV-2; telogen effluvium. ==== Refs References 1 Miola A.C. Florêncio L.C. Ribeiro M.E.B. Alcântara G.P. Ramos P.M. Miot H.A. Early onset effluvium secondary to COVID-19: a clinical and histological characterization J Am Acad Dermatol 2021 10.1016/j.jaad.2021.09.072 2 Rossi A. Magri F. Michelini S. New onset of alopecia areata in a patient with SARS-CoV-2 infection: possible pathogenetic correlations? J Cosmet Dermatol 20 7 2021 2004 2005 10.1111/jocd.14080 33738910 3 Rostey R. Santana I. Almeida C. Alopecia Areata after COVID-19: causal or casual relationship? Surg Cosmet Dermatol 13 2021 1 3 10.5935/scd1984-8773.2021130014 4 Guimarães P.O. Quirk D. Furtado R.H. Tofacitinib in patients hospitalized with Covid-19 pneumonia N Engl J Med 385 5 2021 406 415 10.1056/NEJMoa2101643 34133856 5 Marconi V.C. Ramanan A.V. de Bono S. Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial Lancet Respir Med 9 12 2021 1407 1418 10.1016/S2213-2600(21)00331-3 34480861
PMC008xxxxxx/PMC8665661.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(21)02914-5 10.1016/j.jaad.2021.09.072 JAAD Online Early-onset effluvium secondary to COVID-19: Clinical and histologic characterization Miola Anna Carolina MD, PhD Florêncio Lívia Caramaschi MD Bellini Ribeiro Maria Estela MD Alcântara Giovana Piteri MD, MSc Müller Ramos Paulo MD, PhD ∗ Miot Hélio Amante MD, PhD Department of Dermatology, Universidade Estadual Paulista–UNESP, Botucatu, Brazil ∗ Correspondence to: Paulo Müller Ramos, MD, PhD, Mário Rubens Guimarães Montenegro, SN, Universidade Estadual Paulista - UNESP, Campus Botucatu, 18618687 Botucatu, São Paulo, Brazil 11 12 2021 5 2022 11 12 2021 86 5 e207e208 © 2021 by the American Academy of Dermatology, Inc. 2021 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Key words coronavirus COVID-19 hair loss SARS-CoV-2 telogen effluvium ==== Body pmcTo the Editor: As telogen effluvium (TE) is the most common manifestation of postacute COVID-19 syndrome, we read with keen interest the publication by Abrantes et al1 reporting the clinical characteristics of 30 patients with post-COVID–19 acute TE. We would like to commend the authors and bring some other elements to this relevant discussion. TE is a heterogeneous condition that can be elicited by multiple stimuli.2 Headington3 proposed 5 functional types of TE based on alternations in particular phases of the follicular cycle. Infections are thought to induce TE through the mechanism of immediate anagen release. According to this model, an acute inflammatory state converts the follicles from anagen to catagen, leading to the shedding of telogen hairs around 90 days after the infection. Interestingly, the median time for the onset of hair shedding observed by Abrantes et al1 was 45 days after infection; in the most precocious case, it started 18 days after COVID-19. This early onset was also observed in 2 multicentric studies. Moreno-Arrones et al4 evaluated 214 cases of acute TE after COVID-19 and noted the onset of hair shedding, on average, 57.1 days after the infection. Starace et al5 observed early onset especially when TE was associated with trichodynia. In these cases, the latency from the infection to hair shedding occurred at an average of 3 (range, 2-7.5) weeks.5 We recently assessed 203 hospitalized patients with confirmed COVID-19, of whom 11 (5.4%) reported hair loss with onset early during hospitalization, <30 days after the infection. Seven of them were assessed using trichoscopy, a trichogram, and a histologic evaluation. The detailed information of these cases is presented in Supplementary Table I (available via Mendeley at https://data.mendeley.com/datasets/p254jbh356/1). Clinically, all the cases presented a positive pull test result. Trichoscopy did not reveal broken hairs, anisotrichosis, or yellow dots, but it did reveal some empty follicles. The trichogram obtained from the vertex revealed >10% dystrophic anagen hairs (Fig 1 ) and >20% telogen hairs in all the cases. Histologically, there was predominance of anagen terminal follicles, no relevant miniaturization (>10%), and no cases showing >25% telogen follicles. No inflammation was evident at the epidermis or throughout the hair follicle (Fig 2 ).Fig 1 Early-onset effluvium secondary to COVID-19. A dystrophic hair (absence of root sheath and misshapen bulb) was observed using polarized microscopy. Fig 2 Early-onset effluvium secondary to COVID-19. Histopathology showed predominance of anagen follicles and no inflammation (Haematoxylin & eosin - 100 × magnification). Postinfectious hair shedding has traditionally been classified as acute TE; however, the hair follicle may respond to an infection and inflammation in different ways. A more intense insult could also lead to dystrophic anagen effluvium, which presents as early onset, as we have demonstrated here. In patients with COVID-19, a cytokine storm during the inflammatory phase (especially interleukin 6 and tumor necrosis factor α), severe hypoxia, oxidative stress, microthrombotic events, and the toxicity of multiple drugs used for its treatment could play a role, especially in more severe cases. These issues can elicit TE by multiple mechanisms following COVID-19, which can justify the different patterns of presentation and the time to the onset of hair loss. Further studies exploring the pathogenesis of early-onset effluvium elicited by COVID-19, as well as its prevalence and possible differences compared with other acute postinfectious TE, are needed. Conflicts of interest None disclosed. Funding sources: None. IRB approval status: This study was approved by the FMB-UNESP Institutional Review Board (number 4.688.358). Key words: coronavirus; COVID-19; hair loss; SARS-CoV-2; telogen effluvium. ==== Refs References 1 Abrantes T.F. Artounian K.A. Falsey R. Time of onset and duration of post-COVID-19 acute telogen effluvium J Am Acad Dermatol 85 4 2021 975 976 34302903 2 Rebora A. Telogen effluvium: a comprehensive review Clin Cosmet Investig Dermatol 12 2019 583 590 3 Headington J.T. Telogen effluvium: new concepts and review Arch Dermatol 129 3 1993 356 363 8447677 4 Moreno-Arrones O.M. Lobato-Berezo A. Gomez-Zubiaur A. SARS-CoV-2-induced telogen effluvium: a multicentric study J Eur Acad Dermatol Venereol 35 3 2021 e181 e183 33220124 5 Starace M. Iorizzo M. Sechi A. Trichodynia and telogen effluvium in COVID-19 patients: results of an international expert opinion survey on diagnosis and management JAAD Int 5 2021 11 18 34368790
PMC008xxxxxx/PMC8674109.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 by the American Academy of Dermatology, Inc. S0190-9622(21)02959-5 10.1016/j.jaad.2021.12.004 Research Letter Cross-sectional study of dermatology residency home match incidence during the COVID-19 pandemic Abdelwahab Rewan BA a Antezana Luis A. BS a Xie Katherine Z. BS a Abdelwahab Muhab b Tollefson Megha MD c∗ a Mayo Clinic Alix School of Medicine, Mayo Clinic, Rochester, Minnesota b University of Minnesota–Twin Cities, Minneapolis, Minnesota c Department of Dermatology, Mayo Clinic, Rochester, Minnesota ∗ Correspondence to: Megha Tollefson, MD, Department of Dermatology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905 16 12 2021 10 2022 16 12 2021 87 4 886888 © 2021 by the American Academy of Dermatology, Inc. 2021 American Academy of Dermatology, Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: As per recommendations outlined by the Association of Professors of Dermatology, dermatology residency programs conducted virtual interviews for the 2020-2021 match during the COVID-19 pandemic.1 Leaders from the Association of Professors of Dermatology suggested that away rotations prioritize students without home programs and consider offering virtual experiences.1 Prior to the pandemic, approximately 29% of dermatology residents matched at home programs and 63% matched within home regions.2 Furthermore, in the 2020 National Resident Matching Program survey of program directors, 92% cited “Audition elective/rotation within [the] department” as a major factor for determining whether an applicant should be interviewed,3 emphasizing the importance of away rotations in previous match cycles. While virtual rotations and interviews allow more flexibility, accessibility, and equity for those from low socioeconomic backgrounds, the inability to experience institutions in person may also provide less insight into the culture of each program. This study aims to provide empirical data on how the pandemic may have influenced the incidence of matching into one's home institution during the 2021 dermatology match. We reviewed publicly available match data from 2017 to 2019 and for 2021 on program websites, social media, LinkedIn, and from email correspondence for Electronic Residency Application Service-participating dermatology residency programs in the United States. The 2020 match was excluded because there was limited availability of information on current residents exiting transitional years. Applicants were considered a “home” match if their most recent affiliation is formally associated with their matched institution. Information was available for 56% of programs (n = 69) for the 2021 match and an average of 65 (~50%) programs for the 2017, 2018, and 2019 match cycles. Home matches increased from an average of 23.7% for the 2017-2019 match cycles to 30.9% in 2021 (P = .025) (Table I ). Analysis by logistic regression showed that programs in the 2021 virtual interview cycle had statistically significant greater odds of matching at least 1 home applicant compared with the 2017-2019 interview cycles (odds ratio, 2.3; P = .02) (Table II ). This aligns with previous analyses of COVID-19 match trends.4 Program size was also significant in that home matching appeared to occur more frequently with programs having more spots than the national median of 4 and less often with programs having fewer spots (P = .00001) (Table II).Table I Descriptive statistics summary of dermatology residency programs by year Year Programs (number found) Positions per program (mean) Positions per program (SD) Positions per program (median) Positions per program (IQR) Percent of program filled with home matches (mean) Percent of program filled with home matches (SD) Percent of program filled with home matches (median) Percent of program filled with home matches (IQR) Programs matching ≥1 home applicant Programs matching ≥2 home applicants Number % Number % 2021 69 4.2 1.8 4.0 2.0 30.9 26.3 25.0 42.9 52 75.4 25 36.2 2019 65 4.2 1.8 4.0 2.0 23.9 25.9 20.0 40.0 39 60.0 16 24.6 2018 65 4.1 1.9 4.0 2.0 23.0 23.4 25.0 43.8 37 56.9 20 30.8 2017 65 4.0 1.9 4.0 2.5 24.1 26.0 22.2 40.0 38 58.5 21 32.3 2017-2019 195 4.1 1.9 4.0 2.0 23.7 25.0 20.0 40.0 114 58.5 57 29.2 IQR, Interquartile range. Table II Crude and adjusted odds ratios for a program having at least 1 home match Variable Crude OR (95% CI) P (univariable) Adjusted OR (95% CI) P (multivariable) Year .01∗† .02∗†  2017-2019 ref ref  2021 2.2 (1.2, 4.0) .01∗ 2.3 (1.1, 4.8) .02∗ Number of positions .00∗† .00001∗†  1 – – – –  2 0.2 (0.07, 0.4) <.0001∗ 0.2 (0.1, 0.6) .004∗  3 0.8 (0.4, 1.7) .5 1 (0.4, 2.4) .9  4 ref – ref –  5 3.0 (1.1, 8.4) .04∗ 3.2 (1.1, 9.2) .03∗  6 2.6 (0.7, 10.0) .2 3.1 (0.8, 12.4) .1  7 1.9 (0.6, 6.6) .3 2.2 (0.6, 8.3) .3  8 – – – –  9 – – – –  10 1.0 (0.1, 12.1) 1.0 1.2 (0.1, 16.5) .9 Ranking 0.00∗† .01∗†  1-25 ref ref  26-50 0.9 (0.4, 2.0) .8 1.3 (0.5, 3.4) .5  51-75 0.8 (0.4 1.9) .7 1.7 (0.6, 4.5) .3  76-100 0.1 (0.04, 0.2) <.0001∗ 0.3 (0.1, 1.0) .05∗  100+/No rank 0.4 (0.2, 0.9) .03∗ 1.4 (0.4, 4.6) .6 OR, Odds ratio. ∗ Indicates P value of statistical significance at ⍺ = .05. † Indicates variable category P values, not level specific. If the proportion of interviews allocated to outside 2021 applicants is reflective of past years, the observed increase in home matching likely resulted from the nature of virtual rotations and interviews hindering applicants' ability to familiarize themselves with outside programs. Similarly, programs faced challenges acquainting themselves with unfamiliar applicants, resulting in applicants and institutions ranking their home counterparts higher on their rank lists. Decreased outside applicant interview offers may also explain the rise in “home matches.” Changes in the incidence of home matching are especially significant for applicants without home dermatology departments. Recent literature demonstrates that mentorship and pipeline programs are fundamental to a successful match.5 Thus, students without home programs are at an inherent disadvantage in garnering academic relationships and participating in such initiatives. The paradigm shift to virtual experiences has only widened this disconnect. As institutions move toward hybrid models, these considerations are key to understanding how to best incorporate virtual interviewing while maintaining equity among applicants. Conflicts of interest None disclosed. Funding sources: None. IRB approval status: Not applicable. Key words: COVID-19 match; derm match; Dermatology/education; Dermatology/statistics & numerical data; dermatology match; dermatology residency; education; hybrid model; internal match; Internship and Residency/statistics & numerical data; match; pandemic match; residency; residency match; residency match; residents; virtual interviewing; virtual interviews Reprints not available from the authors. ==== Refs References 1 Dermatology residency program director consensus statement and recommendations regarding the 2020-2021 application cycle. AAMC https://aamc-orange.global.ssl.fastly.net/production/media/filer_public/0f/7b/0f7b547e-65b5-4d93-8247-951206e7f726/updated_dermatology_program_director_statement_on_2020-21_application_cycle_.pdf 2020 2 Narang J. Morgan F. Eversman A. Trends in geographic and home program preferences in the dermatology residency match: a retrospective cohort analysis J Am Acad Dermatol 2021 10.1016/j.jaad.2021.02.011 3 National Resident Matching Program Results of the 2020 NRMP Program Director Survey. 2020. Figures D-1 and D-2 https://www.nrmp.org/wp-content/uploads/2021/08/2020-PD-Survey.pdf 4 Dowdle T.S. Ryan M.P. Wagner R.F. Internal and geographic dermatology match trends in the age of COVID-19 J Am Acad Dermatol 85 5 2021 1364 1366 10.1016/j.jaad.2021.08.004 34375667 5 Vasquez R. Jeong H. Florez-Pollack S. Rubinos L.H. Lee S.C. Pandya A.G. What are the barriers faced by under-represented minorities applying to dermatology? A qualitative cross-sectional study of applicants applying to a large dermatology residency program J Am Acad Dermatol 83 6 2020 1770 1773 10.1016/j.jaad.2020.03.067 32244012
PMC008xxxxxx/PMC8695307.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 Mosby S0190-9622(21)02997-2 10.1016/j.jaad.2021.12.031 This month in JAAD Case Reports This Month in JAAD Case Reports: March 2022. Reactive infectious mucocutaneous eruption secondary to SARS-CoV-2 Sloan Brett MD ∗ Department of Dermatology, University of Connecticut School of Medicine, Farmington, Connecticut ∗ Correspondence to: Brett Sloan, MD, Department of Dermatology, University of Connecticut School of Medicine, 555 Willard Ave, VA Connecticut Healtcare System, Newington, CT 06111. 23 12 2021 3 2022 23 12 2021 86 3 530531 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Abbreviation used RIME reactive infectious mucocutaneous eruption ==== Body pmcA recent cross-sectional analysis of 666 patients with COVID-19 found that approximately 12% had changes to the oral mucosa. Transient anterior U-shaped lingual papillitis (11.5%), tongue swelling (6.6%), aphthous stomatitis (6.5%), burning sensation in the mouth (5.3%), and mucositis (3.9%) were the most common conditions described.1 Reactive infectious mucocutaneous eruption (RIME) is a term the Pediatric Dermatology Research Alliance proposed to include pathogens associated with post-infectious mucositis, in addition to Mycoplasma pneumonia. Although mycoplasma-induced rash and mucositis are specific to 1 cause, RIME encompasses cases attributed to rhinoviruses, enteroviruses, parainfluenzavirus 2, influenza B virus, and Chlamydia pneumonia, among others.2 In the December 2021 edition of Journal of the American Academy of Dermatology Case Reports, Ryder et al3 report a severe case of RIME in a 17-year-old male after developing COVID-19. He initially presented with cough, fever, and fatigue and tested positive for SARS-CoV-2. A week later, he presented to the emergency department with pharyngitis and mucosal sloughing of the lips, hard and soft palates, and tonsillar pillars. After an extensive infectious disease work up and ruling out multisystem inflammatory syndrome in children, he was admitted for 5 days and treated with systemic corticosteroids. Four days after discharge, he was readmitted with worsening oral and new peri-urethral mucositis despite intravenous methylprednisolone. He began to improve shortly after starting cyclosporine and was completely clear of mucosal lesions approximately a week after his second admission. In a recent series of pediatric patients, 42% admitted to the hospital and 60% admitted to the pediatric intensive care unit for COVID-19 had mucocutaneous findings.4 Although multisystem inflammatory syndrome in children and toxic epidermal necrolysis/Stevens-Johnson syndrome need to be ruled out promptly in these patients, RIME should be added to the differential diagnosis. Conflicts of interest None disclosed. Funding sources: None. IRB approval status: Not applicable. Reprints not available from the author. ==== Refs References 1 Nuño González A. Magaletskyy K. Martín Carrillo P. Are oral mucosal changes a sign of COVID-19? A cross-sectional study at a field hospital Actas Dermosifiliogr (Engl Ed) 112 7 2021 640 644 10.1016/j.ad.2021.02.007 33652010 2 Ramien M.L. Bruckner A.L. Mucocutaneous eruptions in acutely ill pediatric patients-think of Mycoplasma pneumoniae (and other infections) First JAMA Dermatol 156 2 2020 124 125 10.1001/jamadermatol.2019.3589 31851301 3 Ryder C.Y. Pedersen E.A. Mancuso J.B. Reactive infectious mucocutaneous eruption secondary to SARS-CoV-2 JAAD Case Rep 18 2021 103 105 10.1016/j.jdcr.2021.10.007 34692963 4 Andina-Martinez D. Nieto-Moro M. Alonso-Cadenas J.A. Mucocutaneous manifestations in children hospitalized with COVID-19 J Am Acad Dermatol 85 1 2021 88 94 10.1016/j.jaad.2021.03.083 33819537
PMC008xxxxxx/PMC8788093.txt
==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 Mosby S0190-9622(22)00098-6 10.1016/j.jaad.2022.01.020 JAAD Online An analysis of public sunscreen distribution in the United States during the COVID-19 pandemic Szeto Mindy D. MS a Kokoska Ryan E. BS b Maghfour Jalal MD c Rundle Chandler W. MD d Presley Colby L. DO e Harp Taylor BA f Hamp Austin BS g Wegener Victoria BS h Hugh Jeremy MD i Dellavalle Robert P. MD, PhD, MSPH aj∗ a Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado b Indiana University School of Medicine, Indianapolis, Indiana c Department of Dermatology, Henry Ford Hospital, Detroit, Michigan d Department of Dermatology, Duke University Medical Center, Durham, North Carolina e Division of Dermatology, Lehigh Valley Health Network, Allentown, Pennsylvania f College of Osteopathic Medicine, Rocky Vista University, Parker, Colorado g Arizona College of Osteopathic Medicine, Glendale, Arizona h Pre-Medical Postbaccalaureate Program, University of California Berkeley, Berkeley, California i Department of Dermatology, Colorado Kaiser Permanente Medical Group, Centennial, Colorado j Rocky Mountain Regional Veterans Affairs Medical Center, Eastern Colorado Health Care System, Aurora, Colorado ∗ Correspondence to: Robert P. Dellavalle, MD, PhD, MSPH, US Department of Veterans Affairs, Eastern Colorado Health Care System, Rocky Mountain Regional VA Medical Center, 1700 N Wheeling St, Rm E1-342, Aurora, CO 80045 25 1 2022 5 2022 25 1 2022 86 5 e241e243 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcTo the Editor: The COVID-19 pandemic might have significantly affected consumer preferences and societal behavior regarding sun protection and skin cancer. We present a pandemic-era follow-up of previous research published in the Journal of the American Academy of Dermatology 1 on public use of sunscreen distributed by IMPACT Melanoma, a prominent nationwide sunscreen distributor and nonprofit organization for skin cancer prevention and education. IMPACT Melanoma’s distribution records from 2020 to 2021 were retrospectively analyzed and compared with those from 2018 to 2019. Health care facilities, public health departments, governmental organizations, parks or recreation centers, educational institutions, nonprofits, and private businesses ordered both sunscreen dispensers and cases of different sunscreen types for public use (Fig 1 ). Every sector showed decreases in the overall orders of sunscreen dispensers (−58%) and cases of sunscreen (−68%). Park or recreation center and nonprofit organization total sunscreen and dispenser orders (the most common in 2018-2019) decreased in 2020 to 2021 by 78% and 42%, respectively. Despite nationwide supply chain disruptions, sunscreens remained available for distribution, with hybrid sunscreens ordered most frequently (no chemical and physical sunscreens were ordered in 2020-2021, perhaps because of their growing unpopularity, as discussed previously by Eason et al1). Orders of hybrid sunscreen grew by 41%, driven primarily by hospitals, which also ordered more sunscreen dispensers and likely experienced increased volume at facilities and outreach events (eg, vaccination drives) during the COVID-19 pandemic. In total, Wyoming, Maine, South Dakota, and Massachusetts received the most dispensers and sunscreens by state population from 2020 to 2021 (Fig 2 ).Fig 1 Comparisons of sunscreen and dispenser distribution records by IMPACT Melanoma between 2018 to 2019 and 2020 to 2021 by purchasing organization type. Color Key: Lowest % change Highest % change in 2020-2021 vs 2018-2019. ∗Physical (mineral) sunscreen: BrightGuard Natural Sunscreen (active ingredients: 6% titanium dioxide and 6% zinc oxide). ∗∗Chemical sunscreen: Coppertone Sport Sunscreen (active ingredients: 3% avobenzone, 8% homosalate, 4.5% octisalate, and 6% octocrylene). ∗∗∗Hybrid sunscreen: Hybrid Sport Sunscreen (active ingredients: 7% octyl methoxycinnamate, 1.25% titanium dioxide, 1.25% zinc oxide, and 1.0% octyl salicylate). ˆCase contains 4 individual 1-L bags of sunscreen. ˆˆThe health care facilities included hospitals, clinics, nursing homes, and cancer centers. Fig 2 Total sunscreen dispensers and cases of sunscreen distributed by IMPACT Melanoma by state per 1 million individuals from 2020 to 2021. State resident population based on United States Census Bureau 2020 data. With social distancing, mask mandates, stay-at-home orders, and popularity of outdoor activities in flux, it remains unclear how COVID-19 has affected cumulative UV exposure. However, reduced public access to sunscreen is concerning and corroborates broader pandemic patterns of falling retail consumer sunscreen sales.2 Furthermore, declining Google search volumes for sunburns3 and precancerous or cancerous UV exposure-related dermatologic conditions4 could suggest a waning consumer interest in sun protection and consequent sun damage, as well as a decreased public perception of UV exposure risk. Additionally, required mask-wearing in public settings might contribute to reduced sunscreen use because combining masks with sunscreens can cause skin irritation, pruritus, and occlusion.5 Additionally, some may equate mask use to sufficient sun protection, although masks confer unknown and variable UV protection. Further research should directly investigate changes in individuals’ sunscreen application behaviors. Although limited by our 2-year periods of organizational distribution analysis, our findings highlight worrisome trends that may be suggestive of increased sun damage risk and warrant additional investigation. Consumer research has suggested that the pandemic has eroded consumer attitudes regarding sun protection, and a large fraction now only uses sunscreen on an as-needed basis (eg, long beach vacations or special occasions).2 Dermatologists can encourage greater awareness about sun protection for everyday outdoor experiences, for indoors, and during colder months, regardless of COVID-19–induced changes and mask-wearing. IMPACT Melanoma’s touch-free automated sunscreen dispensers and extensive virtual or online outreach programs will be advantageous. However, melanoma rates continue to rise, and the pandemic’s long-term effects are yet to be seen. As sunscreen application and UV exposure data become available in the near future, further examination of UV-associated skin cancer by state or region may be useful in informing outreach efforts and policy. Conflicts of interest Dr Dellavalle is a Joint Coordinating Editor for Cochrane Skin, a dermatology section editor for UpToDate, a Social Media Editor for the Journal of the American Academy of Dermatology (JAAD), a Podcast Editor for the Journal of Investigative Dermatology (JID), the Editor-in-Chief of the Journal of Medical Internet Research (JMIR) Dermatology, a coordinating editor representative of the Cochrane Council, and the Co-Chair of the Colorado Skin Cancer Task Force. Dr Dellavalle receives editorial stipends (JAAD and JID), royalties (UpToDate), and expense reimbursement from Cochrane Skin. Dr Hugh participated in fundraising for IMPACT Melanoma. Drs Maghfour, Rundle, and Presley and Authors Szeto, Kokoska, Harp, Hamp, and Wegener have no conflicts of interest to declare. We thank Deb Girard and Laurie Seavey from IMPACT Melanoma for assistance with data access and input on this project and mapchart.net for the use of its map-builder application. Authors Szeto and Kokoska are co-first authors. Funding sources: No funding was received to assist with the preparation of this manuscript. IRB approval status: Not applicable. Key words: COVID-19; IMPACT Melanoma; pandemic; photoprotection; public health; skin cancer; sunscreen; sunscreen dispensers. ==== Refs References 1 Eason C.D. Rundle C. Dunnick C.A. Hugh J. Dellavalle R.P. National trends in free public sunscreen dispensers J Am Acad Dermatol 84 4 2021 1109 1111 10.1016/j.jaad.2020.05.136 32504723 2 Guinaugh O. Skin Protection: Incl Impact of COVID-19 - US - November 2020. Mintel https://www.mintel.com/ 3 Boothby-Shoemaker W. Lim H.W. Kohli I. Ozog D.M. Changes in Google search for “sunburn” during the COVID-19 pandemic Photodermatol Photoimmunol Photomed 37 5 2021 474 475 10.1111/phpp.12684 33830570 4 Guzman A.K. Barbieri J.S. Analysis of dermatology-related search engine trends during the COVID-19 pandemic: implications for patient demand for outpatient services and telehealth J Am Acad Dermatol 83 3 2020 963 965 10.1016/j.jaad.2020.05.147 32505780 5 Kaul S. Jakhar D. Kaur I. Occlusion and face masks: issues with sunscreen use among health care workers during COVID-19 Dermatol Ther 33 6 2020 e14259 10.1111/dth.14259
PMC008xxxxxx/PMC8799990.txt
==== Front Vis Comput Vis Comput The Visual Computer 0178-2789 1432-2315 Springer Berlin Heidelberg Berlin/Heidelberg 35125576 2406 10.1007/s00371-022-02406-4 Original Article Fingerprint-based robust medical image watermarking in hybrid transform http://orcid.org/0000-0002-8972-8860 Vaidya S. Prasanth Dr. S. Prasanth Vaidya is currently working as Associate Professor in Department of Computer Science and Engineering, Aditya Engineering College (A), Surampalem, Andhra Pradesh, India. He received his Ph.D., in Computer Science and Engineering (Digital Watermarking), from Vellore Institute of Technology, Vellore. He received B.Tech degree in Computer Science and Engineering from Acharya Nagarjuna University and M.Tech degree in Information Technology fromGITAM University, India. His current research interests are digital image processing, pattern recognition, computer vision, and digital watermarking. He has published 13 refereed research papers in various international journals and conferences. He is a reviewer for many international conferences and journals. grid.411829.7 0000 0004 1775 4749 Department of Computer Science and Engineering, Aditya Engineering College (A), Surampalem, Andhra Pradesh 533437 India 29 1 2022 2023 39 6 22452260 7 1 2022 © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. To protect the medical images integrity, digital watermark is embedded into the medical images. A non-blind medical image watermarking scheme based on hybrid transform is propounded. In this paper, fingerprint of the patient is used as watermark for better authentication, identifying the original medical image and privacy of the patients. In this scheme, lifting wavelet transform (LWT) and discrete wavelet transform (DWT) are utilized for amplifying the watermarking algorithm. The scaling and embedding factors are calculated adaptively with the help of Local Binary Pattern values of the host medical image to achieve better imperceptibility and robustness for medical images and fingerprint watermark, respectively. Two-level decomposition is done where for the first level LWT is utilized and for the second level decomposition DWT is utilized. At the extraction side, non-blind recovery of fingerprint watermark is performed which is similar to the embedding process. The propounded design is implemented on various medical images like Chest X-ray, CT scan and so on. The propounded design provides better imperceptibility and robustness with the combination of LWT–DWT. The result analysis proves that the proposed fingerprint watermarking scheme has attained best results in terms of robustness and authentication with different medical image attacks. Peak Signal to Noise Ratio and Normalized Correlation Coefficient metrics are used for evaluating the proposed scheme. Furthermore, superior results are obtained when compared to related medical image watermarking schemes. Keywords Medical image watermarking Lifting wavelet transform (LWT) Discrete wavelet transform (DWT) Local binary pattern (LBP) Non-blind watermarking Electronic patient record (EPR) issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2023 ==== Body pmcIntroduction Fig. 1 Various classifications of watermarking schemes The corona virus COVID-19 pandemic is the defining global health crisis of our time and the greatest challenge we have faced since World War Two. The WHO formally declared the novel corona-virus severe acute respiratory syndrome corona-virus 2 [1]. To reduce the risk of person-to-person viral transmission during the COVID-19 pandemic, government introduced social distancing and other measures. Many hospitals have closed their doors to patients who have been trying to avail the facilities and doctors are not encouraged to meet the patient directly [7]. With all these considerations, now-a-days every doctor is meditating the patients through online only. Previously many metropolitan cities and multi-specialty clinics are only maintaining online data of patients reports and records. Due to the present situation, every doctor is asking the patients and hospital management to send the record online to diagnose the patient report. Transfer of medical records of patients over a communication channel is known as telemedicine. American Telemedicine Association (ATA) defined telemedicine as the medical data that are transferred from one location to another location through electronic communication channel for improving the patients health status [32]. During the communication channel, the patients data should not be corrupted or modified or morphed at the receiver side; it may lead to serious trouble to patient while diagnosis. For small hospitals, maintaining and storing Electronic Patient Record (EPR) is of great concern [25]. The EPR data containing patient details, like diagnosis, disease, treatment and so on, have to be maintained confidentially [35]. For this reason, security to the medical image is required, which can be achieved with watermarking technique with minimum probability of error. The medical image is used as host image to deplete the chance of tampering or modification. Depending on the information required at the extraction side to get the watermark along with the key, watermarking is classified into three types: blind, non-blind and semi-blind [40]. Without the watermark information, the watermark can be extracted in blind watermarking. Original host data and keys are required in non-blind watermarking, partial host data and key are required in semi-blind watermarking [39]. In all the three types, non-blind watermarking extraction offers better robustness compared to other two classifications. The watermarking scheme can be classified into spatial and transform domain based on the type of embedding [29]. Transform domain provides better robustness against attacks with high embedding capacity of watermark compared to spatial domain [41]. The watermarking scheme is also classified into visible or perceptible and imperceptible or invisible watermarking based on the perceptibility of the watermark in the watermarked image. Perceptible watermarks are visible to naked eye, whereas imperceptible are not visible to the naked eye. Another watermarking classification that is based on resistance is robust and fragile. Robust watermarking scheme can withstand intentional and unintentional attacks, whereas fragile watermarking schemes cannot withstand minor modifications on the watermarked image. The watermarking scheme is designed based on applications of multimedia like “text, audio, image and video”. The applications of watermarking scheme are Copyright Protection, Copy Control, Data Authentication, Fingerprinting, Broadcast Monitoring and so on. Various classifications of watermarking schemes are provided in Fig. 1. Nowadays much research is going on in hybrid transform by combining different transformation techniques to increase the robustness and embedding capacity. This research article proposed a robust non-blind watermarking scheme for copyright protection, ownership identification and authentication of medical images in hybrid domain. In the proposed approach, fingerprint is considered as watermark for medical data of the patients. As the medical data of the patient are private data where the data should not be authorized by unknown persons. To make the authentic authorization of the data, direct finger print of the data is included to provide security to the medical image. Watermarking can be embedded into a host image through different transform operations, such as discrete cosine transform (DCT), discrete wavelet transform (DWT), lifting wavelet transform (LWT) and so on. However, a single transformation does not ensure all the design requirements simultaneously. To fill this gap, a hybrid digital image watermarking with a combination of LWT-DWT is proposed in this paper. The main purpose of hybrid transform is to develop LWT-DWT-based robust and invisible image watermarking scheme for obtaining a better tradeoff between imperceptibility and robustness requirements. Literature survey Anand et al. [3] propounded an improved DWT–SVD domain watermarking for medical information security. Hamming code is utilized to reduce the noise distortion of the text watermark. They have tested on two different encryption schemes and three different compression schemes and considered Chaotic-LZW (Lempel–Ziv–Welch) as the best. Kahlessenane et al. [14] presented a robust blind watermarking scheme that accepts the incorporation of EPR into computerized tomography scan. Zigzag scanning method is utilized in selecting the subband of wavelet transform. Their results showcase the method is good against geometric and destructive attacks. Fares et al. [7] proposed two blind watermarking schemes with combination of DCT-Schur and DWT-Schur. Their method results provide robust against conventional attacks. Yuan et al. [47] developed color image watermarking method using DCT in spatial domain. An effective watermarking algorithm based on Lagrangian support vector regression (LSVR) & LWT is designed [24] by considering the advantages of fast implementation, fast learning speed and high generation capacity compared to previous conventional methods. Sing et al. [36] developed a semi blind gray scale watermarking scheme by using nonsubsampled contourlet transform and redundant discrete wavelet transform (RDWT) and SVD decomposition methods. Amit et al. [34] presented a paper on spread spectrum depended watermarking system using selective DWT approach. Amit et al. [33] presented a multiple watermarking scheme using DWT, DCT and SVD decomposition. Amit et al. [31] presented a hybrid multilevel watermarking scheme by fusing DWT, DCT and SVD decomposition techniques. Chandan et al. [17] presented a paper on improved watermarking scheme by using DWT, DCT and SVD. Further set partitioning in hierarchical tree and Arnold transform are utilized to improve the security. Priyank et al. [16] proposed a watermarking scheme based on homomorphic transform, RDWT and SVD decompositions. Watermark insertion is done using principal components to handle attacks where region of interest (ROI) of compressed image is hidden using LZW [2]. The watermark generated with compressed image ROI allows 100% reversibility of the ROI. An imperceptible and zero watermarking for robust medical images is proposed [5]. Using modified spread spectrum method, the retaliation of the imperceptible watermarking detector & watermark data, the zero watermarking process authenticates the patient identity. Kannammal et al. [15] developed an algorithm with 2-level security with embedding and also with encryption using RSA and other algorithms. Sharma et al. [30] developed a method using digital multitoning in embedding binary watermark. Combining LSVR and LWT has reduced the time complexity as well. To overcome the issues of information security (authentication), David et al. [23] proposed a hybrid watermarking scheme using quantization index modulation method beneath ditcher modulation in collaboration with error correction forwarding in embedding. Thakur et al. [38] proposed a multilayer security for medial data by utilizing chaotic encryption. Hosny et al. [10] proposed a novel geometrically invariant multiple zero watermarking method for medical images. A set of multi-channels shifted Gegenbauer moments of fractional orders are used to extract invariant features from color medical images. Hosny et al. [11] have computed the moments of the polar complex exponential transform (PCET) and quaternion PCET in securing medical images for authentication. Hosny et al. [9] utilized Quaternion Legendre–Fourier moments for developing color image watermarking. Hosny et al. [8] utilized highly accurate moments of polar harmonic transforms for designing watermarking algorithm. All the literature provided above is related to only medical image watermarking. They have followed different types of watermarking approaches based on extraction, and in embedding watermark different transformation techniques methods are utilized (most commonly DWT, DCT, LWT). The proposed watermarking approach can overcome the problems of authentication by embedding the fingerprint watermark. As the medical images are vulnerable to attacks, the proposed method has overcome that by using hybrid transformation and using adaptive embedding factor values for images. In the proposed scheme, 4 subbands LL, LH, HL and HH are obtained after 1 level LWT. LL is selected based on its efficient properties. The LL subband is again decomposed for 1 level using DWT then embedding the fingerprint watermark into it. The motivation behind this combination is to enhance the imperceptibility and the robustness. The imperceptibility requirement is achieved by using magnitudes of LWT coefficients, while robustness improvements are provided by applying DWT to LWT coefficients. The watermark is embedded by modifying the coefficients of DWT using secret keys.Fig. 2 Decomposition of Lifting Wavelet Transform Fig. 3 1-Level Decomposition of Discrete Wavelet Transform Representation Methods used Lifting wavelet transform Over the past few years, LWT developed by Daubechies [6], enhanced as a husky tool for analysis of image because of systematic and fast implementation of LWT compared to conventional wavelet transform [18]. LWT has given best results in the area of watermarking, image compression, pattern recognition, feature extraction and image de-noising [42]. LWT saves a lot of time and also has superior results in frequency localizing frequency features that conquer the drawback of conventional wavelets [21, 24]. LWT decomposition of a signal is done with splitting, prediction and update steps as shown in Fig. 2. Step 1: Splitting In this step, the host signal S[n] is decomposed into non-overlapping odd and even signal samples as So[n] and Se[n] which can be seen in Eq. 1.1 Se[n]=S[2n],So[n]=S[2n+1] Step 2: Prediction In this step, both odd and even sample signals are correlated for predicting as shown in Eq. 2.2 ds[n]=So[n]-P(Se[n]) where ds[n] is the difference the host signal sample and its predicted signal (high frequency component) using prediction operator P(.). Step 3: Update The even samples are updated with the help of step 1 and step 2 i.e., detailed signal (ds[n] and update operator (U(.)). The rough shape of the host signal can be obtained with low frequency component lfc[n] as shown in Eq. 3.3 lfc[n]=Se[n]+U(ds[n]) Discrete wavelet transform (DWT) DWT breaks down an image or signal into four subbands, SLL lower resolution approximation module, and other three spatial directional modules are horizontal module SHL, vertical module SLH and module SHH. The characteristics of the DWT image multi-resolution break down, and the image features are extremely consistent for selecting the spatial orientation. The filters applied on the DWT will be done along the rows and columns with the help of low pass and high pass resolvers (Lo_D, Hi_D), respectively. Mathematically, the host signal or image S(a, b), the first level break down is shown in Eq. (4). The decomposition of signal into subbands and sample X-ray image 1-level decomposition is represented in Fig. 3.4 LL(i,j)=⟨S(a,b),Ψ0(a-2i,b-2j)⟩LH(i,j)=⟨S(a,b),Ψ1(a-2i,b-2j)⟩HL(i,j)=⟨S(a,b),Ψ2(a-2i,b-2j)⟩HH(i,j)=⟨S(a,b),Ψ3(a-2i,b-2j)⟩ Local binary pattern (LBP) Ojala et al. [26, 27] first developed LBP, initially utilized to calculate the local contrast in analysis of texture in images. LBP is utilized in many fields of image and video processing like text analysis, image authentication and image forgery detection due to its property of efficient texture feature descriptor [20]. LBP breaks down an image into multiple sub-blocks of size n × n. The centre pixel value is utilized as a threshold value to decide the neighbouring pixel values by setting the smaller values as 0 and remaining as 1 by comparing with centre pixel, i.e., threshold value. The clockwise values of the binary values are considered and converted to decimal form. The LBP is formulated as shown in Eq. 5. The sample block operator of 3 × 3 block and its local binary pattern conversion from binary to decimal are shown in Fig. 4.5 LBP(aj,bj)=∑i=0i=∞S(Pi-Pj)2i where Pj is central pixel (aj,bj) value and Pi are corresponding pixel values. S is sign function defined as6 S(a)=1,x≥0,0,otherwise Fig. 4 3 × 3 Block LBP operator a Image block and b Local Binary Pattern of (a) block The most important property of the LBP function in real-world applications is its robustness to monotonic gray-scale changes caused by illumination variations compared to other features. Other advantage of LBP is it has high discriminative power with simple computation. Arnold transform In the propounded watermarking scheme, Arnold Cat Transform is endorsed to provide assurance about the security of the scheme. The general Arnold Cat Transform is interpreted as follows:7 g′h′=1ijij+1gh(modN) where (g, h) is the native position of the pixels in the image and (g′,h′) are the corresponding positions of the pixels in the image after permutation. The controls panels a and b will be used to change the position of the image pixels, and N is the size of the image. For different image sizes and parameters, period T will be different in Arnold transform. The image pixels will be back to its native position after certain permutations. Here, in applying the Arnold transform, the image gets scrambled and also we can use the T value as a key to provide better security to the scheme [44]. The propounded watermarking design In the propounded watermarking scheme, approximation coefficients of LWT and SLL lower resolution approximation module of DWT is utilized in immersing the fingerprint watermark of the patient because of maximum energy of the image is strenuous in low resolution approximation and also more robust and efficient to attacks of image and signal processing. Immersing the fingerprint watermark in the SLL is highly perceivable for human eye. The propounded watermark embedding design using the combination of LWT–DWT with LBP feature values and semi-blind watermark extraction using the keys are given in the following subsections. The idea of applying two transform or hybrid transform is based on the fact that combined transforms could compensate the drawbacks of each other, resulting in effective watermarking. The LBP features are considered for calculating scaling and embedding factor adaptively because of its robustness to monotonic gray-scale changes caused by illumination variations compared to other features. The reason for combination of LWT–DWT combination can be observed from the Table 1. A medical image has been tested with combination of 2 level DWT, 2-level LWT and combination of LWT–DWT with various attacks. From the results, it is clear that the combination is robust to attacks compared to their transformations. For calculating the embedding factor, LBP features are utilized since it extracts texture features of an image which is robustness to monotonic grayscale changes.Table 1 Reason for selecting the combination of transformations Model\attacks DWT 2-Level LWT 2-Level LWT–DWT S & P Attack 0.9920 0.9925 0.9935 Gaussian Attack 0.9605 0.9617 0.9673 Scaling Attack 0.9980 0.9985 1.00 Rotation 0.9905 0.9912 0.9956 Cropping 0.9895 0.9908 0.9937 Mean Filtering 0.9669 0.9684 0.9797 Propounded watermark embedding design using LWT–DWT–LBP In this embedding scheme, adaptive watermark is embedded in the hybrid transform of medical image with patient fingerprint watermark. The propounded watermarking embedding design is represented in Fig. 5.Fig. 5 Propounded Watermark Embedding Design using LWT–DWT–LBP In the above propounded watermark embedding Algorithm 1, HMI represents host medical image, FPW represents fingerprint watermark, and μ represents the mean of the LBP features. The steps of embedding fingerprint watermark into the medical image are given below. Step 1 Scan the fingerprint watermark and host medical image Step 2 Applying LWT for 1–Level to host medical image produces approximation coefficients (CA) and details coefficients (CH, CV, CD) Step 3 For the approximation coefficients (CA), 1–Level DWT is applied by producing low (LL), diagonal (LH, HL) and high (HH) resolution coefficients. Step 4 Low-resolution approximation (LL) is considered for embedding fingerprint watermark using the mean of the LBP features of host medical image Step 5 Embedding of the fingerprint watermark is done using the embedding and scaling factor as represented in Algorithm 1 and is also shown below where α and β are scaling and embedding factor values.8 HMI^=α×LL+β×FPW Step 6 Inverse DWT is applied by combining watermarked LL subband with remaining subbands. Step 7 Inverse LWT is applied by combining watermarked CA with remaining coefficients to form Imperceptible Watermarked Medical Image. Step 8 Further, to improve security, Arnold transform is applied to the watermarked medical image with a secret key in generating the scrambled watermarked medical image. The function of Arnold transform is to scramble the image so that the intruders cannot know the image. The reason for adding at the end of the embedding is to overcome tampering of medical images. To add extra security to the host medical image Arnold Transform is applied at the end of the process. Propounded watermark extraction design using LWT–DWT–LBP In this extraction scheme, adaptive patient fingerprint watermark is extracted in the hybrid transform from watermarked medical image. The propounded watermarking extraction design is represented in Fig. 6.Fig. 6 Propounded Watermark Extraction Design using LWT–DWT–LBP In the above propounded watermark extraction Algorithm 2, AHMIfpw represents scrambled watermarked host medical image, LL represents the decomposition of the watermark with LWT followed by DWT subband, and α&β represents the embedding and scaling factor. The steps of extraction of fingerprint watermark from imperceptible watermarked medical image are given below. Step 1 Scan the scrambled watermarked host medical image(AHMIfpw) Step 2 Apply inverse Arnold transform with secret key (Key-3) to descramble the medical image in generating watermarked host medical image. Step 3 Applying LWT for 1–Level to watermarked host medical image produces watermarked approximation coefficients (CAw) and watermarked details coefficients ((CHw,CVw,CDw)) Step 4 For the watermarked approximation coefficients (CAw), 1–Level DWT is applied by producing watermarked low (LLw), diagonal (LHw,HLw) and watermarked high (HHw) resolution coefficients.Fig. 7 Sample Host Medical images of X-Ray, CT, US, MRI that are utilized in the propounded watermarking scheme Fig. 8 Sample Fingerprint Images Step 5 Watermarked low-resolution approximation (LLw) is considered for extracting fingerprint watermark by using the same keys (Key-1 & Key-2) that are used in embedding the watermark represented in Algorithm 2. Experimental results The propounded medical image watermarked scheme is evaluated and scrutinized by numerous medical images like X-Ray, CT, US and MRI. For the easy analysis, the image names are considered as alphabets. The medical images of size 512×512 pixels and the fingerprint images of size 128×128 pixels are considered and shown in Figs. 7 and 8. “Matlab” is utilized in executing the propounded schemes. The sample twelve medical images are taken from Fontaine medical records [22] dataset. The fingerprints are taken from Kaggle dataset [13]. Effectiveness of the propounded watermarking scheme is thoroughly estimated by applying attacks against it. Peak-signal-to-noise-ratio (PSNR) and structural similarity index (SSIM) are the measures utilized for estimating perceptual characteristics [43]. PSNR is utilized in calculating the visual similarity between the host image and the watermarked image [34]. After embedding the watermark, both the host image and watermarked image should look a like with minor distinction between them [12].9 MSE=∑i=0m-1∑j=0n-1HMIi,j-(HMIfpw)i,j2mn 10 PSNR=20log10MAXHMIMSE where MAXHMI is maximum gray scale value of the image. SSIM is a measure utilized to evaluate structural similarity between the host image and the watermarked image [37, 48]. SSIM includes luminance, contrast and structural functions used for comparing. SSIM value should be near to unity. SSIM is mathematically shown as:11 SSIM(HMI,HMIfpw)=l,c,s{((HMI,HMIfpw))} Normalized Correlation coefficient (NCC) aids in estimating the robustness of the propounded method with attacks [46]. NCC computes the similarity between the patient fingerprint and extracted patient fingerprint. The values nearer to one mean the propounded method is sustain the image and signal processing attacks [4, 19].12 NCC=∑∑fpw×fpwE(∑fpw2)(∑(fpwE)2) Number of changing pixel rate (NPCR) and unified averaged changed intensity (UACI) are the evaluating measures that are utilized for calculating the credibility of the propounded scheme against different attacks [45]. NCPR calculates the number of changing pixel rate, and UACI calculates the difference of average change in the intensities between the watermarked image and encrypted watermarked image [28] Table 2.13 NCPR=∑i,jD{i,j}M×M where M×M is the size of the image and D{i,j} denotes14 D{i,j}=0(HMIfpw)=(AHMIfpw)1(HMIfpw)≠(AHMIfpw) 15 UACI=1M×M∑i,j(HMIfpw)-(AHMIfpw)255×100 The imperceptibility test and robustness testing with the metrics on the twelve medical images with no attacks are shown in Table 3. These measures attained values nearer to one which claims for good structural similarity between the host image and watermarked image. Visible similarity for the propounded scheme is measured with PSNR values which are above 30 dB which means the quality of the watermarked image is good. The SSIM is a metric used to quantify perceptual quality of an image during the communication channel. The SSIM values are calculated between original medical image and watermarked image. The SSIM values for all the images are above 0.98, which means the proposed algorithm has provides good image quality after watermark embedding. The closer the SSIM values to 1 means the quality of the watermarked image is high. From the results table, it is clear that for all the medical images the quality of the image is good. The similarity between the patient fingerprint and the extracted fingerprint is measured with NCC. The closer the value of NCC to one symbolizes for resilience of the propounded method against attacks. NPCR and UACI have the ability to assess potentiality of the propounded scheme against various attacks. The NPCR and UACI measure values are above their limiting values. The embedding factor values are calculated adaptively by utilizing the LBP features of the host medical image. The adaptively calculated values for the sample twelve medical images are given in Table 2.Table 2 Adaptively calculated embedding factor values for medical images Images Embedding factor Images Embedding factor Images Embedding factor a 0.2526 e 0.0905 i 0.2931 b 0.1353 f 0.2322 j 0.1289 c 0.2247 g 0.2743 k 0.2360 d 0.2434 h 0.2004 l 0.0898 Table 3 Propounded scheme performance analysis with help of measure values Images PSNR(dB) SSIM NCPR UACI NCC a 36.00 0.9884 0.9995 0.2321 1.00 b 34.12 0.9863 0.9512 0.2977 1.00 c 37.07 0.9815 0.9948 0.2192 1.00 d 36.09 0.9865 0.9978 0.2761 1.00 e 34.81 0.9806 0.9638 0.2884 1.00 f 36.56 0.9821 0.9989 0.2744 1.00 g 35.43 0.9857 0.9988 0.2837 1.00 h 37.80 0.9665 0.9814 0.2847 1.00 i 34.52 0.9868 0.9971 0.2754 1.00 j 33.85 0.9844 0.9674 0.3333 1.00 k 36.47 0.9878 0.9782 0.2798 1.00 l 34.61 0.9738 0.9723 0.2788 1.00 The watermarked images with fingerprint watermark, scrambled and unscrambled watermarked images with Arnold and Inverse Arnold transform, Extracted fingerprint watermarks are shown in Fig. 9. Robustness analysis of the propounded watermarking scheme under attacks of Salt & Pepper Noise (0.001), Gaussian Noise (0.01, 0.002), Sharpening, Scaling (2, 0.5), and JPEG Compression is shown in Table 4. From this table, the extracted fingerprint watermark is of good quality which can be viewed from third column and NCC values nearer to 1 tell the fingerprint is extracted successfully.Fig. 9 Sample watermarked images after embedding with patient fingerprint watermark, Scrambled watermarked Images, Descrambled Images, Extracted Fingerprint Watermarks Table 4 Robustness analysis of the propounded watermarking scheme under attacks Table 5 Robustness evaluation using NCC under various attacks Attacks Metric value NCC values a b c d e f g h i j k l Salt & Pepper Noise 0.001 0.9935 0.9821 0.9914 0.9958 0.9392 0.9950 0.9888 0.9920 0.9969 0.9792 0.9941 0.9664 0.002 0.9890 0.9707 0.9852 0.9918 0.9116 0.9912 0.9849 0.9871 0.9941 0.9628 0.9899 0.9386 Gaussian noise (0,0.002) 0.9673 0.9453 0.9613 0.9754 0.8529 0.9708 0.9626 0.9682 0.9823 0.9361 0.9745 0.9137 (0.01,0.002) 0.9725 0.9612 0.9696 0.9809 0.8971 0.9771 0.9680 0.9749 0.9856 0.9548 0.9795 0.9410 Speckle Noise 0.0001 0.9964 0.9988 0.9952 0.9994 0.9611 0.9987 0.9899 0.9995 0.9996 0.9974 0.9996 0.9977 Scaling (2,0.5) 0.9999 0.9988 0.9997 0.9997 0.9978 0.9998 0.9998 0.9996 0.9998 0.9985 0.9996 0.9987 JPEG compression 90 0.9997 0.9942 0.9990 0.9992 0.9908 0.9996 0.9997 0.9987 0.9996 0.9943 0.9991 0.9961 Mean filtering 3×3 0.9797 0.9675 0.9882 0.9896 0.8571 0.9833 0.9925 0.9891 0.9925 0.9314 0.9890 0.9508 Median filtering 3×3 0.9977 0.9012 0.9831 0.9892 0.8942 0.9969 0.9962 0.9778 0.9934 0.9370 0.9875 0.9514 Rotation 2 degrees 0.9956 0.9936 0.9928 0.9934 0.9958 0.9914 0.9923 0.9933 0.9941 0.9937 0.9929 0.9916 Cropping 10 % 0.9937 0.9925 0.9778 0.8901 0.9925 0.9003 0.8713 0.9727 0.9759 0.9604 0.9914 0.8197 Scaling + JPEG Compression (0.75, 90) 0.9912 0.9904 0.9715 0.8910 0.9909 0.8998 0.8705 0.9713 0.9741 0.9600 0.9908 0.8188 Scaling + Rotation (0.75, 2 degrees) 0.9865 0.9898 0.9815 0.9010 0.9915 0.9006 0.8815 0.9801 0.9816 0.9649 0.9913 0.8288 The NCC values for all the sample images (a to l) with Salt & Pepper, Gaussian Noise, Speckle Noise, Scaling, JPEG Compression, Mean Filtering, Median Filtering, Rotation and Cropping attacks are provided, respectively. In case of Salt & Pepper noise attack, medical images are distorted by adding salt & pepper noise with density 0.001 and 0.002. The NCC values of the extracted watermark drop from 0.99 to 0.96 on an average when the noise density increases. In Gaussian noise, medical images are distorted in the similar way with mean and variance (0, 0.002) and (0.01, 0.002). The NCC values of extracted fingerprints drop upto 0.95 on average. In Speckle noise with density 0.0001, the extracted fingerprint has a high NCC with 0.98. The medical images are re-sized at various scales: up-sampled twice and down-sampled half the size of the medical image. Even in varying the scaling of the image, the proposed method NCC values achieved high with 0.99. In case of Mean and Median Filtering attacks, the mask of size 3×3 is applied. The extracted fingerprint watermark NCC values have achieved 0.97 for mean filtering and 0.98 for median filtering on an average. In case of rotation attack, the medical images are rotated with 2 degrees in clock wise direction. The extracted fingerprint watermark has a high NCC with 0.97 on an average. In case of cropping, 10 percent of the medical image is cropped. The extracted fingerprint has NCC with 0.98 on an average. NCPR and UACI measure values under five attacks for sample images (a, b, c, d, e) are graphically represented in Figs. 10 and  11. The attacks are “Salt & Pepper noise (0.001), Salt & Pepper noise (0.002), Gaussian noise (0, 0.0002), Gaussian noise (0.01, 0.0002) and Speckle noise(0.001)” indicated as Atk 1 to Atk 5. It can be observed that NPCR and UACI values under different attacks are satisfactory and are under acceptable range Table 5.Fig. 10 Graphical representation of NPCR values under different attacks Fig. 11 Graphical representation of UACI values under different attacks Table 6 Robustness comparison between propounded method and other watermarking prevailing methods Methods/attacks [38] [36] [34] [33] [31] [24] [17] [16] Proposed S & P (0.001) – – – 0.9843 0.9938 0.9657 0.9969 0.9987 0.9969 Gaussian Noise (0,0.001) – 0.9965 – 0.9365 0.9591 0.9342 0.9874 0.9903 0.9941 Median Filt [2 2] 0.6923 0.9949 0.9939 0.9752 0.9379 1 – 0.9981 0.9987 JPEG Comp (90) 0.9896 0.9951 0.9935 0.9785 0.9988 1 – 0.9993 0.9997 Scaling [ 2 0.5] – – – 0.7375 – 0.9957 – 0.9992 0.9999 Mean Filt[2 2] – – 0.9951 – – 1 – 0.9968 0.9983 Fig. 12 Graphical comparison of proposed method Table 7 Imperceptibility comparison between propounded method and other watermarking prevailing methods Methods PSNR values [38] 35.52 [36] 33.21 [34] 34.64 [33] 32.48 [31] 34.64 [24] 45.42 [17] 34.68 [16] 55.85 Proposed 36.00 Potency of the propounded method can be seen in Table 6 where it is compared with the other medical watermarking methods like [16, 17, 24, 31, 33, 34, 36, 38]. From the comparison results, it is clear that the propounded method has competed with the remaining techniques in terms of robustness. In Table 7, the imperceptibility of the watermarking schemes are compared with the proposed scheme, from all the methods the proposed method imperceptibility is high except for [16] method and in comparison with [24] proposed method results are better for noise attacks, and for all the remaining attacks they are almost similar. Graphical comparison (Same attacks of Table 6) of propounded method with [16, 33] is shown in Fig. 12. From the figure, it is clear that the robustness of the propounded method is far above than the other methods under similar attacks. Conclusion and future work The propounded scheme in this paper provides a novel method of medical image watermarking scheme in hybrid domain in which salient features of LWT, DWT and LBP are considered. LBP values are used to calculate the embedding factor values adaptively which acts as keys. Embedding fingerprint watermark of the patient in speculating component safeguards better robustness and imperceptibility of the watermark in resisting image and signal processing attacks. A triple layer security is provided to the scheme with Arnold transform which protects the medical image from modifications and tampering. The performance of the propounded scheme is better compared to other watermarking schemes in terms of metric evaluation. This paper provides an adaptive medical image watermarking scheme using hybrid transform and fingerprint of patient as watermark for e-health care systems. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ==== Refs References 1. Albahri OS Zaidan AA Albahri AS Zaidan BB Abdulkareem KH Al-Qaysi ZT Alamoodi AH Aleesa AM Chyad MA Alesa RM Systematic review of artificial intelligence techniques in the detection and classification of covid-19 medical images in terms of evaluation and benchmarking: taxonomy analysis, challenges, future solutions and methodological aspects J. Infect. Public Health 2020 13 1381 10.1016/j.jiph.2020.06.028 32646771 2. Alshanbari HS Medical image watermarking for ownership & tamper detection Multimed. Tools Appl. 2020 80 1 16 3. Anand A Singh AK An improved DWT–SVD domain watermarking for medical information security Comput. Commun. 2020 152 72 80 10.1016/j.comcom.2020.01.038 4. Aparna P Kishore PVV Biometric-based efficient medical image watermarking in e-healthcare application IET Image Process. 2019 13 3 421 428 10.1049/iet-ipr.2018.5288 5. Cedillo-Hernandez M Cedillo-Hernandez A Nakano-Miyatake M Perez-Meana H Improving the management of medical imaging by using robust and secure dual watermarking Biomed. Signal Process. Control 2020 56 101695 10.1016/j.bspc.2019.101695 6. Daubechies I Sweldens W Factoring wavelet transforms into lifting steps J. Fourier Anal. Appl. 1998 4 3 247 269 10.1007/BF02476026 7. Fares K Khaldi A Redouane K Salah E DCT & DWT based watermarking scheme for medical information security Biomed. Signal Process. Control 2021 66 102403 10.1016/j.bspc.2020.102403 8. Hosny KM Darwish MM Invariant image watermarking using accurate polar harmonic transforms Comput. Electr. Eng. 2017 62 429 447 10.1016/j.compeleceng.2017.05.015 9. Hosny KM Darwish MM Robust color image watermarking using invariant quaternion Legendre–Fourier moments Multimed. Tools Appl. 2018 77 19 24727 24750 10.1007/s11042-018-5670-9 10. Hosny KM Darwish MM New geometrically invariant multiple zero-watermarking algorithm for color medical images Biomed. Signal Process. Control 2021 70 103007 10.1016/j.bspc.2021.103007 11. Hosny KM Darwish MM Li K Salah A Parallel multi-core CPU and GPU for fast and robust medical image watermarking IEEE Access 2018 6 77212 77225 10.1109/ACCESS.2018.2879919 12. Huang Y Niu B Guan H Zhang S Enhancing image watermarking with adaptive embedding parameter and PSNR guarantee IEEE Trans. Multimed. 2019 21 10 2447 2460 10.1109/TMM.2019.2907475 13. JinZhuXing. Fingerprint database. February 2020. https://www.kaggle.com/peace1019/fingerprint-dataset-for-fvc2000-db4-b 14. Kahlessenane F Khaldi A Kafi R Euschi S A DWT based watermarking approach for medical image protection J. Ambient Intell. Humaniz. Comput. 2021 12 2 2931 2938 10.1007/s12652-020-02450-9 15. Kannammal A Subha Rani S Two level security for medical images using watermarking/encryption algorithms Int. J. Imaging Syst. Technol. 2014 24 1 111 120 10.1002/ima.22086 16. Khare P Srivastava VK A secured and robust medical image watermarking approach for protecting integrity of medical images Trans. Emerg. Telecommun. Technol. 2021 32 2 e3918 17. Kumar C Singh AK Kumar P Improved wavelet-based image watermarking through SPIHT Multimed. Tools Appl. 2020 79 15 11069 11082 10.1007/s11042-018-6177-0 18. Lei B Soon Y Zhou F Li Z Lei H A robust audio watermarking scheme based on lifting wavelet transform and singular value decomposition Signal Process. 2012 92 9 1985 2001 10.1016/j.sigpro.2011.12.021 19. Li B-J Wang Q-B Duan D-P Chen J-A Using grey intensity adjustment strategy to enhance the measurement accuracy of digital image correlation considering the effect of intensity saturation Opt. Lasers Eng. 2018 104 173 180 10.1016/j.optlaseng.2017.08.006 20. Liao, S., Zhu, X., Lei, Z., Zhang, L., Li, S.Z.: Learning multi-scale block local binary patterns for face recognition. In: International Conference on Biometrics, pp. 828–837. Springer (2007) 21. Loukhaoukha, K., Chouinard, J.Y.: Hybrid watermarking algorithm based on SVD and lifting wavelet transform for ownership verification. In: 2009 11th Canadian Workshop on Information Theory, pp. 177–182. IEEE (2009) 22. Makhanov, S.: Medical record database. February (2020). https://www.onlinemedicalimages.com/index.php 23. Mata-Mendoza, D., Cedillo-Hernandez, M., Garcia-Ugalde, F., Cedillo-Hernandez, A., Nakano-Miyatake, M., Perez-Meana, H.: Secured telemedicine of medical imaging based on dual robust watermarking. Vis. Comput., 1–18 (2021). https://link.springer.com/article/10.1007/s00371-021-02267-3 24. Mehta R Rajpal N Vishwakarma VP A robust and efficient image watermarking scheme based on Lagrangian SVR and lifting wavelet transform Int. J. Mach. Learn. Cybern. 2017 82 379 395 10.1007/s13042-015-0331-z 25. Memon NA Chaudhry A Ahmad M Keerio ZA Hybrid watermarking of medical images for ROI authentication and recovery Int. J. Comput. Math. 2011 88 10 2057 2071 10.1080/00207160.2010.543677 26. Ojala, T., Pietikainen, M., Harwood, D.: Performance evaluation of texture measures with classification based on kullback discrimination of distributions. In: Proceedings of 12th International Conference on Pattern Recognition, vol. 1, pp. 582–585. IEEE (1994) 27. Ojala T Pietikäinen M Harwood D A comparative study of texture measures with classification based on featured distributions Pattern Recognit. 1996 29 1 51 59 10.1016/0031-3203(95)00067-4 28. Mohamed Parvees MY Samath JA Parameswaran Bose B Secured medical images—a chaotic pixel scrambling approach J. Med. Syst. 2016 40 11 1 11 26573639 29. Sanivarapu PV Rajesh KN Reddy NR Reddy NC Patient data hiding into ECG signal using watermarking in transform domain Phys. Eng. Sci. Med. 2020 43 1 213 226 10.1007/s13246-019-00838-2 30. Sharma S Zou JJ Fang G Significant difference-based watermarking in multitoned images Electron. Lett. 2020 56 18 923 926 10.1049/el.2020.1445 31. Singh AK Improved hybrid algorithm for robust and imperceptible multiple watermarking using digital images Multimed. Tools Appl. 2017 76 6 8881 8900 10.1007/s11042-016-3514-z 32. Singh AK Dave M Mohan A Multilevel encrypted text watermarking on medical images using spread-spectrum in DWT domain Wirel. Pers. Commun. 2015 83 3 2133 2150 10.1007/s11277-015-2505-0 33. Singh AK Dave M Mohan A Hybrid technique for robust and imperceptible multiple watermarking using medical images Multimed. Tools Appl. 2016 75 14 8381 8401 10.1007/s11042-015-2754-7 34. Singh AK Kumar B Dave M Mohan A Multiple watermarking on medical images using selective discrete wavelet transform coefficients J. Med. Imaging Health Inform. 2015 5 3 607 614 10.1166/jmihi.2015.1432 35. Singh AK Kumar B Dave M Mohan A Robust and imperceptible dual watermarking for telemedicine applications Wirel. Pers. Commun. 2015 80 4 1415 1433 10.1007/s11277-014-2091-6 36. Singh S Rathore VS Singh R Singh MK Hybrid semi-blind image watermarking in redundant wavelet domain Multimed. Tools Appl. 2017 76 18 19113 19137 10.1007/s11042-017-4570-8 37. Starovoytov VV Eldarova EE Takuadinovich Iskakov. K Comparative analysis of the SSIM index and the pearson coefficient as a criterion for image similarity. Eurasian J. Math. Comput. Appl. 2020 8 1 76 90 38. Sriti T Singh AK Ghrera SP Elhoseny M Multi-layer security of medical data through watermarking and chaotic encryption for tele-health applications Multimed. Tools Appl. 2019 78 3 3457 3470 10.1007/s11042-018-6263-3 39. Vaidya P Chandra Mouli PVSSR A robust semi-blind watermarking for color images based on multiple decompositions Multimedi. Tools Appl. 2017 76 24 25623 25656 10.1007/s11042-017-4355-0 40. Vaidya, S.P.: Multiple decompositions-based blind watermarking scheme for color images. In: International Conference on Recent Trends in Image Processing and Pattern Recognition, pp. 132–143. Springer (2018) 41. Vaidya SP Chandra Mouli PVSSR Adaptive digital watermarking for copyright protection of digital images in wavelet domain Procedia Comput. Sci. 2015 58 233 240 10.1016/j.procs.2015.08.063 42. Verma VS Jha RK Ojha A Significant region based robust watermarking scheme in lifting wavelet transform domain Expert Syst. Appl. 2015 42 21 8184 8197 10.1016/j.eswa.2015.06.041 43. Wang Z Bovik AC Sheikh HR Simoncelli EP Image quality assessment: from error visibility to structural similarity IEEE Trans. Image Process. 2004 13 4 600 612 10.1109/TIP.2003.819861 15376593 44. Wu, L., Zhang, J., Deng, W., He, D.: Arnold transformation algorithm and anti-Arnold transformation algorithm. In: 2009 First International Conference on Information Science and Engineering, pp. 1164–1167. IEEE (2009) 45. Yue W Noonan JP Agaian S NPCR and UACI randomness tests for image encryption Cyber J. Multidiscip. J. Sci. Technol. J. Sel. Areas Telecommun. 2011 1 2 31 38 46. Yoo J-C Ahn CW Image matching using peak signal-to-noise ratio-based occlusion detection IET Image Process. 2012 6 5 483 495 10.1049/iet-ipr.2011.0025 47. Yuan Z Qingtang S Liu D Zhang X Yao T Fast and robust image watermarking method in the spatial domain IET Image Process. 2020 14 15 3829 3838 10.1049/iet-ipr.2019.1740 48. Zhou M Wei X Wang S Kwong S Fong CK Wong PH Yuen WY Gao W SSIM-based global optimization for CTU-level rate control in HEVC IEEE Trans. Multimed. 2019 21 8 1921 1933 10.1109/TMM.2019.2895281
PMC008xxxxxx/PMC8831119.txt
==== Front Rev Fr Allergol (2009) Rev Fr Allergol (2009) Revue Francaise D'Allergologie (2009) 1877-0312 1877-0320 Elsevier Masson SAS. S1877-0320(22)00265-2 10.1016/j.reval.2022.02.218 Article Tryptase and anaphylaxis: The case for systematic paired samples in all settings, from the playground to the COVID-19 vaccination center Tryptase et anaphylaxie : de l’aire de jeux au centre de vaccination COVID, deux prélèvements sont nécessaires en toutes circonstancesVitte J. abc⁎ Gonzalez C. ab Klingebiel C. d Michel M. abe a IRD, MEPHI, Aix-Marseille Université, IRD, MEPHI, Marseille, France b IHU Méditerranée Infection, Marseille, France c University of Montpellier, Inserm UMR UA11, IDESP, Montpellier, France d Laboratoire Synlab Provence, Marseille, France e Laboratoire d’immunologie, CHU de Nîmes, Nîmes, France ⁎ Corresponding author. 11 2 2022 4 2022 11 2 2022 62 3 287288 7 2 2022 8 2 2022 © 2022 Elsevier Masson SAS. All rights reserved. 2022 Elsevier Masson SAS Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Keywords Anaphylaxis Hypersensitivity Mast cell Tryptase Mots clés Anaphylaxie Hypersensibilité Mastocyte Tryptase Abbreviations sAT serum acute tryptase sBT serum baseline tryptase ==== Body pmcAnaphylaxis is an immediate and potentially life threatening systemic reaction [1], associated with significant morbidity, mortality and much too frequent suboptimal management. Serum tryptase is the main and most widely available mast cell biomarker available for in vitro diagnostics. In the clinical setting, tryptase determination is commonly performed using the “total tryptase assay” (ImmunoCAP Tryptase, Thermo Fisher Scientific, Uppsala, Sweden), which has received significant technical improvement and related changes in median and upper limit values since its first release in 1995 [2]. Taking two tryptase samples with adequate timing has been recommended for the diagnosis of anaphylaxis and may also add mechanistic information. Indeed, anaphylaxis by itself does not provide clues for the underlying mechanism [2]. Adequate timing refers to paired acute (sAT) and baseline (sBT) serum tryptase determination, with sAT sample optimally taken 30-120 min after the onset of signs or symptoms and sBT sample drawn at least 24 hours after the complete resolution of all signs and symptoms. The current international consensus states that a transient elevation of sAT greater than [2 + (1.2 × sBT)] is indicative of mast cell degranulation [3]. This algorithm allows calculating an individual cut-off for each patient, based on sAT and sBT values: sAT exceeding [2 + (1.2 × sBT)] μg/L supports mast cell degranulation, even in cases when sAT remains in the normal reference range. Paired sAT and sBT determination increases both the sensitivity and the specificity of anaphylaxis diagnosis [2], assists with severity grading [4] and since recently help identify patients at increased risk of severe reactions due to the hereditary alpha-tryptasemia genetic trait [5]. In fact, proper interpretation of both sAT and sBT can only be done using paired samples. For example, recent data on hereditary alpha tryptasemia have provided further support for systematic testing of paired sAT and sBT. With a prevalence of up to 8% in general population and most studies showing an increased risk of severe hypersensitivity reactions, no clinician should take the risk of overlooking hereditary alpha-tryptasemia, which can only be suspected through sBT determination and confirmed with digital droplet PCR in specialized laboratories. Missing other mast cell-related disorders, such as mastocytosis, often discovered as an elevated sBT, may lead to substandard patient management, which would have been avoidable through proper tryptase assessment. Among other frequent errors, we would like to cite the assumption that the manufacturer's upper limit for serum tryptase (currently 11.0 μg/L in Europe) is a reliable cut-off for discriminating mast cell degranulation. This assumption has been abundantly demonstrated as false by large cohort studies on perioperative anaphylaxis, showing that up to 60% of confirmed mast cell degranulation events had sAT lower than the manufacturer's cut-off [2], [6]. In some patients, especially in those with extremely high sAT, serum tryptase levels may not return to baseline after 24 h; therefore, if a sample taken after 24 h is higher than 8 μg/L or even 7 μg/L, a control sBT sample should be taken later, for example during the allergy work-up which must be offered to any patient having experienced anaphylaxis. Further support for the paired sAT and sBT determination comes from its robust use in populations such as children [7] and pregnant women [8]. To summarize, taking two tryptase samples at adequate times for acute and baseline serum tryptase assessment and interpretation is the current state of the art recommendation for anaphylaxis (Fig. 1 ). This recommendation should be kept in mind and implemented in any case of anaphylaxis or suspicion of immediate hypersensitivity reaction, should it happen at home, at school, in the office, during an anesthetic procedure, while delivering a COVID-19 vaccine, or in any other setting. Proper sampling time is critical for acute tryptase measurement, and baseline sampling must not be overlooked.Fig. 1 Paired tryptase sampling in anaphylaxis. Disclosure of interest JV reports speaker and consultancy fees in the past 5 years from Meda Pharma (Mylan), Novartis, Sanofi, Thermo Fisher Scientific, outside the submitted work. The other authors declare that they have no competing interests in relation to this study. ==== Refs References 1 de Silva D. Singh C. Muraro A. Worm M. Alviani C. Cardona V. Diagnosing, managing and preventing anaphylaxis: systematic review Allergy 76 5 2021 1493 1506 32880997 2 Vitte J. Sabato V. Tacquard C. Garvey L.H. Michel M. Mertes P.M. Use and interpretation of acute and baseline tryptase in perioperative hypersensitivity and anaphylaxis J Allergy Clin Immunol Pract 9 8 2021 2994 3005 33746087 3 Valent P. Bonadonna P. Hartmann K. Broesby-Olsen S. Brockow K. Butterfield J.H. Why the 20% + 2 tryptase formula is a diagnostic gold standard for severe systemic mast cell activation and mast cell activation syndrome Int Arch Allergy Immunol 180 1 2019 44 51 31256161 4 Garvey L.H. Ebo D.G. Mertes P.M. Dewachter P. Garcez T. Kopac P. An EAACI position paper on the investigation of perioperative immediate hypersensitivity reactions Allergy 74 10 2019 1872 1884 30964555 5 Lyons J.J. Chovanec J. O’Connell M.P. Liu Y. Selb J. Zanotti R. Heritable risk for severe anaphylaxis associated with increased alpha-tryptase-encoding germline copy number at TPSAB1 J Allergy Clin Immunol 147 2 2021 622 632 32717252 6 Egner W. Sargur R. Shrimpton A. York M. Green K. A 17-year experience in perioperative anaphylaxis 1998–2015: harmonizing optimal detection of mast cell mediator release Clin Exp Allergy 46 11 2016 1465 1473 27473884 7 De Schryver S. Halbrich M. Clarke A. La Vieille S. Eisman H. Alizadehfar R. Tryptase levels in children presenting with anaphylaxis: temporal trends and associated factors J Allergy Clin Immunol 137 4 2016 1138 1142 26478007 8 McCall S.J. Bonnet M.P. Ayras O. Vandenberghe G. Gissler M. Zhang W.H. Anaphylaxis in pregnancy: a population-based multinational European study Anaesthesia 75 11 2020 1469 1475 32463487
PMC008xxxxxx/PMC8853159.txt
==== Front Asian Bus Manage Asian Business & Management 1472-4782 1476-9328 Palgrave Macmillan UK London 176 10.1057/s41291-022-00176-4 Original Article How does the absorbed slack impact corporate social responsibility? Exploring the nonlinear effect and condition in China Shang Lu shanglurbs@ruc.edu.cn 1Lu Shang is a Ph.D. candidate student of School of Business, Renmin University of China. His research interests include imprint theory, corporate social responsibility, and human resource management. http://orcid.org/0000-0002-6376-3430 Zhou Yu zhouyuhr@ruc.edu.cn 1Yu Zhou Ph.D., is an associate professor in the Department of Organization and Human Resources at the School of Business of Renmin University of China. He received his doctoral degree in human resource management from Renmin University of China. He was a Wertheim research fellow (2013–2014) at Labor & Worklife Program in Harvard Law School. He specializes his research in people strategy and organization innovation, HRM hybridism in Chinese and global context, partnership governance, and sharing mechanism. Hu Xinyu 2016201575@ruc.edu.cn 1Xinyu Hu is a Ph.D. candidate student of School of Business, Renmin University of China. Her research interests include flexible work arrangements, corporate social responsibility, and human resource management. http://orcid.org/0000-0001-6462-3256 Zhang Zhipeng qingjingsishui@126.com 2Zhipeng Zhang is a lecturer of School of Labor Relations and Human Resources in China University of Labor Relations. He received his PhD degrees from Business School, Renmin University of China, China. His research interests include organizational reform, algorithm management, etc. 1 grid.24539.39 0000 0004 0368 8103 School of Business, Renmin University of China, No. 59, Zhongguancun Street, Haidian District, Beijing, 100872 People’s Republic of China 2 grid.461936.f 0000 0004 0632 3257 School of Labor Relations and Human Resources at China University of Labor Relations, 45# Zengguang Road, Haidian District, Beijing, 100000 People’s Republic of China 15 2 2022 2023 22 3 857877 3 6 2021 9 12 2021 12 1 2022 © Springer Nature Limited 2022 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. This study investigates the impact of absorbed slack on corporate social responsibility (CSR) and the moderating effects of political and equity relationships on the main effect. Multiple regression analysis was used on 2175 samples of 435 publicly listed Chinese firms for the period 2012 to 2016 to empirically test the influence of absorbed slack on CSR. The empirical results show that the impact of absorbed slack on CSR is inverted U-shaped. Furthermore, when compared to companies with low political connections, the inverted U-shape between the absorbed slack and CSR in highly politically connected companies is more pronounced. Compared to companies with low ownership concentrations, the inverted U-shape between absorbed slack and CSR in high ownership concentration enterprises is more pronounced. Keywords Absorbed slack Corporate social responsibility Political connection Ownership concentration China http://dx.doi.org/10.13039/100014718 Innovative Research Group Project of the National Natural Science Foundation of China 72072180 Zhou Yu issue-copyright-statement© Dr. Harukiyo Hasegawa and Springer Nature Limited 2023 ==== Body pmcIntroduction China, as the world’s largest developing country, has recently made remarkable achievements in its economic development. Overall, Chinese society is becoming more conscious of corporate social responsibility (CSR). Companies’ production and operations consume a significant amount of societal resources, and their social responsibility is of great significance to charities and social development. On the one hand, the current research on CSR in China needs further theoretical exploration (Wang et al., 2016). On the other hand, because of the vast differences between Chinese and Western culture, research on CSR is still needed in the Chinese context (Chu et al., 2020; Ma & Bu, 2021). The concept of CSR was first proposed in the West in the early twentieth century (Bowen, 1953), and it has piqued the interest of academic and practical circles ever since. The idea that enterprises should fulfill some responsibilities to society beyond making profits for the shareholders has been a consensus in both academic and practitioner communities for centuries (Carroll, & Shabana, 2010). As part of CSR, enterprises spontaneously integrate societal and environmental concerns into their internal production processes and operations, as well as in their other activities related to their stakeholders. Although some scholars have argued that the only goal of an enterprise as a utilitarian organization is to create wealth for its shareholders (Friedman, 2007), the majority of scholars believe that enterprises do not operate in a vacuum, but rather achieve their goals by using resources from all sectors of society (Mulligan, 1986; Schaefer, 2008). Therefore, enterprises should achieve their goals through various forms to meet the expectations of different stakeholders (Wang et al., 2016). An increasing number of scholars have investigated CSR in China, such as in environmental protection and CSR reports (Marquis & Qian, 2014). There are numerous theoretical perspectives on CSR; the agency theory regards CSR as an agency cost (McWilliams et al., 2006), the stakeholder theory stresses that enterprises must fulfill social responsibilities to meet the requirements of multiple stakeholders (Freeman, 1984), and the legitimacy theory emphasizes that CSR can help enterprises obtain legitimacy (Campbell, 2007). Although several existing studies on CSR exist, there are still gaps. First, the present research on CSR primarily focuses on the outcome of CSR (Graafland & Mazereeuw-Van der Duijn Schouten, 2012) and has focused less on its antecedents, particularly the relationship between absorbed slack and CSR. Unabsorbed slack, including enterprise’s cash flow, has a higher liquidity and conversion ability than absorbed slack. Liquidity and conversion have direct impacts on an enterprise’s behavior (e.g., over-investment and easy-decision) (Latham & Braun, 2008; Miller & Chen, 2004). Thus, as a type of enterprise behavior, CSR is closely related to internal absorbed slack. Second, the findings on the impact of absorbed slack on CSR are inconsistent. For example, Xu et al. (2015) found that absorbed slack is not related to CSR. However, Mattingly and Olsen (2018) found that absorbed slack positively impacts CSR. Thus, we aim to reexamine this relationship and assume that the relationship has an inverted U-shaped effect. Third, in China’s current market conditions, CSR behaviors are internally constrained by equity relationships and externally affected by political relationships (Qin et al., 2018). However, few studies have highlighted the effect of absorbed slack on CSR under different internal and external conditions. Therefore, it is necessary to investigate the impacts of various situations on CSR. In this study, we investigate the impact of absorbed slack on CSR from the perspectives of firm behaviors, goals, and resource allocations based on the behavioral theory of the firm. Absorbed slack includes idle human resources, management expenses, wages, production equipment, and other important illiquid assets (Bourgeois, 1981; Greve, 1998; Voss et al., 2008). When a resource is fully utilized, highly specialized, and strategically important to an organization, it is considered an absorbed slack resource (Lawson, 2011). Research on slack has gradually evolved from an early focus on enterprise performance and innovation to decision-making behaviors. Political connections imply that enterprises develop relations with government departments through formal or informal means. Previous studies have shown that CSR behavior is affected by political connections (Li & Xie, 2014). Developing political connections is important for enterprises because it can help them carry out certain actions that are impossible for those without political connections (e.g., longer debt maturities, larger financing amounts, higher financial leverage, and entering monopolistic industries) (Fan et al., 2007). A previous study found that in Pakistan, enterprises with political connections received bank financing twice as often as enterprises without political connections (Sapienza, 2004). In addition, Li et al. (2008) found that Chinese private entrepreneurs’ party memberships allowed them to easily obtain loans from state-owned banks and financial institutions. Additionally, entrepreneurs who are representatives of the National People's Congress, in China, can improve their market shares (Lu, 2011). Studies have further found that politicians assist enterprises with political connections in obtaining more loans from banks, resulting in increased political donations from enterprises (Dinc, 2005). Ownership concentration is an important factor in corporate governance (Shleifer & Vishny, 1997). CSR is affected by the capital structure of a company’s internal governance elements (Gao & Zheng, 2010). The ownership structure affects the controlling rights and interests of shareholders in an enterprise. Additionally, it may lead to a series of agency problems. For example, enterprises tend to actively disclose social responsibility reports to dispel the public’s doubts about their legitimacy (Chen et al., 2018) and to ensure the stability of their governance structures. Khan et al. (2013) discussed the impact of corporate governance structures on CSR disclosures in emerging economies. A series of empirical studies have shown that when discussing CSR, external political relationships and the internal equity structures of corporate governance cannot be separated (Li & Xie, 2014; Qin et al., 2018). Therefore, this study investigates the moderating effects of political connections and ownership concentrations on the relationship between absorbed slack and CSR. Our research develops the literature on organizational slack and CSR. Compared to previous studies on unabsorbed slack and CSR (Islam et al., 2021; Vanacker et al., 2017), this study focuses on the impact of absorbed slack on CSR behavior and discovers an inverted U-shaped relationship. We explored the moderating mechanisms affecting CSR from internal ownership concentration and external political connection perspectives. Based on existing literature and specifically the request for Chinese CSR (Ma & Bu, 2021), our study contributes to the literature on extant behavioral theory of the firm by using Chinese enterprises’ data and explores the applicability of slack, the core concept of this theory, in the Chinese context. Theoretical analysis and hypotheses development Absorbed slack and CSR Slack refers to potentially available resources that can be transformed and allocated to achieve organizational goals. Slack is a core concept of a firm’s behavioral theory (Argote & Greve, 2007; Bromiley, 2009; Cyert & March, 1963), which has two major forms: unabsorbed and absorbed slack (Voss et al., 2008). Slack reflects the ease of recovery and use of various idle resources. Unabsorbed slack refers to the resources that can be used at any time and are held in idle funds; it is the most liquid form of slack. Greve (1998) defined unabsorbed slack as a capital reserve that can cover corporate financial expenditures in a short period of time. Absorbed slack refers to non-liquid resources accumulated in an organization. Absorbed slack is the slack with the highest degree of absorption in an organization and is characterized by a higher degree of organization specificity and has a stronger strategic value than unabsorbed slack (Vanacker et al., 2017). Cyert and March (1963) proposed that absorbed slack is an organizational buffer, which is something that buffers the organization against unexpected problems. (Chen & Huang, 2010). Although the liquidity of absorbed slack is lower than that of unabsorbed slack, absorbed slack can still provide flexibility to help enterprises cope with environmental uncertainty, which guarantees enterprises’ strategic decisions. Instead of merely possessing resources, it is critical that resources are utilized to achieve enterprises’ goals through rational resource allocations (Sirmon et al., 2007). Corporate goals comprise internal production goals, operational goals, and external non-economic long-term goals. Enterprise managers’ decision-making processes in the pursuit of corporate goals are important. They have the right to allocate and dispose of enterprise resources, as well as to use those resources to achieve internal and external goals (Vanacker et al., 2017). The utilization of unabsorbed slack not only contributes to daily operations, but also helps enterprises cope with unexpected events (Bourgeois, 1981). In the Chinese context, CSR is the external goal that enterprises must pursue. Current research also finds that possessing absorbed slack can help enterprises make decisions that exceed financial goals (Nohria & Gulati, 1996). Absorbed slack has the following advantages for enterprises to fulfill CSR: First, it can help enterprises retain key employees (Campbell et al., 2012), idle human resources in one section of an enterprise can help alleviate the pressure caused by a shortage of human resources in another section to maintain the stability of the enterprise (Welbourne & Cyr, 1999; Williamson, 2000). Idle human resources can also assist in CSR by allowing employees to perform community or voluntary services. Second, absorbed slack can help enterprises reduce the cost of fulfilling CSR and improve resource utilization efficiencies, for example, Xu et al. (2015) found that companies donate inventories rather than cash during an earthquake. Third, absorbed slack can help enterprise decision-makers solve problems effectively and make long-term strategic decisions (Moch & Pondy, 1977; Sirmon et al., 2007), which assists managers in avoiding short-sighted behaviors and allows them to complete additional strategic tasks and activities (Simon, 1957). For example, during the COVID-19 pandemic in 2020, Chinese enterprises with slack employees, idle equipment, and inventory could effectively deal with emergency recruitment, personnel shortages, and raw material supplies, helping society by reallocating redundant personnel, using idle equipment capacities, and redistributing inventories during the pandemic. Although absorbed slack can benefit an enterprise, the behavioral theory of the firm holds that there are disadvantages in maintaining excessive absorbed slack within an enterprise (Bromiley, 1991). Nohria and Gulati (1996) highlighted that excessive absorbed slack restricts managers’ decision-making behaviors. Some studies found that absorbed slack can cause managers to be overly optimistic about the operations and management of enterprises. Therefore, they do not make additional strategic decisions or exhibit innovative behaviors (Kim et al., 2008; Simon, 1957). When there is little or no slack, the primary goal of an organization is to use the limited resources to run the organization and achieve its goals. Absorbing slack is an efficiency-oriented function in an enterprise (Singh, 1986). However, the continuous increase in absorbed slack has adverse effects on CSR once it exceeds a critical point. According to the behavioral theory of the firm, excessive slack is not conducive to achieving corporate goals. This may lead to idleness in managers’ decision-making. Corporations’ efficiencies in resource utilization may decline as a result of ample budgets (Cyert & March, 1963). Bromiley (2009) proposed that appropriate slack is conducive to the realization of enterprise goals. Thus, we argue that excessive absorbed slack leads to decreased motivations to fulfill CSR and a reduction in CSR outcomes. First, from the perspective of corporate motivation, Nohria and Gulati (1996) found that excessive slack led to a decrease in innovative decision-making, and an increase in managers’ complacency and idleness, and thereby a lack of initiatives to fulfill CSR. Overconfident managers may result in decision inertia, resulting in them being slow to send the correct market signals, being unmotivated, and not setting objectives to implement additional strategic actions (Cheng & Kesner, 1997), being unmotivated, and not setting objectives to implement additional strategic actions (Cheng & Kesner, 1997). Additionally, a few studies have found that excessive absorbed slack may lead managers to focus on behaviors that are not conducive to an enterprise’s development. For example, the managers of an enterprise may use slack human resources for inefficient merger and acquisition projects (Roberts, 1990), achieve managers’ personal goals by reallocating idle resources, such as selling inventory to companies associated with the managers at low prices, expanding production capacities into saturated markets, and taking actions to improve managers’ business records. These behaviors negatively impact CSR. Second, excessive slack leads to a decrease in decision-making efficiency (Cyert & March, 1963). Thus, even though CSR is fulfilled, the outcomes are not satisfactory. Therefore, this study proposes that excessive slack may lead to a decrease in CSR, while appropriate slack maximizes CSR. Based on the above analyses, this study proposes the following hypothesis. Hypothesis 1 The relationship between absorbed slack and CSR is an inverted U-shape. Levels of absorbed slack that are too high or too low lead to reduced CSR levels, and moderate levels of absorbed slack maximize CSR. The moderating effect of political connection Political connections refer to enterprises’ establishment of contacts with government agencies or government officials through formal or informal means to obtain political resources (Faccio, 2006). There are two forms of political connections. First, top managers of enterprises are employed by government legislature, or other political institutions. Second, an enterprise’s senior managers and top executives establish contact with officials or government departments through other ties, such as relatives and friends (Sheng et al., 2011). The strength of political connections can assist enterprises to obtain absorbed slack. Previous studies have found that political connections positively impact enterprises, including improved performances and returns on investments, and through tax subsidies (Li et al., 2008; Roberts, 1990). In China, compared to enterprises with low political connections, enterprises with high political connections are more likely to have absorbed slack. For example, government policy in recruitment may influence whether enterprises can recruit more employees, qualify to purchase more equipment or operate a business. The differences in abilities to absorb slack further affect the levels of CSR. Simultaneously, companies need to allocate more slack resources to CSR behaviors to maintain their political party relationships. For example, Sims (2003) found that corporate donations can help build political reputations, decision-maker relationships, and political bargaining capital, resulting in the acquisition of political resources (Sims, 2003). CSR is an important way to strengthen and stabilize political connections (Li et al., 2013). Enterprises can undertake community actions by using idle human resources and surplus inventory, protecting the environment, and supporting disaster-stricken areas to help the government undertake social security functions. In summary, enterprises with high political connections may achieve higher CSR levels through the utilization of absorbed slack (Zheng & Zhang, 2016). However, Simon (1957) found too much slack may lead to overconfidence in managers, which ultimately leads to inefficient decision-making. We believe that when the internal absorbed slack is too high, managers from enterprises with high political connections have both “absorbed slack confidence” and “political connection confidence.” This dual confidence may lead to higher levels of decision-making inertia among managers, preventing them from engaging in additional strategic activities, ultimately resulting in a decline in CSR. From a political point of view, when an enterprise has low political connections and absorbed slack, its first priority is only to improve performance. Such enterprises may fail to fulfill CSR, waste internal resources and not have any positive impacts on corporate performances. In contrast, when absorbed slack is too high, managers from enterprises with low political connections do not need to adopt CSR to maintain their political relationships with political parties because they do not have many connections. However, although such managers also have decision inertia compared to the dual decision inertia of enterprises with high political connections, the impacts of not implementing CSR activities may be lessened. Based on the above analysis, this study proposes the following hypothesis. Hypothesis 2 Political connections may strengthen the inverted U-shaped relationship between absorbed slack and CSR. Compared to enterprises with low political connections, the inverted U-shaped relationship between absorbed slack and CSR is more pronounced in enterprises with high political connections. The moderating effect of ownership concentration Ownership concentration is an important factor in corporate governance structures (Shleifer & Vishny, 1997). In a company with a low concentration of ownership, the major shareholders’ control ability is weak and conflicts of interest between different shareholders may exist. The higher the ownership concentration, the stronger the control of the major shareholders over an enterprise, and two effects are generated: the support effect and the tunneling effect (Li et al., 2015a, 2015b). The major shareholders may have a strong willingness and motivation to supervise management to realize the enterprise’s goals because of their high share concentrations. Large shareholders may use their control advantages to maximize their own private interests at the expense of other shareholder interests, effectively tunneling the company (Demsetz & Lehn, 1985). We believe that ownership concentration affects resource allocations and the decision-making and behavior of enterprises (Feng et al., 2011). Large shareholder interests tend to be consistent with the long-term goals of enterprises with high ownership concentrations. Large shareholders tend to take the initiative to fulfill their social responsibilities out of the long-term interests of enterprises. When the absorbed slack in an enterprise is high it indicates that large shareholders, who have the advantage of actual controlling rights, promote the reallocation of unabsorbed slack by directly participating in the decision-making processes, such as donating surplus inventory, supervising and controlling management, calling on idle human resources to provide community services to fulfill CSR, maintaining internal and external communications, forming a good corporate reputation, and further promoting long-term developments. However, when the absorbed slack is too high, large shareholders may use absorbed slack to engage in behaviors that are not conducive to CSR. Previous studies have found that a high ownership concentration may lead to large shareholder tunneling behaviors, such as damaging the interests of small and medium shareholders through repurchasing securities, asset transfers, internal transactions, and so on (Johnson et al., 2000), leading to a decline in CSR. When ownership concentration is low, the decentralization of ownership implies that the goals of different shareholders may not be consistent with long-term development goals, leading to conflicts within organizations. When absorbed slack is low, the enterprise will solve the problem of inconsistency of interests between different shareholders and internal conflicts within the organization through the allocation of absorbed slack. For example, resources are used to first realize the enterprise’s goal of maximizing the company’s value or shareholders' wealth. Absorbed slack may not fulfill CSR that consumes enterprise resources and may not bring immediate returns to the enterprise. However, when the absorbed slack is too high, the balance between shareholders, which is caused by the decentralization of ownership, inhibits individual shareholders’ behavior in tunneling the company. In this case, CSR may solve the contradictions and conflicts between shareholders. Hence, enterprises may choose to fulfill their social responsibilities. In summary, low ownership concentration may weaken the relationship between absorbed slack and CSR. Based on the above analysis, this study proposes the following hypothesis. Hypothesis 3 Ownership concentration strengthens the inverted U-shaped relationship between absorbed slack and CSR. Compared to enterprises with low ownership concentrations, the inverted U-shaped relationship between absorbed slack and CSR is more pronounced in enterprises with high ownership concentrations. Methodology Sample selection and data sources This study used second-hand data for the analysis. The data come from publicly listed Chinese firms in the China Stock Market and Accounting Research (CSMAR) database, and CSR ratings come from the CSR Rating Agency, which creates the Runling Global CSR Report database (also known by its English acronym, RKS; http://www.rksratings.com). To ensure the reliability and authenticity of the data, this study also combines the annual reports of listed companies, internet media, and other channels to supplement the executive information data, and strives for accurate and reliable data quality. Reference to previous studies (He et al., 2017; Zhao et al., 2019), we first conducted the following screening and processing of the research data: we eliminated the following data. First, listed companies in the financial and insurance industries; in China, their financial statements are significantly different from those of other industries. The main business revenue of these companies is represented in data that are not included in the financial statements. Second, ST (special treatment) companies, which are typically those companies that have drawn attention to unusual financial situations; they show negative profits, and their business data are full of extremes and outliers. Third, foreign-funded enterprises, since the purpose of our research is to investigate absorbed slack and CSR in the Chinese context. Forth, samples from the associated data had multiple missing values, a high number of missing values may affect the accuracy of our model. Finally, a balanced panel data spanning five years were created for this study, comprising a set with a sample of 435 A-share listed companies, and a data volume of 2175. Stata 15.0 was used for data processing and empirical analysis. Empirical research model Previous studies have found that CSR lags, which means that changes in indicators in the current year affect CSR in the following year rather than having an immediate impact in the current year (Marquis & Qian, 2014; Yu et al., 2015). Therefore, in this study, CSR is lagged by one year in the model. This can solve the model’s endogenous problem to a certain extent. The following models were constructed to test the three hypotheses:1 CSRi,t+1=β0+β1Slacki,t+β2Slacki,t2+β3Controli,t+εi,t CSRi,t+1=β0+β1Slacki,t+β2Slacki,t2+β3Pci,t+β4Slacki,t∗Pci,t 2 +β5Slacki,t2∗Pci,t+β6Controli,t+εi,t CSRi,t+1=β0+β1Slacki,t+β2Slacki,t2+β3Oci,t+β4Slacki,t∗Oci,t 3 +β5Slacki,t2∗Oci,t+β6Controli,t+εi,t CSR represents CSR as the explained variable, Slack represents the level of absorbed slack, Slack2 represents the square of absorbed slack as the explanatory variable, Pc is the degree of political connection, Oc is the degree of ownership concentration as the moderator variable, and Control is another variable that may affect CSR, which is controlled in the model. Model (1) was used to verify the main effect of Hypothesis 1. Model (2) is based on Model (1) by adding the interaction term of absorbed slack and political connection and the interaction term of absorbed slack squared and political connection, used to test Hypothesis 2. Model (3) is based on Model (1) by adding the interaction term of absorbed slack and ownership concentration and the interaction term of absorbed slack squared and ownership concentration, used to test Hypothesis 3. Measures Explained variable: CSR This study uses a third-party professional report scoring method to measure CSR based on previous research methods. The Runling Global RKS CSR report score was used to create the CSR index used in this study. The full score is 100. The higher the corporate score, the better the CSR. Runling Global is an authoritative third-party social responsibility assessment agency for China’s A-share listed companies. Since its establishment in 2007, the social responsibility scores of A-share listed companies have been reported annually. Its social responsibility report has the advantages of objectivity and systematism (Marquis & Qian, 2014). Explanatory variable: absorbed slack To measure absorbed slack, most empirical studies use the work of Bourgeois (1981) as the measurement index. Absorbed slack is organizational slack with low liquidity, difficult transformation, and strong specificity, including fixed assets, human resources, and inventory. It is generally measured by management and financial cost rates and other indicators (Iyer & Miller, 2008; Singh, 1986; Su & Liu, 2018; Wang & Cheng, 2014; Wiseman & Bromiley, 1996). In this study, our measure of absorbed slack is the management ratio (i.e., management cost divided by sales). In the CSMAR database, management cost refers to different expenses incurred by the management of an enterprise to organize and manage production and operation activities. The management cost and sales in the CSMAR database are sorted using an algorithm according to the financial statements of an enterprise, so they can be used directly. Moderating variables: political connection and ownership concentration This study refers to the research methods of Faccio (2006) and Fan et al. (2007). It judges whether an enterprise has a political connection by collecting the publicly available background information on the boards of directors and supervisors. Specifically, this study totals the number of directors and supervisors who have been in government organizations, deputies to the National People’s Congress, or members of the Chinese People’s Political Consultative Conference. It then compares them to the number of directors and supervisors. The higher the proportion, the stronger the political connection. Information on the political connections of Chinese enterprises is primarily obtained from the annual reports of enterprises, in which the resumes of senior executives, as well as the boards of directors and supervisors, are recorded in detail in the column of “directors, supervisors, senior managers, and employees” from which the political connections of enterprises can be determined. In this study, the CSMAR database sorted out the number of people using an algorithm. For the missing samples in the database, we manually collected the annual reports of each company to determine the number of people with political connections. This study draws on the research of Hu et al. (2018) and Xiong and Huang’s (2016) research on the measurement of ownership concentration. It selects the sum of the shareholding ratios of the top ten shareholders to measure ownership concentration. Control variables This study controls the influence of financial leverage, enterprise size, enterprise age, enterprise performance, type of ownership, two-position integration, year, and industry on the level of CSR, referring to previous literature. (1) Financial leverage: Financial leverage indicates an enterprise’s equity structure (Li et al., 2013). Enterprises with higher amounts of slack are believed to have financial flexibility because of their low leverage (Graham & Harvey, 2001). Li et al. (2013) found a positive relationship between leverage and CSR reports. Thus, this study takes financial leverage as a control variable. This variable is measured as the ratio of total liabilities to total assets. (2) Enterprise size: Generally, large enterprises are more capable of fulfilling CSR missions than small enterprises. It is measured by the natural logarithm of total corporate assets. (3) Enterprise age: We calculate the enterprise age by subtracting the time of establishment from the current year, 2021. (4) Enterprise performance: Enterprises with better performances are more likely to engage in CSR because they are more capable of doing so. We measure performance using the return on assets (ROA) ratio which is net profit divided by average total assets. (5) Type of ownership: It reflects whether enterprises are state-owned enterprises (SOEs). If they are, then this variable is assigned the value of 1; otherwise, 0. (6) Two-position integration: In our analysis, if the same person is the chairperson, and general manager, then this variable is assigned the value of 1; otherwise, 0. (7) Year: The variable is a virtual variable of the year. (8) Industry: Enterprises in different industries may differ in their CSR goals and performances. We refer to the China Securities Regulatory Commission 2012 to determine the industries of listed companies. The main variables and measurement methods used in this study are listed in Table 1.Table 1 Main variables and measurement Types Name Definition Measurement Explained variable CSR Corporate social responsibility Runling global RKS corporate social responsibility report score The full score is 100, the higher the corporate score, the better the performance of corporate social responsibility Explanatory variables Slack Absorbed slack Management cost/sales revenue Slack2 The square of absorbed slack (Management cost/sales revenue)2 Moderators Pc Political connection If a company executive has been or is now a government agency, an NPC representative or a CPPCC member, the value shall be 1, otherwise 0, divided by the sum of the number of board of directors and board of supervisors Oc Ownership concentration The sum of the shareholding ratio of the top ten shareholders Control variables Leverage Financial leverage Total liabilities/total assets Asset Enterprise size Natural logarithm of total corporate assets Age Enterprise age Year minus time of establishment Roa Enterprise performance Net profit/total assets Soe Property right nature State-owned enterprises 1, non-state-owned enterprises 0 Post Two-position integration If the chairman and general manager are one, then 1, otherwise 0 Year Year Virtual variable of year Industry Industry According to China Securities Regulatory Commission 2012 industry standards of listed companies Results Descriptive statistics Table 2 reports the descriptive statistics of the main variables and the correlation coefficients between the explanatory variables and the explained variables. The average value of CSR is 39.552, the standard deviation is 12.291, the minimum value is 15.115, and the maximum value is 87.947, which indicates that there are obvious differences in the levels of CSR between 2012 and 2016. The average value of enterprises’ absorbed slack (Slack) is 0.078, the standard deviation is 0.056, the minimum value is 0.002, and the maximum value is 0.0412, which shows that different enterprises have different levels of absorbed slack. The correlation coefficient between absorbed slack and CSR is significant at a 1% confidence level. The correlation coefficient between the square of absorbed slack and CSR is significant at a 5% confidence level.Table 2 Descriptive statistics Variable Average value Standard deviation Minimum Maximum Correlation coefficient CSR 39.552 12.291 15.115 87.947 – Slack 0.078 0.056 0.002 0.412 − 0.083*** Slack2 0.009 0.015 0 0.170 − 0.058** Political connection 0.268 0.228 0 1 0.071*** Ownership concentration 0.589 0.166 0.127 0.985 0.313*** Financial leverage 0.513 0.205 0.007 1.344 0.100*** Asset 23.272 1.518 19.197 28.508 0.470*** Age 16.724 4.966 2 36 − 0.095*** Enterprise performance 0.038 0.168 − 0.682 7.44 0.007 Two-position integration 0.142 0.349 0 1 − 0.059** Property right nature 0.701 0.457 0 1 0.135*** *p < .10 **p < .05 ***p < .01 Hypothesis testing The data were processed prior to executing a regression analysis. This study conducted a tail reduction of the main continuous variables at a significance level of 1% to avoid the influence of abnormal values on the empirical results. Furthermore, this study standardized the main explanatory variables to standardize the data results and the variance inflation factor (VIF) test was conducted on the model’s main variables. The results show that the VIF of all variables is less than 10, eliminating the multicollinearity problem. Finally, this study used the Hausman test to check the data of the fixed-effect and random-effect models, respectively. The results show that P < 0.001, rejecting the original hypothesis; thus, this study used a fixed-effect model for analysis. The fixed-effects model can partially solve the endogenous problem caused by missing variables. Table 3 shows the regression analysis results for absorbed slack, political connections, ownership concentrations, and CSR. Model 0 is the basic model, and Model 1 tests the main effect of the relationship between absorbed slack and CSR. The results show that there is a significant positive correlation between absorbed slack and CSR (β = 0.125, P < 0.001), and a significant negative correlation between the square of absorbed slack and CSR (β =  − 0.0214, P < 0.05). The results show that there is a significant inverted U-shaped relationship between absorbed slack and CSR. When the level of absorbed slack is low, the level of CSR is low. With an increase in absorbed slack, the level of CSR also increases. However, once the level of absorbed slack is too high, CSR declines. Therefore, Hypothesis 1 of this study was verified.Table 3 The regression analysis results Variables Model 0 Model 1 Model 2 Model 3 Slack 0.125*** 0.128*** 0.130*** Slack2 − 0.0214** − 0.0257** − 0.0236** Political connection 0.00323 Ownership concentration 0.0292 Slack * political connection 0.0206 Slack2 * political connection − 0.0138* Slack * ownership concentration 0.0250 Slack2 * ownership concentration − 0.0165* Financial leverage − 0.0332 − 0.0313 − 0.0336 − 0.0284 LnAsset 0.0932 0.127** 0.129** 0.129** Age 0.143 0.103 0.103 0.0972 Enterprise performance − 0.0114 0.000199 0.000950 0.00122 Two-position integration − 0.0349 − 0.0331 − 0.0281 − 0.0339 Industry Yes Yes Yes Yes Year Yes Yes Yes Yes R2 0.114 0.120 0.121 0.120 *p < .10 **p < .05 ***p < .01 Models 2 and 3 test the moderating effect of political connection and ownership concentration on the main effect. In Model 2, the interaction terms of absorbed slack and political connection and the interaction terms of the absorbed slack squared and political connection are added. The results show that the regression coefficient of the interaction between absorbed slack and political connection is positive but not significant (β = 0.0206, P > 0.01). In contrast, the interaction between absorbed slack squared, and political connection was significant and negative (β =  − 0.0138, P < 0.01). In Model 3, we add the interaction term of absorbed slack and ownership concentration and the interaction term of absorbed slack squared and ownership concentration. The results show that the interaction between the square of absorbed slack and ownership concentration is significantly negative (β =  − 0.0165, P < 0.01). Therefore, it can be said that political connection and ownership concentration strengthen the inverted U-shaped relationship between absorbed slack and CSR. Robustness test The measurement methods for the two regulatory variables were replaced to test the robustness of the model. According to previous studies (Li et al., 2015a, 2015b), political connections can be measured by the number of government officials or deputies to the National People’s Congress in the top management team. Ownership concentration can be measured by the sum of the shareholding ratios of the top five shareholders. The regression results of this study, after changing the variable measurement method, are presented in Table 4.Table 4 The results of robustness test Variables Model 4 Model 5 Model 6 Model 7 Slack 0.125*** 0.111*** 0.130*** Slack2 − 0.0214** − 0.0260** − 0.0231** Political connection 0.0276 Ownership concentration 0.0240 Slack * political connection 0.0282 Slack2 * political connection − 0.0166* Slack * ownership concentration 0.0372 Slack2 * ownership concentration − 0.0165* Financial leverage − 0.0332 − 0.0313 − 0.0747** − 0.0304 LnAsset 0.0932 0.127** 0.128* 0.133** Age 0.143 0.103 0.0895 0.0951 Enterprise performance − 0.0114 0.000199 − 0.0145 0.000919 Two-position integration − 0.0349 − 0.0331 − 0.0890* − 0.0334 Industry Yes Yes Yes Yes Year Yes Yes Yes Yes R2 0.114 0.120 0.044 0.120 *p < .10 **p < .05 ***p < .01 In Table 4, Model 4 is the basic model. Model 5 tested the main effect. Models 6 and 7 test Hypotheses 1 and 2, respectively. It is found that after the alternative measurement of key variables, the results of the robustness test in Models 5, 6, and 7 are still significant; that is, political connection and ownership concentration strengthen the inverted U-shaped relationship between absorbed slack and CSR. Discussion Based on the behavioral theory of the firm, our study empirically tests the relationship between absorbed slack and CSR, and the moderating effects of political connections and ownership concentrations. The empirical results are as follows. First, our study finds that the relationship between absorbed slack and CSR has an inverted U-shape. With an improvement in the level of absorbed slack, on the one hand, the managers of enterprises have sufficient slack to resist uncertainty. On the other hand, they can realize the external goals of enterprises and fulfill social responsibilities through the allocation of resources, so that the levels of CSR also improve. So, there is a critical value for the level of absorbed slack. Once it exceeds that critical value, with continuous increases in the levels of absorbed slack, managers may produce redundant “inertia,” that is, they will relax their minds, observations and anticipations of their external environments, and the level of CSR will decline. A moderate level of absorbed slack is conducive to maximizing CSR. A level of absorbed slack that is too high or too low will inhibit the level of CSR. Second, political connections strengthen the inverted U-shaped relationship between absorbed slack and CSR. Compared to enterprises with low levels of political connections, enterprises with high levels of political connections will grow faster, with an increase in absorbed slack. Highly politically related enterprises need to maintain political relations through stronger levels of social responsibility and obtain scarce external political resources. However, after the level of absorbed slack reaches a critical point, because of the coexistence of political and redundant resources, managers will double their overconfidence. The higher the level of absorbed slack, the faster CSR will fall. Therefore, political connections strengthen the inverted U-shaped effect of absorbed slack on CSR. Third, ownership concentration strengthens the inverted U-shaped relationship between absorbed slack and CSR. The higher the concentration of equity, the stronger the control of the top shareholders. Based on long-term goals and relying on the control and supervision of management, major shareholders will be more inclined to fulfill CSR. However, if there is too much absorbed slack, large shareholders may also choose inefficient mergers and acquisitions, asset transfers, and other avenues that damage the interests of other shareholders, and the level of CSR will decline. When the ownership concentration is low, due to the different interests of different shareholders, and when the absorbed slack level is low, the first consideration is the maximization of common interests, rather than the level of CSR. However, when the absorbed slack level is too high, the fulfillment of CSR mitigates the conflict of interests among shareholders. Theoretical implications Our study offers several important theoretical implications. First, previous studies mainly explored the relationship between unabsorbed slack and CSR, among which the existing findings are inconsistent (Miller & Chen, 2004; Xu et al., 2015). Additionally, less attention has been paid to the impact of absorbed slack on CSR (Kim et al., 2019; Xiao & Li, 2018). Our study investigates the inverted U-shaped relationship between absorbed slack and CSR based on the behavioral theory of the firm. Low or high levels of absorbed slack are not conducive to achieving the maximum level of CSR, and a moderate level of absorbed slack is conducive to it. By investigating the impact mechanism of CSR from the perspective of absorbed slack, this study enriches the theoretical model of the relationship between absorbed slack and CSR. Second, existing literature rarely explores the impact mechanism of internal and external relations on CSR (Gao & Zheng, 2010; Khan et al., 2013). In China, both managers’ resource allocation behaviors and enterprises’ social goals are influenced by internal capital relationships and external political ties (Rauf et al., 2021). Our study examines the moderating effects of external political relations and internal equity relations on the main effect, finding that political connections and ownership concentration strengthen the inverted U-shaped impact of absorbed slack on CSR. Our discussion of the boundary conditions enriches the relevant research. Third, our study contributes to the extant literature on the behavioral theory of the firm (Argote & Greve, 2007; Cyert & March, 1963). The relationship between resource allocation and firm objectives is an important proposition in the behavioral theory of the firm (Cyert & March, 1963; George, 2005), and managers are the individuals empowered to make decisions about dealing with and allocating resources in an enterprise. Our study fully demonstrates how senior executives influence CSR through resource allocation. In addition, existing research calls for the application and development of more Western theories in Chinese contexts (Barkema et al., 2015; Ma & Bu, 2021). Future studies can further explore the effects of absorbed slack in a Chinese context based on our study. Practical implications The findings from our study can be applied as follows: first, an appropriate level of absorbed slack can maximize CSR. Therefore, enterprise managers will be able to maintain certain levels of absorbed slack on the basis of normal operations, including inventory and personnel slack, which is conducive to the realization of CSR goals. Second, in the Chinese context, the performance of CSR helps enterprises obtain political connections, and thereby obtain the necessary legitimacy for their survival. In turn, political connections strengthen the levels of CSR. For some enterprises with high political connections, it is necessary to maintain their status by increasing their CSR activities, simultaneously, they should be cautious to not use CSR in bribery and corruption. Third, in terms of ownership structure, the concentration of the ownership structure is conducive to the improvement of the level of CSR. Finally, since CSR is a long-term strategic investment, it cannot increase an enterprise’s financial returns in the short term. However, it has the potential to add value to an enterprise (Porter & Kramer, 2006). In the long term, it can attract talent and reduce hidden costs. Enterprises must maintain certain levels of absorbed slack. It can help them resist external risks and uncertainties and also maximize CSR. Research limitations and outlooks Although our study finds that a moderate level of absorbed slack is conducive to the optimal performance of CSR, the optimal structural proportion of absorbed slack and unabsorbed slack within enterprises has not yet been explored. Future research can further explore the structural relationships between these two factors and explore the optimum levels of absorbed slack that are conducive to their CSR. Political connections are important situational factors in Chinese enterprise management (Peng & Luo, 2000; Wang et al., 2017). It is necessary for future researchers to combine the influence of political factors when exploring CSR in China. We explored the inverted U-shaped relationship between absorbed slack and CSR. However, we did not expand this to the impact mechanism of absorbed slack on different CSR dimensions, such as charitable donations and environmental protection (Wang et al., 2015; Zhang et al., 2019). After Carroll (1991) proposed a pyramid model of CSR, research in this area has been further classified and refined. Therefore, researchers can further explore the impact mechanisms of absorbed slack on different types of CSR in future, for example, the influence between slack and environmental protection in China. Funding This study has been partially supported by financial aid from the Projects of the National Social Science Foundation of China (Grant No. 72072180) and supported by the outstanding innovative talents cultivation funded programs 2020 of Renmin University of China. Declarations Conflict of interest The authors declare that they have no conflict of interest. Research involving human participants This article does not contain any studies with human participants performed by any of the authors. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ==== Refs References Argote L Greve HR A behavioral theory of the firm-40 years and counting: Introduction and impact Organization Science 2007 18 3 337 349 10.1287/orsc.1070.0280 Barkema HG Chen XP George G Luo Y Tsui AS West meets East: New concepts and theories Academy of Management Journal 2015 58 2 460 479 10.5465/amj.2015.4021 Bourgeois LJ On the measurement of organizational slack Academy of Management Review 1981 6 1 29 39 10.2307/257138 Bowen H Social responsibilities of the businessman 1953 Harper Bromiley P Testing a causal model of corporate risk taking and performance Academy of Management Journal 1991 34 1 37 59 10.2307/256301 Bromiley P The behavioral foundations of strategic management 2009 Wiley Campbell BA Ganco M Franco AM Agarwal R Who leaves, where to, and why worry? Employee mobility, entrepreneurship and effects on source firm performance Strategic Management Journal 2012 33 1 65 87 10.1002/smj.943 Campbell JL Why would corporations behave in socially responsible ways? An institutional theory of corporate social responsibility Academy of Management Review 2007 32 3 946 967 10.5465/amr.2007.25275684 Carroll AB The pyramid of corporate social responsibility: Toward the moral management of organizational stakeholders Business Horizons 1991 34 4 39 48 10.1016/0007-6813(91)90005-G Carroll AB Shabana KM The business case for corporate social responsibility: A review of concepts, research and practice International Journal of Management Reviews 2010 12 1 85 105 10.1111/j.1468-2370.2009.00275.x Chen CJ Huang YF Creative workforce density, organizational slack, and innovation performance Journal of Business Research 2010 63 411 417 10.1016/j.jbusres.2009.03.018 Chen JC Patten DM Roberts RW Corporate charitable contributions: A corporate social performance or legitimacy strategy? Journal of Business Ethics 2018 82 1 131 144 10.1007/s10551-007-9567-1 Cheng JL Kesner IF Organizational slack and response to environmental shifts: The impact of resource allocation patterns Journal of Management 1997 23 1 1 18 10.1177/014920639702300101 Chu SC Chen HT Gan C Consumers’ engagement with corporate social responsibility (CSR) communication in social media: Evidence from China and the United States Journal of Business Research 2020 110 260 271 10.1016/j.jbusres.2020.01.036 Cyert RM March JG A behavioral theory of the firm 1963 Prentice-Hall Demsetz H Lehn K The structure of corporate ownership: Causes and consequences Journal of Political Economy 1985 93 6 1155 1177 10.1086/261354 Dinc IS Politicians and banks: Political influences on government-owned banks in emerging markets Journal of Financial Economics 2005 77 2 453 479 10.1016/j.jfineco.2004.06.011 Faccio M Politically connected firms American Economic Review 2006 69 1 369 386 10.1257/000282806776157704 Fan JPH Wong TJ Zhang T Politically connected CEOs, corporate governance, and post-IPO performance of China’s newly partially privatized firms Journal of Financial Economics 2007 84 2 330 357 10.1016/j.jfineco.2006.03.008 Feng LL Lin F Xu JL Nature of property rights, ownership concentration and social responsibility fulfillment Journal of Shanxi University of Finance and Economics 2011 18 9 100 107 Freeman RE Strategic management: A stakeholder perspective 1984 Prentice Hall Friedman M The social responsibility of business is to increase its profits. In corporate ethics and corporate governance 2007 Springer 173 178 Gao HX Zheng JX Corporate governance and corporate social responsibility: Isogeny, distributary and syncretism Accounting Research 2010 52 2 737 783 George G Slack resources and the performance of privately held firms Academy of Management Journal 2005 48 4 661 676 10.5465/amj.2005.17843944 Graafland J der Duijn M-V Schouten C Motives for corporate social responsibility De Economist 2012 169 4 377 396 10.1007/s10645-012-9198-5 Graham JR Harvey CR The theory and practice of corporate finance: Evidence from the field Journal of Financial Economics 2001 60 2–3 187 243 10.1016/S0304-405X(01)00044-7 Greve HR Performance, aspirations, and risky organizational change Administrative Science Quarterly 1998 1 58 86 10.2307/2393591 He XG Deng H Lu WW Li XC Dynamic relationship between negative attainment discrepancy and R&D investments: Moderating effect of organizational slack and competitive threat Journal of Management Sciences in China 2017 20 5 13 34 Hu ZM Liu J Mo QY Ownership concentration, agency cost and firm performance Finance and Accounting Monthly 2018 2 25 31 Islam SMT Ghosh R Khatun A Slack resources, free cash flow and corporate social responsibility expenditure: Evidence from an emerging economy Journal of Accounting in Emerging Economies 2021 11 4 533 551 10.1108/JAEE-09-2020-0248 Iyer DN Miller KD Performance feedback, slack, and the timing of acquisitions Academy of Management Journal 2008 51 4 808 822 Johnson S La Porta R Lopez-de-Silanes F Shleifer A Tunneling American Economic Review 2000 90 2 22 27 10.1257/aer.90.2.22 Khan A Muttakin MB Siddiqui J Corporate governance and corporate social responsibility disclosures: Evidence from an emerging economy Journal of Business Ethics 2013 114 2 207 223 10.1007/s10551-012-1336-0 Kim, H. (Hicheon), Kim, H. (Heechun), & Lee, P. M. (2008). Ownership structure and the relationship between financial slack and RD Investments: Evidence from Korean firms. Organization Science, 19(3), 404–418. Kim, S. I., Shin, H. Hyejeong), Shin, H. (Heejeong), & Park, S. (2019). Organizational slack, corporate social responsibility, sustainability, and integrated reporting: Evidence from Korea. Sustainability, 11(16), 4445. Latham SF Braun MR The performance implications of financial slack during economic recession and recovery: Observations from the software industry (2001–2003) Journal of Managerial Issues 2008 20 30 50 Lawson MB In praise of slack: Time is of the essence Academy of Management Perspectives 2011 15 3 125 135 10.5465/ame.2001.5229658 Li, S., & Xie, X. Y. (2014). Corporate social responsibility, political relationship and debt financing of private enterprises: Evidence from Chinese capital market. Nankai Business Review, 17(6), 30–40+95. Li H Meng L Wang Q Zhou LA Political connections, financing and firm performance: Evidence from Chinese private firms Journal of Development Economics 2008 87 2 283 299 10.1016/j.jdeveco.2007.03.001 Li S Song X Wu H Political connection, ownership structure, and corporate philanthropy in China: A strategic-political perspective Journal of Business Ethics 2015 129 2 399 411 10.1007/s10551-014-2167-y Li WA Wang PC Xu YK Philanthropy, political connection and debt finance: Reciprocal behavior of governments and private enterprises Nankai Business Review 2015 18 1 4 14 Li Y Li Y Zhang J Foo CT Towards a theory of social responsibility reporting Chinese Management Studies 2013 7 4 519 534 10.1108/CMS-09-2013-0167 Lu Y Political connections and trade expansion: Evidence from Chinese private firms Economics of Transition 2011 19 2 231 254 10.1111/j.1468-0351.2010.00402.x Ma Z Bu M A new research horizon for mass entrepreneurship policy and Chinese firms’ CSR: Introduction to the thematic symposium Journal of Business Ethics 2021 169 4 603 607 10.1007/s10551-020-04549-7 Marquis C Qian C Corporate social responsibility reporting in China: Symbol or substance? Organization Science 2014 25 1 127 148 10.1287/orsc.2013.0837 Mattingly JE Olsen L Performance outcomes of investing slack resources in corporate social responsibility Journal of Leadership Organizational Studies 2018 25 4 481 498 10.1177/1548051818762336 McWilliams A Siegel DS Wright PM Corporate social responsibility: Strategic implications Journal of Management Studies 2006 43 1 1 18 10.1111/j.1467-6486.2006.00580.x Miller KD Chen WR Variable organizational risk preferences: Tests of the March-Shapira model Academy of Management Journal 2004 47 1 105 115 10.2307/20159563 Moch MK Pondy LR The structure of chaos: Organized anarchy as a response to ambiguity Administrative Science Quarterly 1977 22 2 351 362 10.2307/2391967 Mulligan T A critique of Milton Friedman's essay ‘the social responsibility of business is to increase its profits’ Journal of Business Ethics 1986 5 4 265 269 10.1007/BF00383091 Nohria N Gulati R Is slack good or bad for innovation? Academy of Management Journal 1996 39 5 1245 1264 10.2307/256998 Peng MW Luo Y Managerial ties and firm performance in a transition economy: The nature of a micro-macro link Academy of Management Journal 2000 43 3 486 501 10.2307/1556406 Porter ME Kramer MR Strategy and society: The link between competitive advantage and corporate social responsibility Harvard Business Review 2006 84 12 78 92 Qin XZ Wang ZS Zhao H Corporate governance and CSR disclosures: Evidence from the SMEs of ChiNext Board Management Review 2018 30 3 188 200 Rauf F Voinea CL Naveed K Fratostiteanu C CSR disclosure: Effects of political ties, executive turnover and shareholder equity Evidence from China. Sustainability 2021 13 7 3623 Roberts BE A dead senator tells no lies: Seniority and the distribution of federal benefits American Journal of Political Science 1990 31 1 31 58 10.2307/2111510 Sapienza P The effects of government ownership on bank lending Journal of Financial Economics 2004 72 2 357 384 10.1016/j.jfineco.2002.10.002 Schaefer BP Shareholders and social responsibility Journal of Business Ethics 2008 81 2 297 312 10.1007/s10551-007-9495-0 Sheng S Zhou KZ Li JJ The effects of business and political ties on firm performance: Evidence from China Journal of Marketing 2011 75 1 1 15 10.1509/jm.75.1.1 Shleifer A Vishny RW A survey of corporate governance The Journal of Finance 1997 52 2 737 783 10.1111/j.1540-6261.1997.tb04820.x Simon HA Models of man; social and rational 1957 Wiley Sims GC Rethinking the political power of American business: The role of corporate social responsibility 2003 Stanford University Singh JV Performance, slack, and risk taking in organizational decision making Academy of Management Journal 1986 29 3 562 585 10.2307/256224 Sirmon DG Hitt MA Ireland RD Managing firm resources in dynamic environments to create value: Looking inside the black box Academy of Management Review 2007 32 1 273 292 10.5465/amr.2007.23466005 Su X Liu HL Effects of diversified operation on research and development investment—The mediating role based on organizational slack Science Research Management 2018 39 1 126 134 Vanacker T Collewaert V Zahra SA Slack resources, firm performance, and the institutional context: Evidence from privately held European firms Strategic Management Journal 2017 38 6 1305 1326 10.1002/smj.2583 Voss GB Sirdeshmukh D Voss ZG The effects of slack resources and environmental threat on product exploration and exploitation Academy of Management Journal 2008 51 1 147 164 10.5465/amj.2008.30767373 Wang H Tong L Takeuchi R George G Corporate social responsibility: An overview and new research directions: Thematic issue on corporate social responsibility Academy of Management Journal 2016 59 2 534 544 10.5465/amj.2016.5001 Wang S Gao Y Hodgkinson GP Rousseau DM Flood PC Opening the black box of CSR decision making: A policy-capturing study of charitable donation decisions in China Journal of Business Ethics 2015 128 3 665 683 10.1007/s10551-014-2123-x Wang YN Cheng XS Environmental uncertainty, absorbed slack and enterprise innovation: Evidence from Chinese listed enterprises in manufacture industry Studies in Science of Science 2014 32 08 1242 1250 Wang Z Chen MH Chin CL Zheng Q Managerial ability, political connections, and fraudulent financial reporting in China Journal of Accounting and Public Policy 2017 36 2 141 162 10.1016/j.jaccpubpol.2017.02.004 Welbourne TM Cyr LA The human resource executive effect in initial public offering firms Academy of Management Journal 1999 42 6 616 629 10.2307/256983 Williamson IO Employer legitimacy and recruitment success in small businesses Entrepreneurship Theory and Practice 2000 25 1 27 42 10.1177/104225870002500104 Wiseman RM Bromiley P Toward a model of risk in declining organizations: An empirical examination of risk, performance and decline Organization Science 1996 7 5 524 543 10.1287/orsc.7.5.524 Xiao HJ Li JL The dynamic test of iron law of responsibility: Empirical evidence from the M&A samples of Chinese listed companies Management World 2018 34 7 27 42 Xiong FH Huang J Ownership concentration, major shareholder balance and corporate performance Research on Financial and Economic Issues 2016 5 69 75 Xu E Yang H Quan JM Lu Y Organizational slack and corporate social performance: Empirical evidence from China’s public firms Asia Pacific Journal of Management 2015 32 1 181 198 10.1007/s10490-014-9401-0 Yu YH Huang XZ Cao X The relationship between corporate social responsibility and corporate performance, the moderating role of enterprises’ social capital Management Review 2015 27 1 169 180 Zhang J Cheng M Wei X Gong X Zhang S Internet use and the satisfaction with governmental environmental protection: Evidence from China Journal of Cleaner Production 2019 212 1025 1035 10.1016/j.jclepro.2018.12.100 Zhao J Chen XY Li R Ranking mobility and enterprise innovation: An analysis based on the perspective of legitimacy Economic Theory and Business Management 2019 2019 5 88 102 Zheng H Zhang Y Do SOEs outperform private enterprises in CSR? Evidence from China. Chinese Management Studies 2016 10 3 435 457 10.1108/CMS-10-2015-0225
PMC008xxxxxx/PMC8920748.txt
==== Front sppfe PFE Policy Futures in Education 1478-2103 SAGE Publications Sage UK: London, England 10.1177_14782103221078401 10.1177/14782103221078401 Special Issue: Higher Education Policy and Management in the Post-Pandemic Response of learning analytics to the online education challenges during pandemic: Opportunities and key examples in higher education https://orcid.org/0000-0002-5027-8284 Celik Ismail Gedrimiene Egle https://orcid.org/0000-0002-2191-2194 Silvola Anni Muukkonen Hanni Faculty of Education, Learning and Learning Processes Research Unit, 6370 University of Oulu , Oulu, Finland Ismail Celik, Faculty of Education, Learning and Learning Processes Research Unit, University of Oulu, Oulu 90014, Finland. Email: ismail.celik@oulu.fi 5 2022 12 3 2022 12 3 2022 21 4 387404 © The Author(s) 2022 2022 SAGE Publications This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections. Emerging technological advancements can play an essential role in overcoming challenges caused by the COVID-19 pandemic. As a promising educational technology field, Learning Analytics (LA) tools or systems can offer solutions to COVID-19 pandemic-related needs, obstacles, and expectations in higher education. In the current study, we systematically reviewed 20 papers to better understand the responses of LA tools to the online learning challenges that higher education students, instructors, and institutions faced during the pandemic. In addition, we attempted to provide key cases in which LA has been effectively deployed for various purposes during the pandemic in the higher education context. We found out several prominent challenges for stakeholders. Accordingly, learners needed of timely support and interaction, and experienced difficulty of time management. Instructors lacked pedagogical knowledge for online teaching. In particular, individual and collaborative assessment have been a challenge for them. Institutions have not been ready for a digital transformation and online teaching. In response to these challenges, LA tools have been deployed for the following opportunities: monitoring, planning online learning process, fostering learners’ engagement and motivation, facilitating assessment process; increasing interaction, improving retention, being easy to use. Understanding these promises can also give insight into future higher education policies. Learning analytics pandemic online learning policy making higher education typesetterts10 ==== Body pmcIntroduction The ongoing COVID-19 pandemic has dramatically disrupted higher education institutions all over the world. Therefore, as a response to the rapid spread of the pandemic, higher education institutions have suspended face-to-face education temporarily (Bao, 2020; Usher et al., 2021). For instance, at the end of April 2020, higher education institutions from approximately 180 countries closed their campuses (Marinoni et al., 2020). After the closure of the campus, the institutions had swiftly changed their instruction to online education. This is most probably because online education has been regarded as the safest and most responsible approach during the pandemic for keeping social isolation (Openo, 2020). However, the rapid transition to online education has led to many challenges for all stakeholders including the institutions, teachers, and learners (Chetty et al., 2020; Hodges et al., 2020). For example, the institutions had to update and broaden their servers to meet the mass deployment of online learning environments (Balderas and Caballero-Hernández, 2020). In addition to these technical issues, the institutions had to struggle in providing the instructors with pedagogical support for online teaching. In fact, many instructors conceived online teaching and learning as “painful, worrisome, and anxiety-inducing” during the pandemic (Kimmons et al., 2020, p.2). For instance, the instructors failed to effectively monitor students’ behavioral, emotional, and cognitive aspects of learning because of the lack of an effectively designed system (Van der Spoel et al., 2020). Also, instructors were unable to assess and evaluate the learners due to students’ cheating behavior, which is hard to detect in online learning environments (Balderas and Caballero-Hernández, 2020). From the student perspective, the concern regarding cheating behavior was leading instructors to take immensely demanding exams (Lancaster and Cotarlan, 2021). It has been evidenced that higher education students also have dissatisfied with and challenged the online learning process (Ludlow, 2020). One possible reason for the dissatisfaction is regarded as non-stop online lectures throughout all day, causing Zoom fatigue in the students (Bonk, 2020). Therefore, pure online lectures that are far from meeting the psychological well-being, needs, and expectations of students may escalate the drop-out rate during pandemic (Baber, 2020; Diver and Martinez, 2015; Teuber et al., 2021). Furthermore, the pandemic process increased the inequality among the students. In this regard, Chetty et al. (2020) found out students with high socio-economic status outperform those of low socio-economic status during the pandemic. This is because students from low-income areas may lack the necessary technical equipment such as the Internet or personal computer; these students may receive less support from their parents (Zhang et al., 2021). Emerging technological advancements can play an essential role in overcoming challenges caused by the pandemic (Richter, 2020). Indeed, this period might be a unique opportunity to better understand the implication of technological solutions in learning and teaching (Dwivedi et al., 2020; Sein, 2020). As an emerging technology field, Learning Analytics (LA) tools or systems can offer solutions to pandemic-related needs, obstacles, and expectations in higher education (O’Leary, 2020). For example, dashboards as one of the most common LA tools can provide teachers with important information about their students, including time management, material use, and social interactions (Safsouf et al., 2021). Hence, LA dashboards can serve as a monitoring tool for students by creating and reporting several visualizations on student progress and learning outcomes during the pandemic (Conde et al., 2020). Instructors can straightforwardly recognize specific learning/support needs of students through LA dashboards; ultimately, this provides instructors with possibilities for timely and individualized interventions (He et al., 2021; Molenaar and Knoop van Campen, 2018). Moreover, with the help of machine learning algorithms, the dashboards can create predictive models based on student real-time data (Dabbebi et al., 2017; Diana et al., 2017). These models can be specified in the process of the pandemic, considering students’ needs and guidance (Safsouf et al., 2021). In addition to dashboards, LA tools might be utilized by instructors, for measuring and monitoring students’ individual and group performance and for assessing progress (Conde et al., 2020). Also, some LA tools have been developed for the detection of students’ cheating behavior during online exams (Balderas and Caballero-Hernández, 2020). In order to better support learners with current and emerging technologies, there is a need to understand how LA has been utilized for mitigating pandemic-related challenges. In the current study, we systematically reviewed a selection of the papers to better understand the responses of LA tools to the online learning challenges that higher education students, instructors, and institutions faced during the pandemic. In addition, we attempted to provide key cases in which LA has been effectively deployed for various purposes during the pandemic in the higher education context. Having a positive understanding of the advantages regarding LA tools accelerates the adoption of LA (De Laet et al., 2020; Park and Jo, 2019). Then, it is likely that higher education stakeholders, who perceive LA as useful, can benefit from tools in future natural crises or emergency situations. Learning Analytics in higher education The extensive use of big data technologies enables us to collect a massive amount of data on the learning process (Gašević et al., 2016). This data has been regarded as a valuable asset and promising source of information to support and enhance effective learning behavior and played a role in the emergence of the field of LA (Siemens and Gasevic, 2012; Larrabee Sønderlund et al., 2019). LA is defined as the measurement, collection, analysis, and reporting of data about learners and their contexts to better understand and optimize the learning process (Siemens and Gasevic, 2012). Meanwhile, LA tools are designed to provide customized information for supporting the learning process by analysis of stored data when learners interact with the learning environment (Dyckhoff et al., 2012). Considering these definitions, online learning environments might be one of the most suitable platforms for the successful deployment of LA (Heath, 2021). In fact, students in online learning leave a large amount of data while interacting with course materials and assignments (Alexandron et al., 2019; Schwendimann et al., 2017). Therefore, these environments may contribute to data-driven decision-making in higher education, also in non-emergency days (Tsai et al., 2019; Zhang et al., 2021). LA tools have provided possibilities and approaches to support learners in online and hybrid settings in higher education (e.g., Larsen et al., 2019). We argue that these tools could be used effectively to support higher education institutions, instructors and learners in post-pandemic higher education. To better understand the ways of how and the purposes to which these tools could be used, an overview of LA use during pandemic is needed. Understanding LA promises can also give insight for future higher education policies (Ifenthaler and Yau, 2020). In this context, the synthesis of the current study is important for higher education students, instructors, and policy-makers. We addressed the following research questions (RQs) in the current study:RQ1- What are the online education challenges that institutions, instructors, and students face during the COVID-19 pandemic? RQ2- What are the advantages of LA with the purpose of optimizing online education during the COVID-19 pandemic? RQ3- What are the key cases from the pandemic process in which LA tools have been effectively deployed in response to online education challenges during the COVID-19 pandemic? Method The manuscript search processes We adopted the guidelines of systematic literature review procedure suggested by Kitchenham and Charters (2007). These guidelines start with a manuscript search process followed by employment of selection of criteria. Next, we performed analysis and synthesis of findings of the selected manuscripts. In the current study, four databases have been used for the manuscript search processes: ACM Digital-Library, IEEE XPLORE, Thomson Reuters’ Web of Science, Elsevier’s SCOPUS. These databases consist of several high-ranking journals (Shih, et al., 2008) including high-quality studies (Crescenzi-Lanna, 2020). The search terms used comprised the following words and combinations: “Learning analytics,” “educational data mining,” “dashboard,” “visualization,” “remote teaching,” “remote learning,” “online learning,” “distance education,” “higher education,” “pandemic,” and “covid” (Table1). After accessing the articles, we employed a set of inclusion and exclusion criteria. Following the relevant criteria, we selected empirical (1) articles and conference papers that have been conducted in higher education context (2) during the COVID-19 pandemic (3). Lastly, one more inclusion criterion is the actual use of LA analytical tools as a response to online learning challenges. As the time period, the conference papers and articles (in English) published started from the first of January 2020 to first of September 2021. The editorials, reviews and the studies conducted in the K-12 context have been excluded. As a result of the application of the criteria, 20 articles and conferences remained for the further analysis and synthesis process. Table 1 indicates the search string for each database and the number of articles selected/accessed.Table 1. The search string used in each database and its results. Data base Search string (Selected/Accessed) Web of Science TS = Topic. covers title, abstract and keywords (((TS = (“learning analytics” or “analytic* " or “educational data mining")) AND TS=(“pandemic” OR “COVID”)) AND TS=(“remote teaching” or “remote learning” or “online learning” or “distance education")) AND TS=(“higher education” or “univers*") ((TS=(“automated feedback” or “dashboard” or “visualization")) AND TS=(“higher education")) AND TS=(“pandemic” or “covid”) (5/23) Scopus TITLE-ABS-KEY = Title, abstract and keywords TITLE-ABS-KEY ((((“learning analytics” or “analytic* “ or “educational data mining”) AND (“higher education” or “univers*”) AND (“remote teaching” or “remote learning” or “online learning” or “distance education”) AND (“pandemic” OR “covid”)))) (4/38) ACM Digital-Library “learning analytics” AND pandemic (6/52) IEEE Xplore “learning analytics” AND pandemic (5/45) The data coding and analysis processes In order to get an overview of the studies, we coded the selected articles in terms of data modality, analytical tool, country, and domain. Table 2 shows the overview of the studies on the response of LA to the online learning challenges during the COVID-19 pandemic. We performed the qualitative content analysis for these 20 studies. Considering that the preliminary or template coding scheme could unnecessarily direct researchers to the out of research aims (Şimşek and Yıldırım, 2011), we employed the open coding approach (Williamson, 2015) in the process of qualitative content analysis. For this, we firstly familiarized with the whole by picking a few of papers randomly and considered their basic meaning. Secondly, we defined preliminary thought in the margin, made a list of all thoughts, and grouped similar thoughts. In this process, we also made columns to differentiate key, unique, and leftover thoughts. Thirdly, after coding the text, we decided the most illustrative phrasing for our thoughts and turned them into categories. Fourthly, a certain abbreviation was decided for each category, to alphabetize these codes. Lastly, we incorporated the last code and employed initial analysis and recode, if necessary. The first author initially completed coding the studies individually and then shared the codes with the second and third authors. Disagreements were negotiated by checking the code list and the relevant studies. Some categories were merged and renamed. Finally, we recorded the 20 studies according to the latest code list (Table 2).Table 2. An analysis of studies on the response of Learning Analytics to the COVID-19 pandemic (n = 20). Author(s) Article title Data modality Analytic tool Domain Country Dias et al. (2020) DeepLMS: a deep learning predictive model for supporting online learning in the Covid-19 era Discourse Log Moodle Engineering Greece UAE Liang et al. (2020) Opportunities for Improving the Learning/Teaching Experience in a Virtual Online Environment Video Discourse Moodle Sutori ComputerSci Engineering China Japan Lapitan et al. (2021) An effective blended online teaching and learning strategy during the COVID-19 pandemic Self-reported Log Blackboard Moodle Chemistry Philippines Campanyá et al. (2021) Mixed Analysis of the Flipped Classroom in the Concrete and Steel Structures Subject in the Context of COVID-19 Crisis Outbreak. A Pilot Study Self-reported Log Blackboard Moodle Engineering Spain Mata et al., (2021) How to Teach Online? Recommendations for the assessment of online exams with University students in the USA in times of pandemic Performance Code of Conducts Business USA Anteby et al. (2021) Development and Utilization of a Medical Student Surgery Podcast During COVID-19 Log Podcast Medicine Israel Tabuenca et al., (2021) Mind the gap: smoothing the transition to higher education fostering time management skills Performance log self-reported Moodle ComputerSci Spain Farah et al. (2020) Bringing computational thinking to non-STEM undergraduates through an integrated notebook application Clickstream video CodeApp Dashboard Business Switzerland Prat et al. (2021) A Methodology to Study the University’s Online Teaching Activity from Virtual Platform Indicators: The Effect of the Covid-19 Pandemic at Universitat Politècnica de Catalunya Log Discourse Moodle Atenea Mixed Spain Zhang et al. (2021) Measuring the Impact of COVID-19 Induced Campus Closure on Student Self-Regulated Learning in Physics Online Learning Clickstream Log e-Learning Modules Physics USA Safsouf et al. (2021) TABAT: Design and Experimentation of A Learning Analysis Dashboard for Teachers And Learners Log Moodle Dashboard Engineering Business Morocco Günther (2021) The impact of social norms on students’ online learning behavior: Insights from two randomized controlled trials Log Discourse Dashboard ComputerSci Germany Balderas Caballero-Hernández (2020) Analysis of Learning Records to Detect Student Cheating on Online Exams: Case Study during COVID-19 Pandemic Video Moodle Py-Cheat Engineering ComputerSci Spain Conde et al. (2020) A Learning Analytics tool for the analysis of students’ Telegram messages in the context of teamwork virtual activities Discourse Heroku ComputerSci Spain Perez-Sanagustin et al. (2021) Can Feedback based on Predictive Data Improve Learners’ Passing rates in MOOCs? A Preliminary Analysis Log Clickstream DapMOOC ComputerSci Chile Zikas (2021) Covid-19—VR Strikes Back: innovative medical VR training Log CVRSB Medicine Switzerland Naidoo and Naidoo (2021) Linking Formative and Summative Performance in an online L2 module: Insights from Learning Analytics Log Moodle Mixed S.Africa Maher et al., (2020) Learners on Focus: Visualizing Analytics Through an Integrated Model for Learning Analytics in Adaptive Gamified E-Learning Log Discourse Moodle Mixed Egypt Rahmah et al. (2020) Developing Distance Learning Monitoring Dashboard with Google Sheet: An Approach for Flexible and Low-Price Solution in Pandemic Era Observation discourse assignment Google Sheet Mixed Indonesia Liu et al. (2020) MapOnLearn: The Use of Maps in Online Learning Systems for Education Sustainability Self-reported MaponLearn Dashboard English Math China According to Table 2, log data was found to be the main source of data for the LA tool. Also, Moodle and dashboards have been the most deployed tools for analytical purposes. LA tools have been commonly utilized in engineering and computer science departments. Findings and discussion Online distance education challenges (RQ1) We found a number of reported challenges that stakeholders faced during online distance education in the COVID-19 pandemic. We addressed these challenges in terms of higher education stakeholders, namely, learners, instructors and institutions (see Table 3).Table 3. The challenges that stakeholders faced during online distance education. Stakeholders Challenges (f) Learner (f = 19) Lack of timely support (f = 9) Lack of interaction (f = 3) Having difficulty of time management (f = 3) Lack of motivation for engagement (f = 2) Lack of digital literacy (f = 1) Increasement of digital inequalities (f = 1) Instructor (f = 9) Individual and collaborative assessment (f = 4) Assessment reliability (f = 2) Lack of pedagogical knowledge for online teaching (f = 1) Stress from heavy dependence on technologies (f = 1) Less chance for real time monitoring of learners (f = 1) Institutions (f = 6) Not being ready for digital transformation (f = 2) Providing pedagogical support for online teaching (f = 2) Insufficient infrastructure (f = 2) According to the results of our review, the most commonly reported problem for students was lack of timely support. For instance, Maher et al. (2020) revealed that students needed support for their learning but could not receive it sufficiently during online education. The support is needed because students were less familiar with online learning before pandemic (Landrum et al., 2021). Students had also struggled to understand course goals and instructor’s expectations; thus, they had a sense of ambiguity about the assessment process of their online learning (Platt et al., 2014). Similarly, lack of interaction appeared to be another challenge from the learner side. In fact, having less interaction chance is an important factor negatively affecting learners’ online learning satisfaction (Cole et al., 2014). We also found that having difficulty with time management was a prominent challenge for students (e.g., Tabuenca et al., 2021). This result is similarly evidenced with another study conducted during pandemic (Barrot et al., 2021). During COVID-19 pandemic, empirical studies have shown that poor quality Internet access and less digital literacy skills were associated with lower use of the Internet for educational purposes (Van Deursen, 2020). Similarly, in the current review, we reported students’ digital inequalities to properly access learning content and lack of digital skills to utilize online environments as two important challenges (e.g., Günther, 2021; Rahmah et al., 2020). From the instructor`s side, our review revealed that assessment was a challenging issue for online learning (Conde et al., 2020; Naidoo and Naidoo, 2021). Therefore, reliability of online exam results has been a conflicting issue for instructors. We also observed that instructors rarely had trust in the reliability level of the online assessment process (Balderas and Caballero-Hernández, 2020). For instructors, this may be due to the decreased chance/opportunity for real time monitoring of learners. Similar to students, higher education instructors were not ready for online learning; therefore, we found that instructors were far from delivering best quality online lecture pedagogically and technically (e.g., Rahmah et al., 2020). It has been also found that the online learning process due to the pandemic situations lead to stressful situations for in the higher education instructors (Boyer-Davis, 2020). One of the reasons for this stress was depending on online education technologies without necessary digital skills. In the current review, we also observed that instructors had stress from heavy dependence on online learning technologies (Maher et al., 2020). The advantages of LA for online distance education challenges (RQ2) As a result of the qualitative analysis, nine main categories were formed for the opportunities: providing timely support (1), automated adaptive feedback (2), planning online learning process (3), fostering learners’ engagement and motivation (4), monitoring (5), facilitating assessment process (6), increasing interaction (7), improving retention (8), easy to be deployed (9). We then grouped each main category into separate sub-categories, based on where the reported opportunity naturally fit (see Table 4). It is important to note that some papers showed more than one opportunity. For such papers, more than one code was assigned for the opportunities. We also used “+” to indicate which stakeholders benefited from the relevant opportunity.Table 4. Opportunities of LA tools for online distance education challenges. Opportunities Relevant stakeholders Categories (f) Sub-categories (f) Learners Instructor Institution Monitoring (f = 12) Instructor monitoring (f = 5) + Early detection of students’ learning outcome (f = 3) + + Learner self-monitoring (f = 4) + Planning online learning process (f = 12) resource allocation (f = 2) + + set up learning goals (f = 6) + + setting completion times and conditions (f = 3) + + Fostering learners’ engagement and motivation (f = 7) + Facilitating assessment process (f = 6) formative (f = 3) + summative (f = 1) + individual (f = 1) + group (f = 1) + Increasing interaction (f = 2) student-student (f = 1) + student-instructor (f = 1) + + Improving retention (f = 2) + + + Being easy to use (f = 2) + + + According to results from the reviewed papers, two of the most remarkable opportunities of LA tools were that the tools supported learners and instructors in the planning the online learning process and monitoring. In the process of planning, learners and instructors can determine learning goals (Tabuenca et al., 2021) and set up completion times and conditions (Liang et al., 2020) by utilizing LA tools. This helps the learners with self-regulating their learning and the instructors with pedagogical planning (e.g., Zhang et al., 2021). Also, LA tools helped the institutions’ and instructors’ resource allocation during planning online learning (e.g., Anteby et al., 2021). Instructors benefited from monitoring opportunities when they monitor their students during a lecture or the whole online course (Farah et al., 2020) or when they receive information of students’ early detected outcome (Dias et al., 2020). In addition, students can monitor their own online learning progress using LA tools (e.g., Lapitan et al., 2021). As a result of our review, providing timely support was found to be a crucial opportunity for LA tools (e.g., Liu et al., 2020). Given that one of the challenging issues for online learning is lack of support, LA tools can be a solution for this challenge. Similarly, the opportunity of automated adaptive feedback from LA tools can save teachers’ time and may help learners when they have a difficulty (Günther et al., 2021). This adaptive feedback promotes personalized learning. According to our findings, LA tools might play an important role in fostering learners’ engagement and motivation in online learning environments. In their study, Safsouf et al., (2021) identified that students shared their positive experience when they used the LA dashboard. In particular, students might have positive feelings when they monitor their learning progress through various useful visualizations. Also, students are more satisfied with having a chance of setting up their learning goal through the reminder systems (Safsouf et al., 2021). When students face tough conditions such as pandemic, it is difficult for them to be highly motivated for learning and ultimately engage in the learning process (Mishra et al., 2020). For this, successful deployment of LA tools offer opportunities for supporting their engagement (Chen et al., 2021). LA facilitated online learning assessment was identified as an important support for instructors during pandemic. Specifically, the formative (Lapitan et al., 2021) and/or summative (Mata et al., 2021) assessment can be performed with the help of LA tools. For instance, Naidoo and Naidoo (2021) utilized visualizations of students’ learning progress, which is beneficial for formative assessment. Further, it is possible to use LA individual (Balderas and Caballero-Hernández, 2020) and group assessment (Conde et al., 2020) in the process of online learning. Another LA opportunity is found to be the increment of student-student (Maher et al., 2020) and students-instructor interaction (Campanyà et al., 2021). One possible explanation for increment in students-instructor interaction is the advantages of LA tools to teachers for understanding students' learning progress. This contributes to timely support from teachers, eventually resulting in the students-instructor interaction (Hernández-Lara et al., 2019). Some studies reported that LA tools have benefits for improving students' retention as a response to increased dropping-out risk (Perez-Sanagustin et al., 2021). Instructors generally have time limitation for detecting students at-risk and offering adaptive feedback for students (Günther, 2021). Students at-risk who cannot receive adaptive support are more likely to drop out the course (Martin et al., 2020). In such times, LA tools with the advantages of timely support and intervention can increase student retention (Perez-Sanagustin et al., 2021). It has been also reported that LA tools were perceived as easy to use (Maher et al., 2020; Liu et al., 2020). Hence, this could be regarded as an opportunity for deployment. Key case examples regarding deployment of LA tools during the pandemic (RQ3) Anteby et al. (2021), aimed at exploring the cost and effectiveness of implementation of a set of podcasts for medical students in online distance education during the COVID-19 pandemic. The podcast series were released on a website and well-known podcast platforms. A total of 10 podcast episodes were available for free download within 9 months starting from March 2020. Podcast analytics acquired from transistor.fm that is a hosting platform for measuring audience and interest. The measuring is based on a set of metrics such as the number of downloads per episode by the day. Utilizing podcast analytics, the researchers conducted a cost-analysis process of podcast-supported online teaching methods. As a result of this process, it has been estimated that the total cost to create podcast series is comparatively less than other educational modalities. Hence, podcast analytics as a LA tool might offer premises for decision-making on the efficacy and effectiveness of a teaching and content delivery method. In a study by Balderas and Caballero-Hernández (2020), a LA tool has been developed to detect students’ cheating behavior when higher education students take online exams. For this, the students’ data on the Moodle platform has been obtained. Then, this data has been transformed into a spreadsheet format and analyzed using process mining (Disco) and cheating detection software (By-Cheat). After the analysis, a variety of reports and visualizations have been formed representing students’ information (grade, starting exam time, IP address from the student`s location, resources accessed during the exam, etc.). The LA tool has been deployed in the Degree in Computer Science and Engineering of the University of Cadiz (Spain). Results indicated that students have taken online exams in groups, so they have been seeking the answers to the questions among a few. It has been detected that some students who prefer taking the exam later, obtained higher grades within less time. This study highlighted that LA tools might be utilized for contributing to a valid and reliable assessment for distance education during or even after the pandemic. Safsouf et al. (2021), utilized a LA dashboard entitled TaBAT that enabled instructors and students to monitor students’ learning process with numerous visualizations. Specifically, the dashboard provided instructors with descriptive and/or predictive graphs regarding students. These graphs and visualizations helped to understand students’ engagement, academic performance and probability of drop-out. This process led to timely interventions that might promote learners’ self-reflection, autonomy, and academic performance. In the development process of TaBAT, researchers used a set of indicators (e.g., course, participation, success) for the three types of notifications, namely, students in difficulty, students in risk of dropping-out, and recommendations. According to the authors, automated feedback and timely support offered by LA tools such as TaBAT dashboard might play an important role in reducing drop-out rate at online distance education. In another study, a LA tool has been created and employed with the purposes of evaluation of students’ interactions (Conde et al., 2020). The tool has been tested in a computer animation course during the pandemic. The students worked in groups of four members for a collaborative task. It was possible to monitor and assess student participation and interaction by using the number of short and long messages. Further, the number of initiated conversations was considered as an indicator of student leadership. Therefore, the Telegram Instant Messaging Tool facilitated teachers to better understand the individual acquisition of teamwork competence. The results pointed out that the usage of the tools was associated with better academic performance. Higher education students were willing to use Telegram Instant Messaging Tool, since they were familiar with instant messaging software. According to Conde et al. (2020), the individual assessment from a collaborative work during online education requires online tools. This study indicated that LA tools revealed the frequency and contributions from students’ messages which can be an important asset for collaborative work evaluation. Maher et al. (2020) integrated gamification principles into the LA dashboard. In particular, they suggested the Personalized Adaptive Gamied E-learning (PAGE) model as a response to online learning challenges such as learner’s lack of motivation and lack of enjoyment. The suggested model is designed as independent of any domain so that it fits any sort of course for learners with different backgrounds. These flexible options enable teachers to make a dynamic course plan or/and practice. In addition, the PAGE model supports learners in overcoming the miscommunication challenges caused by distance learning. The results presented that LA dashboard supported with gamification principles had the potential for personalizing the higher education courses to each individual learner. During pandemic times, it is necessary to make the learning process as enjoyable as possible especially when higher education students feel isolated. Hence, the study of Maher et al. (2020) offers empirical evidence that using gamificated-LA dashboard might support instructors for making the courses more interesting. Future studies and implications for post-pandemic Previous review studies indicated opportunities of LA in higher education (e.g., Viberg et al., 2018; Tsai and Gasevic, 2017). However, the educational needs and expectations of stakeholders are most likely to vary in crisis situations such as pandemic. Therefore, the deployment of LA in higher education can differentiate compared to regular life conditions. In this regard, it is crucial to understand the role of LA in mitigating the learning and teaching challenges related to pandemic. The current study is the first attempt to provide an overview on the usage of the LA tools for overcoming online education challenges during COVID-19 pandemic. The implications of the current study might be important for post-pandemic policies of the higher education institutions. In fact, successful deployment of LA can be inspiring for another educational context such as K-12 level. For instance, when pre-service teachers increase their awareness of LA benefits in the higher education, they can utilize these tools in their professional life, specifically in K-12 context. Based on our findings students have faced the most difficulties during online learning in COVID-19 pandemic. Further, the instructors have been identified as the stakeholder group potentially most benefiting from LA services. Thus, this leads to believe that LA has the potential to provide solutions to the challenges that institutions and especially instructors face during crises now and in the future. However, the nature of students’ difficulties remains a challenge to address. From the student perspective, lack of timely support for learning activities, lack of human interaction and time management difficulties were the most prominent problems in the online education. As responses to these challenges, LA tools served as supportive tools for monitoring and planning online learning process and increasing their motivation for engagement. In light of this result, we suggest that the institutions and policy-makers should encourage the instructors and students to use LA tools effectively to overcome interaction, planning and time management challenges in particularly crisis time. According the results from our synthesis, instructors had difficulties in terms of individual and group assessment reliability of those assessments. In addition, they had less chance for real time monitoring of learners. For the difficulties that the instructors had, LA offers opportunities such as detecting students at-risk as a function of monitoring and facilitating assessment process. Moreover, the current study pointed out instructors might use some LA tools for more valid and reliable online exams. As seen from the current and previous studies, higher education institutions are not ready for digital transformation with insufficient infrastructure. This might lead to insufficient online learning management. Particularly, the current study showed that universities failed to provide the instructors with pedagogical support for online teaching during pandemic. We argue that preparing the instructors for giving online lecture should be agenda in the post-pandemic higher education policies. In this preparation, the opportunities of LA tools for online learning should be introduced to instructors. This can lessen instructors’ stress stem from intense use of technologies. However, online education challenges identified at the institutional level also indicated that similar initiatives are needed to support learners. For example, improvement of the data infrastructure and improving the readiness for digital transformation could involve actions such as providing students with the platforms that enable students’ study planning, monitoring and time management, or instructors’ online monitoring and reliable assessment of student work during online courses. These implications might be considerable for post-pandemic higher education. The results of this study are in line with the previous findings of LA opportunities and challenges in higher education context. As identified in this study, previous studies have identified LA tools opportunities to support learners’ self-regulation of learning, including study planning and monitoring (e.g., Matcha et al., 2019), as well utilization of LA tools as an instructors support for pedagogical design, monitoring and assessment of online learning processes (e.g., Molenaar and Knoop van Campen, 2018). Additionally, institutional leadership and investment on the development of data infrastructure and development of LA tools has been identified as one of the key issues in implementing high quality LA supported practices and processes in educational institutions (Tsai et al., 2019). Despite addressing a topical and highly relevant area of research, this study has several limitations. First, extant literature focuses on the topic of LA and challenges experienced by the stakeholders of higher education are analyzed in this context. Literature reviews with different foci might uncover a variety of other online learning challenges, which would be important to take into account for a holistic perspective needed to organize distance education in the future. Some challenges such as difficulties with time management experiences by students have so far been only addressed by LA to a very limited extent. We see further possibilities for exploration in this area, as problems with time management will likely remain a challenge after a pandemic as well, for example, in organized hybrid education. Other identified challenges, such as a lack of social interactions, need to be investigated as a complex problem of students’ well-being and the LA role in solving this issue has to be evaluated critically. We, however, see possibilities in this largely unaddressed area with involvement of other institutional resources, such as academic advisors, whose role in LA utilization has so far been underexplored. For future research, the impact of implementing LA tools in post-pandemic education as supporting teacher and student engagement, fluency of institutional practices and student learning should be explored. Conclusions According to the results of this study, LA as an emerging technology provides promising solutions to tackle the online education challenges faced by higher education institutions during COVID-19 pandemic. However, it is still unclear, what kind of educational practices higher education institutions will build for post-pandemic time. LA tools should be further investigated in the context of online and hybrid education practices. Key finding from our study is that while students were identified to experience the greatest number of challenges during distance education, instructors were potentially greatest beneficiaries from the LA tools. Key implication from this finding is the need for the institutions to initiate, supervise, and continually examine that investments into LA tools for teachers translates into support for students. Hence, the results of this study show that educational institutions have a responsible and critical role in understanding the challenges and needs of their stakeholders and in exploration of LA tools to address unique needs of these stakeholders in post-pandemic educational practices. Author Biographies Ismail Celik is a postdoctoral researcher in the Learning and Learning Processes Research Unit at the Faculty of Education, University of Oulu (Finland). He holds a PhD in educational technology. His research areas cover social media use, technology integration models in education, epistemological beliefs, artificial intelligence, and learning analytics. Egle Gedrimiene is a PhD student in Faculty of Education, at the University of Oulu, Finland. She has a background in psychology and is currently involved in research project investigating technology supported transitions in education. Her research interests are career guidance, self-efficacy and learning analytics. Anni Silvola is a PhD student at the Faculty of Education, at the University of Oulu, Finland. Her doctoral thesis focuses on researching how to support study engagement with learning analytics during university studies. Her research interests are study engagement and competence development during higher education studies, collaborative learning and learning analytics. Currently, she is working on a national learning analytics research and development project, funded by the Ministry of Culture and Education Hanni Muukkonen is a professor in Educational Psychology at the Faculty of Education, University of Oulu (Finland). She holds a PhD in psychology. Her research has addressed collaborative learning and knowledge creation in higher education, design for learning and technology-mediated collaboration. Technology design and development of related knowledge practices has continued through multiple large R&D projects in educational technology and learning analytics. ORCID iDs Ismail Celik https://orcid.org/0000-0002-5027-8284 Anni Silvola https://orcid.org/0000-0002-2191-2194 The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. ==== Refs References *References marked with an asterisk show the articles used in the review Alexandron G Yoo LY Ruipérez-Valiente JA , et al. (2019) Are MOOC learning analytics results trustworthy? With fake learners, they might not be! International Journal of Artificial Intelligence in Education 29 (4 ): 484–506. DOI: 10.1007/s40593-019-00183-1 10.1007/s40593-019-00183-1. * Anteby R Amiel I Cordoba M , et al (2021) Development and utilization of a medical student surgery podcast during COVID-19. Journal of Surgical Research 265 : 95–99.33894454 Baber H (2020) Determinants of students’ perceived learning outcome and satisfaction in online learning during the pandemic of COVID19. Journal of Education and E-Learning Research 7 (3 ): 285–292. DOI: 10.20448/journal.509.2020.73.285.292 10.20448/journal.509.2020.73.285.292. * Balderas A Caballero-Hernández JA (2020) Analysis of learning records to detect student cheating on online exams: case study during COVID-19 Pandemic. In: The Eighth International Conference on Technological Ecosystems for Enhancing Multiculturality, 752–757. DOI: 10.1145/3434780.3436662 10.1145/3434780.3436662. Bao W (2020) COVID ‐19 and online teaching in higher education: a case study of Peking university. Human Behavior and Emerging Technologies 2 (2 ): 113–115. DOI: 10.1002/hbe2.191 10.1002/hbe2.191.32510042 Barro JS Llenares II Del Rosario LS (2021) Students’ online learning challenges During the pandemic and how they cope with them: the case of the Philippines. Education and Information Technologies online ahead of print, 1–18. DOI: 10.1007/s10639-021-10589-x 10.1007/s10639-021-10589-x. Bonk CJ (2020) Pandemic ponderings, 30 years to today: Synchronous signals, saviors, or survivors? Distance Education 41 (4 ): 589–599. Boyer-Davis S (2020) Technostress in higher education: An examination of faculty perceptions before and during the COVID-19 pandemic. Journal of Business and Accounting 13 (1 ): 42–58. Campanyá C. Fonseca D. Amo D. Martí N Peña E. (2021) Mixed Analysis of the Flipped Classroom in the Concrete and Steel Structures Subject in the Context of COVID-19 Crisis Outbreak. A Pilot Study. Sustainability 13 (11 ): 5826. Chen S Ouyang F Jiao P (2021) Promoting student engagement in online collaborative writing through a student‐facing social learning analytics tool. Journal of Computer Assisted Learning 1–17, DOI: 10.1111/jcal.12604 10.1111/jcal.12604. Chetty R Friedman J Hendren N , et al. (2020) The Economic Impacts of COVID-19: Evidence from a New Public Database Built from Private Sector Data, Opportunity Insights Cole MT Shelley DJ Swartz LB (2014) Online instruction, e-learning, and student satisfaction: a three-year study. The International Review of Research in Open and Distributed Learning 15 (6 ): 111–131. * Conde MÁ Rodríguez-Sedano FJ Fernández C , et al. (2020) A learning analytics tool for the analysis of students’ Telegram messages in the context of teamwork virtual activities. In: The Eighth International Conference on Technological Ecosystems for Enhancing Multiculturality, 719–724. Crescenzi‐Lanna L (2020) Multimodal learning analytics research with young children: a systematic review. British Journal of Educational Technology 51 (5 ): 1485–1504, DOI: 10.1111/bjet.12959 10.1111/bjet.12959. Dabbebi I Iksal S Gilliot JM , et al. (2017) Towards adaptive dashboards for learning analytic: An approach for conceptual design and implementation. In: The 9th International Conference on Computer Supported Education. CSEDU, 120–131. De Laet T Millecamp M Ortiz‐Rojas M , et al. (2020) Adoption and impact of a learning analytics dashboard supporting the advisor-Student dialogue in a higher education institute in Latin America. British Journal of Educational Technology 51 (4 ): 1002–1018. DOI: 10.1111/bjet.12962 10.1111/bjet.12962. Diana N Eagle M Stamper J , et al. (2017) An instructor dashboard for real-time analytics in interactive programming assignments. In: Proceedings of the Seventh International Learning Analytics & Knowledge Conference, 272–279. * Dias SB Hadjileontiadou SJ Diniz J , et al. (2020) DeepLMS: a deep learning predictive model for supporting online learning in the Covid-19 era. Scientific Reports 10 (1 ): 1–17. DOI: 10.1038/s41598-020-76740-9 10.1038/s41598-020-76740-9.31913322 Diver P Martinez I (2015) MOOCs as a massive research laboratory: opportunities and challenges. Distance Education 36 (1 ): 5–25. DOI: 10.1080/01587919.2015.1019968 10.1080/01587919.2015.1019968. Dyckhoff AL Zielke D Bültmann M , et al. (2012) Design and implementation of a learning analytics toolkit for teachers. Journal of Educational Technology and Soceity 15 (3 ): 58–76. Dwivedi YK Hughes DL Coombs C Constantiou I Duan Y Edwards JS Gupta B Lal B Misra S Prashant P Raman R. (2020) Impact of COVID-19 pandemic on information management research and practice: Transforming education, work and life. International journal of information management 55 : 102211. * Farah JC Moro A Bergram K , et al. (2020) Bringing computational thinking to non-STEM undergraduates through an integrated notebook application. In: The 15th European Conference on Technology Enhanced Learning. (No. CONF). Gašević D Dawson S Pardo A (2016) How do we start? State and directions of learning analytics adoption. 2016 ICDE Presidents Summit, December, 1–24. DOI: 10.13140/RG.2.2.10743.42401. Günther SA (2021) The impact of social norms on students’ online learning behavior: insights from two randomized controlled trials. In: LAK21: 11th International Learning Analytics and Knowledge Conference, 12–21, DOI: 10.1145/3448139.3448141 10.1145/3448139.3448141. He W Zhang Z Li W (2021) Information technology solutions, challenges, and suggestions for tackling the COVID-19 pandemic. International Journal of Information Management 57 : 102287, DOI: 10.1016/j.ijinfomgt.2020.102287 10.1016/j.ijinfomgt.2020.102287.33318721 Heath MK (2021) Buried treasure or Ill-gotten spoils: the ethics of data mining and learning analytics in online instruction. Educational Technology Research and Development 69 (1 ): 331–334. Hernández-Lara AB Perera-Lluna A Serradell-López E (2019) Applying learning analytics to students’ interaction in business simulation games the usefulness of learning analytics to know what students really learn. Computers in Human Behavior 92 : 600–612. Hodges C Moore S Lockee B , et al. (2020) Remote teaching and online learning. Educause Review 1–15. Ifenthaler D Yau JY-K (2020) Utilising learning analytics to support study success in higher education: a systematic review. Educational Technology Research and Development 68 (4 ): 1961–1990. DOI: 10.1007/s11423-020-09788-z. Kimmons R Veletsianos G VanLeeuwen C (2020) What (some) faculty are saying about the shift to remote teaching and learning. Educause Review. https://er.educause.edu/blogs/2020/5/what-some-faculty-are-saying-about-the-shift-to-remote-teaching-and-learning. Kitchenham B Charters S (2007) Guidelines for Performing Systematic Literature Reviews in Software Engineering. Staffordshire, Durham: EBSE 2007-001 Technical Report. Keele University and Durham University Joint Report. * Lapitan LD Jr Tiangco CE Sumalinog DAG , et al. (2021) An effective blended online teaching and learning strategy during the COVID-19 pandemic. Education for Chemical Engineers 35 : 116–131. DOI: 10.1016/j.ece.2021.01.012 10.1016/j.ece.2021.01.012. Lancaster T Cotarlan C (2021) Contract cheating by STEM students through a file-sharing website: a Covid-19 pandemic perspective. International Journal for Educational Integrity 17 (1 ): 1–16. DOI: 10.1007/s40979-021-00070-0 10.1007/s40979-021-00070-0. Landrum B Bannister J Garza G , et al. (2021) A class of one: students’ satisfaction with online learning. Journal of Education for Business 96 (2 ): 82–88. Larrabee Sønderlund A Hughes E Smith J (2019) The efficacy of learning analytics interventions in higher education: a systematic review. British Journal of Educational Technology 50 (5 ): 2594–2618. DOI: 10.1111/bjet.12720. * Liang Z da Costa Junior MG Piumarta I (2020) Opportunities for improving the learning/teaching experience in a virtual online environment. In: 2020 IEEE International Conference on Teaching, Assessment, and Learning for Engineering (TALE). IEEE, 243–250. * Liu S Guo D Sun J , et al. (2020) MapOnLearn: the use of maps in online learning systems for education sustainability. Sustainability 12 (17 ): 7018. DOI: 10.3390/su12177018 10.3390/su12177018. * Maher Y Moussa SM Khalifa ME . (2020) Learners on focus: visualizing analytics through an integrated model for learning analytics in adaptive gamified e-learning. IEEE Access 8 : 197597–197616. Marinoni G Van't Land H Jensen T (2020) The impact of Covid-19 on higher education around the world. IAU global survey report 23 . Martin F Dennen VP Bonk CJ (2020) A synthesis of systematic review research on emerging learning environments and technologies. Educational Technology Research and Development 68 (4 ): 1613–1633. DOI: 10.1007/s11423-020-09812-2 10.1007/s11423-020-09812-2.32837122 Mata JR (2021) How to Teach Online? Recommendations for the assessment of online exams with University students in the USA in times of pandemic. IJERI: International Journal of Educational Research and Innovation 15 (4 ): 188–202. Matcha W Gašević D Uzir A Jovanović J Pardo A Maldonado-Mahauad J Pérez-Sanagustín M (2019) Detection of learning strategies: A comparison of process, sequence and network analytic approaches. In European conference on technology enhanced learning (pp. 525–540). Springer, Cham. Mishra L Gupta T Shree A (2020) Online teaching-learning in higher education during lockdown period of COVID-19 pandemic. International Journal of Educational Research Open 1 : 100012.35059663 Molenaar I Knoop-van Campen CA (2018) How teachers make dashboard information actionable. IEEE Transactions on Learning Technologies 12 (3 ): 347–355. * Naidoo S Naidoo K (2021) Linking Formative and Summative Performance in an online L2 module: Insights from Learning Analytics. In: 2021 9th International Conference on Information and Education Technology (ICIET). IEEE, 227–231. O’Leary DE (2020) Evolving information systems and technology research issues for COVID-19 and other pandemics. Journal of Organizational Computing and Electronic Commerce. DOI: 10.1080/10919392.2020.1755790 10.1080/10919392.2020.1755790. Openo J (2020) Education’s Response to the COVID-19 Pandemic Reveals Online Education’s Three Enduring Challenges. Canadian Journal of Learning and Technology 46 (2 ). DOI: 10.21432/cjlt27981 10.21432/cjlt27981. Park Y Jo I-H (2019) Factors that affect the success of learning analytics dashboards. Educational Technology Research and Development 67 (6 ): 1547–1571. DOI: 10.1007/s11423-019-09703-1 10.1007/s11423-019-09703-1. * Perez-Sanagustin M Pérez-Álvarez R Maldonado-Mahauad J , et al. (2021) Can feedback based on predictive data improve learners’ passing rates in MOOCs? A preliminary analysis. In: Proceedings of the Eighth ACM Conference on Learning@ Scale, 339–342. DOI: 10.1145/3430895.3460991 10.1145/3430895.3460991. * Prat J Llorens A Salvador F , et al. (2021) A methodology to study the university’s online teaching activity from virtual platform indicators: the effect of the covid-19 pandemic at universitat politècnica de catalunya. Sustainability 13 (9 ): 5177. Platt CA Raile ANW Yu N (2014) Virtually the same?: student perceptions of the equivalence of online classes to face-to-face classes. Journal of Online Learning & Teaching 10 (3 ): 489–503. * Rahmah A Sukmasetya P Romadhon MS , et al. (2020) Developing distance learning monitoring dashboard with google sheet: an approach for flexible and low-price solution in pandemic era. In: 2020 International Conference on ICT for Smart Society (ICISS). IEEE, 1–6. DOI: 10.1109/ICISS50791.2020.9307558 10.1109/ICISS50791.2020.9307558. Richter A (2020) Locked-down digital work. International Journal of Information Management Article 102157 55 : 102157. DOI: 10.1016/j.ijinfomgt.2020.102157 10.1016/j.ijinfomgt.2020.102157.32836629 * Safsouf Y Mansouri K Poirier F (2021) TaBAT: design and experimentation of a learning analysis dashboard for teachers and learners. Journal of Information Technology Education: Research 20 (1 ): 331–350. DOI: 10.28945/4820 10.28945/4820. Schwendimann BA Rodriguez-Triana MJ Vozniuk A , et al. (2017) Perceiving learning at a glance: a systematic literature review of learning dashboard research. IEEE Transactions on Learning Technologies 10 (1 ): 30–41. DOI: 10.1109/TLT.2016.2599522 10.1109/TLT.2016.2599522. Sein MK (2020) The serendipitous impact of COVID-19 pandemic: A rare opportunity for research and practice. International Journal of Information Management Article 102164 55 : 102164, DOI: 10.1016/j.ijinfomgt.2020.102164 10.1016/j.ijinfomgt.2020.102164.32836630 Shih M Feng J Tsai C-C (2008) Research and trends in the field of e-learning from 2001 to 2005: a content analysis of cognitive studies in selected journals. Computers & Education 51 (2 ): 955–967. Siemens G Gasevic D (2021) Learning analytics special issue. Journal of Educational Technology & Society 15 (3 ): 1–2, http://www.ifets.info/journals/15_3/ets_15_3.pdf. Şimşek H Yıldırım A (2011) Qualitative Research Methods in Social Sciences. Ankara: Seçkin Publishing. Tabuenca B Greller W Verpoorten D (2021) Mind the gap: smoothing the transition to higher education fostering time management skills. Universal Access in the Information Society 1–13. Teuber Z Jia H Niewöhner T (2021) Satisfying students’ psychological needs during the covid-19 outbreak in German higher education institutions. Frontiers in Education 6 : 679695. Tsai YS Gasevic D (2017) Learning analytics in higher education---challenges and policies: a review of eight learning analytics policies. In: Proceedings of the seventh international learning analytics & knowledge conference, 233–242. Tsai YS Poquet O Gašević D , et al. (2019) Complexity leadership in learning analytics: drivers, challenges and opportunities. British Journal of Educational Technology 50 (6 ): 2839–2854. Usher M Hershkovitz A Forkosh‐Baruch A (2021) From data to actions: Instructors' decision-making based on learners' data in online emergency remote teaching. British Journal of Educational Technology. DOI: 10.1111/bjet.13108 10.1111/bjet.13108. van der Spoel I Noroozi O Schuurink E , et al. (2020) Teachers’ online teaching expectations and experiences during the Covid19-pandemic in the Netherlands. European Journal of Teacher Education 43 (4 ): 623–638. van Deursen AJ . Digital inequality during a pandemic: quantitative study of differences in COVID-19-related internet uses and outcomes among the general population. Journal of Medical Internet Research 2020; 22 (8 ): e20073.32750005 Williamson M . I Wasn’t Reinventing the Wheel Just Operating the Tools”: The Evolution of the Writing Processes of Online First-Year Composition Students (Unpublished Doctoral Dissertation). USA: Arizona State University, 2015. Viberg O Hatakka M Bälter O , et al. (2018) The current landscape of learning analytics in higher education. Computers in Human Behavior 89 : 98–110. DOI: 10.1016/j.chb.2018.07.027 10.1016/j.chb.2018.07.027. * Zhang T Taub M Chen Z (2021) Measuring the impact of covid-19 induced campus closure on student self-regulated learning in physics online learning modules. In: LAK21: 11th International Learning Analytics and Knowledge Conference, 110–120. DOI: 10.1145/3448139.3448150 10.1145/3448139.3448150. * Zikas P Kamarianakis M Kartsonaki I , et al. (2021) Covid-19-VR strikes back: innovative medical VR training. In: Special Interest Group on Computer Graphics and Interactive Techniques Conference Immersive Pavilion, 1–2. DOI: 10.1145/3450615.3464546 10.1145/3450615.3464546.
PMC008xxxxxx/PMC8958303.txt
==== Front Illn Crises Loss Illn Crises Loss ICL spicl Illness, Crises, and Loss 1054-1373 1552-6968 SAGE Publications Sage CA: Los Angeles, CA 10.1177/10541373221090019 10.1177_10541373221090019 Articles Separation and Discrimination: The Lived Experience of COVID-19 Survivors in Philippine Isolation Centers https://orcid.org/0000-0002-0177-7896 Romulo Sheilalaine G. 1 Urbano Ryan C. 2 1 Center for Social Innovation, 317511 Cebu Technological University , Cebu City, Philippines 2 College of Arts and Sciences, 317511 Cebu Technological University , Cebu City, Philippines Sheilalaine G. Romulo, Ed.D., Center for Social Innovation, Cebu Technological University, Main Campus, M. J. Cuenco Avenue corner R. Palma Street, Cebu City, 6000, Philippine. Email: sheilalaine.romulo@ctu.edu.ph 24 3 2022 7 2023 24 3 2022 31 3 525539 © The Author(s) 2022 2022 SAGE Publications This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections. Social isolation in times of pandemic can affect the well-being of individuals infected with a contagious disease. This study explores the lived experience of the 12 COVID-19 survivors placed in community-based isolation centers in Cebu City, Philippines and whose cases were mild and asymptomatic. In describing their lived experience, we employed Max van Manen's phenomenology of practice. Results show that the COVID-19 survivors have suffered more from the consequences of separation and discrimination than the disease's physiological effects. Educating the whole community about social responsibility and ethical behavior in dealing with COVID-19 survivors is essential to minimize social stigma and discrimination. COVID-19 survivors discrimination isolation center lived experience separation typesetterts19 ==== Body pmcIntroduction The surge of COVID-19 cases in the Philippines from March to August 2020 overwhelmed the country's entire health care system. To address the large-scale health crisis, the government issued a directive to the local authorities to dedicate community isolation facilities. These facilities are primarily public schools converted into isolation and quarantine facilities. Community quarantine is a strategy aimed at reducing community-level transmission of COVID-19. It involves, among others, contact tracing, testing, quarantine of persons, and where needed, isolation of patients (Department of Health -Department of Interior and Local Government, 2020). Since hospitals prioritized severe COVID-19 patients and other critical illnesses, the community-based isolation facilities were strategically designed to provide care for COVID-19 patients with confirmed asymptomatic and mild cases. The trend in COVID-19 studies using phenomenological approaches is mainly on the experiences of healthcare providers (Gunawan et al., 2021; Iheduru–Anderson, 2021; Liu et al., 2020; Sun et al., 2020a), patients during hospitalization (Sun et al., 2021; Sun et al., 2020b; Wang et al., 2020) and stranded college students (Cahapay, 2020). We found three studies (Mansoor et al., 2020; Olufadewa et al., 2020; Sahoo et al., 2020) applying a phenomenological method to the experiences of COVID-19 survivors. However, the study of Sahoo et al. (2020) does not specify the phenomenological framework it employs, considering that there are many phenomenological lenses (Dowling, 2007; Finlay, 2012; Moran, 2000; Spiegelberg, 1960, p. 1971; van Manen, 2014), either as a philosophical movement (e.g., Husserl, Heidegger, Merleau-Ponty, Gadamer, and Ricoeur) or as a method in qualitative research (e.g., Benner, Colaizzi, Giorgi, van Kaam & van Manen), through which one can view the phenomenon in question. While a Heideggerian phenomenology is applied in the study of Shaban et al. (2020) in the understanding of isolation as a subject of contextual meaning with patients in an Australian hospital, our present study looks into the experience per se of COVID-19 sufferers quarantined in community isolation facility using van Manen’s phenomenology of practice. COVID-19 survivors have rich experience before, during, and after their isolation period, which can provide the public with a deeper understanding of the psychological and social impact of the disease. Studies reveal that isolated COVID-19 patients felt stigmatized, rejected, blamed, anxious, and confused but could cope with their situation (Chen et al., 2020; Rahmatinejad et al., 2020). The purpose of the study is to describe the lived experience of the COVID-19 survivors who were quarantined in the community isolation centers. These descriptions reveal the deeper meaning of the COVID-19 survivors’ experience, which may be relevant to improving COVID-19 psychosocial support and management in community isolation facilities. Phenomenological research such as this study can provide context-specific and granular data, valuable for evidence-informed policy. Evidence derived from research findings and context-related information may serve as a sound basis for decision-making in public health care. The Department of Health has also recognized this approach to pursuing a universal health care system in the country (DOH AO-2020). Thus, gathering relevant data from the qualitative resource will inform policy-makers in crafting effective policies and programs. Design and Methods Since the study employs a phenomenological inquiry, we used purposive sampling to identify the research participants who survived the COVID-19 ordeal. The phenomenon (i.e. the lived experience of the COVID-19 survivors) investigated determines the method, including the selection of participants (Hycner, 1999 as cited in Groenewald, 2004). We interviewed 12 COVID-19 survivors from varied socio-economic backgrounds who are residents of Cebu City, Philippines. They were selected through purposive sampling with the following criteria: (1) a resident of Cebu City, (2) a COVID-19 survivor who was asymptomatic or who had mild symptoms, and (3) confined in a community quarantine center in Cebu City. The participants were referred to us by the community health workers after a permit to conduct an interview was granted by the city government and after securing an ethical clearance from a local university. The interview was arranged through the assigned health worker in the respective communities and was held inside the community center to ensure the participants’ privacy and comfort. We obtained the informed consent from each participant following the ethical procedures (e.g., disclosing the complete research information, ensuring that the research participants understood the risk involved, and giving them enough time to decide whether to participate or not). We interviewed the participants in a face-to-face physical setting observing the health protocols imposed by the local authorities, such as wearing of face mask, face shield, and physical distancing. We employed the unstructured in-depth interview to access the lifeworld of the COVID-19 survivors. The interview gives us the tool to "understand the world from the subjects’ point of view" to make sense of their experiences in their own context (Kvale, 1996 as cited in Groenewald, 2004). To secure the accuracy of our documentation, we took notes while recording the interview after asking permission from the participants. After every interview session set for the day, we reviewed our notes and discussed our observations during the interview. Our notes captured what we saw, heard, and experienced during each interview session (Groenewald, 2004). This kind of information served as our reference and guide in our transcription of the recorded interview and our description of the participants’ lived experience. The 12 interview recordings were transcribed literally in the original language (Cebuano). After listening several times to the voice record while referring to our field notes, we transcribed. The next step that follows is the heart of our phenomenological writing. Van Manen's phenomenology mainly informs our investigation of the lived experience of practice. Although van Manen et al. (2016) "dissociate" phenomenology from saturation "owing to the concern to obtain full and rich personal accounts," the researchers decided to interview 12 participants to get more data of their lived experiences. The researchers also based their choice of 12 participants on Liu et al.'s (2020) study, which employed Colaizzi's phenomenological method. Other scholars (Boyd, 2001& Creswell, 1998 as cited in Groenewald, 2004) suggest up to 10 participants to reach saturation. The whole trajectory of the study covers the pre-isolation, during, and post-isolation experience of the COVID-19 survivors. Van Manen's phenomenology of practice, labelled as interpretive phenomenology (Finlay, 2012), draws from many phenomenological models. He thinks that these models can contribute to the rich understanding of the meaning of the phenomenon since they provide different ways of 'seeing.' As van Manen (2014) explains,What is fascinating about phenomenology is that the influential thinkers who have presented various versions of phenomenological inquiry do not just offer variations in philosophies or methods. They inevitably also provide alternative and radical ways of understanding how and where meaning originates and occurs first. And yet, it is the search for the source and mystery of meaning that we live in everyday life lies at the basis of these various inceptual phenomenological philosophies. Looking back at the landscape of phenomenological thought, we discern a series of mountains and mountain ranges from which particular views are afforded to those willing to attempt scaling the sometimes challenging and treacherous ascents and descents. (p. 22) Phenomenology cannot be reduced to a single method or procedure. This is so because a phenomenon can manifest itself in many different ways, "depending in each case on the kind of access we have to it" (Heidegger, 1927/1927/1962, p. 51). Such an attempt to reduce phenomenology in a single method simplifies a complex and enigmatic reality. A single thought cannot encompass the world nor its meaning thoroughly exhausted even if we are "open" to and in "communication" with it (Merleau-Ponty, 1945/1945/1962, p. xvii). The downside of a single model approach to phenomenology leads to an inadequate understanding of reality. As van Manen (2014) argues,Phenomenology does not let itself be seductively reduced to a methodical schema or an interpretive set of procedures. Indeed, relying on procedural schemas, simplified inquiry models, or a series of descriptive-interpretive steps will unwittingly undermine the inclination for the practitioner of phenomenology to deepen themselves in the relevant literature that true research scholarship requires, and thus acquire a more precise grasp of the project of phenomenological thinking and inquiry. (p. 22) In phenomenological research, rigor does not mean adherence to a single method. Instead, it is achieved through a thoughtful process of heuristic questioning, experiential description, phenomenological thematizing, insighting, voking, and interpretation (van Manen, 2014, pp. 376–377). After going through this rigorous process which is the key to accessing the pre-reflective experience, the ultimate goal of phenomenology is to describe the 'originary' essences of the lived experience to arrive at other possible and deeper meanings. To reiterate, van Manen (2014) suggests the following steps in describing the lived experience: (1) heuristic questioning, (2) experiential description, (3) phenomenological thematizing, (4) ‘insighting’ and ‘voking,' and (5) interpretation. The starting point of phenomenological inquiry is to ask a critical question that sets the agenda of the entire interview process. This process is heuristic questioning which involves asking the overarching question, "What does it feel like to have COVID-19?' In asking this question, the four fundamental structures of the lifeworld: lived-body, lived-space, lived-time, and lived-human relation or lived-other (van Manen, 1990, pp. 101–102), were invoked. The second step is an experiential description which extracts vivid accounts from the interview transcripts. This process involves looking at rich accounts of the experience (1) as one lived through it, avoiding explanations and generalizations about the experience, (2) told from the state of mind evoking feelings and moods, (3) focusing on a specific event, (4) attending to what stands out for its vividness, and (5) attending to sensory details (van Manen, 1990, pp. 64–65). This explication is intended to make the phenomenon show itself 'be seen from itself in the very way in which it shows itself from itself' (Heidegger, 1927/1927/1962, p. 58). Hycner (1999 as cited in Groenewald, 2004) warns researchers to be cautious with “data analysis” as the term (analysis) implies “breaking into parts.” Phenomenology does not break the parts to understand the whole, but rather, it looks through the parts to understand the whole. In response to what is being shown, the perceiver has to maintain an attitude of openness, wonder, and attentiveness to the revelation of reality. The third step, phenomenological thematizing, uncovers and isolates thematic statements. To determine the suitable themes of the lived experience, van Manen (1990) reminds us that themes are not like universal concepts or axioms but are the essential structures of experience. Themes are a linguistic arrangement that "captures the phenomenon one tries to understand" (van Manen, 1990, p. 79). Themes arise from the interpreter's 'desire to make sense’ of the lived experience which involves ‘openness to something,’ ‘insightful invention, discovery, and disclosure' (van Manen, 1990, p. 88). Through the themes, the researcher or reader can see and explore the specific aspect of the lived experience transformed from being taken-for-granted realities into meaningful experiences. The fourth step is ‘insighting,’ and ‘voking.' Insighting is used to aid reflection on the lived experience by drawing from related scholarly literature (van Manen, 2014, p. 377). However, we are careful not to impose our constructions of reality. Instead, we utilized relevant scholarly texts to clarify our interpretation of the lived experience themes. In addition to ‘insighting’ is 'voking,' which involves the careful attentiveness to the vocative nature of language and is part of the phenomenological reflective writing process (van Manen, 2014, p. 377). The last step is interpretation. This articulates our insights to make the themes visible to have a 'fuller grasp of what it means to be in the world' (van Manen, 1990, p. 12) for those infected by the novel coronavirus. We used the English language in doing the phenomenological writing. The original Cebuano transcriptions were then translated to English while retaining the nuances of the original language. From the English translation, we highlighted the lived-experience description. A lived-experience description is a rich account of the experience, (1) as one lived through it avoiding explanations and generalizations about the experience, (2) told from the state of mind evoking feelings and moods, (3) focusing on a specific event, (4) attending to what stands out for its vividness, and (5) attending to sensory details (van Manen, 1990, pp. 64–65). In Heideggerian parlance, phenomenological explication is a matter of letting 'that which shows itself be seen from itself in the very way in which it shows itself from itself' (Heidegger, 1927/1927/1962, p. 58). This requires, on the part of the perceiver, an attitude of openness, wonder, and attentiveness to the revelation of reality. It is then the task of the phenomenological researcher to use compelling language that could bring this revelation to an experience-near level. Results (Themes of the Lived-Experience) The COVID-19 survivors lived experience is categorized into five themes. These themes are drawn from the experiential data of the interview transcripts from the 12 research participants quarantined in the community-based isolation facility. We used anecdote fragments or vignettes as examples of the phenomenological experience for presentation purposes. We employed fictitious names to protect the identity of the participants and for narrative effect. Because stories are easy to remember and relatable, they are credible sources of understanding experiences and world views of others (Zwack, M. et. al., 2016; Lämsä & Sintonen, 2006). In fact, stories and other creations of our imagination cultivate human solidarity – “the imaginative ability to see strange people as fellow sufferers”- which “is not discovered by reflection” and theory “but created. . . . by increasing sensitivity to the particular details of the pain and humiliation of the other, the unfamiliar sorts of people” and which “makes it more difficult to marginalize people different from ourselves by thinking” (Rorty, 1979). Since the outbreak of the COVID-19 reached the Philippines, people have been hearing various stories of heroism, kindness, suffering, and recovery. Of all these stories, it is the story of a COVID-19 survivor that matters the most because it bears a new experience that can change the way we see the world in this pandemic era. Theme 1: Feeling Confused and Miserable When the research participants knew about their results, they were confused and anxious about contracting the disease. Rene, single and a mild COVID-19 patient with comorbidities, shared his experience and revealed his battle against COVID-19. He recalled, “Why do I have to undergo this kind of suffering? I do not understand why this happened to me. Nobody can help me there (isolation center).” He claimed that his first few weeks in the isolation center made him more vulnerable. He could no longer ask for the attention and support from his parents and siblings, whom he depends on for his health needs. He was also not given the appropriate care he expected in the isolation center. Belinda, a 21-year-old asymptomatic patient, confessed that she cried when the local health workers took her to the isolation center because she had never been separated from her child. She recounted, “Listening to the voice of my son is like dagger plunged into my heart. It was unbearable. I need to lie to him that I would just be gone for a while.” Feeling miserable is also experienced by Mica, 24 years old. She narrated, "During the first four days, it was tough. We suffered a lot in there, and nobody helped us. We were famished for two days." The effect of separation from her other healthy family members who were not allowed by the authorities to visit them aggravated their daily struggle at the isolation center. Based on the narratives above, feeling miserable is associated with the lack of understanding of the disease, the restriction to connect physically with family members, and the lack of basic provisions and amenities in the isolation center. Theme 2: More Worried for the Loved Ones They Left Behind Than Their Illness When the five COVID-19 survivors learned about their positive results, their loved ones first came to their minds. Who would take care of them? They were more anxious about their family members’ welfare, whom they would leave when the local authorities brought them to the quarantine facility. Among these COVID-19 survivors, Anton, 38 years old, married, shared how worried he was for his wife, who was pregnant at the time of his isolation. He painfully recalled, “She was all alone by herself, and the thought of her suffering, both physical and emotional, is unbearable to me. The physical pain brought by COVID-19 is no match to my constant restlessness for my wife.” Anton's separation from his wife for 25 days was an ordeal. He even entertained the thought of escaping from the isolation center. He recalled, “My longing to escape from the facility becomes like a burning desire.” Two research participants, Belinda, mentioned in theme 1, and Jonel, both parents, felt devastated by their situation. Belinda, who left her son at home, had to face the sad reality of separation. To recall, Belinda narrated the moment when she called her son over the mobile phone, "Listening to the voice of my son is like dagger plunged into my heart." Similarly, Jonel, a young father confirmed to be a mild case, was more worried about his seven-year-old son. The latter also contracted the disease and was with him in the isolation facility. He indicated, "I'm kinda depressed. I was crying at that time (when they brought me to the isolation center). I have a child, but as for me, I was okay." The other research participants also have their painful separation stories to tell. Mike, who has a terminally ill father brought about by complications of COVID-19, could not bear being isolated from him, who eventually died of the disease. He recalled, "I was not so much bothered by it (COVID-19) because I am more anxious (for my father's condition)." Susan, a grandmother, quit smoking when she learned she is positive with COVID-19 to stay healthy. She gave up her smoking habit for the sake of her grandchildren. According to Susan, "I need to build my resistance (against COVID-19). I have to do it for my grandchildren." For these COVID-19 survivors, the disease is not so much a medical concern. They claim they were not so worried about their physical condition. However, being separated from their loved ones for whom they felt a great responsibility caused their constant fear and worry. For example, Anton had wanted to escape from the isolation center just to be reunited with his family. Also, Mike had agonized for his father's death because he could not stay by his side. For these survivors, COVID-19 is not something as dreadful as the separation they were made to go through. Theme 3: The Pain of Discrimination is More Potent Than the Virus The participants experienced discrimination in varying degrees. A full description of this account is given by Patricia, a young mother at 21. She narrated how the neighbors’ act of "throwing bottles and stones” has hurt her family more than fearing the virus. She recalled, “Although my neighbors’ insensitive words are like swords, the physical act of throwing bottles and stones at our house is deadlier than the virus.” Similarly, Anabel, a 62-year-old widow, disclosed that discrimination takes the form of simple gestures of avoidance. She recounted, “When they saw you coming, they would avoid you. What happened to me? I was confused at that time.” Grace, 19-year-old mother, also shared how surprised she knew that her neighbors had learned of the news (of her positive result) before she knew it. She felt stigmatized by this invasion of her privacy. She narrated, “The rumor has spread much faster than my result. I was shocked, and that was why my uncle was so mad. We didn't expect things so private became the concern of everyone in the village!” Another form of discrimination was experienced by Edgar, a husband blamed by his spouse for contracting the disease and for exposing his family to significant risk. Edgar worked as a janitor and was isolated for 14 days in the isolation center. He recalled, "I was broken-hearted. I was utterly blamed (by my wife) that I could have also infected them." These COVID-19 survivors encountered various forms of discrimination. Discrimination, even in subtle ways, such as turning away or just saying "do not go near them," is deeply painful for the participants. The pain becomes more intense if this comes from one's family, as in the case of Edgar. Theme 4: Witty and Funny Response to Discrimination Some participants countered discrimination with witty and funny responses. In one account, in theme 3, Anabel put on a witty response to her neighbors, who gave insensitive comments after her release from the isolation center. She narrated what she said to her neighbors, “Why would you fear me? I am already negative! I should be the one to fear you because you are not tested yet! You used to avoid me then, and I should be the one to stay away from you from now on. In another account, participants employed funny language to their detractors. Jonel, mentioned in theme 1, jokingly warned his friends by “spitting on the face” to respond to their subtle ridicule. Another participant, Marga, used the famous zombie imagery to defend herself from her disparagers. She cautioned them with humor, “I already have the antibody, and if you would be tested (and when found positive), you would turn to a zombie.” Theme 5: Relationship as Source of Strength COVID-19 survivors claimed that their relationship with God and family was a source of strength. As mentioned in theme 2, Rene held on to his faith in God and family to keep his spirit up. Also strengthened by her deep faith, Anabel, mentioned in theme 4, pleaded to God not to take her yet as she needed to care for her youngest grandchild, who inspires her to fight for life. Anabel recalled, “I always prayed to God. I was not ready (to go) yet because I still had my youngest grandchild, who was still schooling. That was my source of strength for me to fight against COVID.” Another participant, Grace, mentioned in theme 3, a young mother of two, was allowed to bring her breastfeeding child to the isolation center. She shared with us, “I knew I could win this battle against this (COVID-19) for my baby." The COVID-19 survivors testified they could adjust to their new environment because of the facility management's daily activities, which brought them closer. The regular exercise routine like dancing the Zumba (a trendy dance workout in the Philippines) positively affects the participants’ well-being. As Anabel testified, “I got cheered up through Zumba, and also I was taking care of the elderly in the facility.” Also mentioned in theme 3, Patricia claimed she found new friends in the isolation facility. She recalled, “We just enjoyed doing the activities together in the center like dancing. I even have more friends now and many from the center.” Discussion The study's findings disclose the possible deeper meanings of the whole gamut of experience of the COVID-19 survivors. Although the lived experience is a personal journey that cannot be fully captured by describing the familiar underlying narratives among the survivors, we will turn our gaze to the compelling insights of their experiences that lead us to see the multi-faceted meanings of the COVID-19 experience. The survivors have gone through the vicissitudes of affliction characterized by their experience of fear and care, helplessness and support, separation and reconnection, pain and ease, and doubt and faith. Propelling the gravity of these variables is the relational aspect of the lived experience – that is, how others 'see' them and how they 'see' others in the most uncertain moment of their life. Social isolation in times of pandemic can impair mental health (Usher et al., 2020). The COVID-19 survivors’ stay in the quarantine facility has also adversely affected their relational bonds with family members. Anton's separation from his pregnant wife, who also suffered from discrimination, has taken a toll on his mental health. Studies have shown that separation can lead to anxiety (Bowlby, 1960). In the same vein, this lived experience is also found in the narratives of Belinda, Jonel, and Mike, who painfully went through the isolation period with their minds fixed on their loved ones. Even as an elderly, Susan conditioned her mind to survive for her grandchildren. One's beloved can be a reason for someone not to give up on life amidst suffering (Frankl, 1984, p. 133). From these experiences, we pose a challenge to see what lies beyond COVID-19 and see how it impacts the space that mentally and emotionally connects family members. Confusion and misery among COVID-19 sufferers are associated with feelings of anxiety, shock, and doubt (Shaban et al., 2020; Vindegaard & Benros, 2020) and extreme worry for their family members (Wang et al., 2020), and discomfort due to the poor amenities of the isolation center. The feelings of confusion and doubt were particularly true to the asymptomatic patients. They could not reconcile their positive test results and what they felt physically. They claimed they did not feel anything wrong with their bodies, yet they were confirmed positive. Confinement in the isolation centers was unnecessary because they preferred to be home quarantined. Misery in the isolation center, as described by the COVID-19 survivors, is a mixed feeling of longing to reconnect with family members and pain of confinement. The isolation center was generally described as 'uncomfortable,' and necessities were 'insufficient' during the first few days. In effect, the COVID-19 sufferers feel more dejected and their persons dishonored. The theme "the pain of discrimination is more potent than the virus" reflects how human words and actions can be more harmful than the deadly virus. As experienced by the COVID-19 survivors, discrimination left an indelible scar in their memory. Stigma or discrimination brings devastating consequences for the overall well-being of the stigmatized (Bhanot et al., 2021; Wesselmann et al., 2013). The house of Patricia was stoned by people whom they considered neighbors. Edgar, the husband blamed by his spouse for contracting the disease, experienced the most painful discrimination. The very person closest to him is the one who turned against him. This implies that the impact of discrimination is proportional to our proximity to another human being, i.e., the more significant that human other is, the stronger is their impact. If discriminatory words are employed to inflict pain, the survivors use witty and funny responses to cope with discrimination. For example, Anabel's subtle warning to her neighbors, "I should be the one to fear you," serves as her way of protecting her dignity as a person. The silliness in Jonel's language to "spit on one's face' and Marga's use of 'zombie" as visual imagery in her response serves to address discrimination in a nonconfrontational and fun manner. Levity is employed to avoid straining the close relationship with their friends and neighbors. The COVID-19 experience is not all negative responses. The emerging and growing camaraderie and friendship in the isolation facility, as narrated by the COVID-19 sufferers, has encouraged them to take things lightly and believe that their affliction and discomfort would soon be over one day. The emotional and social support provided by their family members, friends, and fellow patients and strong faith in God has helped improve their mental health and well-being. This matches with the results of a previous study (Mansoor et al., 2020) that family support and spiritual connections are factors of effective stress coping. In general, religious involvement tends to positively affect mental health (Schieman et al., 2013). To recall, the COVID-19 sufferers, quarantined and separated from their families, were more concerned with the welfare of their family members left at home than their illness. This characterizes an ethic that puts the human other above the self (Levinas 1969, ). Here, the moral character of the 'subject' is shaped by its response to the ethical appeal of the human other. We become better people through the care and compassion of our fellow human beings. The human other can be a reason for us not to give up on life amidst suffering. As Frankl (1984, p. 133) reminds us, Being human always points, and is directed, to something, or someone, other than oneself—be it a meaning to fulfill or another human being to encounter. The more one forgets himself—by giving himself to a cause to serve or another person to love—the more human he is, and the more he actualizes himself. Conclusion The crucial aspect of the lived experience of the COVID-19 survivors is the pain of separation and discrimination, which strained family and social relationships. The COVID-19 survivors have suffered more from the consequences of separation and discrimination than the disease's physiological effects. Looking at this reality, we recommend that the health care management consider improving the psychological and emotional support for the COVID-19 sufferers. Although the COVID-19 survivors received psychosocial support from the health authorities, these were not enough to address their mental health needs. There is also a need to understand the context of COVID-19 sufferers’ personal and social realities. Considering the strong family bonds among COVID-19 patients, we also suggest that the psychosocial support program be tailored to the family needs (Tanoue et al., 2020). Educating the whole community about social responsibility and ethical behavior in dealing with COVID-19 survivors is essential to minimize social stigma and discrimination. Most importantly, the health authorities can maximize family and community care to help mitigate suffering by providing a community-based peer support program (Hope et al., 2021). Even after confinement, the program needs to continue to facilitate the survivors’ seamless and successful reintegration into the community. Notes on Contributors Sheilalaine G. Romulo is an Assistant Professor at the Department of Languages and Literature in the College of Arts and Sciences, Cebu Technological University (CTU), Philippines. Other than teaching, she held various administrative functions in CTU as Director for Research Ethics Committee, Director of Gender and Development, and recently as Director of the Center for Social Innovation. Her research interests include phenomenology, language and gender, and discourse analysis. Ryan C. Urbano is an Associate Professor in the Department of Social Sciences, Cebu Technological University, Philippines. He was a visiting fellow at the Center for Advanced Studies at Goethe University, Frankfurt am Main, Germany in 2019 and a fellow for South and Southeast Asian Region of King Abdullah Bin Abdulaziz International Centre for Interreligious and Intercultural Dialogue (KAICIID) in Vienna, Austria. Since 2019, he is a member of the pool of experts of Globethics.net, Geneva, Switzerland. His research interests are in the areas of applied ethics, political philosophy and philosophy of religion. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. ORCID iD: Sheilalaine G. Romulo https://orcid.org/0000-0002-0177-7896 ==== Refs References Bhanot D. Singh T. Verma S. K. Sharad S. (2021). Stigma and discrimination during COVID-19 pandemic. Frontiers in Public Health, 8 , 577018. 10.3389/fpubh.2020.577018 33585379 Bowlby J. (1960). Separation anxiety: A critical review of the literature. Journal of Child Psychology and Psychiatry, 1 (4 ), 251–269. 10.1111/j.1469-7610.1960.tb01999.x Cahapay M. B. (2020). Stranded college students amid coronavirus disease 2019 pandemic: An existential phenomenology. Journal of Loss and Trauma, 25 (6-7 ), 598–604. 10.1080/15325024.2020.1770955 Chen D. Song F. Tang L. Zhang H. Shao J. Qiu R. Wang X. Ye Z. (2020). Quarantine experience of close contacts of COVID-19 patients in China: A qualitative descriptive study. General Hospital Psychiatry, 66 , 81–88. 10.1016/j.genhosppsych.2020.07.006 32736195 Department of Health and Department of Interior and Local Government Joint Administrative Order 2020–0001 (2020, April 15). Guidelines on local isolation and general treatment areas for Covid-19 cases (LIGTAS COVID) and the community-based management of mild Covid-19 cases. URLhttps://doh.gov.ph/sites/default/files/health-update/jao2020-0001_0.pdf. Dowling M. (2007). From husserl to van manen: A review of different phenomenological approaches. International Journal of Nursing Studies, 44 (1 ), 131–142. 10.1016/j.ijnurstu.2005.11.026 16412442 Finlay L. (2012). Debating phenomenological methods. In Hermeneutic phenomenology in education (pp. 17–37). Sense Publishers. Frankl V. (1984). Man's search for meaning (revised & updated). Washington Square Press. Groenewald T. (2004). A phenomenological research design illustrated. International Journal of Qualitative Methods, 3 (1 ), 42–55. .10.1177/160940690400300104 Gunawan J. Aungsuroch Y. Marzilli C. Fisher M. L. Nazliansyah & Sukarna A (2021). A phenomenological study of the lived experience of nurses in the battle of COVID-19. Nursing Outlook, 69 (4 ), 652–659. 10.1016/j.outlook.2021.01.020 33648743 Heidegger M. (1962). Being and time (J. Macquarrie & E. Robinson, Trans.). Harper & Row. (Original work published 1927). Hope A. A. Johnson A. McPeake J. Felt H. Sevin C. M. Mikkelsen M. E. Williams C. (2021). Establishing a peer support program for survivors of COVID-19: A report from the critical and acute illness recovery organization. American Journal of Critical Care, 30 (2 ), 150–154. 10.4037/ajcc2021675 Iheduru–Anderson K. (2021). Reflections on the lived experience of working with limited personal protective equipment during the COVID–19 crisis. Nursing Inquiry, 28 (1 ), 1–15. 10.1111/nin.12382 Lämsä A. M. Sintonen T. (2006). A narrative approach for organizational learning in adiverse organisation. Journal of Workplace Learning, 18 (2 ), 106–120. 10.1108/13665620610647818 Levinas E (1969). Totality and infinity: An essay on exteriority (A. Lingis, Trans.). Duquesne University Press. Liu Q. Luo D. Haase J. E. Guo Q. Wang X. Q. Liu S. Yang B. X. (2020). The experiences of healthcare providers during the COVID-19 crisis in China: A qualitative study. The Lancet Global Health, 8 (6 ), e790–e798. 10.1016/S2214-109X(20)30204-7 32573443 Mansoor T. Mansoor S. Bin Zubair U. (2020). 'Surviving COVID-19': Illness narratives of patients and family members in Pakistan. Annals of King Edward Medical University, 26 (Special Issue) , 157–164. https://www.annalskemu.org/journal/index.php/annals/article/view/3630/2204 . Merleau-Ponty M. (1962). Phenomenology of perception (C. Smith, Trans.). Routledge & Kegan Paul. (Original work published 1945). Moran D. (2000). Introduction to phenomenology. Routledge. Olufadewa I. I. Adesina M. A. Oladokun B. Baru A. Oladele R. I. Iyanda T. O. Ajibade O. J. Abudu F. (2020). “I was scared I might die alone”: A qualitative study on the physiological and psychological experience of COVID-19 survivors and the quality of care received at health facilities. International Journal of Travel Medicine and Global Health, 8 (2 ), 51–57. 10.34172/ijtmgh.2020.09 Rahmatinejad P. Yazdi M. Khosravi Z. Shahisadrabadi F. (2020). Lived experience of patients with coronavirus (COVID-19): A phenomenological study. Journal of Research in Psychological Health, 14 (1 ), 71–86. https://rph.khu.ac.ir/article-1-3713-en.html Rorty R. (1979). Philosophy and the mirror of nature. Princeton University Press. Sahoo S. Mehra A. Suri V. Malhotra P. Yaddanapudi L. N. Puri G. D. Grover S. (2020). Lived experiences of the corona survivors (patients admitted in COVID wards): A narrative real-life documented summaries of internalized guilt, shame, stigma, anger. Asian Journal of Psychiatry, 53 , 102187. 10.1016/j.ajp.2020.102187 32512532 Schieman S. Bierman A. Ellison C. G. (2013). Religion and mental health. In Aneshensel C. S. Phelan J. C. Bierman A. (Eds.), Handbook of the sociology of mental health (pp. 457–478). Springer. Shaban R. Z. Nahidi S. Sotomayor-Castillo C. Li C. Gilroy N. O'Sullivan M. V. N. Sorrell T. White E. Hackett K. Bag S. (2020). SARS-CoV-2 infection and COVID-19: The lived experience and perceptions of patients in isolation and care in an Australian healthcare setting. American Journal of Infection Control, 48 (12 ), 1445–1450. 10.1016/j.ajic.2020.08.032 32890549 Spiegelber H. (1971). The phenomenological movement: A historical introduction (volume 2). Springer. Spiegelberg H. (1960). The phenomenological movement: A historical introduction (volume 1). Springer. Sun N. Wei L. Shi S. Jiao D. Song R. Ma L. Wang H. Wang C. Wang Z. You Y. Liu S. Wang H. (2020a). A qualitative study on the psychological experience of caregivers of COVID-19 patients. American Journal of Infection Control, 48 (6 ), 592–598. 10.1016/j.ajic.2020.03.018 32334904 Sun N. Wei L. Wang H. Wang X. Gao M. Hu X. Shi S. (2021). Qualitative study of the psychological experience of COVID-19 patients during hospitalization. Journal of Affective Disorders, 278 , 15–22. 10.1016/j.jad.2020.08.040 32949869 Sun W. Zhou Y. Chen W. T. Huang F. Sun M. Shen L. Lu H. (2020b). Disclosure experience among COVID–19–confirmed patients in China: A qualitative study. Journal of Clinical Nursing, 00 (00 ), 1–10. 10.1111/jocn.15616 Tanoue Y. Nomura S. Yoneoka D. Kawashima T. Eguchi A. Shi S. Miyata H. (2020). Mental health of family, friends, and co-workers of COVID-19 patients in Japan. Psychiatry Research, 291 , 113067. 10.1016/j.psychres.2020.113067 32535504 Usher K. Bhullar N. Jackson D. (2020). Life in the pandemic: Social isolation and mental health. Journal of Clinical Nursing, 29 , 2756–2757. 10.1111/jocn.15290 32250493 van Manen M. (1990). Researching lived experience: Human science for an action sensitive pedagogy. State University of New York Press. van Manen M. (2014). Phenomenology of practice: Meaning-giving methods in phenomenological research and writing. Left Coast Press. van Manen M. Higgins I. van der Riet P. (2016). A conversation with Max van Manen on phenomenology in its original sense. Vindegaard N. Benros M. E. (2020). COVID-19 pandemic and mental health consequences: Systematic review of the current evidence. Brain, Behavior, and Immunity, 89 , 531–542. 10.1016/j.bbi.2020.05.048 32485289 Wang S. Liu Y. She H. Wang T. Chen J. Feng X. Hsia C. (2020). Psychological experiences of patients with COVID-19: A phenomenological study. Journal of Nursing and Practice, 3 (1 ), 193–201. 10.36959/545/383 Wesselmann E. D. Wirth J. H. Pryor J. B. Reeder G. D. Williams K. D. (2013). When do we ostracize? Social Psychological and Personality Science, 4 (1 ), 108–115. https://doi.org/10.1177%2F1948550612443386 Zwack M. (2016). Storytelling and cultural family value transmission: Value perception of stories in family firms. Management Learning, 47 (5 ), 590–614. 10.1177/1350507616659833
PMC008xxxxxx/PMC8987521.txt
==== Front Vis Comput Vis Comput The Visual Computer 0178-2789 1432-2315 Springer Berlin Heidelberg Berlin/Heidelberg 35411122 2445 10.1007/s00371-022-02445-x Original Article A paced multi-stage block-wise approach for object detection in thermal images Kera Shreyas Bhat f20181119@pilani.bits-pilani.ac.in Shreyas Bhat Kera is currently pursuing his bachelor’s degree in Computer Science with the Birla Institute of Science and Technology, Pilani, Rajasthan, India. His research interests include machine learning, deep learning, computer vision, processing of images in various domains, object detection in images, and activity recognition of humans in videos. Tadepalli Anand f20181117@pilani.bitspilani.ac.in Anand Tadepalli is currently pursuing his bachelor’s degree in Computer Science with the Birla Institute of Technology and Science, Pilani, Rajasthan, India. His research interests include machine learning, neural networks, deep learning and computer vision in the area of object detection. http://orcid.org/0000-0001-8555-929X Ranjani J. Jennifer j.jenniferranjani@yahoo.co.in J. Jennifer Ranjani received her B.E. degree in Electronics and Communication Engineering, from Noorul Islam College of Engineering, Nagercoil, India, M.Tech. Degree in Computer and Information Technology from Manonmaniam Sundaranar University, Tirunelveli, India, and Ph.D. in Information and Communication Engineering from Anna University, Chennai, India, in 2002, 2005, and 2011, respectively. From July 2005 to August 2012, she was with the Department of Information Technology, Thiagarajar College of Engineering, Madurai. Later she joined Vivekanandha College of Engineering for Women, Tiruchengode, as an Associate professor. From June 2014 to November 2017, she was with the School of Computing, SASTRA University, Thanjavur, India. From December 2017 to August 2021, she was working in the Department of Computer Science and Information Systems at Birla Institute of Technology and Science, Pilani, Rajasthan, India. Her research interests include computer vision, statistical image processing, multiresolution signal analysis, data hiding, and embedded systems. She is a reviewer for journals like IEEE Transaction on Geoscience and Remote Sensing, IEEE Geoscience and Remote Sensing Letters, IET Image Processing, IET Radar, Sonar and Navigation, Multimedia Tools and Application, etc. grid.418391.6 0000 0001 1015 3164 Department of Computer Science and Information Systems, Birla Institute of Technology and Science, Pilani Campus, Pilani, 333 031 India 7 4 2022 2023 39 6 23472363 20 2 2022 © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022, corrected publication 2022 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. The growing advocacy of thermal imagery in applications, such as autonomous vehicles, surveillance, and COVID-19 detection, necessitates accurate object detection frameworks for the thermal domain. Conventional methods could fall short, especially in situations with poor lighting, for instance, detection during night-time. In this paper, we propose a paced multi-stage block-wise framework for effectively detecting objects from thermal images. Our approach utilizes the pre-existing knowledge of deep neural network-based object detectors trained on large-scale natural image data to enhance performance in the thermal domain constructively. The employed, multi-stage approach drives our model to achieve higher accuracies. And the introduction of the pace parameter during domain adaption enables efficient training. Our experimental results demonstrate that the framework outperforms previous benchmarks on the FLIR ADAS dataset on the person, bicycle, and car categories. We have also illustrated further analysis of the framework, such as the effect of its components on accuracy and training efficiency, its generalizability to other thermal datasets, and its superior performance on night-time images in contrast to state-of-the-art RGB object detectors. Keywords Object detection Thermal images Pace Multi-stage Domain adaptation Transfer learning EfficientDet issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2023 ==== Body pmcIntroduction With the increasing popularity of artificial intelligence and machine learning in recent years, more techniques are being developed for object detection. However, the majority of interest has been focused on object detection in the visible spectrum [2] for applications such as surveillance and self-driving vehicles. Although very effective with the current state-of-the-art technologies, its limitations arise in situations like difficult lighting conditions, camouflaging colours, and environmental occlusions. Attention has turned towards thermal imaging with the infrared (IR) spectrum to solve the problems in the RGB images, and thus, the thermal sensors are seeing an industry boom [19]. Another vital advantage that thermal imaging has over RGB format is the added property of privacy protection. People captured in the visible spectrum are readily identifiable, which is not the case in thermal images [25]. The recent COVID-19 pandemic may cause the global thermal sensing market to reach 6.7 billion dollars within the next four years, according to [18]. This increase in thermal cameras also increases the importance of a robust object detection methodology on thermal images, especially when considering the vital class of objects in pedestrian detection applications, such as persons, cars, and bicycles. The need for both an accurate and efficient framework for training such models is a challenging task since the pursuit for increased accuracy often leads to decreased efficiency and vice versa. We aimed to create a framework that learns object detection in IR images as efficiently as possible while attaining increased accuracy. Another challenging aspect of object detection in thermal images is the limited number of object detection algorithms in the IR domain compared to its RGB counterparts. This might be due to factors such as a limited number of datasets and the markedly smaller size of these datasets compared to their RGB counterparts [5, 7, 10, 13, 14, 16]. For example, the popular RGB dataset, Common Objects in Context (COCO) [29] contains over 200,000 labelled images, while the FLIR system’s Advanced Driver Assistance Systems dataset (FLIR ADAS) [20] consists of 10,000 labelled thermal images only. We address this challenge by utilizing state-of-the-art detectors with rich visible information and applying it to the IR domain. Some researchers have worked with multi-spectral datasets [23], wherein the detectors make use of aligned RGB-thermal pairs and can benefit from the advantages of both domains. However, this may not always be practical since applications like self-driving cars, surveillance, etc., do not have access to cameras that capture the required synchronized multi-modal inputs. Thus, focusing only on thermal imagery reduces the computational burden, and it facilitates the usage of our method more suitable for daily application. Specific aspects of thermal images in object detection have been largely unexplored, such as the generalizability of models to other thermal datasets, as well as a quantifiable approach to the effect that occlusion has on thermal object detection. We have addressed these challenges also in our work. In this paper, we propose a novel framework for object detection in thermal images, namely the paced multi-stage block-wise framework, for object detection on thermal images. We have introduced the usage of multiple stages of training to accurately adapt a state-of-the-art detector to the thermal domain while also leveraging information from the visible domain. We have also introduced the concept of pace in the block-wise domain adaptation, which improves efficiency without a significant accuracy drop. Using this, to the best of our knowledge, we report the highest accuracy on the FLIR ADAS dataset on the classes of persons, cars, and bicycles for any existing thermal object detection framework. Also, we have demonstrated several inferences, such as how the detector retained information in the visible domain while adapting to the thermal, the framework’s efficacy when dealing with night-time images, the effectiveness on other thermal datasets, and the performance of our detector when objects are occluded. Related works Researches have come up with solutions that bridge the gap between thermal and RGB detectors, which can be categorized into two types, those that use multispectral imagery and those that use solely thermal imagery. Multispectral pedestrian detection Several works such as [37, 39, 45, 46] rely on visual images for detection; [37] proposed a novel backbone architecture for pedestrian detection based on the human visual system that can be applied to most of the existing architectures. In many cases combining RGB and thermal images has improved the accuracy of object detectors. For example, improved detection in difficult lighting conditions with a cross-modality learning comprised of a region reconstruction network (RRN) and multi-scale detection network (MDN) was used in [44]. [42] devised a fusion network of RGB and thermal image pairs and explored two different types of networks, early fusion, and late fusion. Illumination-aware faster R-CNN (IAF RCNN) [27] used FRCNN to perform multi-spectral pedestrian detection by leveraging a two-stage network to combine RBG and thermal image features. [28] also proposed the use of a fusion network by combining results from a multi-spectral proposal network (MPN) and a multi-spectral classification network (MCN) to perform pedestrian detection. A region feature alignment module along with weighted feature fusion was proposed by [48]. Pseudo-multi-modal thermal object detector (MMTOD) [12] consists of parallel ResNet branches for thermal and RGB images, respectively. These branches capture the features connecting the two spectra before being passed through a Faster-RCNN [36]. It performs inference on only thermal images as it does image-to-image translation and creates a pseudo-RGB image using CycleGAN [51], which acts as a second input. Though the above detectors leverage the power of two-stage networks, they are preferred when learning features of the thermal and RGB inputs fall short in speed. These detectors have a high inference time because of their complex frameworks. A popularly used solution to speed up the inference time is to use a single-stage framework. For example, two single-shot detectors (SSDs) were adopted by [50] to fuse RGB and thermal features with gated fusion units (GFU). Many works also use RGB-Depth images for object detection or pose estimation. In [39], transfer learning on a pre-trained deep CNN is utilized to provide a rich feature set, and it incorporates a depth channel according to distance from the object centre. In [45], a multistream input of flow, RGB, and depth combined with the contextual region of interest pooling layers that deal with contextual information for joint human detection and head pose estimation, is proposed. Utilization of 3D physical structure and colour information along with a multi-channel colour shape descriptor proposed in [46] works as a physical blob detector to detect humans. Occlusion is another factor that affects the performance in the realm of multi-object tracking, as observed in [49]. Pedestrian detection in thermal imagery Initial attempts such as [24] use an adaptive fuzzy C-means clustering for segmentation and retrieval of candidate pedestrians, which were then classified with the CNNs. The resultant architecture was computationally less complex as compared to the sliding window framework. The work in [1] uses thermal position intensity histogram of oriented gradients (TPIHOG) and additive kernel SVM (AKSVM) for night-time only detection. The authors in [17] use a pixel-wise contextual attention network (PiCA-Net [30]) or R3-Net [11] to create saliency maps. Then, faster R-CNN [36] is trained for pedestrian detection using the original thermal image, replacing the last channel with the generated saliency map. A few approaches leverage RGB images as a data augmentation by performing thermal to RGB image translation. For instance, several data pre-processing steps were applied by [22] to make thermal images look more similar to greyscale-converted RGB images, then a fine-tuning step was performed on a pre-trained SSD300 [31] detector. The common drawbacks of most of the methods mentioned above are the use of many complex pre-processing steps or handcrafted features, negatively impacting performance. In [6], as thermal images contain lesser information as compared to RGB images ( colour, texture), the paper attempts to capture as much information from the ResNet backbone as possible using a dual-pass fusion block (DFB) and a channel-wise enhance module (CEM) to retrieve information from every layer, combining each of the features with varying weightage. More recently, the authors of [8] prioritized efficiency using a VGG network and made robust with a residual branch, which was used only during training thereby retaining the inference time performance. It was also improved using their proposed continuous fusion strategy. In [47], a dilation and deconvolution single-shot multibox detector (DDSSD) that improves SSD with feature fusion using dilation convolution and deconvolution modules for better performance on smaller objects was proposed. Domain adaptation [26], a form of transfer learning, attempts to use the learned knowledge from the source domain on the new target domain. Early works of domain adaptation used feature transformations (inversion, equalization, and histogram stretching) to convert the thermal images to as close as RGB images. Another approach [21] used a shallow CNN before the main model that transforms the input image to the target. The authors of [26] later tried a top-down domain adaptation approach [25] where pre-trained weights from the RGB spectrum were retrained for the thermal spectrum using top-down loss. Another approach to domain adaptation was explored in [34], where the style of an RGB image was applied to a thermal image to transfer the low-level features of RGB images to thermal images, while still maintaining the high-level features. This was carried out by a multi-style generative network (MS-GNet) which draws inspiration from GANs such as CycleGAN. The resultant image is fed into a cross-domain detection model which is a pre-trained RGB detector, fine-tuned on the outputs of the MS-GNet. The layer-wise domain adaptation builds on [26] slowing down the training procedure to retain more knowledge from the original RGB domain. The approach also trains using a bottom-up approach rather than top-down loss to train the network. This is done by progressively training the network one layer at a time from the bottom to the top. The rest of this paper is organized as follows: Sect. 3 describes our approach to create the proposed object detection framework and its finer details. Section 4 describes the datasets used, evaluation metrics, baseline, set-up, and the experimental results. We summarize our contribution and discuss further research plans in Sect. 5. Proposed methodology Our objective was to improve over the industry-standard architectures used in thermal object detection by implementing a combination of transfer learning and domain adaptation with the help of state-of-the-art research on RGB object detection in the form of EfficientDet [41]. In this section, we discuss the motivation behind choosing the base architecture and the process of multi-stage domain adaptation.Fig. 1 A simplified diagram of the EfficientDet architecture, highlighting the modules used to construct it, i.e. the EfficientNet backbone, the weighted bidirectional feature pyramid network (BiFPN), the classifier, and the regressor. In our case, a thermal image is given as input to produce appropriate output detections, i.e. bounding boxes around detected objects and the corresponding class label for each object Choice of base architecture The first motive for selecting EfficientDet is its ability to support compound scaling as it provides a range of configurations by varying resolution, depth, and width of the architecture. This aids in finding the suitable architecture needed for our motive to transfer knowledge accurately and efficiently from the RGB to thermal spectrum for object detection. The second criterion that EfficientDet satisfies is the ability of the model to borrow features from the rich visible spectrum [12]. An accurate object detection model trained on a substantial RGB object detection dataset is needed to obtain this information. EfficientDet (D7x configuration) obtained a new state-of-the-art average precision (AP) of 55.1 on the large-scale RGB object detection dataset, MS-COCO [29]. Further, EfficientNet [40], the backbone of EfficientDet, is pre-trained on the ImageNet [10] dataset, providing further insight and information into features in the visible domain. Third, the modularity of the architecture can efficiently adapt information from the RGB to the thermal domain. EfficientDet comprises four modular components: the backbone, bidirectional feature pyramid network (BiFPN), regressor, and classifier, as shown in Fig. 1. Further, the EfficientNet backbone comprises a multitude of mobile inverted bottleneck blocks (MBConv) [38] which makes the design within the backbone modular. We utilized these features during block-wise and multi-stage training in our framework, described in Sect. 3.2. Model efficiency is the last criterion for choosing an architecture. Among the various configurations, EfficientDet-D0 achieves accuracy similar to YOLOv3 [35] with 28x fewer FLOPs. Similarly, even the largest and most accurate configuration EfficientDet-D7x uses 7x lesser number of FLOPs than the prior state-of-the-art methods. With all these considered, we further endeavour to improve training efficiency with the pace parameter used in our framework, described in Sect. 3.2.1. In the next section, we describe the features of the proposed paced multi-staged block-wise approach. Multi-stage domain adaptation The principal component of the proposed framework is the multi-stage domain adaptation approach that transfers knowledge from the RGB to the thermal domain. The base architecture, EfficientDet [41], comes with different components, each serving a specific purpose. The EfficientNet [40] backbone generates features which are fed into the BiFPN to perform fast, multi-scale feature fusion followed by the bounding box and class prediction networks. We hypothesized that training specific components of the architecture in multiple stages could successfully adapt the entire network for the thermal spectrum and give accurate results. The initial state of the EfficientDet model loaded with information-rich pre-trained weights from the RGB domain is used rather than training the network from scratch. Thus, the model, when trained with the multi-staged approach, adds information to the features it has already learned from the COCO dataset [29]. Conversely, replacing the said features would be detrimental to the model’s performance since these features contain a large amount of helpful information for object detection. In the proposed design, we carried out the multi-stage procedure in three stages: block-wise backbone training, first round fine-tuning, and second round fine-tuning. We have detailed them in the following sections. To better elucidate the framework, we first introduce and explain some notations. Notations Let E denote the entire EfficientDet network used in this approach, and let x refer to the input image such that xϵX, where X represents the thermal domain, i.e. images in the thermal dataset. As explained in [41], there are different configurations of the EfficientDet model, and we have represented it by a compound coefficient denoted by ϕ. In this paper, we use four configurations of EfficientDet; in other words, the values of ϕ we use are D0, D1, D2, and D3. Let the network with configuration ϕ working on an input image x be denoted by Eϕ(x). The network consists of four different modules denoted as follows: the backbone, Γ, the BiFPN, β, the classifier, C, and the regressor, R. Thus, the entire network with default settings of its modules is denoted as Eϕ(Γ, β, C, R). When a particular module is frozen, the weights for all parameters in all the layers in that module are not learnable, and we denote such modules with a bar. For instance, if the entire BiFPN is frozen, then it is denoted by β¯. Since the backbone, Γ, is comprised of several MBConv blocks [38], let ψ signify this number. If the first n blocks in the backbone are unfrozen, while the remaining are frozen, then let this setting of the backbone be denoted by, Γ¯n:ψ. The pace parameter, explained in the next section, is denoted by P.Table 1 Compound coefficients D0–D3 and their corresponding number of blocks in the backbone Sl. No. ϕ ψ 1 D0 16 2 D1 23 3 D2 23 4 D3 26 Fig. 2 An overview of block-wise backbone training: a exhibits a simplified version of the initial setting of the framework with all blocks frozen (gray), b displays the first epoch when the first block is unfrozen (green) and c represents the final epoch of the first stage where all the blocks have become unfrozen, after ψ epochs Block-wise backbone training As stated earlier, the chosen backbone architecture, EfficientNet, acts as a feature extractor and incorporates several MBConv blocks. Though this backbone can have varying depths, widths, and resolutions based on the compound scaling method, for the first stage of training, we focus on the depth of the backbone, as this controls the number of MBConv blocks used in the architecture. Each block can be assigned a number from 0 to ψ-1 in a sequential manner. The value of ψ is dependent on the configuration of EfficientDet, which is decided by the compound coefficient ϕ. Based on the original implementation of EfficientDet, we have assigned the values of ψ and ϕ as shown in Table 1. Note that we only include the values of ψ for those configurations used in our experiments. After determining the number of blocks used in the backbone, it becomes necessary to adapt their weights to the thermal domain methodically. The authors of [25] demonstrated that a bottom-up adaptation of the network could provide accurate results. We integrate a similar approach to training the backbone of the network, specializing it for the architecture of EfficientNet. Initially from the network Eϕ(Γ, β, C, R), we set the network to Eϕ(Γ¯, β, C, R) by freezing all the parameters of every block from 0 to ψ-1 in the backbone. Following this, we unfreeze one block at a time, i.e. unfreezing one block per epoch till all the blocks have unfrozen. Therefore, for any epoch e (e<ψ ), the network would be Eϕ(Γ¯e:ψ, β, C, R). This gradual, sequential unfreezing of layers ensures that the backbone has successfully adapted to the thermal domain with satisfactory accuracy. Figure 2 portrays the block-wise backbone training.Fig. 3 An overview of block-wise backbone training with the use of the pace parameter to make the training process efficient: a a simplified version of the initial setting of the framework with all blocks frozen (gray), b displays the first epoch when the first P blocks are unfrozen (green), with each subsequent epoch unfreezing P more blocks and c represents the final epoch of the first stage where all the blocks have become unfrozen, after ψP epochs Pace The training time of the traditional block-wise backbone training increases in proportion to the values of ϕ as the size of the architecture increases. We have introduced a paced block-wise backbone training to reduce the training time without drastically affecting the detection accuracy by adding a pace parameter (P). This parameter (P) takes an integer value and works as follows: starting with the network Eϕ(Γ¯, β, C, R), we unfreeze P layers at a time rather than just one. Therefore, for any epoch e (e<ψ ), the network would be1 Eϕ(Γ¯x:ψ,β,C,R),wherex=e∗Pife∗P≤ψ,ψife∗P>ψ The pace process, visualized in Fig. 3, speeds up the training process, making the framework more efficient. The number of epochs required for this stage of training is ψP when compared to ψ using the traditional approach. Here, the number of epochs decreases for a given compound coefficient as the pace parameter increases. However, we expect that, even intuitively, after a certain level, the pace might become too quick for the model to transfer to the thermal domain accurately. Hence, to achieve efficient training and accurate results, a moderate value for the pace parameter is required, which is demonstrated in Sect. 4.6.1. After this initial stage of adapting the backbone to the target domain, the results can be further improved with the use of the following two stages. First round fine-tuning During the first stage, we have trained only the layers of the EfficientNet Backbone, and hence it becomes necessary to train the remaining components of the detector using fine-tuning. The backbone, having been trained for ψP epochs, can also be trained further in this stage. Thus, the purpose of this additional stage of training is to focus on fine-tuning the entire network, which allows all the parameters in the network to further adapt to the new domain, thereby improving the framework’s accuracy. A fixed network parameter setting, Eϕ(Γ, β, C, R), is used for the training procedure in this stage; the backbone, BiFPN, classifier, and regressor are unfrozen. Training continues until there is no further improvement in the network.Fig. 4 Examples of the FLIR ADAS dataset Second round fine-tuning The final stage of our multi-staged approach has a similar purpose as the previous stage, but the target modules are only the classifier and regressor, i.e. only the head of the detector. We observed that training the model for a number of epochs with the network set to the configuration of Eϕ(Γ¯, β¯, C, R), consistently results in a small boost in performance over the first round of fine-tuning and allows the detector to be as accurate as possible. Performing this round of fine-tuning is also computationally inexpensive as the training is done only on the classifier and regressor, thus serving the purpose of efficiently attaining even higher accuracy, enough to obtain a new state of the art. The number of epochs needed for this round is usually very less before saturation. We cease at this stage of training once the reported accuracies have saturated, which we observed to have more visible outcomes for larger values of ϕ. The entire training procedure is summarized in Algorithm 1. It was evident that increasing the value of ϕ would also improve accuracies, as shown in [41]. However, the effect of increasing ϕ appears to be more significant, especially when dealing with small objects. This detail is discussed further in Sect. 4.5. Experimental results and discussion Datasets FLIR starter thermal dataset The dataset used for training was the FLIR starter thermal dataset [20]. This dataset contains 10,288 thermal images captured on a FLIR Tau2 camera, with a collection of RGB images that may or may not have a pair with a thermal counterpart. For our approach, we solely utilized the thermal images in the dataset for training and testing. The dataset consists of 8862 images for training and 1366 images for testing. The annotations of the dataset followed the COCO Dataset [29] format, and only the classes of person, bicycle, car, and dog were used during the annotation. However, following the precedence of the baseline and previous research, we train and test on only the three main categories, i.e. person, bicycle, and car. Although the dataset contains RGB images, it does not have any annotations. The annotations corresponding to the thermal counterpart may be inaccurate and misaligned for the RGB images. The final dataset comprises 67,618 annotations (22,372 for person, 3986 for bicycle, 41,260 for car) in the training set and 11,682 annotations (5779 for person, 471 for bicycle, 5432 for car) in the test set. Each image resolution is 640×512. Some sample images can be seen in Fig. 4. Other datasets We utilize the thermal images of databases present in the OTCBVS benchmark dataset collection, including the OSU thermal pedestrian database [9], the terravic motion IR database [33], and the BU-TIV (Thermal Infrared Video) benchmark [43]. Thermal cameras such as the Raytheon PalmIR 250D and Raytheon L-3 Thermal-Eye 2000AS were used to capture these datasets. These cameras differ from the FLIR Tau2 images on which we have trained the models. We consider only the person category, as these datasets are specialized for pedestrians/people. The hiding subset of the LTIR dataset [3] contains 358 images of a single annotated instance of the person category. We sectioned the dataset into two based on occlusion: no occlusion, which consists of 213 images, without any obstruction in front of the person, and full or partial occlusion, which consists of 145 images with some object. We used this dataset to test the model’s performance when detecting occluded objects or subjects in an image. Evaluation metrics We use the evaluation metric of mean average precision (mAP) for all experiments using the paced multi-staged block-wise framework for object detection in thermal images. The process of calculating this metric begins with calculating Precision and Recall as follows:2 Precision=TPTP+FP 3 Recall=TPTP+FN where TP denotes the number of accurately detected bounding boxes for a given Intersection of Union (IoU). IoU is the ratio of the area of overlap to the union between the ground truth and prediction. FP denotes the number of incorrect detections, while FN denotes the number of ground truth detections that were missed during prediction. To compare with other state-of-the-art methodologies, we follow the COCO 101 point metric of determining AP (average precision), i.e.:4 AP=1101∑xϵMP(x) where MP denotes the maximum precision in the recall area (for COCO, it is 0 to 1 in steps of 0.01). As mentioned earlier, for evaluation purposes, we use three main classes of the FLIR ADAS dataset: person, bicycle, and car. Let us denote this set of classes as C. We calculate the AP values for these classes, and the following averaging equation gives the final mAP value:5 mAP=∑cϵCAPc|C| where in this case |C|=3. We have used the official pycocotools package (https://pypi.org/project/pycocotools/) for the source code. The IoU is fixed at 0.5, similar to state-of-the-art models. We also calculate the mAP for different object sizes: small, medium, and large, denoted by APS, APM, and APL, respectively. Small objects have an area less than 322, medium objects between 322 and 962 and large objects greater than 962. Baseline A baseline accuracy was established from the FLIR ADAS dataset [20], with an mAP of 54.0% at IoU of 0.5. Further, we compare the performance of our framework with the state-of-the-art models, primarily those who have dealt with the FLIR ADAS dataset, to show that our approach is not only competitive with prior work but also provides the highest overall mAP values. As a point of reference, the prior state-of-the-art method [6] achieved an mAP of 74.6%. Experimental setup We have conducted all the experiments using PyTorch implementation of EfficientDet, and we have made the training code available at https://github.com/shreyas-bk/PMBW_Object_Detection_In_Thermal_Images. The EfficientDet series comes with pre-trained weights on the COCO dataset, which serves as the starting point for all training instances. The maximum coefficient used in our experiments is D3, for two reasons: we found no significant increase in performance between coefficients D2 and D3, and the computational power increases for higher network configuration. We apply only the first two stages of our framework when working with coefficients D0 and D1 and the complete framework for coefficients D2 and D3. The pace parameter is varied primarily when using coefficient D1 to determine which pace is the most optimal, as shown in Table 4. Before feeding the thermal images into the network, we normalize them with the calculated mean and standard deviation of 0.53 and 0.19, respectively (assuming image pixel intensities are in the range [0, 1]). The optimizers we have used vary for the different stages of training: we use the AdamW optimizer [32] (a variant of the Adam optimizer that uses decoupled weight decay regularization) for the block-wise backbone training for both the first and second round of fine-tuning we select the stochastic gradient descent (SGD) optimizer with a Nesterov momentum of 0.9. A vital factor in our setup was the learning rate. When training is in the first stage, we used an exponential decay of learning rate, as we found it provided better performance without affecting the efficiency. The γ parameter (multiplicative factor of the learning rate for every epoch) was set to 0.75 for the given decay, with a base learning rate of 0.001. Also, this exponentially decaying learning rate was applied to coefficients D2 and D3 during the first round of fine-tuning. For all other training stages, we have used a fixed learning rate of 0.001. Results Systematic results for the coefficients This section systematically describes how each coefficient from D0–D3 was trained and tested. Here, in order to represent a completely trained system of our proposed paced multi-stage block-wise framework, we denote it with PMBW(ϕ, P), where ϕ is the compound coefficient and P is the pace parameter used in the block-wise backbone stage of training. More precisely, the term PMBW entails all training stages of the multi-stage approach detailed earlier with its various settings of the base network Eϕ(Γ, β, C, R). All three stages are assumed to have been performed unless specified otherwise. Compound coefficient ϕ=D0 The framework used for this coefficient was PMBW(D0, 1), with only the initial two stages of training. The results for this setting are tabulated in Table 2. Notably, the mAP value, 55.6%, exceeded the baseline using only the first coefficient. We can easily observe that the performance of this setting on small objects is nearly 50% off the mAP values for medium and large objects. With this observation, we can discuss the base object detector’s capabilities when detecting objects of varied sizes. From Table 3 taken from [4] we can see that the AP values are proportional to the coefficient value. However, it is also important to note that the values of APS increase quicker than the values of APM and APL; for example, the increase in APS from D0 to D3 is 14.6%, which is a substantially larger increase when compared to the 8.6% increase of APL. Since the APS values of our framework are poor for this coefficient, we shifted our attention majorly to ϕ = 1 and beyond. The values for APM and APL are already comparatively high and are not the primary area that needs to be enhanced, though there is room for improvement. Further, the mAP is still nearly 20% off the state of the art, giving us another reason to focus our efforts on higher compound coefficients.Table 2 Results with ϕ=D0 Framework APS APM APL mAP PMBW(D0, 1) 29.0 81.2 81.6 55.6 Table 3 EfficientDet results for different sizes on the COCO dataset ϕ APS APM APL mAP D0 12.0 38.3 51.2 33.8 D1 17.9 44.3 56.0 39.6 D2 22.5 47.0 58.4 43.0 D3 26.6 49.4 59.8 45.8 Table 4 Results with ϕ=D1 Framework APS APM APL mAP PMBW(D1, 1) 43.6 86.3 85.2 67.7 PMBW(D1, 2) 43.8 85.0 85.2 67.4 PMBW(D1, 3) 42.7 85.3 86.0 67.2 PMBW(D1, 4) 35.3 78.1 74.8 58.6 Table 5 Results with ϕ=D2 Framework After second stage After third stage APS APM APL PMBW(D2, 2) 73.4 73.9 58.8 85.3 84.8 PMBW(D2, 3) 75.6 77.2 61.4 88.7 87.6 Compound coefficient ϕ=D1 Starting with ϕ = 1 we implemented different values for the pace parameter of the block-wise backbone training with the networks PMBW(D1, 1), PMBW(D1, 2), PMBW(D1, 3), and PMBW(D1, 4). All implementations used just the first two stages. The results for this setting can be seen in Table 4. Among the different pace variations, the trained network PMBW(D1, 1) obtained the greatest performance with an mAP of 67.7%. However, as we had hypothesized, there was a marginal difference compared to the other pace settings. For example, using a larger pace parameter resulted in similar mAP values for PMBW(D1, 2) and PMBW(D1, 3). Both had a marginal drop in performance of 0.3% and 0.5%, respectively, from PMBW(D1, 1). As delineated in the methodology, the training time for these two settings was markedly lower than PMBW(D1, 1). Hence, the training efficiency (explained in Eq. 6) improved without drastically hampering the performance. As predicted earlier, improvement in efficiency without a significant loss in accuracy is observed when we increased the pace parameter further, which is apparent from the results for PMBW(D1, 4), where the mAP values were nearly 9% off PMBW(D1, 1). Thus, we can find an optimal value of the pace parameter, providing increased efficiency with competitive accuracy. From the results, it is evident that there was a considerable boost of 13.3% in overall mAP compared to ϕ=D0. However, the highest mAP value obtained was still 5% off of the state of the art. Also, the performance on small objects was poor, i.e. 40% away from medium and large objects. We also experimented with the effect of block-wise backbone training compared to training without block-wise domain adaptation. The network setting of ED1(Γ, β,C,R), when trained for the same number of epochs as the block-wise backbone stage of PMBW(D1, 1), resulted in a maximum mAP of only 60%. Compound coefficient ϕ=D2 Following the idea from ϕ=D1, that implementing pace could improve training efficiency without reducing performance, we directly applied a pace of 2 and 3 for ϕ=D2, i.e. the networks used were PMBW(D2, 2) and PMBW(D2, 3). The results can be found in Table 5. The first stage was carried out normally, using the specified pace, while for the second stage, we observed an average increase of 1% in mAP using the exponential decay of learning rate. The network PMBW(D2, 3) gave the highest mAP of 75.6% after the second stage. Following this, we applied the final stage of the second round of fine-tuning for both configurations. From the results, we can verify that an increase of 0.5% and 1.6% were achieved for PMBW(D2, 2) and PMBW(D2, 3), respectively. Notably, PMBW(D2, 3) reached an mAP value of 77.2%, thereby improving upon the state of the art. In this case, the gap between mAP values for small objects and medium and large objects reduced to 25%. Compound coefficient ϕ=D3 For this final coefficient, using the knowledge we had gained from the previous experiments, we took the single configuration of PMBW(D3, 3) with all three stages. The results given in Table 6 show that the final value procured only slightly exceeds that of ϕ=D2, but it is the highest mAP value obtained in all the configurations of our framework and a new state-of-the-art on the FLIR ADAS dataset. Examples of detections using PMBW(D3, 3) can be found in Fig. 5. Final results and discussion Table 7 shows the highest mAP value and paced multi-stage block-wise setting for each value of ϕ. To the best of our knowledge, the proposed PMBW(D3, 3) framework achieves the highest overall mAP, among existing thermal object detectors, for the FLIR ADAS dataset. PMBW(D3, 3) yields the highest mAP for person and car, whereas PMBW(D2, 3) for the bicycle class. Table 8 demonstrates this by comparing with other methodologies [6, 12, 15, 25, 34]. We consider the mAP for only the person, bicycle, and car categories from [15], which is simply the mean of the reported AP’s. Our new state-of-the-art mAP value is 77.26% (person-81.19%, bicycle-64.04%, car-86.55%), and in Table 8 these values are marked in bold. We demonstrate the utility of the procedural components we have introduced in this paper in the following section.Table 6 Results with ϕ=D3 Framework APS APM APL mAP PMBW(D3, 3) 64.6 86.7 82.1 77.3 Fig. 5 Examples of detections on thermal images from the FLIR ADAS dataset using our PMBW(D3, 3) framework Further discussion Effect of pace To demonstrate the effectiveness of Pace, we are required to quantify the training efficiency. The training efficiency depends on the performance of the model and the number of epochs required to achieve the desired performance. The time taken per epoch is nearly the same across different values of Pace, as we consider only the coefficient D1 for our experiments. To measure the performance, we have devised Eq. (6):6 ηP,ϕ=mAP(PMBW(ϕ,P))-mAP(Baseline)e where ηP,ϕ is the training efficiency and mAP(PMBW(ϕ, P) is the achieved mAP value for a particular coefficient and pace. mAP(Baseline) is the mAP value of the baseline (54.0%), and e is the number of epochs taken for training. The results can be seen in Fig. 6 for different pace values when ϕ = 1. Thus, as we had intended, adding a certain amount of pace can speed up the training process without hampering the overall performance. Further, we had also expected that after a certain point, the pace would be too quick for the model to successfully adapt to the thermal domain, which is visible when using the PMBW(D1, 4) framework. Effect of multiple stages We can demonstrate the effect of multiple stages by plotting the mAP values for each value of ϕ across stages. In Fig. 7, we represent the stages on the x-axis, with stage 0 implying the mAP value calculated using the EfficientDet detector loaded with the pre-trained weight for the respective value of ϕ, without any training. As shown in Fig. 7 for every value of ϕ taken, there is an increase in mAP values for each consecutive stage. The average increase in mAP was 7.7% for block-wise backbone training, 5.45% for first-round fine-tuning, and 2.55% for second-round fine-tuning. Thus, the necessity of multiple stages as well the effectiveness of the block-wise backbone training is evident. We have examined the training efficiency of the fine-tuning round by calculating the average increase in mAP per epoch from the first stage to the second stage. The results from Fig. 8 show that for pace value of 2 for PMBW(D1, P) has a large improvement in training efficiency. The low training efficiency for PMBW(D1, 1) may be since it took a larger number of epochs to train in the first stage and may already be nearly saturated before the second stage. However, the result that this ablation study indicates in Fig. 8 is similar to that of Sect. 4.6.1; there is an initial increase in training efficiency followed by a decrease. Performance of the trained model on other datasets OTCVBS We tested our trained model on the images of the OTCVBS [9, 33, 43] dataset to show that the model can adapt other thermal datasets that the detector has not previously seen. Visual evaluation of the model is shown in Fig. 9. Because they were captured on different sensors as mentioned in Sect. 4.1 the images of these datasets are diverse and present a contrasting collection of thermal images than the FLIR ADAS dataset. We can infer from the detections in Fig. 9 that the trained model is capable of generalizing over a broad set of thermal images with reasonable accuracy and no additional training cost.Table 7 Best result for each value of ϕ Framework Person Bicycle Car mAP PMBW(D0, 1) 58.2 41.9 66.7 54.4 PMBW(D1, 1) 70.2 55.7 77.1 67.7 PMBW(D2, 3) 80.6 66.5 84.5 77.2 PMBW(D3, 3) 81.2 64.0 86.5 77.3 Table 8 Comparison with baseline and prior state-of-the-art methods (all values rounded to 1 decimal place for consistency) Method Person Bicycle Car mAP Baseline 54.7 39.7 67.6 54.0 MMTOD-UNIT(MSCOCO) [12] 64.5 49.4 70.7 61.5 Transfer learning on SSD + VGG16 [15] 61.9 46.1 85.1 64.4 ODSC (SSD512 + VGG16) [34] 71.0 55.5 82.3 69.6 BU(LT, T) [25] 75.6 57.4 86.5 73.2 ThermalDet [6] 78.2 60.0 85.5 74.6 PMBW(D2, 3) (ours) 80.6 66.5 84.5 77.2 PMBW(D3, 3) (ours) 81.2 64.0 86.5 77.3 LTIR Previous works [12, 25] yielded hindered performance when these thermal object detectors were presented with occluded objects, both fully or partially. To get a concrete idea of the impact of occlusion, we consider the hiding subset of the LTIR dataset. For testing on this dataset, we have considered the PMBW(D2, 3) framework. As shown in Table 9, the mAP when there is no occlusion present is much higher than when there is some form of occlusion present. Further, the confidence scores for these images are very high, as shown in Fig. 10a. As expected, our proposed detector suffers when there is close to full-occlusion as shown in Fig. 10c. However, when there is partial occlusion, the model can detect a person, albeit with low confidence, as shown in Fig. 10b. Importance of thermal object detection at night-time Although images taken in the visible domain can be rich in semantic information during the daytime, the same is not true about night conditions. From the road safety viewpoint, especially in the context of self-driving cars, errors in detections made on images captured in the RGB spectrum can have untoward consequences. However, we can overcome these unfavourable outcomes using object detection in thermal images. It can be made evident by comparing the detections made on RGB images by a fully trained RGB detector (row 1 of Fig. 11) and comparing it with the respective thermal counterpart, using our framework (row 2 of Fig. 11). It is clear that when compared to the thermal, RGB detector may fail in certain instances such as unfavourable lighting, missing objects that are smaller/more concealed, or even misconstruing a crowd and output the wrong number of detections. More accurate results can be obtained, simply by switching to thermal inference as shown in Row 2 of Fig. 11. Retention of visible information As mentioned earlier, we intended to perform transfer learning without replacing the information possessed by the RGB pre-trained weights to prevent the loss of a vast amount of readily available knowledge. Thus, the effect was an amelioration of the model’s performance in this domain while still retaining an admissible detection capability in the visible sphere. To demonstrate this, we visually compare the results of the RGB trained detector, i.e. EfficientDet trained on the COCO dataset and our framework, using the value of ϕ as D3. As shown in Fig. 12, both RGB and thermal predictions do not differ by a vast amount when considering detections among person, bicycle, and car classes. Hence, there was minimal visible information loss during the training process.Fig. 6 Training efficiencies for different values of pace for PMBW(D1, P) Fig. 7 mAP values for different coefficients across the stages Fig. 8 Training efficiencies of fine-tuning for different values of pace for PMBW(D1, P) Fig. 9 Predictions on OTCBVS dataset Failure cases and explanations The proposed framework, when applied to EfficientDet, performs with significantly high accuracy. However, there are still cases where the trained model fails. The most accurate setting (PMBW(D3, 3)) still fails to detect small, i.e. distant objects. Although the performance concerning small objects increased with each value of ϕ, the mAP value of PMBW(D3, 3) for small objects (64.6%) is still much lower than that of medium and large objects (86.7% and 82.1%, respectively). The qualitative results also show this result, as is evident in the first two columns of Fig. 13, where we can observe that the model is capable of detecting nearer cars, which appear larger in the image, while the cars farther away and smaller in the image are undetected.Table 9 Results of occlusion testing with PMBW(D2, 3) on LTIR-Hiding Subset of LTIR-Hiding Number of images mAP No occlusion 213 89.2 Full or partial occlusion 145 55.4 Overall 358 72.0 Fig. 10 Results on LTIR-Hiding dataset with varying levels of occlusion Further, occlusion was also a hindrance to performance, as already observed in the LTIR dataset in Sect. 4.6.3. We have demonstrated this with the FLIR dataset in the last two columns of Fig. 13, where the presence of multiple persons or cars close to each other are labelled erroneously, primarily because one object occludes the others.Fig. 11 Contrast in detections between RGB and thermal detectors on night-time images. Row 1 contains detections made by EfficientDet (ϕ=3) trained on the COCO dataset, while Row 2 contains the detections made on thermal images by our framework PMBW(D3, 3) Fig. 12 Information retention tested on RGB images. Row 1 contains detections made by EfficientDet (ϕ=3) trained on the COCO dataset, while Row 2 contains the detections made on thermal images by our framework PMBW(D3, 3) Fig. 13 Failure cases of PMBW(D3, 3). Row 1 contains the predictions made by PMBW(D3, 3), while Row 2 contains the ground truths. The first two columns demonstrate failure to detect smaller objects, while the last two columns demonstrate failure to distinguish occluded objects Conclusion In this paper, we have explored a domain adaptation approach to re-purpose the state-of-the-art, EfficientDet object detector, to work in the thermal domain. We have created a paced multi-staged block-wise framework for efficient and accurate training of the EfficientDet model to detect objects in thermal imagery. By introducing block-wise adaptation and pace parameter, we have also shown that we can improve the training efficiency for larger and more complex detectors. The highlight of this paper was the creation of a framework that provides state-of-the-art performance for object detection in the thermal dataset, namely the FLIR ADAS dataset, with an mAP of 77.3%. In doing so, we obviated the necessity of RGB counterpart images during training to make the model more suitable for real-life applications. The experimental results have shown us a highly flexible, paced multi-staged block-wise framework that achieves increased accuracy while striking a balance with available computational power. Further, the results demonstrate its versatility and capability to variations in the thermal domains, especially when it comes to occlusion. We have also shown that thermal domain features add to the pre-existing knowledge from the RGB spectrum, giving favourable results on visible images even after training on a thermal dataset. The thermal object detector we have presented here is a step forward, but still, there is much to improve. We have observed that small or distant objects have the chance of not being detected, for example, PMBW(D3, 3), which provided the best overall results, still had an mAP disparity of roughly 20% for small objects. Additionally the proposed approach is practically applicable and can potentially be implemented in self-driving cars and surveillance, as it can be inexpensively trained only on thermal images, thereby preserving privacy and still acquiring accurate results. Further research can tackle these problems through increased resolution or augmented data and can push the state-of-the-art further. Approaches involving thermal image-based pre-processing could yield better results for small objects. Additionally, implementing this approach on other state-of-the-art detectors could produce improvements. Our framework provides new insights into domain adaptation, especially for object detection in thermal images. However, we can utilize the maximum potential of this framework by making it a general guideline for improving efficiency while maintaining accuracy to enhance performance in various other computer vision and domain adaptation tasks. Declarations Conflict of interest The authors declare that they have no conflict of interest. This work was submitted when J. Jennifer Ranjani was associated with the Institute. The original online version of this article was revised: Author name was abbreviated. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Change history 5/10/2022 A Correction to this paper has been published: 10.1007/s00371-022-02512-3 ==== Refs References 1. Baek J Hong S Kim J Kim E Efficient pedestrian detection at nighttime using a thermal camera Sensors 2017 17 8 1850 10.3390/s17081850 28796190 2. Benenson R., Omran, M., Hosang J., Schiele, B.: Ten years of pedestrian detection, what have we learned? In: Agapito, L., Bronstein, M., Rother, C. (eds.) Computer Vision–ECCV 2014 Workshops. ECCV 2014. Lecture Notes in Computer Science, vol. 8926. Springer, Cham (2015). 10.1007/978-3-319-16181-5_47 3. Berg, A., Ahlberg, J., Felsberg, M.: A thermal object tracking benchmark. In: 2015 12th IEEE International Conference on Advanced Video and Signal Based Surveillance (AVSS) (2015). 10.1109/AVSS.2015.7301772 4. Bochkovskiy, A., Wang, C.Y., Liao, H.Y.M.: Yolov4: Optimal speed and accuracy of object detection (2020). arXiv:2004.10934 5. Braun M Krebs S Flohr FB Gavrila DM Eurocity persons: a novel benchmark for person detection in traffic scenes IEEE Trans. Pattern Anal. Mach. Intell. 2019 41 1844 1861 10.1109/TPAMI.2019.2897684 6. Cao, Y., Zhou, T., Zhu, X., Su, Y.: Every feature counts: an improved one-stage detector in thermal imagery. In: 2019 IEEE 5th International Conference on Computer and Communications (ICCC), pp. 1965–1969 (2019). 10.1109/ICCC47050.2019.9064036 7. Cordts, M., Omran, M., Ramos, S., Rehfeld, T., Enzweiler, M., Benenson, R., Franke, U., Roth, S., Schiele, B.: The cityscapes dataset for semantic urban scene understanding. In: 2016 IEEE Conference on Computer Vision and Pattern Recognition (CVPR), 2016, pp. 3213–3223. 10.1109/CVPR.2016.350 8. Dai X Yuan X Wei X Tirnet: object detection in thermal infrared images for autonomous driving Appl. Intell. 2021 51 3 1244 1261 10.1007/s10489-020-01882-2 9. Davis, J.W., Keck, M.A.: A two-stage template approach to person detection in thermal imagery. In: 2005 Seventh IEEE Workshops on Applications of Computer Vision (WACV/MOTION’05), vol. 1, pp. 364–369 (2005). 10.1109/ACVMOT.2005.14 10. Deng, J., Dong, W., Socher, R., Li, L.-J., Li, K., Fei-Fei, L.: ImageNet: A large-scale hierarchical image database. In: 2009 IEEE Conference on Computer Vision and Pattern Recognition, pp. 248–255 (2009). 10.1109/CVPR.2009.5206848 11. Deng, Z., Hu, X., Zhu, L., Xu, X., Qin, J., Han, G., Heng, P.A.: R3net: recurrent residual refinement network for saliency detection. In: Proceedings of the Twenty-Seventh International Joint Conference on Artificial Intelligence, IJCAI-18, pp. 684–690. International Joint Conferences on Artificial Intelligence Organization (2018). 10.24963/ijcai.2018/95 12. Devaguptapu, C., Akolekar, N., Sharma, M.M., Balasubramanian, V.N.: Borrow from anywhere: pseudo multi-modal object detection in thermal imagery. In: 2019 IEEE/CVF Conference on Computer Vision and Pattern Recognition Workshops (CVPRW) (2019). 10.1109/cvprw.2019.00135 13. Dollar, P., Wojek, C., Schiele, B., Perona, P.: Pedestrian detection: A benchmark. In: 2009 IEEE Conference on Computer Vision and Pattern Recognition, pp. 304–311 (2009). 10.1109/CVPR.2009.5206631 14. Everingham M Van Gool L Williams CKI Winn J Zisserman A The pascal visual object classes (VOC) challenge Int. J. Comput. Vis. 2010 88 2 303 338 10.1007/s11263-009-0275-4 15. Gaus, Y.F.A., Bhowmik, N., Isaac-Medina, B.K., Breckon, T.P.: Visible to infrared transfer learning as a paradigm for accessible real-time object detection and classification in infrared imagery. In: Counterterrorism, Crime Fighting, Forensics, and Surveillance Technologies IV, vol. 11542, p. 1154205. International Society for Optics and Photonics (2020) 16. Geiger A Lenz P Stiller C Urtasun R Vision meets robotics: the kitti dataset Int. J. Rob. Res. 2013 32 11 1231 1237 10.1177/0278364913491297 17. Ghose, D., Desai, S.M., Bhattacharya, S., Chakraborty, D., Fiterau, M., Rahman, T.: Pedestrian detection in thermal images using saliency maps. In: 2019 IEEE/CVF Conference on Computer Vision and Pattern Recognition Workshops (CVPRW), pp. 988–997 (2019). 10.1109/CVPRW.2019.00130 18. globenewswire: The global thermal scanners market size is expected to reach $6.7 billion by 2025. https://www.globenewswire.com/news-release/2020/04/17/2017896/0/en/The-Global-Thermal-Scanners-Market-size-is-expected-to-reach-6-7-billion-by-2025-rising-at-a-market-growth-of-10-3-CAGR-during-the-forecast-period.html (2020) 19. govtech: Interest in thermal imaging is growing as covid-19 rages on. https://www.govtech.com/products/Interest-in-Thermal-Imaging-Is-Growing-as-COVID-19-Rages-On.html (2020) 20. Group, F.A.: Flir starter thermal dataset. https://www.flir.com/oem/adas/adas-dataset-form (2018) 21. Hazan, A., Shoshan, Y., Khapun, D., Aladjem, R., Ratner, V.: Adapternet-learning input transformation for domain adaptation. arXiv preprint arXiv:1805.11601 (2018) 22. Herrmann, C., Ruf, M., Beyerer, J.: CNN-based thermal infrared person detection by domain adaptation. In: Autonomous Systems: Sensors, Vehicles, Security, and the Internet of Everything, vol. 10643, p. 1064308. International Society for Optics and Photonics (2018) 23. Hwang, S., Park, J., Kim, N., Choi, Y., Kweon, I.S.: Multispectral pedestrian detection: Benchmark dataset and baseline. In: 2015 IEEE Conference on Computer Vision and Pattern Recognition (CVPR), pp. 1037–1045 (2015). 10.1109/CVPR.2015.7298706 24. John, V., Mita, S., Liu, Z., Qi, B.: Pedestrian detection in thermal images using adaptive fuzzy c-means clustering and convolutional neural networks. In: 2015 14th IAPR International Conference on Machine Vision Applications (MVA), pp. 246–249 (2015). 10.1109/MVA.2015.7153177 25. Kieu M Bagdanov AD Bertini M Bottom-up and layer-wise domain adaptation for pedestrian detection in thermal images ACM Trans. Multimed. Comput. Commun. Appl. (ACM TOMM) 2020 17 1 19 26. Kieu, M., Bagdanov, A.D., Bertini, M., Del Bimbo, A.: Domain adaptation for privacy-preserving pedestrian detection in thermal imagery. In: International Conference on Image Analysis and Processing, pp. 203–213. Springer (2019) 27. Li, C., Song, D., Tong, R., Tang, M.: Illumination-aware faster R-CNN for robust multispectral pedestrian detection. In: Pattern Recognition, vol. 85, pp. 161–171 (2019). 10.1016/j.patcog.2018.08.005 28. Li, C., Song, D., Tong, R., Tang, M.: Multispectral pedestrian detection via simultaneous detection and segmentation. In: British Machine Vision Conference (BMVC) (2018) 29. Lin, T.Y., Maire, M., Belongie, S., Bourdev, L., Girshick, R., Hays, J., Perona, P., Ramanan, D., Zitnick, C.L., Dollár, P.: Microsoft COCO: Common Objects in Context. In: Fleet, D., Pajdla, T., Schiele, B., Tuytelaars, T. (eds.) Computer Vision - ECCV 2014. Lecture Notes in Computer Science, vol. 8693. Springer, Cham. (2014). 10.1007/978-3-319-10602-1_48 30. Liu, N., Han, J., Yang, M.H.: Picanet: learning pixel-wise contextual attention for saliency detection. In: Proceedings of IEEE Conference on Computer Vision and Pattern Recognition (CVPR), pp. 3089–3098 (2018) 31. Liu, W., Anguelov, D., Erhan, D., Szegedy, C., Reed, S., Fu, C.Y., Berg, A.C.: Ssd: single shot multibox detector. In: Lecture Notes in Computer Science, pp. 21–37 (2016). 10.1007/978-3-319-46448-0_2 32. Loshchilov, I., Hutter, F.: Decoupled weight decay regularization. In: Proceedings of 7th International Conference on Learning Representations (ICLR) (2019) 33. Miezianko, R.: Terravic research infrared database. http://vcipl-okstate.org/pbvs/bench/ 34. Munir, F., Azam, S., Rafique, M.A., Sheri, A.M., Jeon, M.: Thermal object detection using domain adaptation through style consistency (2020). arXiv:2006.00821v1 35. Redmon, J., Farhadi, A.: Yolov3: an incremental improvement (2018). arXiv:1804.02767 36. Faster R-CNN: towards real-time object detection with region proposal networks. In: Proceedings of Advances in Neural Information Processing Systems Conference, vol. 28 (2015) 37. Saeidi M Arabsorkhi A A novel backbone architecture for pedestrian detection based on the human visual system Vis. Comput. 2021 10.1007/s00371-021-02280-6 38. Sandler, M., Howard, A., Zhu, M., Zhmoginov, A., Chen, L.C.: Mobilenetv2: inverted residuals and linear bottlenecks. In: Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition (CVPR), pp. 4510–4520 (2019) 39. Schwarz, M., Schulz, H., Behnke, S.: RGB-D object recognition and pose estimation based on pre-trained convolutional neural network features. In: 2015 IEEE International Conference on Robotics and Automation (ICRA), pp. 1329–1335 (2015). 10.1109/ICRA.2015.7139363 40. Tan, M., Le, Q.V.: Efficientnet: rethinking model scaling for convolutional neural networks (2020). arXiv:1905.11946 41. Tan, M., Pang, R., Le, Q.V.: Efficientdet: scalable and efficient object detection (2020). arXiv:1911.09070 42. Wagner, J., Fischer, V., Herman, M., Behnke, S.: Multispectral pedestrian detection using deep fusion convolutional neural networks. In: ESANN, vol. 587, pp. 509–514 (2016) 43. Wu, Z., Fuller, N., Theriault, D., Betke, M.: A thermal infrared video benchmark for visual analysis . In: Proceedings of the 2014 IEEE Conference on Computer Vision and Pattern Recognition, pp. 201–208 (2014). 10.1109/CVPRW.2014.39 44. Xu, D., Ouyang, W., Ricci, E., Wang, X., Sebe, N.: Learning cross-modal deep representations for robust pedestrian detection. In: 2017 IEEE Conference on Computer Vision and Pattern Recognition (CVPR), pp. 4236–4244 (2017). 10.1109/CVPR.2017.451 45. Zhang G Liu J Li H Chen YQ Davis LS Joint human detection and head pose estimation via multistream networks for RGB-D videos IEEE Signal Process. Lett. 2017 24 11 1666 1670 10.1109/LSP.2017.2731952 46. Zhang G Liu J Liu Y Zhao J Tian L Chen YQ Physical blob detector and multi-channel color shape descriptor for human detection J. Vis. Commun. Image Represent. 2018 52 13 23 10.1016/j.jvcir.2018.01.013 47. Zhang H Hong XG Zhu L Detecting small objects in thermal images using single-shot detector Autom. Control Comput. Sci. 2021 55 2 202 211 10.3103/S0146411621020097 48. Zhang, L., Liu, Z., Chen, X., Yang, X.: The cross-modality disparity problem in multispectral pedestrian detection. arXiv preprint arXiv:1901.02645 (2019) 49. Zhang X Wang X Gu C Online multi-object tracking with pedestrian re-identification and occlusion processing Vis. Comput. 2021 37 1089 1099 10.1007/s00371-020-01854-0 50. Zheng, Y., Izzat, I.H., Ziaee, S.: GFD-SSD: gated fusion double SSD for multispectral pedestrian detection (2019). arXiv:1903.06999 51. Zhu, J., Park, T., Isola, P., Efros, A.A.: Unpaired image-to-image translation using cycle-consistent adversarial networks. In: 2017 IEEE International Conference on Computer Vision (ICCV), pp. 2242–2251 (2017). 10.1109/ICCV.2017.244
PMC008xxxxxx/PMC8992246.txt
==== Front J Nutr J Nutr The Journal of Nutrition 0022-3166 1541-6100 American Society for Nutrition. Published by Elsevier Inc. S0022-3166(22)00733-7 10.1093/jn/nxac025 Article Self-Reported Impacts of the COVID-19 Pandemic on Diet-Related Behaviors and Food Security in 5 Countries: Results from the International Food Policy Study 2020 Acton Rachel B 1 Vanderlee Lana 2 Cameron Adrian J 3 Goodman Samantha 1 Jáuregui Alejandra 4 Sacks Gary 3 White Christine M 1 White Martin 5 Hammond David 1* 1 School of Public Health Sciences, University of Waterloo, Waterloo, Canada 2 École de Nutrition, Centre Nutrition, santé et société (Centre NUTRISS), and Institut sur la nutrition et les aliments fonctionnels (INAF), Université Laval, Québec, Canada 3 Global Obesity Centre, Institute for Health Transformation, Deakin University, Geelong, Australia 4 Centre for Health and Nutrition Research, National Institute of Public Health, Cuernavaca, Mexico 5 Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom * Address correspondence to DH (e-mail:dhammond@uwaterloo.ca). 19 1 2023 6 2022 19 1 2023 152 35S46S 31 10 2021 8 12 2021 28 1 2022 Copyright © 2022 American Society for Nutrition. Published by Elsevier Inc. All rights reserved. 2022 American Society for Nutrition. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Background The coronavirus disease 2019 (COVID-19) pandemic has impacted many aspects of daily life, including dietary intake; however, few studies have reported its impacts on dietary behaviors and food security across multiple countries. Objectives We examined self-reported impacts of COVID-19 on food behaviors, food security, and overall diet healthfulness in 5 countries. Methods Adults aged 18–100 years (n = 20,554) in Australia, Canada, Mexico, the United Kingdom, and the United States completed an online survey in November and December 2020 as part of the International Food Policy Study, an annual, repeat cross-sectional survey. Survey measures assessed perceived impacts of the COVID-19 pandemic on eating food prepared away from home, having food delivered from a restaurant, and buying groceries online, as well as perceived food security and overall diet healthfulness. Regression models examined associations between each outcome and sociodemographic correlates. Results Across all countries, 62% of respondents reported eating less food prepared away from home due to the pandemic, while 11% reported eating more. Some participants reported having less food delivered from a restaurant (35%) and buying fewer groceries online (17%), while other respondents reported more of each (19% and 25%, respectively). An average of 39% reported impacts on their food security, and 27% reported healthful changes to their overall diet. The largest changes for all outcomes were observed in Mexico. Participants who were younger, ethnic minorities, or had lower income adequacy tended to be more likely to report food-related changes in either direction; however, these relationships were often less pronounced among respondents in Mexico. Conclusions Respondents reported important changes in how they sourced their food during the pandemic, with trends suggesting shifts towards less food prepared away from home and more healthful diets overall. However, changes in diet and food behaviors occurred in both healthful and less healthful directions, suggesting that dietary responses to the pandemic were highly variable. Keywords: COVID-19 coronavirus nutrition food behaviors diet food security pandemic ==== Body pmcIntroduction On 11 March 2020, the WHO declared coronavirus disease 2019 (COVID-19) to be a global pandemic (1). In response, many countries introduced a variety of measures to curb transmission rates and minimize the burden on health-care systems, which fundamentally changed social, work, and daily routines (2). The nature and severity of COVID-19 public health measures (and the impact of the disease itself) varied across and within countries (2,3). Some of the most common measures implemented included travel bans and border closures, restrictions on social gatherings, temporary closure of schools and nonessential businesses, workplace policies encouraging employees to work from home, and mandatory face coverings in shared public spaces (2,4). Some countries and regions enforced more restrictive measures for select periods of time, such as curfews or stay-at-home orders, while others introduced fewer measures. COVID-19 lockdowns and restrictions are likely to have impacted a variety of food behaviors, such as eating out compared with preparing meals at home, having food delivered from restaurants, and purchasing groceries from nontraditional sources (e.g., online or from convenience/corner stores) (5). Similarly, COVID-19 infection rates may have impacted food behaviors if individuals opted to avoid public contact out of fear of contracting the virus, regardless of the public health measures in place. Observational evidence to date suggests that self-reported food behaviors shifted in many countries during the COVID-19 pandemic, with most studies reporting increases in more healthful behaviors, such as more frequent cooking, fewer ready-made meals, and fewer fast food or takeout foods (6., 7., 8., 9., 10., 11., 12., 13., 14., 15.). There is also early evidence that modes and sources of grocery purchasing were impacted by the pandemic. Commercial retail data from many countries have shown that the pandemic accelerated the already growing use of online grocery ordering (16., 17., 18.); the small number of peer-reviewed, observational studies assessing online grocery ordering during the pandemic suggest similar trends (13,19,20). In addition, stay-at-home orders and hesitancy to visit large or crowded grocery outlets may have increased use of convenience or corner stores as food sources. Given these potential changes in food behaviors, dietary intake may have shifted for many individuals throughout the COVID-19 pandemic (5). Observational studies conducted thus far suggest that the impacts of COVID-19 were variable, but showed some tendency towards healthful changes (21). For example, 2 cross-sectional studies in the United States found that over half of adults reported dietary changes, with a larger proportion indicating a shift towards a more healthful diet overall, but a substantial proportion indicating less healthful changes (6,7). Similar conclusions were drawn from a web-based cohort of adults in Quebec, Canada, which identified a small increase in diet quality (measured by the Healthy Eating Index 2015) in April and May 2020 relative to before the pandemic (22). Food security is a key driver of food behaviors and dietary intake, and there is already preliminary evidence suggesting that the COVID-19 pandemic substantially impacted the food security of some populations (23., 24., 25.). Some evidence suggests that the food security of individuals with lower incomes, those experiencing anxiety or depression, or those who are otherwise socially vulnerable has been disproportionately impacted during the pandemic (23, 25). However, the impact on food security may also have been alleviated in some contexts by pandemic-related financial assistance measures intended to mitigate the economic impact of the pandemic (26). Food security has implications for all food behaviors and overall diet healthfulness, and is important to assess in the context of the financial and social challenges raised by the COVID-19 pandemic. Although evidence of COVID-19’s impacts on diet-related outcomes is growing, few studies have reported and compared its impacts on food behaviors, food security, or overall diet healthfulness across multiple countries, particularly with sample sizes that allow for international comparisons. Among the small number of studies that provide comparisons across countries, there is evidence that changes in dietary behaviors differed by country, often reflecting the status of the COVID-19 pandemic and/or public health measures at the national level (10,11). For example, online, cross-sectional surveys of adults in Ireland, Great Britain, and the United States found that the European samples reported increases in more healthful food habits during the pandemic, including preparing dinners using fresh ingredients and time spent cooking. These changes, however, were not observed in the United States, where fewer comprehensive COVID-19 restrictions were implemented nationwide (10, 11). Multi-country comparisons are important for assessing how COVID-19 policies and other contextual variables across countries may have differentially impacted food behaviors and dietary intake. The International Food Policy Study (IFPS) conducts annual, repeat cross-sectional surveys on dietary patterns and policy-relevant behaviors among adults in Australia, Canada, Mexico, the United Kingdom, and the United States. The IFPS provides a unique opportunity to assess self-reported impacts of COVID-19 on dietary behaviors approximately 8 months into the pandemic. Our study aimed to evaluate self-reported impacts of the COVID-19 pandemic on food behaviors, food security, and overall diet healthfulness among adults in 5 countries with varying levels of COVID-19 infection rates and pandemic-related restrictions (see Supplemental Table 1). This study also explored associations between self-reported impacts and correlates of interest, including sociodemographic characteristics and COVID-19 illness status. Methods Study design and participants Data were from the 2020 wave of the IFPS. Data were collected via self-completed, web-based surveys conducted in November and December 2020 with adults aged 18 to 100 years in Australia, Canada, Mexico, the United Kingdom, and the United States. Respondents were recruited through the Nielsen Consumer Insights Global Panel and their partners’ panels. Email invitations with unique survey access links were sent to a random sample of panelists within each country after targeting for demographics; panelists known to be ineligible were not invited. Potential respondents were screened for eligibility and quota requirements based on age and sex. Surveys were conducted in English in Australia and the United Kingdom; Spanish in Mexico; English or French in Canada; and English or Spanish in the United States. Members of the research team who were native in each language reviewed the French and Spanish translations independently. The median survey time was 44 minutes. Respondents provided consent prior to survey completion. Respondents received remuneration in accordance with their panel's usual incentive structure (e.g., points-based or monetary rewards, chances to win prizes). The study was reviewed by and received ethics clearance through a University of Waterloo Research Ethics Board (ORE# 30,829). A full description of the study methods can be found in the International Food Policy Study: Technical Report – 2020 Survey (Wave 4) (27). Survey measures Self-report survey measures examined perceived impacts of COVID-19 on food purchasing and consumption behaviors, food security, and changes in overall diet healthfulness. Measures using 5-point Likert scales were used to assess participants’ perceived impacts of the COVID-19 pandemic on their frequency of eating food prepared away from home, having food delivered from a restaurant, buying groceries online, and buying groceries from convenience/corner stores. Response options included “I [eat/have/buy] a lot less …,” “I [eat/have/buy] a little less …,” “no difference,” “I [eat/have/buy] a little more …,” and “I [eat/have/buy] a lot more …,” with additional wording corresponding to each food behavior. Perceived COVID-19-related impacts on food security were assessed using the question “has the COVID-19 pandemic affected whether your household has had enough food to eat?,” with response options not at all, a little, and a lot. The reported healthfulness of participants’ overall diets compared to before the COVID-19 pandemic was assessed using a 5-point Likert-scale measure (“a lot less healthy” to “a lot more healthy”). It was hypothesized that being infected with and experiencing symptoms of COVID-19 may have an impact on individuals’ food behaviors and overall diet; therefore, COVID-19 illness status was assessed by asking “have you had COVID-19?,” with response options “no,” “yes–confirmed by test,” “I believe I had COVID-19, but was not tested,” and “don't know.” Participant age, sex, ethnicity, education level, BMI, and perceived income adequacy were collected using measures drawn from population-level surveys within each country (28., 29., 30., 31., 32., 33.). BMI levels were calculated and categorized into underweight, normal weight, overweight, and obesity using the WHO thresholds (34). Ethnicity measures were recoded as minority or majority and education measures as low, medium, or high, to allow for comparisons across countries. “Don't know” and “refuse to answer” were available as response options for all survey questions. The full survey measures are available on the IFPS project website (27). Data analysis A total of 30,131 adults completed the survey. Respondents were excluded for the following reasons: region was missing, ineligible, or had an inadequate sample size (i.e., Canadian territories); invalid response to a data quality question; survey completion time under 15 minutes; and/or invalid responses to at least 3 of 21 open-ended measures (n = 8378). For the analysis in this paper, a further 1199 participants were excluded for missing data (“refuse to answer” for all COVID-19-related variables and/or “refuse to answer” or “don't know” for all sociodemographic characteristic variables). Data were weighted with poststratification sample weights constructed using a raking algorithm, with population estimates from the census in each country based on age group, sex, region, ethnicity (except in Canada), and education (except in Mexico). Estimates reported are weighted unless otherwise specified. Analyses were conducted using SAS statistical software (SAS Institute Inc.). Descriptive statistics examined the weighted percentages of participants, stratified by country, who reported changes in the frequency of eating food prepared away from home, having food delivered from a restaurant, buying groceries online, buying groceries from a convenience/corner store, perceived food security, and overall healthfulness of their diet compared to before the COVID-19 pandemic. Multinomial logistic regression models were used to evaluate between-country differences and potential associations between the dependent variables and covariates of interest. All regression models incorporated poststratification sample weights and included the following covariates: country, age, sex, ethnicity, education level, BMI, income adequacy, COVID-19 illness status, and perceived COVID-19 impacts on food security (except for the models assessing food security as the dependent variable). To assess potential country differences in the relationship between the dependent variables and covariates of interest, additional models with country × covariate interactions were run. A significance level of P < 0.01 was used to account for multiple comparisons. Results A total of 20,554 respondents were included in the final analytic sample (Australia, n = 4115; Canada, n = 4067; Mexico, n = 3961; United Kingdom, n = 4058; United States, n = 4354). Table 1 presents the characteristics of the weighted sample, by country. Distributions of age, sex, ethnicity (except in Canada), and education groups (except in Mexico) correspond to the poststratification sample weights applied to each country. Across the entire sample, 29% were classified as having overweight and 21% as having obesity. The majority of respondents reported high perceived income adequacy. Overall, 3.4% reported that they had contracted COVID-19 (confirmed by a test); an additional 5.4% believed they had COVID-19, but were not tested.Table 1. Weighted characteristics of respondents in the International Food Policy Study 20201 Table 1Characteristic Total sample N = 20,554 Australia n = 4115 Canada n = 4067 Mexico n = 3961 United Kingdom n = 4058 United States n = 4354 % (n) % (n) % (n) % (n) % (n) % (n) Age 18–29 years 20.9 (4287) 20.5 (842) 18.5 (753) 27.4 (1085) 18.3 (742) 19.9 (865) 30–44 years 26.2 (5387) 26.8 (1102) 24.9 (1013) 30.7 (1217) 24.2 (981) 24.7 (1075) 45–59 years 26.1 (5361) 24.2 (996) 24.9 (1013) 30.5 (1210) 25.9 (1049) 25.1 (1093) ≥60 years 26.9 (5520) 28.6 (1175) 31.7 (1289) 11.3 (449) 31.7 (1286) 30.3 (1321) Sex Male 48.9 (10,056) 49.1 (2021) 49.6 (2015) 48.5 (1919) 48.8 (1980) 48.7 (2120) Female 51.1 (10,498) 50.9 (2093) 50.4 (2052) 51.5 (2041) 51.2 (2078) 51.3 (2234) Ethnicity2 Majority group 77.2 (15,863) 74.0 (3045) 78.7 (3199) 81.1 (3212) 89.2 (3620) 64.0 (2787) Minority group 22.8 (4691) 26.0 (1069) 21.3 (868) 18.9 (749) 10.8 (438) 36.0 (1567) Education level3 Low 42.7 (8786) 41.8 (1721) 41.7 (1696) 22.5 (890) 52.0 (2111) 54.4 (2369) Medium 21.8 (4487) 32.3 (1331) 33.7 (1370) 13.5 (534) 19.7 (799) 10.4 (453) High 35.4 (7281) 25.8 (1063) 24.6 (1001) 64.0 (2537) 28.3 (1148) 35.2 (1532) BMI Underweight (<18.5 kg/m2) 2.6 (540) 3.5 (145) 3.1 (125) 1.5 (58) 2.9 (117) 2.2 (95) Normal weight (18.5–24.9 kg/m2) 35.2 (7226) 33.3 (1371) 35.3 (1436) 37.7 (1492) 35.8 (1451) 33.9 (1477) Overweight (25.0–29.9 kg/m2) 28.7 (5903) 27.7 (1140) 27.2 (1106) 32.4 (1283) 27.1 (1099) 29.3 (1275) Obesity (≥30 kg/m2) 21.0 (4325) 22.8 (938) 22.8 (926) 15.6 (618) 18.1 (733) 25.5 (1110) Missing 12.4 (2559) 12.7 (521) 11.6 (473) 12.9 (510) 16.2 (658) 9.1 (397) Income adequacy4 Low 29.3 (6031) 20.7 (850) 24.7 (1005) 50.6 (2003) 20.3 (823) 31.0 (1351) High 70.7 (14,523) 79.3 (3264) 75.3 (3062) 49.4 (1958) 79.7 (3235) 69.0 (3003) COVID-19 illness status No/don't know 91.3 (18,758) 96.3 (3962) 95.4 (3879) 86.7 (3435) 89.3 (3623) 88.6 (3859) Yes–confirmed by test 3.4 (690) 1.8 (74) 1.3 (53) 5.2 (204) 3.6 (145) 4.9 (213) I believe I had COVID-19, but was not tested 5.4 (1106) 1.9 (79) 3.3 (136) 8.1 (321) 7.1 (290) 6.5 (281) 1 Abbreviations: COVID-19, coronavirus disease 2019. 2 Ethnicity categories as per census questions asked in each country: 1) in Australia, majority indicates the participant only speaks English at home and minority indicates the participant speaks a language besides English at home; 2) in Canada, the United Kingdom, and the United States, majority indicates the participant is White race and minority indicates the participant is of other ethnicity; and 3) in Mexico, majority indicates the participant is nonindigenous and minority indicates they are indigenous. 3 Participants were asked, “what is the highest level of formal education that you have completed?” Responses were categorized as low (completed secondary school or less), medium (some postsecondary qualifications), or high (university degree or higher) according to country-specific criteria. 4 Participants were asked, “thinking about your total monthly income, how difficult or easy is it for you to make ends meet?” Response options were very easy, easy, and neither easy nor difficult, which were all categorized as high income adequacy, and difficult and very difficult, which were categorized as low income adequacy. Self-reported impacts of COVID-19 on food behaviors and overall diet Figure 1 shows the proportions of respondents who indicated the COVID-19 pandemic impacted their food behaviors, food security, and overall diet. Out of the 6 measures, eating food prepared away from home was reported to have changed the most: across all countries, the greatest proportion of participants reported that they ate a little less or a lot less food prepared away from home, ranging from about half of respondents in Australia to over three-quarters in Mexico (Figure 1A). In contrast, only 9%–16% of respondents reported eating more food prepared away from home. For the remaining measures, the majority of respondents in most countries indicated no changes. When asked about having food delivered from a restaurant, 29%–42% of respondents reported less deliveries, and 15%–25% reported more (Figure 1B). Across all countries, 17%–31% of respondents reported that the pandemic led them to purchase more groceries online, while 13%–31% bought fewer groceries online (Figure 1C). In terms of purchasing groceries from convenience/corner stores, 20%–37% of respondents reported buying less and 7%–29% reported buying more (Figure 1D).Figure 1. Weighted, unadjusted percentages of participants’ reported impacts of the COVID-19 pandemic on (A) eating food prepared away from home, (B) having food delivered from a restaurant, (C) buying groceries online, (D) buying groceries from convenience/corner stores, (E) food security, and (F) overall diet healthfulness in November to December 2020, from the International Food Policy Study (N = 20,554). Abbreviations: COVID-19, coronavirus disease 2019. Figure 1 Approximately one-quarter of respondents in Australia, Canada, and the United Kingdom reported that the pandemic affected their food security a little or a lot, with higher proportions in the United States (approximately 40%) and Mexico (nearly 70%; Figure 1E). Most respondents reported no difference in their overall diet compared to before the pandemic. Among those who did report a difference, a greater proportion indicated that their diet was more healthy compared to less healthy (Figure 1F). Weighted proportions across all response options for each of the 6 measures are available in Supplemental Table 2. Between-country differences Results from regression models ( Table 2; Supplemental Table 3) and patterns in Figure 1 demonstrate several differences across countries. Australian respondents were significantly less likely than respondents in the other countries to report changes in eating food prepared away from home (in either direction) and buying groceries less often from convenience stores (compared with no difference). Respondents from Mexico tended to be more likely to report changes in food behaviors than respondents in the other countries, but were significantly more likely to report that the pandemic affected their food security (i.e., having enough food to eat) a little or a lot. Similarly, US respondents were more likely than respondents in Australia, Canada, and the United Kingdom to report COVID-19-related impacts on their food security. Mexican respondents were more likely than those in all other countries to report that their overall diet was more healthy compared to before COVID-19. Participants’ reported changes in having food delivered from a restaurant showed the fewest differences between countries across all 6 outcomes.Table 2. Results from multinomial logistic regression models assessing self-reported impacts of the COVID-19 pandemic on food behaviors, food security, and overall diet healthfulness among respondents of the International Food Policy Study (N = 20,554)1 Table 2 Has the COVID-19 pandemic affected how often you eat food prepared away from home? Has the COVID-19 pandemic affected how often you have food delivered from a restaurant? Has the COVID-19 pandemic affected how often you buy groceries online (for delivery or pick-up)? Has the COVID-19 pandemic affected how often you buy groceries from convenience/corner stores? Has the COVID-19 pandemic affected whether your household has had enough food to eat? Compared to before the COVID-19 pandemic, my overall diet is … I eat a lot less/a little less2 I eat a little more/a lot more2 I have a lot less/a little less2 I have a little more/a lot more2 I buy a lot less/a little less2 I buy a little more/a lot more2 I buy a lot less/a little less2 I buy a little more/a lot more2 A little3 A lot3 A lot less healthy/A little less healthy4 A little more healthy/A lot more healthy4 AOR(99% CI) AOR(99% CI) AOR(99% CI) AOR(99% CI) AOR(99% CI) AOR(99% CI) AOR(99% CI) AOR(99% CI) AOR(99% CI) AOR(99% CI) AOR(99% CI) AOR(99% CI) Country5 Australia 0.28 (0.24–0.34)6 0.64 (0.49–0.84)6 0.64 (0.54–0.76)6 0.62 (0.51–0.76)6 0.35 (0.29–0.43)6 0.44 (0.36–0.52)6 0.41 (0.34–0.49)6 0.28 (0.22–0.34)6 0.27 (0.23–0.32)6 0.25 (0.19–0.33)* 1.03 (0.84–1.26) 0.64 (0.54–0.76)6 Canada 0.51 (0.42–0.63)6 0.85 (0.63–1.13) 0.94 (0.79–1.12) 0.84 (0.68–1.04) 0.37 (0.30–0.46)6 0.51 (0.42–0.61)6 0.51 (0.42–0.61)6 0.21 (0.17–0.27)6 0.27 (0.22–0.32)6 0.24 (0.18–0.33)6 1.20 (0.98–1.47) 0.56 (0.47–0.67)6 Mexico [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] United Kingdom 0.52 (0.43–0.63)6 0.83 (0.63–1.09) 0.96 (0.81–1.14) 0.89 (0.73–1.09) 0.45 (0.36–0.55)6 1.03 (0.87–1.21) 0.78 (0.65–0.93)6 0.82 (0.68–1.00) 0.25 (0.21–0.29)6 0.23 (0.18–0.31)6 1.24 (1.02–1.52)6 0.62 (0.52–0.73)6 United States 0.49 (0.40–0.59)6 1.28 (0.98–1.67) 0.81 (0.69–0.97)6 1.10 (0.91–1.35) 0.43 (0.35–0.52)6 0.90 (0.76–1.06) 0.70 (0.59–0.83)6 0.46 (0.38–0.57)6 0.41 (0.35–0.49)6 0.59 (0.46–0.76)6 1.14 (0.94–1.39) 0.65 (0.55–0.77)6 Age 18–29 years [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] 30–44 years 0.86 (0.73–1.01) 0.60 (0.49–0.74)6 0.98 (0.85–1.13) 0.71 (0.60–0.83)6 0.96 (0.81–1.14) 1.12 (0.97–1.29) 1.05 (0.90–1.21) 0.84 (0.71–0.99)6 0.78 (0.67–0.90)6 0.99 (0.79–1.24) 0.81 (0.69–0.95)6 0.89 (0.77–1.03) 45–59 years 0.85 (0.72–1.00)6 0.33 (0.26–0.42)6 0.86 (0.74–0.99)6 0.37 (0.31–0.44)6 0.83 (0.69–0.99)6 0.71 (0.61–0.83)6 0.88 (0.75–1.02) 0.55 (0.46–0.66)6 0.45 (0.38–0.52)6 0.50 (0.39–0.64)6 0.62 (0.52–0.73)6 0.80 (0.69–0.93)6 ≥60 years 0.91 (0.78–1.08) 0.25 (0.19–0.32)6 0.71 (0.61–0.83)6 0.21 (0.17–0.26)6 0.82 (0.67–1.00) 0.66 (0.56–0.77)6 0.86 (0.73–1.01) 0.40 (0.32–0.50)6 0.22 (0.19–0.26)6 0.20 (0.14–0.28)6 0.46 (0.38–0.55)6 0.70 (0.59–0.82)6 Sex Female 1.32 (1.19–1.45)6 1.03 (0.88–1.20) 1.14 (1.03–1.25)6 0.98 (0.87–1.11) 0.97 (0.86–1.10) 1.25 (1.13–1.38)6 1.04 (0.94–1.15) 1.01 (0.89–1.15) 0.95 (0.85–1.06) 0.91 (0.76–1.08) 1.54 (1.37–1.73)6 1.20 (1.09–1.33)6 Male [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] Ethnicity7 Majority group [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] Minority group 1.38 (1.19–1.59)6 1.36 (1.13–1.65)6 1.39 (1.22–1.58)6 1.29 (1.10–1.50)6 1.65 (1.41–1.92)6 1.08 (0.94–1.23) 1.45 (1.27–1.65)6 1.59 (1.35–1.87)6 1.58 (1.38–1.80)6 1.68 (1.36–2.07)6 1.04 (0.89–1.21) 1.27 (1.12–1.45)6 Education level8 Low 0.56 (0.50–0.63)6 0.50 (0.42–0.60)6 0.79 (0.71–0.89)6 0.55 (0.48–0.64)6 0.94 (0.81–1.09) 0.55 (0.49–0.62)6 0.76 (0.67–0.86)6 0.67 (0.58–0.78)6 1.02 (0.90–1.16) 1.12 (0.91–1.38) 0.75 (0.65–0.86)6 0.55 (0.48–0.62)6 Medium 0.74 (0.66–0.85)6 0.69 (0.57–0.84)6 0.87 (0.77–0.99)6 0.70 (0.60–0.81)6 0.88 (0.74–1.04) 0.73 (0.64–0.83)6 0.87 (0.77–1.00)6 0.75 (0.64–0.89)6 1.03 (0.90–1.19) 1.28 (1.02–1.60)6 0.90 (0.78–1.05) 0.73 (0.64–0.83)6 High [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] BMI Underweight (<18.5 kg/m2) 0.85 (0.62–1.18) 0.70 (0.44–1.11) 0.90 (0.66–1.22) 1.00 (0.72–1.41) 1.31 (0.92–1.86) 1.06 (0.78–1.45) 1.08 (0.79–1.48) 1.36 (0.95–1.96) 1.05 (0.77–1.45) 1.59 (0.98–2.57)6 1.15 (0.82–1.61) 0.82 (0.59–1.13) Normal weight (18.5–24.9 kg/m2) [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] Overweight (25.0–29.9 kg/m2) 1.04 (0.92–1.18) 1.17 (0.97–1.42) 1.07 (0.95–1.21) 1.04 (0.90–1.21) 1.02 (0.87–1.19) 0.93 (0.82–1.06) 0.97 (0.85–1.10) 0.98 (0.83–1.14) 0.86 (0.75–0.98)6 0.79 (0.63–1.00) 1.50 (1.29–1.75)6 1.10 (0.97–1.25) Obesity (≥30 kg/m2) 1.04 (0.91–1.20) 1.286 (1.03–1.58) 1.08 (0.95–1.24) 1.08 (0.92–1.28) 1.03 (0.86–1.23) 0.95 (0.82–1.10) 1.07 (0.93–1.24) 1.03 (0.86–1.24) 0.88 (0.76–1.03) 0.78 (0.61–1.00)6 2.01 (1.71–2.37)6 1.15 (1.00–1.33) Missing 0.70 (0.59–0.82)6 0.80 (0.63–1.03) 0.93 (0.79–1.10) 0.79 (0.65–0.96)6 1.06 (0.87–1.29) 0.77 (0.65–0.92)6 0.90 (0.76–1.07) 0.85 (0.69–1.05) 1.25 (1.05–1.49)6 1.59 (1.22–2.06)6 1.06 (0.87–1.29) 0.74 (0.62–0.88)6 Income adequacy9 High [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] Low 1.16 (1.02–1.32)6 0.92 (0.76–1.12) 1.16 (1.03–1.31)6 0.96 (0.83–1.11) 1.10 (0.95–1.27) 0.81 (0.71–0.92)6 1.15 (1.01–1.30)6 0.97 (0.83–1.13) 4.63 (4.09–5.23)6 8.75 (7.31–10.49)6 2.08 (1.82–2.37)6 0.95 (0.83–1.08) COVID-19 illness status No [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] Yes–confirmed by test 1.58 (1.11–2.24)6 1.71 (1.12–2.62)6 1.71 (1.28–2.27)6 1.64 (1.19–2.25)6 2.65 (1.96–3.58)6 1.59 (1.20–2.11)6 2.05 (1.55–2.71)6 1.83 (1.34–2.49)6 1.91 (1.42–2.58)6 2.91 (1.93–4.38)6 1.83 (1.32–2.53)6 1.94 (1.47–2.56)6 I believe I had COVID-19, but was not tested 1.10 (0.86–1.42) 1.19 (0.85–1.65) 1.20 (0.97–1.49) 1.29 (1.00–1.67) 1.20 (0.92–1.56) 1.13 (0.91–1.41) 1.17 (0.94–1.46) 1.36 (1.05–1.76)6 2.07 (1.67–2.58)6 2.48 (1.79–3.43)6 1.20 (0.93–1.56) 1.23 (0.99–1.54) COVID-19 impacts on food security A little 1.80 (1.57–2.06)6 2.37 (1.96–2.87)6 1.96 (1.74–2.22)6 1.80 (1.56–2.08)6 2.69 (2.32–3.12)6 1.82 (1.61–2.07)6 2.38 (2.10–2.69)6 2.92 (2.50–3.41)6 — — 2.00 (1.73–2.30)6 1.44 (1.27–1.63)6 A lot 1.78 (1.40–2.27)6 2.91 (2.16–3.92)6 2.50 (2.03–3.07)6 2.34 (1.85–2.96)6 3.68 (2.92–4.63)6 2.70 (2.20–3.32)6 3.09 (2.51–3.81)6 4.69 (3.71–5.93)6 — — 3.48 (2.81–4.33)6 2.45 (1.98–3.04)6 Not at all/don't know [ref] [ref] [ref] [ref] [ref] [ref] [ref] [ref] — — [ref] [ref] 1 Abbreviations: AOR, adjusted odds ratio; COVID-19, coronavirus disease 2019. 2 Participants reporting that they [eat/have/buy] “a lot less/a little less” or “a little more/a lot more” compared with “no difference/don't know.” 3 Participants reporting that the COVID-19 pandemic affected whether their household had enough food to eat by “a little” or “a lot” compared with “not at all/don't know.” 4 Participants reporting that their overall diet is “a lot less healthy/a little less healthy” or “a little more healthy/a lot more healthy” compared to before the COVID-19 pandemic, compared with “no difference/don't know.” 5 Full cross-country comparisons are provided in Supplemental Table 3. 6 P < 0.01. 7 Ethnicity categories as per census questions asked in each country: 1) in Australia, majority indicates the participant only speaks English at home and minority indicates the participant speaks a language besides English at home; 2) in Canada, the United Kingdom, and the United States, majority indicates the participant is White race and minority indicates the participant is of other ethnicity; and 3) in Mexico, majority indicates the participant is nonindigenous and minority indicates they are indigenous. 8 Participants were asked, “what is the highest level of formal education that you have completed?” Responses were categorized as low (completed secondary school or less), medium (some postsecondary qualifications), or high (university degree or higher) according to country-specific criteria. 9 Participants were asked, “thinking about your total monthly income, how difficult or easy is it for you to make ends meet?” Response options were very easy, easy, and neither easy nor difficult, which were all categorized as high income adequacy, and difficult and very difficult, which were categorized as low income adequacy. Sociodemographic characteristics and self-reported impacts of COVID-19 Self-reported impacts of the pandemic also differed across sociodemographic characteristics. As Table 2 indicates, respondents who reported that they had a confirmed case of COVID-19 were more likely to report changes in all of the food behaviors and overall diet healthfulness, in either direction. Both respondents with confirmed and unconfirmed COVID-19 were more likely to report that COVID-19 had an impact on their food security. Across the demographic variables, older participants tended to be less likely to report changes in food behaviors, overall diet healthfulness, and food security compared to participants aged 18 to 29 years. Female respondents were more likely than males to report eating less food prepared away from home, having less food delivered from a restaurant, buying more groceries online, and changes to the overall healthfulness of their diet (in either direction). Respondents who reported that COVID-19 impacted their food security a little or a lot were more likely to report changes in all of the food behaviors and overall diet healthfulness, in either direction (i.e., more or less). Respondents with low income adequacy were more likely to report eating less food away from home, having less food delivered from a restaurant, buying fewer groceries from convenience stores, and having a less healthy diet compared to before the COVID-19 pandemic. They were also less likely to report buying more groceries online, and more likely to report that the pandemic had impacted their food security. Respondents of a minority ethnicity were more likely than those from a majority ethnicity to report changes in either direction for eating food prepared away from home, having food delivered from a restaurant, buying groceries from convenience/corner stores, and buying fewer groceries online. Ethnic minority respondents were also more likely to report that COVID-19 impacted their food security a little and a lot, and were more likely to report that their diet was more healthful than before the pandemic. Respondents with low and medium education levels tended to be less likely to report changes in food behaviors or overall diet healthfulness (in either direction). No association was observed between education level and perceived food security. Respondents with BMIs corresponding to obesity were more likely to report eating more food prepared away from home and that their diet was less healthy than before the pandemic and less likely to report buying more groceries online compared to respondents with BMIs corresponding to normal weight. Respondents with BMIs corresponding to overweight and obesity were less likely than those with normal weight to report that the pandemic impacted their food security a little or a lot, respectively. Between-country differences in sociodemographic effects Statistically significant interactions between country and the covariates of interest were observed for eating food prepared away from home (country × age, country × ethnicity), having food delivered from a restaurant (country × age, country × sex, country × ethnicity, country × food security), buying groceries online (country × ethnicity, country × education, country × income adequacy, country × COVID-19 illness status), buying groceries from convenience stores (country × age, country × sex, country × COVID-19 illness status, country × food security), food security (country × age, country × education, country × income adequacy, country × COVID-19 illness status), and overall diet healthfulness (country × age, country × food security). Some notable interaction results are highlighted in the following paragraphs. Illustrations of all significant interactions are provided in Supplemental Figure 1. Many of the significant interactions were a result of differences in the magnitude, rather than direction, of covariate-outcome relationships across countries. For example, a significant interaction between country × age for eating food prepared away from home indicated that the inverse relationship between age and eating more food prepared away from home during the pandemic was weaker in Mexico than it was in the other countries. Similarly, the relationship between income adequacy and reporting that COVID-19 impacted food security a little was present in all countries, but less pronounced among Mexican respondents. In comparison, some interactions revealed contrasting results across countries. For example, in the United States, female respondents were less likely than males to report having more food delivered from a restaurant during the COVID-19 pandemic, while minimal differences by sex were observed in the other countries. Mexican respondents who reported that the pandemic impacted their food security a lot were less likely than those who reported no impacts to have more food delivered during the pandemic, while the opposite was observed in the other countries. Further, in Mexico, respondents with high income adequacy were more likely to buy more groceries online than before the pandemic, but there were minimal differences by income adequacy in the other countries. Discussion Our findings indicate that approximately 8 months into the pandemic, many respondents reported changes in food consumption and purchasing behaviors, overall diet, and food security; however, the impact was highly variable, sometimes with inverse relationships across countries and demographic groups. The largest impacts observed were for reductions in eating food prepared away from home. These results reflect those reported in other early COVID-19 studies from Canada, the United States, and the United Kingdom, which have found that individuals reported more time spent cooking, making more meals from scratch, and eating fewer ready-made or takeout meals (8,10,11, 14,15). Similar trends were observed across all countries, but differences in magnitude were apparent: over three-quarters of Mexican respondents reported eating less food prepared away from home, compared to less than half of respondents in Australia. It is difficult to identify the source of these cross-country differences; however, cultural differences may have played a role. In Mexico, it was very common to go out for lunch at restaurants or fondas prior to the pandemic (as opposed to bringing a lunch from home, as is more common in the United States and Canada). Therefore, as more employees began to work from home, a major source of food prepared away from home disappeared. It also may be that in Australia, where COVID-19 lockdowns were more localized, impacts on food behaviors were less pronounced over the broader population compared to other countries. Although the Australian state of Victoria had just emerged from a strict lockdown period prior to our data collection, the remainder of Australia had been predominantly living as usual, with very few COVID-19 cases and minimal to no restrictions (35). Overall, the reported reductions in eating food prepared away from home may be a positive outcome of the increased time spent at home during the pandemic, as greater consumption of meals prepared outside the home has been associated with poorer diet quality and weight gain (36). Whether these reductions in eating out are offset by increases in other less healthful food behaviors remains to be seen, as does the extent to which these changes will persist in the long run. A smaller but still meaningful proportion of respondents reported changes in their frequency of having food delivered from a restaurant, buying groceries online, and buying groceries from a convenience store. More than one-third of respondents in Canada, Mexico, the United Kingdom, and the United States had less food delivered from a restaurant, and close to that many reported buying more groceries online in Mexico, the United Kingdom, and the United States. Over a quarter of all Mexican, UK, and US respondents bought fewer groceries from convenience stores. However, despite these general trends, a notable proportion of respondents also reported changes in the opposite direction, suggesting differential impacts of COVID-19 on individuals. Changes in food delivery and grocery behaviors were again largest in Mexico, which may be partly explained by the COVID-19 restrictions in place at the time of data collection: nationwide school closures were in place in Mexico (as opposed to more varied regional restrictions in other countries), which would have had far-reaching implications on employment and the day-to-day schedules of households with children (37). Another explanation may be the lower income levels of the Mexican population overall, and therefore the larger proportion of individuals vulnerable to the financial and social shifts of the pandemic. Alternatively, the disproportionate percentage of highly educated individuals in our Mexican sample may have played a role, given that higher income groups in Mexico are more likely than lower income groups to use online grocery ordering (38). There is limited comparable evidence thus far on restaurant food delivery and grocery sources during the pandemic in the regions analyzed in this study; however, 1 study of adults in European countries, including the United Kingdom, reported increases in online grocery shopping during the pandemic, similar to the results observed in this study (13). Similarly, results from a study assessing sales at a Dutch online supermarket found that online grocery sales increased substantially overall at the onset of COVID-19, and fluctuated throughout the pandemic in tandem with local hospital admission rates (20). Sales data reported by industry sources also suggest that the growth of both restaurant food delivery and online grocery ordering accelerated substantially during the pandemic (16., 17., 18.,39., 40., 41., 42.). If use of these online food sources continues to grow after the pandemic, it will be important to monitor whether and how restaurants and retailers incorporate novel marketing strategies into the online shopping experience, and whether the healthfulness of online grocery and meal purchases differ from those of traditional in-store purchases. In line with some estimates, over a quarter of respondents in all countries experienced at least some impacts on their household's food security as a result of the pandemic. The proportion of respondents affected by the pandemic was highest in Mexico, where the COVID-19 pandemic was associated with reductions in food security among households with children (43). The overall evidence thus far suggests that the pandemic had significant impacts on food security in many populations, particularly among those who are more socially vulnerable (23,25,43). However, there has been evidence of government safety nets mitigating the pandemic's impacts on rates of food insecurity (26), and our results reflect this to some extent: income supports were made available early in the pandemic in Australia, Canada, the United Kingdom, and the United States, but were not available in Mexico until October 2020 (see Supplemental Table 1), where the proportion of respondents reporting food security impacts was highest. In terms of overall diet healthfulness, about 40%–60% of respondents across all countries reported changes in their diet compared to before the COVID-19 pandemic. A slight trend towards healthful changes was apparent in all countries, but a notable proportion reported less healthful changes as well. The bidirectional nature of these results suggests that the impacts of COVID-19 on dietary intake have been highly variable, and these results to some extent mirror the evidence available thus far on COVID-19 dietary patterns. A study assessing self-reported dietary changes among adults in Los Angeles Country in July 2020 reported results similar to those observed in the current study: 28% reported eating more healthful food and 25% reported eating less healthful food since the beginning of the pandemic (7). A similar study of adults from the United States in October 2020 found that among the three-quarters of respondents who reported their household's eating habits had changed, 64% and 19% reported more healthful and less healthful eating habits, respectively (6). Values from the latter study suggest greater increases in overall diet healthfulness than those observed among US respondents in this study; however, this may be explained by the previous study's focus on changes in eating habits across the respondent's entire household (6). This study also provided a preliminary look at potential associations between COVID-19-related dietary changes and sociodemographic characteristics. Country-by-covariate interactions confirmed that the relationships between individual characteristics and COVID-19-related dietary outcomes were not always consistent across countries. There were strong relationships between income-related variables (income adequacy and COVID-19 impacts on food security) and changes in food behaviors and overall diet, with results suggesting that respondents of lower socioeconomic status were more likely to have their food behaviors and overall diet impacted by the pandemic. In particular, respondents with low income adequacy were far more likely than those with higher income adequacy to report that COVID-19 has impacted whether their household has had enough food to eat, and more likely to indicate that their diet is less healthful than before the pandemic. However, in Mexico, lower-income respondents were sometimes less likely to report increased frequency of food behaviors like purchasing groceries online, which may be due to limited access to online grocery ordering among lower income groups in Mexico, whose internet access is more likely to be limited to a mobile phone (38). Associations also suggested that older respondents were less likely to report changes in food behaviors, overall diet, and food security, and female participants were more likely to report some healthier shifts in food behaviors in response to the pandemic, such as less eating food prepared away from home and less food delivered from a restaurant. It is possible that the more stable income provided by pensions among older adults in most countries in this study may have partially mitigated the financial-related impacts of COVID-19 on their food behaviors relative to younger people. Interaction results, however, indicated that the age-outcome relationships were often less pronounced in Mexico. Respondents reporting a minority ethnicity were more likely than those of majority ethnicities to report healthful changes in their overall diet, while respondents with higher BMI values were more likely to report a less healthful diet since the COVID-19 pandemic compared to those classified as having a normal BMI. Previous studies have reported similar associations with sociodemographic characteristics: a study among Los Angeles County adults found that non-Hispanic Black and Hispanic/Latino respondents were more likely than non-Hispanic Whites to report healthful dietary changes following COVID-19, while respondents who were younger or had BMIs corresponding to obesity were more likely to report less healthful changes (7). In a survey among adults living in England, young adults and those from minority ethnic groups reported greater impacts of COVID-19 on their purchasing decisions of more healthful foods (9). In addition to sociodemographic variables, the current study also observed associations between study outcomes and COVID-19 illness status. Respondents who had contracted COVID-19 (confirmed by test) were more likely than those who had not to report changes in all examined food behaviors and overall diet (in both directions); again, this relationship was often less pronounced among Mexican respondents. Further research will be required to identify the characteristics of individuals who made healthful and less healthful changes in response to the COVID-19 pandemic. Strengths and limitations This study is among the first to examine COVID-19-related changes in food behaviors and food security across multiple countries. The large sample sizes and consistent methods across countries provide valuable insights into these outcomes across countries and sociodemographic groups. This study is, however, subject to limitations common to survey research. Respondents were recruited using nonprobability-based sampling; therefore, the findings do not provide nationally representative estimates. For example, although the data were weighted by age group, sex, region, ethnicity (except in Canada), and education level (except in Mexico), the Mexico sample had notably higher levels of education and lower levels of overweight and obesity compared to national benchmark estimates. In other countries, estimates of overweight and obesity in the study sample were similar or somewhat lower than national benchmarks. Further, the study relied on self-reported changes in behaviors, which are important and valuable indicators of change in the absence of pre- and postpandemic data; however, the responses assessed in the current study may be subject to social desirability bias or recall bias. Given that our study queried respondents’ food behaviors in the present tense, our results are also limited to the time of data collection (November–December 2020), meaning that behavioral changes that occurred earlier in the pandemic may not have been captured. Future research should assess changes in behaviors and health status using data from before, during, and after the pandemic, where possible. Lastly, the analyses in this paper did not consider subnational differences. There were likely strong regional differences in the way the pandemic was experienced, particularly in countries where COVID-19 restrictions were largely under state or provincial control, including Canada, the United States, and Australia. For example, exploratory analyses within Australia indicated much higher prevalences of changes in food behaviors and food security among respondents in the state of Victoria—where a strict 4-month lockdown period (July–October 2020) had just been lifted prior to our data collection (44)—compared to other Australian respondents (data not shown). Therefore, a full examination of the impact of COVID-19 on dietary patterns will require a closer examination of subnational trends at the regional level. Conclusions The data reported here provide empirical evidence from 5 countries on significant shifts in food behaviors, food security, and overall diet during the COVID-19 pandemic. Approximately 8 months into the pandemic, the largest change reported was a decrease in eating food prepared away from home, but shifts towards ordering less food from restaurants, buying more groceries online, and buying fewer groceries from corner stores were also observed. Many respondents reported impacts on their household's food security, as well as some shifts towards a more healthful diet overall. However, changes in both directions were observed for all outcomes, suggesting that the response to COVID-19 was highly variable. Reported changes for all outcomes tended to be largest in Mexico, where national COVID-19-related policies and other contextual factors may have played a role. Across all 5 countries, individuals with characteristics corresponding to a lower socioeconomic status, as well as those experiencing food security effects from the pandemic, were more likely to report shifts in their dietary patterns, suggesting that COVID-19 response plans should include a focus on these populations. In light of the results observed in this study, decision-makers should consider how existing or future food policies (e.g., national dietary guidance, food labeling, marketing restrictions) could be leveraged to encourage healthful dietary changes and discourage less healthful changes in the contexts of current or future pandemics. Perhaps more importantly, social safety nets that guarantee income among citizens will be critical to help to build resilience of populations to the economic shocks and subsequent impacts on food security resulting from pandemics. Longitudinal research is needed to evaluate whether the observed changes persist after the pandemic, and there is a need for research and policy to catch up with the rapid change in food purchasing practices, particularly in the digital market. Supplementary Material Acknowledgements The authors’ responsibilities were as follows—DH, LV, and CMW: were major contributors to the conception and design of the study; CMW: supervised data collection; RBA: analyzed the data and performed the statistical analyses; RBA, LV, and DH: were major contributors in drafting the manuscript; LV, AJC, SG, AJ, GS, CMW, MW, and DH: contributed to interpreting the data and substantively revising the manuscript; RBA: had primary responsibility for the final content; and all authors: read and approved the final manuscript. This supplement was supported by funding from a Project Grant from the Canadian Institutes of Health Research (PJT-162167). The views expressed herein are solely the responsibility of the authors and do not necessarily represent the official views of the Canadian Institutes for Health Research or other sources of funding. Funding for the International Food Policy Study was provided by a Canadian Institutes of Health Research (CIHR) Project Grant (PJT-162167), with additional support from Health Canada, the Public Health Agency of Canada (PHAC), and a CIHR-PHAC Applied Public Health Chair (DH). MW is supported with funding for a research programme in the MRC Epidemiology Unit, University of Cambridge, UK (MRC grant number: MC/UU/00006/7). Author disclosures: DH has served as a paid expert witness on behalf of public health authorities in the legal challenge to San Francisco’s health warning ordinance for sugar-sweetened beverages. All other authors report no conflicts of interest. Supplemental Tables 1–3 and Supplemental Figure 1 are available from the “Supplementary data” link in the online posting of the article and from the same link in the online table of contents at https://academic.oup.com/jn/. ==== Refs References 1. WHO Listings of WHO's response to COVID-19. 2020 WHO Geneva (Switzerland) [Internet]. Available from https://www.who.int/news/item/29-06-2020-covidtimeline 2. Ritchie H Ortiz-Ospina E Beltekian D Mathieu E Hasell J Macdonald B Giattino C Appel C Roser M OurWorldInData.org—policy responses to the coronavirus pandemic. 2020 Oxford University Press Oxford [Internet]. Available from https://ourworldindata.org/coronavirus 3. Center for Systems Science and Engineering (CSSE) at Johns Hopkins University COVID-19 data explorer—daily new confirmed COVID-19 cases per million people. 2021 Oxford University Press Oxford [Internet]. Available from https://ourworldindata.org/explorers/coronavirus-data-explorer?zoomToSelection=true&time=2020-11-19.2020-12-23&facet=none&pickerSort=asc&pickerMetric=location&Metric=Confirmed+cases&Interval=7-day+rolling+average&Relative+to+Population=true&Color+by+test+positivity=false&country=USA∼GBR∼CAN∼MEX∼AUS 4. Islam N Sharp SJ Chowell G Shabnam S Kawachi I Lacey B Massaro JM D'Agostino RB White M Physical distancing interventions and incidence of coronavirus disease 2019: natural experiment in 149 countries. BMJ. 370 2020 m2743 32669358 5. Parekh N Deierlein AL Health behaviours during the coronavirus disease 2019 pandemic: implications for obesity. Public Health Nutr. 23 2020 3121 3125 32746955 6. Cosgrove K Wharton C Predictors of COVID-19-related perceived improvements in dietary health: results from a US cross-sectional study. Nutrients. 13 2021 2097 34205306 7. Miller S Bruine de Bruin W Livings M Wilson J Weber K Frazzini A Babboni M de la Haye K Self-reported dietary changes among L.A. county adults during the COVID-19 pandemic. Appetite. 166 2021 105586 34217761 8. Carroll N Sadowski A Laila A Hruska V Nixon M Ma DWL Haines J The impact of COVID-19 on health behavior, stress, financial and food security among middle to high income Canadian families with young children. Nutrients. 12 2020 2352 on behalf of the Guelph Family Health Study 32784530 9. Ogundijo DA Tas AA Onarinde BA Exploring the impact of COVID-19 pandemic on eating and purchasing behaviours of people living in England. Nutrients. 13 2021 1499 33946799 10. Murphy B Benson T McCloat A Mooney E Elliott C Dean M Lavelle F Changes in consumers’ food practices during the COVID-19 lockdown, implications for diet quality and the food system: a cross-continental comparison. Nutrients. 13 2020 20 33374619 11. Benson T Murphy B McCloat A Mooney E Dean M Lavelle F From the pandemic to the pan: the impact of COVID19 on parental inclusion of children in cooking activities–A cross-continental survey. Public Health Nutr. 2021 1 17 12. Ammar A Brach M Trabelsi K Chtourou H Boukhris O Masmoudi L Bouaziz B Bentlage E How D Ahmed M Effects of COVID-19 home confinement on eating behaviour and physical activity: results of the ECLB-COVID19 international online survey. Nutrients. 12 2020 1583 32481594 13. Skotnicka M Karwowska K Kłobukowski F Wasilewska E Małgorzewicz S Dietary habits before and during the COVID-19 epidemic in selected European countries. Nutrients. 13 2021 1690 34065655 14. Bakaloudi D, Jeyakumar D, Jayawardena R, Chourdakis M. The impact of COVID-19 lockdown on snacking habits, fast-food and alcohol consumption: a systematic review of the evidence. Clin Nutr. [accessed 2022 Feb 14]. doi:10.1016/j.clnu.2021.04.020. 15. Flanagan EW Beyl RA Fearnbach SN Altazan AD Martin CK Redman LM The impact of COVID-19 stay-at-home orders on health behaviors in adults. Obesity. 29 2021 438 445 33043562 16. Blázquez A Coronavirus: grocery delivery & pickup sales U.S. 2021 Statista Hamburg (Germany) [Internet]. Available from https://www.statista.com/statistics/1120211/coronavirus-grocery-delivery-pickup-sales-us/ 17. Bedford E Past-week online grocery service usage Canada 2016–2020. 2020 Statista Hamburg (Germany) [Internet]. Available from https://www.statista.com/statistics/1175029/past-week-online-grocery-service-usage-canada/ 18. Hinton T Australia: monthly online food retail revenue 2020. 2021 Statista Hamburg (Germany) [Internet]. Available from https://www.statista.com/statistics/1186876/australia-monthly-online-food-retail-revenue/ 19. Grashuis J Skevas T Segovia MS Grocery shopping preferences during the COVID-19 pandemic. Sustainability. 12 2020 5369 20. Baarsma B, Groenewegen J. COVID-19 and the demand for online grocery shopping: empirical evidence from the Netherlands. Economist (Leiden). [Accessed 2022 Feb 14]. doi:10.1007/s10645-021-09389-y. 21. Dono J Ettridge K Wakefield M Pettigrew S Coveney J Roder D Durkin S Wittert G Martin J Miller C Intentions to reduce sugar-sweetened beverage consumption: the importance of perceived susceptibility to health risks. Public Health Nutr. 24 17 2021 5663 5672 33472724 22. Lamarche B Brassard D Lapointe A Laramée C Kearney M Côté M Bélanger-Gravel A Desroches S Lemieux S Plante C Changes in diet quality and food security among adults during the COVID-19–related early lockdown: results from NutriQuébec. Am J Clin Nutr. 113 2021 984 992 33398347 23. Picchioni F, Goulao L, Roberfroid D. The impact of COVID-19 on diet quality, food security and nutrition in low and middle income countries: a systematic review of the evidence. Clin Nutr. [accessed 2022 Feb 14]. doi:10.1016/j.clnu.2021.08.015. 24. Fitzpatrick KM Harris C Drawve G Willis DE Assessing food insecurity among US adults during the COVID-19 pandemic. J Hunger Environ Nutr. 16 2020 1 18 25. Wolfson JA Leung CW Food insecurity and COVID-19: disparities in early effects for US adults. Nutrients. 12 2020 1648 32498323 26. USDA Economic Research Service Household food security in the United States in 2020. 2021 U.S. Department of Agriculture Washington (DC) Economic Research Report No. (ERR-298). [Internet]. Available from https://www.ers.usda.gov/publications/pub-details/?pubid=102075 27. Hammond D White CM Rynard VL Vanderlee L International food policy study: technical report—2020 survey (Wave 4). 2021 International Food Policy Study Waterloo (Canada) [Internet]. Available from http://www.foodpolicystudy.com/methods 28. Australia Bureau of Statistics Census of population and housing. 2016 Australian Bureau of Statistics Canberra (Australia) [Internet]. Available from https://www.abs.gov.au/websitedbs/censushome.nsf/home/2016 29. Australia Bureau of Statistics Australian Health Survey: users’ guide, 2011–13. 2013 Australian Bureau of Statistics Canberra (Australia) [Internet]. Available from https://www.abs.gov.au/ausstats/abs@.nsf/Lookup/4363.0.55.001main+features12011-13 30. Public Health England National diet and nutrition survey. 2016 Public Health England London [Internet]. Available from https://www.gov.uk/government/collections/national-diet-and-nutrition-survey 31. Statistics Canada Canadian Community Health Survey—annual component (CCHS). 2020 Statistics Canada Ottawa (Canada) [Internet]. Available from https://www23.statcan.gc.ca/imdb/p2SV.pl?Function=getSurvey&SDDS=3226&lang=en&db=imdb&adm=8&dis=2 32. Centers for Disease Control and Prevention National Health and Nutrition Examination Survey. 2021 U.S. Department of Health & Human Services Washington (DC) [Internet]. Available from https://www.cdc.gov/nchs/nhanes/index.htm 33. Centers for Disease Control and Prevention Behavioral risk factor surveillance system. 2016 U.S. Department of Health & Human Services Washington (DC) [Internet]. Available from https://www.cdc.gov/brfss/index.html 34. WHO Body mass index—BMI. 2020 WHO Geneva (Switzerland) [Internet]. Available from http://www.euro.who.int/en/health-topics/disease-prevention/nutrition/a-healthy-lifestyle/body-mass-index-bmi 35. The New York Times Tracking coronavirus in Australia: latest map and case count. 2021 The New York Times New York (NY) [Internet]. Available from https://www.nytimes.com/interactive/2021/world/australia-covid-cases.html 36. Wellard-Cole L, Davies A, Allman-Farinelli M. Contribution of foods prepared away from home to intakes of energy and nutrients of public health concern in adults: a systematic review. Crit Rev Food Sci Nutr. [accessed 2022 Feb 14]. doi:10.1080/10408398.2021.1887075. 37. UNICEF COVID-19 and school closures: one year of education disruption. 2021 UNICEF [Internet]. Available from https://data.unicef.org/resources/one-year-of-covid-19-and-school-closures/ 38. Mendoza J Online grocery shopping in Mexico—statistics & facts. 2021 Statista Hamburg (Germany) [Internet]. Available from https://www.statista.com/topics/7819/online-grocery-shopping-in-mexico/ 39. Blumtritt C Number of users forecast for the online food delivery market in United States from 2017 to 2024. 2021 Statista Hamburg (Germany) [Internet]. Available from https://www.statista.com/forecasts/891084/online-food-delivery-users-by-segment-in-united-states 40. eMarketer Editors Food delivery orders in Canada increased substantially amid the pandemic. 2021 eMarketer New York [Internet]. Available from https://www.emarketer.com/content/food-delivery-orders-canada-increased-substantially-amid-pandemic 41. Roy Morgan Research Meal delivery services Uber Eats, Menulog, Deliveroo and DoorDash experienced rapid growth during 2020—a year of lockdowns & work from home. 2021 Roy Morgan Melbourne (Australia) [Internet]. Available from http://www.roymorgan.com/findings/8713-food-delivery-services-may-2021-202105280627 42. Statista Research Department Online food delivery revenue in Mexico 2017–2024. 2021 Statista Hamburg (Germany) [Internet]. Available from https://www.statista.com/forecasts/1220827/revenue-online-food-delivery-mexico 43. Gaitán-Rossi P Vilar-Compte M Teruel G Pérez-Escamilla R Food insecurity measurement and prevalence estimates during the COVID-19 pandemic in a repeated cross-sectional survey in Mexico. Public Health Nutr. 24 2021 1 32662385 44. Parliament of Victoria Public Accounts and Estimates Committee Inquiry into the Victorian government's response to the COVID-19 pandemic. 2021 Parliament of Victoria Melbourne (Australia) [Internet]. Available from https://www.parliament.vic.gov.au/file_uploads/PAEC_59-08_Vic_Gov_response_to_COVID-19_pandemic_YKNbjt2Y.pdf
PMC009xxxxxx/PMC9014349.txt
==== Front sppfe PFE Policy Futures in Education 1478-2103 SAGE Publications Sage UK: London, England 10.1177_14782103221088154 10.1177/14782103221088154 Special Issue: Higher Education Policy and Management in the Post-Pandemic Policy concern about university students’ online professionalism in the post-pandemic era in UK context https://orcid.org/0000-0003-1533-1067 O’Dea X The Business School, 41872 York St John University , York, YO, UK Zhou X 4617 School of Business and Management, Queen Mary University , London, UK X O’Dea, York Business School, York St John University, Lord Mayor’s Walk, York, YO YO31 7EX, UK. Email: c.odea@yorksj.ac.uk 5 2022 17 4 2022 17 4 2022 21 4 372386 © The Author(s) 2022 2022 SAGE Publications This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections. The extensive and intensive online teaching and learning during the pandemic has provided good opportunities for academic staff and students to experiment with learning and teaching using synchronous communication technology and learning platforms. This experience is highly valuable for helping higher education institutions move learning and teaching practices forward after the pandemic. Indeed, many universities are considering adopting blended learning in the new era. However, it is worth noting that a number of emerging issues related to student behaviour also appeared during online learning, such as teaching to blank screens, students’ inappropriate use of social media icons, languages and their inappropriate outfits. It appears that these issues have not yet been investigated properly, and are not addressed by the existing codes of conduct, since these have been written mainly for face-to-face teaching. This study offers some important insights into students’ unprofessional online behaviour from tutors’ perspective, and also the experiences of academic tutors in managing such behaviour in formal online learning and teaching environments. It used semi-structured interviews to collect data, and analysed the narratives of 20 academic staff working in UK universities. The findings report and describe students’ unprofessional online behaviours witnessed by academic tutors in different academic disciplines. The findings also suggest that special attention needs to be paid to policymaking regarding online learning, in particular, in the area of students’ online professionalism. Higher education online learning online professionalism UK universities unprofessional online behaviour COVID-19 typesetterts10 ==== Body pmcIntroduction The COVID-19 pandemic has enabled universities worldwide, including those in the UK, to experiment with online learning on a large scale, and for a prolonged period of time. Many UK universities have already considered adopting blended learning in the post-pandemic era because of the benefits of online learning to students, such as flexibility, accessibility and self-paced learning (Bayne and Gallagher, 2021; O’Dea and Stern, 2022; Verawardina et al., 2020). In the meanwhile, academic staff have started noticing some student behaviours that they perceived as unprofessional, such as inappropriate use of emojis, disrespectful languages and inappropriate outfits (Dendir and Maxwell, 2020; Getachew et al., 2020; Sharif, 2020). These behaviours seem to not only have an impact on these students’ own involvement and engagement, but also disturb the learning environment and affect other students’ learning (Noviyanti et al., 2021; O’Dea and Zhou, 2021). Even though there has been a large body of research on students’ professionalism, the focus has been on face-to-face environments or the use of social media (Wright and Gunderman, 2021), students’ online professionalism and unprofessional online behaviours have not yet been clearly defined. Existing literature has also paid less attention to policy development and formation relating to students’ online professionalism at the institutional level. It is necessary and important for university students to develop an understanding of online professionalism, and learn how to behave professionally in a formal online learning environment. This is partially because they may participate in synchronous online learning continuously in the post-pandemic era (Bothwell, 2020), and also because online professionalism is increasingly viewed as a new key graduate employability attribute since remote working, for many businesses, has become a ‘new normal’ (Castrillon, 2021). In addition, it is critical to explore and understand how academic staff have dealt with students unprofessional online behaviours during the pandemic, so that new policies and guidance can be developed based on the experiences gained and the lessons learnt. This study aims to fill the gaps mentioned above and to address the following two questions:1. What are the perceived views of academic tutors on unprofessional online behaviours of university students during the pandemic? 2. What are the experiences of academic staff managing student unprofessional online behaviours during the pandemic? Online professionalism In the context of higher education, it appears that a significant body of research on online professionalism focuses upon health professional students’ use of social media sites in private settings, and its impact on patients’ trust, safety and the reputation of medical professions (Gormley et al., 2021; Rocha and De Castro, 2014; Cain and Romanelli, 2009). Online professionalism thus is defined as ‘the attitudes and behaviours reflecting traditional professionalism paradigms that are manifested through digital media’ (Cain and Romanelli, 2009: 67). To date, the common unprofessional online behaviours identified in published studies have revolved predominately around blurring their professional and private life by posting and discussing private patient information publically on their personal social media sites through means of comments, videos, images and blog posts (Gormley et al., 2021; O’Connor et al., 2021). Therefore, existing codes of conduct in higher education tend to address unprofessional online behaviours in relation to the use of social media, rather than in formal online learning environments (Wright and Gunderman, 2021). In addition, much less is known about students (e.g., undergraduates and postgraduates) in other academic disciplines in the context of online teaching and learning. This has not been a major issue until the emergency switch to online learning during the pandemic, when academic tutors and students have had to rely on learning technologies, tools and platforms solely and intensively for learning and teaching activities. For the reasons given above, this study defines online professionalism as the way that students studying at different levels, and of different subject areas engage themselves in a formal online learning environment relating to their profession as students, including their attitudes and behaviours to a relevant university code of conduct. Based on this definition, unprofessional online behaviours of students, as with in face-to-face environments, include repeated and one-off behaviours that disrupt and break down learning and teaching processes in online environments. A summary of commonly seen unprofessional behaviours in face-to-face teaching is provided in the section below. Unprofessional behaviours: 4I’s framework The 4I’s framework is the theoretical foundation for the study and was proposed by Mak-van der Vossen and her colleagues (2017). The framework was developed upon a systematic literature review of medical students’ unprofessional behaviours. These behaviours were either reported by academic staff, or admitted by students themselves. The 4I’s framework is felt appropriate for the study because it categorizes and describes unprofessional behaviours that appear to be common across all disciplines and of different types of students in an in-person learning environment. As shown in the figure (Figure 1) below, the framework consists of 4 categories and 30 descriptors of unprofessional behaviours. The four categories are involvement, integrity, interaction and introspection.Figure 1. The 4I’s framework (Mak-van Der Vossen et al., 2017). Involvement is related to the level of students’ engagement in learning activities inside and outside the classroom. Unprofessional behaviours in this category are described as failure to engage. In other words, students lack the ability and motivation to handle their learning tasks sufficiently. Some examples of common unprofessional behaviours identified include a lack of participation in class activities, missing deadlines and using the minimum effort. Integrity is concerned with students’ academic honesty. Unprofessional behaviours in this category are referred to as dishonest behaviours. They are linked closely with plagiarism and rule breaking, and include behaviours such as cheating in exams, lying to tutors and acting without required consent. Interaction broadly describes how individuals connect and communicate with others verbally and non-verbally. Unprofessional behaviours in this category predominately refer to any disrespectful behaviours that have a negative effect on others. Examples include inappropriate clothing, bullying and inappropriate use of social media. Introspection is the final category and is associated with students’ self-awareness. Unprofessional behaviours in this category are associated with their inappropriate handling of feedback, advice and constructive criticism towards their academic performance, and include avoiding feedback, blaming external factors and not accepting feedback. Although the 4I’s framework was developed for medical sciences, many of these unprofessional behaviours identified, such as plagiarism, disruptive behaviours in teaching, and absent or late for assigned activities, were witnessed and reported in other subject disciplines, including social sciences, arts and business studies (Ali and Gracey, 2013; Bašić et al., 2019). Managing unprofessional online behaviours Existing research (Barnhoorn et al., 2019; Mak-van der Vossen et al., 2020; McGurgan et al., 2020; Tricco et al., 2018) has provided various recommendations for managing students’ unprofessional behaviours with different emphases. Some seem to emphasize developing students’ awareness of professionalism through integrated training programmes (Tricco et al., 2018). Some put priority on understanding the factors and contexts that influence students’ professionalism (McGurgan et al., 2020; Yuan and Che, 2012). A number of studies have proposed a framework or roadmap to address students’ unprofessional behaviours (Barnhoorn et al., 2019; Mak-van der Vossen et al., 2020). The multi-level professionalism framework (Barnhoorn et al., 2019), in particular was developed to help students understand the impact of unprofessional behaviours through self-reflection. Nevertheless, the above-mentioned strategies appear to be designed mainly for face-to-face learning environments, and at teachers’ individual level. Research to date has not yet paid much attention to online learning environments, and also institutional level plans and policies. Even though several studies exploring online professionalism have suggested embedding training into academic curriculum, and updating departmental or institutional level code of contact to reinforce the development of students’ online professionalism, the main attention, as discussed already, has been paid to the use of social media in medical education (Rocha and De Castro, 2014; Cain and Romanelli, 2009). Methodology Participants Participants of this study were selected using a convenience sampling method. This was because both authors were academic tutors working in a university in the UK, and the recruitment emails were sent to academic colleagues in UK universities, with whom the authors have contact (e.g., current and former work colleagues, or research collaborators). Twenty academic staff from six UK universities responded to the invitation. The subject disciplines they work within include Business Studies, Engineering, Computer Science, Sports Science and Education. Further details about the participants are provided in the table blow (Table 1). All participants gave their consent to be interviewed for this study, and they were notified clearly about their rights. Ethical approval for this study was granted at both universities where the authors were working.Table 1. Participant profile. Gender Age Tenure Male Female 20–29 30–39 40–49 >50 0–5 6–10 11–15 >16 No 11 9 2 8 5 5 9 7 2 2 Percentage 55% 45% 10% 40% 25% 25% 45% 35% 10% 10% Instrument and data analysis Semi-structured interviews were used to collect data because this type of interview is considered particularly useful in not only ‘exploring the views of a person towards something’, but also in providing the opportunity for the researcher to gain a profound understanding of these views (Van Teijlingen, 2014:20) All interviews were conducted by one author, and took place online using Microsoft Teams or Zoom. Each lasted approximately 60 min. Within each informed consent form, agreement was requested to record the interviews. At the start of the interviews, permission was asked again and granted to allow the author to record the interview. Participants were also provided with a brief explanation of the research, and their rights and responsibilities as research participants. The principal interview questions were derived from the literature and were also based on the 4I’s framework (Appendix 1). Data transcription and analysis were then carried out by the other author. The raw data were comprised of the audio recordings of the interviews. There were in total 20-hour audio recordings. The first cycle coding started immediately after the data transcription was completed, and its purpose was to reduce the size of the data without losing quality. During this process, the author annotated all transcripts. This included highlighting the key and important areas or factors that had emerged and assigning some initial codes. Once the first cycle was completed, the second cycle coding started. During this process, data were condensed further with the use of NVivo. The software enabled the author to create nodes (categories) and sub nodes (sub-categories) based on the annotations made at the first cycle coding. By doing so, the author was getting much more familiar with the data, which subsequently helped group and cluster the nodes into themes. They were then used to answer the research questions of the study. Findings Themes of unprofessional online behaviours Almost all participants said that they witnessed a degree of students’ unprofessional online behaviours during the pandemic, which seemed to disrupt the learning and teaching process. These behaviours are grouped into four themes: involvement, integrity, interaction and introspection. A detailed list of the behaviours is provided below (Table 2).Table 2. A list of students’ unprofessional online behaviours. Category Descriptors  Involvement Absence or lateness for assigned activities Poor team work Integrity  Cheating in exams Lying Plagiarism Interaction Inappropriate clothing Disruptive behaviour Poor verbal and non-vocal communication Inappropriate use of social media Privacy and confidentiality violations Introspection  Not sensitive to other person’s need Not aware of limitations Involvement In this category, the main unprofessional online behaviours reported are absence or lateness for assigned activities, and poor team work. For instance, 85% of participants commented that they experienced what Stephensen (2019) describes as ‘ghosts’ or ‘no-show’ students. Even though they appeared to have joined their timetabled sessions on time, these students did not actually take part in learning activities. They kept silence by keeping their camera and microphone off simultaneously, and also by avoiding inputting any contributions using the chat function.When the COVID-19 pandemic first started... there were a lot of: “turn on your mic, turn on your camera”. But students didn't want to. As lecturer I got really frustrated at some point because I felt like they (the students) were not getting what they paid for. In face-to-face teaching, I could walk around [the classroom] and check on students when they are working on their group activities. But in online teaching, I am unable to do so, because some students just keep silence, and don’t participate. ‘Teaching to blank screens’ was a common issue identified by all participants, and they said that they became increasingly ‘frustrated’ with the situation. Since they were unable to see students’ facial expressions, body movements and eye contact, the participants commented that compared with face-to-face teaching, it became much harder for them to interact with their students, and monitor student engagement and learning progress in online environments. This consequently broke down the teaching process, and had an impact on some tutors’ motivation.For me, one of the main tasks of an educator is to build and maintain relationships with students, so that their learning journey is less about them being an empty vessel and us giving them knowledge. However, it becomes particularly difficult [to build and maintain such relationship] when you can’t see and hear them. Whether students should turn their camera and/or microphone off during online learning has triggered a heated debate in academic communities worldwide (Castelli and Sarvary, 2021; Nicandro et al., 2020), and the literature does not yet have a clear answer. Whilst not participating class activates is clearly considered as unprofessional behaviours, as discussed below (e.g., in the discussions section), there may be good reasons for students to keep their camera and/or mic off (Nicandro et al., 2020). Academic tutors should investigate the reasons behind and encourage student to participate positively. Integrity It appears that cheating in exams, lying and plagiarism were the main unprofessional behaviours identified by participants in this category. A possible explanation for this, as the data indicate, was that universities had to reduce or remove face-to-face exams and replaced them with online fixed time assessments. For instance, those (55% of respondents) who used exams as an assessment method reported that they had to convert close book exams into open book exams for online teaching at the beginning of the pandemic. The majority of these participants (91%) commented that they found it much harder to detect students’ cheating behaviours since they were physically apart from students when the exam took place. Some also commented on the difficulty in investigating suspected plagiarism relating to student essays, as it appeared to be easier for their students to tell lies in an online environment.We had an open book exam in the first semester for a 2nd year module. Students were told explicitly that they were strictly forbidden to contact each other [during the exam]. However, some still did. The student was willing to answer questions [relating to his essay] but refused to turn his camera on. The excuse was the Internet connection was poor. It was important for us to identify the person we were speaking with was our student. We suggested him to try to use an Internet Café, which should give him a better Internet connection. But he never turned up again. In addition, 65% of participants said that they witnessed a rapid increase in contract cheating, that is, students who buy or employ others to write essays or site in exams for them (Harper et al., 2021).Academic conduct cases have increased dramatically during the pandemic. We found out that some students either copied their colleagues’ coursework or purchased coursework from essay mills. It has become increasingly hard to tell whether students did their coursework by themselves or not. Existing research and also the data collected in this study indicate that there has been a large increase in dishonest behaviours in this category since the emergency switch to online learning during the pandemic. However, none of the participants said that they used any proctoring systems for online exams. ‘My university did not provide such tool’ appeared to be the main reason for this (60% of participants). Some (20% of participants) also commented ‘I have never head of this type of software’. Interaction 85% of participants believed that they were not treated respectfully by their students during online teaching, because they encountered many, what they described as disrespectful behaviours. These behaviours seem to fall into the following areas: poor verbal and non-vocal communication, inappropriate clothing, inappropriate use of social media, disruptive behaviour, and privacy and confidentiality violations. As discussed above, ghost students were a major concern among the participants, as such behaviour not only hindered student engagement, but also prevented tutors from providing support and guidance. Inappropriate use of social media includes ‘sending inappropriate emojis’ to their peers in group chats, and also to their tutors.I was really shocked when I saw the comments on Aula, because a number of students used some highly inappropriate emojis, such as bomb and poo. These students should be trained to understand what they can do and can’t do in an online learning environment. Disruptive behaviours include ‘playing music in the background’, and ‘drinking alcohol during class’. Some students also tended to ‘jump the queue’ and interrupted their tutor or peers in class. Privacy and confidentiality violations involved behaviours such as recording the teaching sessions without their tutor’s permission.Once I saw one student was actually lying in bed when attending the class. I honestly can’t believe it! [I think] he might have turned his camera on by accident! A couple of students in one module often interrupted my teaching suddenly and asking questions without any indications. I don’t mind questions, but it would be nice to be forewarned. As with integrity, a large number of unprofessional behaviours were reported relating to online interaction. In online environments, there seems to be a close connection between involvement and interaction. For example, when students are absent or late for assigned activates, they often exhibit poor verbal or non-verbal communication. Introspection Unprofessional behaviours identified in this category appear to be in two areas mainly: not sensitive to other person’s need, and not aware of limitations. 60% of participants reported that their university provided students with additional learning support through extra online communication channels, such as Microsoft Teams, Zoom and learning management system messaging function. This way, their students were enabled and supported by the university to communicate with their tutors anytime, and anywhere. However, these participants said that the multi-communication channels not only created additional workload for them, but also caused stress. This is because their students, as they explained, expected instant responses regardless of time. They were lacking basic manners when approaching their tutors for support. The participants then called for a clearer guidance for tutor–student online communication. They also suggested that universities should revisit and update the existing code of conduct accordingly to point students to the correct and expected professional behaviour in this area.I have downloaded Microsoft Teams app on my phone and I normally do not switch the phone off in the evening. There are a number of cases that I received students’ calls or messages through Teams in the middle of night. It is very depressing and stressful to get woken up by students. What are they expecting me to do during my sleep? (Participant described the situation with very angry tone) There are no clear rules [on online communication]…I think the university really needs to provide some clarifications to staff and students, rather than leave us to deal with all issues on our own. Tutor action towards student unprofessional online behaviour It appears that all participants agreed that it was important and necessary to manage student unprofessional online behaviour so that they could provide an orderly, equal and learner friendly learning environment for their students. The data indicate that the participants took either positive (70% of participants) or non-positive actions in dealing with student unprofessional behaviour Positive actions Positive actions can be divided further into three sub-categories: raising awareness, proving training and support and seeking extra helping hands. For example, some participants (around 55%) said they believed that their students might not intend to behave inappropriately, and probably were not fully aware that their behaviours were unprofessional and disruptive. Therefore, they focused on educating students about the importance of online professionalism and creating classroom rules explicitly.At the beginning of the 2nd semester, I set up clear ground rules with my students for my online classes. For example, students should attend class on time as they normally do in a face-to-face environment. they should also turn off their Mic when someone is talking; in addition, they were expected to actively participate in group discussions. In addition, some participants (6 out of 14) reported that they emphasized training students on how to act professionally in online environments. One participant said that she was responsible for students’ CPD training in her university and described her action toward addressing unprofessional communication:As soon as I noticed poor online communication behaviours such as writing emails without subject; writing unpleasant comments or feedback on their colleagues’ work online, I discussed with CPD tutors and created additional CPD work on the topic of “online communication” and “social media presence”. Other participants reported that they sought extra help and referred misbehaved students to existing students’ supporting mechanisms such as ‘progress coach’, ‘Academic tutor’, ‘Course director’, and ‘students’ Rep’ to get further guidance of expected online academic behaviour. Less positive actions In contrast, 30% of participants (7 out of 20) appeared to manage students’ online unprofessional behaviours in a less positive manner. Among them, some (4 out of 7) reported that they took a tough stance against unprofessional behaviours. For instance, they tried to make camera on mandatory, regardless of students’ personal situations. Some (2 out of 7) adopted peer observation as a means of observing and reporting unprofessional behaviours. Furthermore, one participant in particular chose to take little action towards students’ unprofessional behaviours.For me, it is very important to see their faces when I teach....I made it clear to my students [at the beginning of each class] that I needed them to turn their camera on if they want to attend my classes. I repeat rules and my expectations at the start of each class. However, it is up to my students to decide how they want to behave in class, because they are all adults, and should be able to make the right decision themselves. My job is to teach them, but not to discipline them in the classroom. However, it appears that these less positive actions did not achieve the effect, and some participants (3 out of 7) remarked that they received negative feedback and comments online. This, as the result, affected their module and motivations.They (the students) got really annoyed with me [after I forced them to turn their cameras on]. Some even complained to the Head of School about me. I am feeling quite upset about this. I had to back off....now I only ask them to put a photograph of themselves instead. It is upsetting to read these [negative comments]…I was really trying my best to help them learn. But I simply removed these comments. I try not to react and take them personally, because I think students are just angry about online teaching. Discussion This study adopts the 4I’s framework to explore the views and perceptions of academic tutors regarding students’ unprofessional behaviours during online learning. It is important and necessary to help university students develop online professionalism. This is not only because of the high probability of post-COVID blended learning adoption in higher education (Wright and Gunderman, 2021), but also because online professionalism is considered a key employability skill for graduates (Castrillon, 2021). To the best of the authors’ knowledge, this study is among one of the first investigating university student online professionalism in formal online learning and teaching environments. The 4I’s framework was designed initially to identify unprofessional behaviours of medical students in mainly face-to-face environments, and has not yet been applied to other subject disciplines. It includes four categories, namely involvement, integrity, interaction and introspection, and 30 descriptors in total. The findings of the study show that the 4I’s framework is also appropriate for examining and documenting unprofessional behaviours of students studying other subject disciplines and in online environments. The data collected did not suggest new descriptors, and the problematic behaviours that participants reported fall within the existing four categories. However, it is worthwhile noting that the study focused on the perceived views and opinions of a small group of academic tutors. Thus, their views need to be explored and confirmed further. Students’ views and perceptions should also be investigated in future research. Even though it is not stated explicitly, the four categories of the framework seem to carry equal weight. However, the findings of the study indicate that, in the context of online learning, it appears that academic tutors witnessed more unprofessional behaviours relating to the categories of integrity and interaction. For example, data show that there has been a noticeable increase in essay and exam plagiarism during the pandemic. It also became more challenging and difficult for tutors to detect and investigate cheating behaviours online. Participants also reported a variety of unprofessional behaviours that were related specifically to online interaction. Keeping camera and mic off and not participating in online activities were one of the main issues reported. It appears that students also exhibited various disruptive behaviours, such as playing music in the background, and eating and drinking while attending classes. Using inappropriate emojis when communicating with peers and tutors was another main problematic behaviour reported. There seems to be a number of reasons that could help explain why more unprofessional behaviours falling into interaction and integrity categories during the pandemic. Firstly, students were probably not keen and/or motived to study online, since many of them felt that they were not fully prepared and were not ready for the emergency move to online learning. This could be due to a combination of online learning specific contexts and individual factors, such as skill issues (e.g., technology competence of students), technology issues (e.g., students’ lack of access to technology and equipment and limited weak Wi-Fi connection),and psychological issues (e.g., stress and anxiety) (Al-Kumaim et al., 2021). Secondly, it could be that online learning takes away the physical proximity and the non-verbal cues, which are considered essential for effective communications (Burgoon et al., 2021; O’Dea, 2021). And finally, students might have considered online learning environment as a more informal environment compared with face-to-face learning, since they did not need to attend class in person, and could easily remain invisible if they wished to. The findings mentioned above seem to support what has already been identified in the literature. A recent study conducted by Lancaster and Cotarlan (2021) reported ‘an alarming increase’ in STEM students in the UK purchasing essays online from essay mills during the pandemic. Hill and colleagues (2021) expressed a similar concern over contract cheating and focused on illegal services university students in Australia have used during the pandemic such as exam takers for hire, and live chat assistance during exams. Furthermore, new legislation is introduced formally in the UK to ban essay mills (GOV.UK, 2021). In addition, research carried out by Harsch and colleagues (2021) revealed the difficulty in enabling active and engaging online interactions between students and tutors on online language courses. Also in relation to online interaction, Crombie (2020) reinforced the importance of setting up shared and common ground rules and avoiding issues of ambiguity when using emojis for communications between students and students, and students and tutors. For example, what emojis are appropriate to use in a formal learning environment, and also the meanings of the emojis students choose to use. Apart from confirming that the 4I’s framework is appropriate for tutors exploring and documenting students’ unprofessional behaviours in online environments, the findings of the study also raise the concern that there does not seem to be any dedicated policies, guidance and codes of conduct at the departmental and institutional level, and participants had to address students’ unprofessional online behaviours individually at module level. As discussed above, some adopted what they believed to be more positive actions, whilst others adopted less positive actions, and the results of their actions varied. Nevertheless, data show that the majority of participants were actually struggling with managing some of the emerging unprofessional online behaviours, and were unsure about the most appropriate action towards them. The findings are consistent with the results reported by Gibbs (2020), Nicandro et al., (2020) and Terada (2021). The lack of consistency seems to have made it much more challenging for academic tutors to manage online classes, and have also sent mixed messages to students, which, as the result, did not help them develop and practice online professionalism. Future research therefore needs to be conducted to explore the effectiveness of tutors’ action in further detail. Lessons learnt The present study shows emerging evidence about students’ unprofessional online behaviours from the tutor perspective and the challenges tutors face in managing such behaviour at the micro level. Moving forward, in order to design and develop appropriate polices and guidelines, the authors feel the need to analyse and discuss the following lessons learnt from the study. Firstly, the study finds that the traditional classroom management strategies for face-to-face learning environments are not entirely suitable for online learning environments. This is mainly due to some essential differences between these two different types of learning environments in the areas such as interpersonal interactions, tutors’ control of class activities, and physical proximity. Managing students’ online unprofessional behaviour thus became a new challenge for academic tutors when they had to move teaching online. Even though adjusting to fully teaching online was also a new experience, and a steep learning curve to academic staff, it seems that they were largely neglected by their institutions and little training and support was provided to them in this area. And secondly, the findings demonstrate examples of the meso and micro level problems and challenges in dealing with students’ unprofessional behaviours, and exemplify that there is a cause-effect relationship between these two levels. For instance, a lack of policy consistency at the institutional level made it much more difficult for academic staff to manage these behaviours in their own classroom appropriately and effectively. This, as the result, affected their teaching quality and mental health, as well as students’ learning effectiveness. Conclusion The findings of this study shed lights on developing a nuanced understanding of university student unprofessional online behaviour in the context of online learning, and raised policy concerns relating to student online professionalism in higher education in the post-pandemic era. This study suggests that the 4I’s framework (Mak-van Der Vossen et al., 2017, 2020) is appropriate for identifying student unprofessional behaviours in other subject disciplines, and in formal online learning environments. The findings also show that more unprofessional online behaviours fell into the categories of interaction and integrity, due to a combination of online learning specific contexts and students’ personal reasons. In addition, the evidence from the study highlights the disconnection between the micro and meso levels in defining and managing students’ unprofessional online behaviour. At the meso level (institutional level), there appeared to be a lack of clear university-wide guidance. At the micro level (individual, module level), the participants felt that they were left alone to deal with the situation, and had to adopt some ‘ad-hoc’ strategies without appropriate institutional support. However, none of these actions seems to have solved the issues and/or have prevented student unprofessional online behaviour successfully. Some possible reasons for the disconnection could be that the universities might not be fully aware of the difficulties and challenges academic staff were facing or did not have the capacity and resources to deal with such issues because of the unexpected sudden digital disruption. Meanwhile, it could also be because teaching remotely made it much harder for academic staff to keep the lines of communication open with the University. Consequently, this study specifies the importance of designing and producing appropriate guidance and polices such as codes of conduct to help students understand how they are expected to behave professionally in online learning, and the associated methods/actions in dealing with unprofessional online behaviours. The policies, for example should state explicitly how students should act professionally in an online learning across the four areas as shown in the 4I’s framework, namely involvement, integrity, interaction and introspection. Examples of unprofessional behaviours in each category, as well as step-by-step disciplinary procedure should also be provided. Author Biographies Xianghan O'Dea, PhD, is senior lecturer, course leader in York Business School, York St John University, UK. Her major research interests lie in the areas of digital education, global education, and technology enhanced learning. Xu Zhou, PhD, is senior lecturer (associate professor) in the school of Business and Management, Queen Mary University of London. Her research interests fall in the area of digital literacy and cross-cultural adjustment. ORCID iD X O’Dea https://orcid.org/0000-0003-1533-1067 Appendix: A Selection of principal interview questions 1. How long have you worked in the Higher Education in the UK? 2. What is your current position? 3. What is your overall experience of online teaching? 4. Have you experienced any student unprofessional behaviours during online teaching?a. If the answer is yes, can you please provide some examples? b. How often do you experience these behaviours? 5. Did you encounter these behaviours in face-to-face teaching before the pandemic? 6. Whether and how did these unprofessional behaviours affect your teaching? 7. How did you manage these unprofessional behaviours?a. What was the result? b. Were you satisfied with the result? 8. Did you seek any support in dealing with student unprofessional behaviours?a. If the answer is yes, what kind of support did you use? b. If the answer is no, can you explain why? 9. In your opinion, what should your university do to help develop student online professionalism? The authors declare that they have no relevant or material financial interests that relate to the research described in this study. Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. ==== Refs References Ali A Gracey D (2013). Dealing with student disruptive behavior in the classroom–A case example of the coordination between faculty and assistant dean for academics. In: Proceedings Of the Informing Science And Information Technology Education Conference, Porto, Portugal, PA, USA. Informing Science Institute, 1–6 July , pp. 1–15. Al-Kumaim N H Alhazmi AK Mohammed F , et al. (2021) Exploring the impact of the COVID-19 pandemic on university students’ learning life: An integrated conceptual motivational model for sustainable and healthy online learning. Sustainability 13 (5 ): 2546. Barnhoorn PC Houtlosser M Ottenhoff-de Jonge MW , et al. (2019) A practical framework for remediating unprofessional behavior and for developing professionalism competencies and a professional identity. Medical Teacher 41 (3 ): 303–308.29703096 Bašić Ž Kružić I Jerković I , et al. (2019) Attitudes and knowledge about plagiarism among university students: cross-sectional survey at the University of Split, Croatia. Science and Engineering Ethics 25 (5 ): 1467–1483.30357562 Bayne S Gallagher M (2021) Near Future Teaching: Practice, policy and digital education futures. Policy Futures in Education 19 (5 ): 607–625. Bothwell E (2020) UK Universities Favour Blended Learning Approach for 2020-21. Available at: https://www.timeshighereducation.com/news/uk-universities-favour-blended-learning-approach-2020-21 (accessed 07 09 2021). Burgoon JK Manusov V Guerrero LK (2021) Nonverbal Communication. England, UK: Routledge. Cain J Romanelli F (2009) E-professionalism: a new paradigm for a digital age. Currents in Pharmacy Teaching and Learning 1 (2 ): 66–70. Castelli FR Sarvary MA (2021) Why students do not turn on their video cameras during online classes and an equitable and inclusive plan to encourage them to do so. Ecology and Evolution 11 (8 ): 3565–3576.33898009 Castrillon C (2021) This Is the Future of Remote Work in 2021. Available at: https://www.forbes.com/sites/carolinecastrillon/2021/12/27/this-is-the-future-of-remote-work-in-2021/?sh=201421081e1d (accessed 12 05 2021). Crombie P (2020) Faces, hearts and thumbs: Exploring the use of Emoji in online teacher-student communications in higher education. Journal of Academic Language and Learning 14 (1 ): 30–41. Dendir S Maxwell RS (2020) Cheating in online courses: Evidence from online proctoring. Computers in Human Behavior Reports 2 : 100033. Getachew A Tekle T Bayisa K (2020) Nature and causes of students’ misbehaviour as perceived by Ambo University teachers. Journal of the Social Sciences 48 (2 ): 762–771. Gibbs T (2020) The Covid-19 pandemic: Provoking thought and encouraging change. Medical Teacher 42 (7 ): 738–740. DOI: 10.1080/0142159X.2020.1775967.32608302 Gormley M Collins L Schofield S , et al. (2021) Exploring the impact of digital professionalism awareness training on dental undergraduate students. European Journal of Dental Education 25 (2 ): 271–281.32949078 Harper R Bretag T Rundle K (2021) Detecting contract cheating: examining the role of assessment type. Higher Education Research & Development 40 (2 ): 263–278. Lancaster T Cotarlan C (2021) Contract cheating by STEM students through a file sharing website: a Covid-19 pandemic perspective. International Journal for Educational Integrity 17 (1 ): 1–16. Mak-van der Vossen M van Mook W van der Burgt S , et al. (2017) Descriptors for unprofessional behav- iours of medical students: a systematic review and categorisation. BMC Medical Education 17 (1 ): 164.28915870 Mak-van der Vossen M Teherani A van Mook W , et al. (2020) How to identify, address and report students’ unprofessional behaviour in medical school. Medical Teacher 42 (4 ): 372–379.31880194 McGurgan P Calvert KL Narula K , et al. (2020) Medical students’ opinions on professional behaviours: the Professionalism of Medical Students’(PoMS) study. Medical Teacher 42 (3 ): 340–350.31738619 Nicandro V Weitzman A Khandelwal A (2020) Please let students turn their video off in class. Available at: https://medium.com/@vincentnicandro/please-let-students-turn-their-videos-off-in-class-52417acc6ea9 (accessed 02 09 2021). Noviyanti R Abdullah T Tukiran M (2021) Increasing teacher innovativeness through strengthening achievement motivation, teamwork, and organizational climate. Multicultural Education 7 (10 ). O’Connor S Zhang M Honey M , et al. (2021) Digital professionalism on social media: A narrative review of the medical, nursing, and allied health education literature. International Journal of Medical Informatics 153 : 104514.34139621 O’Dea X (2021) Providing Business school students with online social networking opportunities during remote learning. Journal of Learning Development in Higher Education 22 . doi: 10.47408/jldhe.vi22.658. Available at: https://journal.aldinhe.ac.uk/index.php/jldhe/article/view/658. O’Dea X Stern J (2022) Virtually the same?: Online higher education in the post Covid-19 era. British Journal of Educational Technology. doi: 10.1111/bjet.13211. Available at: https://bera-journals.onlinelibrary.wiley.com/doi/full/10.1111/bjet.13211. O’Dea X Zhou X (2021) How to manage the ‘unprofessional’ online behaviour of students: An emerging dilemma in higher education. BERA blog. Available at: https://www.bera.ac.uk/blog/how-to-manage-the-unprofessional-online-behaviour-of-students-an-emerging-dilemma-in-higher-education. Rocha PN de Castro NAA (2014) Opinions of students from a Brazilian medical school regarding online professionalism. Journal of General Internal Medicine 29 (5 ): 758–764.24395103 Sharif MS (2020) Etiquettes to follow during online classes. Available at: https://thefinancialexpress.com.bd/public/index.php/education/etiquettes-to-follow-during-online-classes-1586361639 (accessed 08 09 2021). Stephenson B (2019) Universities must exorcise their ghost students. Available at: https://www.timeshighereducation.com/opinion/universities-must-exorcise-their-ghost-students (accessed 20 08 2021). Terada Y (2021) The camera on/camera off dilemma. Available at: https://www.edutopia.org/article/camera-oncamera-dilemma (accessed 07 09 2021). Tricco AC Rios P Zarin W , et al. (2018) Prevention and management of unprofessional behaviour among adults in the workplace: a scoping review. Plos One 13 (7 ): e0201187.30048512 Van Teijlingen E (2014) Semi-structured interviews. Available at: https://intranetsp.bournemouth.ac.uk/documentsrep/PGRWorkshop-InterviewsDec2014.pdf (accessed 19 05 2017). Verawardina U Asnur L Lubis AL , et al. (2020) Reviewing online learning facing the Covid-19 outbreak. Talent Development & Excellence, 12 . Wright WH Gunderman RB (2021) Pandemic Lessons: online Professionalism Education. Academic Radiology 28 (1 ): 142.33041196 Yuan X Che L (2012) How to deal with student misbehaviour in the classroom? Journal of Educational and Developmental Psychology 2 (1 ): 143.
PMC009xxxxxx/PMC9065662.txt
==== Front Ann. Data. Sci. Annals of Data Science 2198-5804 2198-5812 Springer Berlin Heidelberg Berlin/Heidelberg 404 10.1007/s40745-022-00404-w Article Monitoring COVID-19 Cases and Vaccination in Indian States and Union Territories Using Unsupervised Machine Learning Algorithm http://orcid.org/0000-0003-4744-1949 Chakraborty S. chakrabartysonali@gmail.com grid.444525.6 0000 0000 9398 3798 Department of Mathematical and Computational Sciences, National Institute of Technology Karnataka, Mangalore, 575025 India 4 5 2022 2023 10 4 967989 10 7 2021 20 10 2021 30 10 2021 © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. The worldwide spread of the novel coronavirus originating from Wuhan, China led to an ongoing pandemic as COVID-19. The disease being a contagion transmitted rapidly in India through the people having travel histories to the affected countries, and their contacts that tested positive. Millions of people across all states and union territories (UT) were affected leading to serious respiratory illness and deaths. In the present study, two unsupervised clustering algorithms namely k-means clustering and hierarchical agglomerative clustering are applied on the COVID-19 dataset in order to group the Indian states/UTs based on the pandemic effect and the vaccination program from the period of March, 2020 to early June, 2021. The aim of the study is to observe the plight of each state and UT of India combating the novel coronavirus infection and to monitor their vaccination status. The research study will be helpful to the government and to the frontline workers coping to restrict the transmission of the virus in India. Also, the results of the study will provide a source of information for future research regarding the COVID-19 pandemic in India. Keywords COVID-19 Corona virus Pandemic Data analysis Clustering k-means clustering Hierarchical clustering Agglomerative clustering issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2023 ==== Body pmcIntroduction The COVID-19 pandemic [1–4] originating from Wuhan, China, in December 2019 is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The cause of the respiratory disease was confirmed by WHO [4] as a novel coronavirus on 12th January 2020. The variable symptoms observed in the COVID-19 patients are fever, cough, fatigue, breathing difficulties, loss of smell and taste. Severe consequences were observed in the patients such as cytokine storms, multi-organ failure, septic shock, blood clots, damage to the lungs and heart. The transmission increased rapidly in all countries through the people having travel histories to the affected countries and their contacts. In India, the first case of COVID-19 was reported in Kerala on 30th January 2020, which rose to three cases by 3rd February. After a gap of almost one month, 22 new cases were reported on 4th March 2020. Eventually, the transmission rate grew in March 2020, and the first COVID-19 fatality of India was reported on 12th March of a 76-year-old man, who returned from Saudi Arabia. The rapid spread of the disease led to a nationwide lockdown for 21 days starting from 25th March, 2020 which was further extended by 14 days and thereafter by further two weeks with convinced relaxations. Considering the population of India [3] of about 121,05,69,573, controlling the extensive consequences of the pandemic was quite challenging for the administrative officials. Initially, the authorities decided to test only those people who returned from high-risk countries or who came in contact with the positive cases. Due to the substantial increase in the number of cases, later the government decided to test the people with pneumonia cases, irrespective of travel or contact history. With strict restrictions and guidelines imposed by the government, the number of cases decreased to 9000 per day by February, 2021. A second wave was observed throughout India from early April, 2021and by the end of the month over 4 lakh cases and more than 3500 deaths were reported in a day. India began its vaccination program from 16th January, 2021with two DCGI (Drug Controller General of India) approved drugs. The frontline workers i.e., doctors, nurses, hospital staff and policemen were the first one to receive doses of the vaccine. Thereafter, the vaccination drive was extended to all the residents over the age of 45 and later for all residents over the age of 18. In the present study, two unsupervised clustering algorithms [5–8]; namely k-means clustering and hierarchical agglomerative clustering is applied on the Indian states/UTs to group them on the basis of their demographic characteristics, the number of confirmed and death cases due to COVID-19 and their vaccination status. The use of data science in monitoring COVID-19 cases and vaccination status helps in gaining insight from the dataset and extracting meaningful information which can be further used for predicting future patterns and behaviours. The popular unsupervised clustering algorithms are used due to the fact the available COVID-19 data set for India is untagged. The number of clusters to be formed is not known as so it is desirable that the clustering algorithm will divide the dataset into groups based on their similarities. Wide-ranging research is being carried out about the COVID-19 pandemic; therefore, a brief review is presented in Sect. 2 from the available limited literatures. Sections 3.3 and 3.4 discusses the COVID-19 confirmed and death situation in India and each state and UT of India respectively. The vaccination status for India and its states/UT considering their population is discussed in Sects. 3.5 and 3.6. Section 4 performs cluster analysis on the COVID-19 dataset using k-means and hierarchical agglomerative clustering algorithms. The concluding remarks and the future scope of the research are discussed in Sect. 5. Review of Literatures Extensive research is being carried out both pathologically and statistically on the COVID-19 dataset across the world in order to observe the trend of infection transmission and to combat the spread of novel corona virus. In India as on 8th June, 2021, more than two crore people got infected with novel corona virus and approximately 3.5 lakh people succumbed to COVID-19 [9]. As on 8th June, 2021, the total number of people affected with coronavirus across the world is more than 18 crore and more than 39 lakh deaths are reported [4]. Apart from losing precious lives, the pandemic has a severe impact on the Indian economy and led to a negative growth rate for the first time in decades. The pathological research aims to study the evolution, replication, pathogenesis [10] the transmission trend of the novel corona virus [11], its clinical features, diagnosis, treatment [12], and to observe the impact of the pandemic based on the parameters such as air temperature, relative humidity [13], age and gender. To perform statistical research on the COVID-19 dataset, various statistical models are being used by the researchers [14–21] and artificial intelligence techniques [22] are being suggested for predicting the further spread of the pandemic. Gondauri et al. [23] uses BAILEY’s model to study and analyse the cases based on corona virus spread in different countries. Based on the experimental results, the author concluded the state of the virus spread and recovery up to 30th March, 2020. A spline-based time series with Bayesian model is used by Kumar et al. [24] to identify the transmission stages of COVID-19 infection in India. The Susceptible-Exposed-Infectious-Recovered (SEIR) model is used by researchers Pai et al. [25] to forecast the active COVID-19 cases in India considering the effect of nationwide lockdown and the possible inflation in the active cases after unlocking the nation. Data Analysis Analysis Domain The research data included in the present study is for India which is the second most populated country in the world having 28 states and 8 union territories. The total population [3] of the country is 121,05,69,573 with a density of 382/km2. The rural and the urban population of India is 69% and 21% respectively. The states and UTs used in the study are listed alphabetically and their abbreviations used are: Andaman and Nicobar (AN), Andhra Pradesh (AP), Arunachal Pradesh (AR), Assam (AS), Bihar (BH), Chandigarh (CH), Chhattisgarh (CG), Dadra and Nagar Haveli (DNH), Delhi (DL), Goa (GA), Gujarat (GJ), Haryana (HR), Himachal Pradesh (HP), Jammu and Kashmir (JK), Jharkhand (JH), Karnataka (KA), Kerala (KL), Ladakh (LD), Lakshadweep (LK), Madhya Pradesh (MP), Maharashtra (MH), Manipur (MN), Meghalaya (MG), Mizoram (MZ), Nagaland (NG), Odisha (OD), Pondicherry (PD), Punjab (PJ), Rajasthan (RJ), Sikkim (SK), Tamil Nadu (TN), Telangana (TL), Tripura (TR), Uttar Pradesh (UP), Uttarakhand (UT), West Bengal (WB). Data Collection and Tools Used for Analysis The COVID-19 dataset for India and the demographic details of each state and UT used in this study is extracted from the official website administered by the government of India [1, 2, 9]. The analysis includes approximately 16,000 records in comma separated values (CSV) format containing day wise information of the number of confirmed cases, active cases, cured cases and the number of deaths from March, 2020 to 8th June, 2021. The vaccination details contain the total number of people vaccinated for the first and the second dose starting from 16th January, 2021 in all states and UTs of the country for different age groups. The computations are performed using Microsoft Excel 2010 and RStudio Desktop 1.3.1093 is used for implementing the clustering algorithms. Analysis of COVID-19 Confirmed and Death Cases of India Table 1 depicts the total COVID-19 confirmed cases and deaths in India from March, 2020 to 8th June, 2021. A graphical representation of the same is depicted in Figs. 1 and 2 respectively.Table 1 COVID-19 confirmed cases and deaths in India from March, 2020 to 8th June, 2021 Month, Year Total confirmed cases Total deaths March, 2020 1397 35 April, 2020 31,653 1039 May, 2020 1,49,093 4090 June, 2020 3,84,697 11,729 July, 2020 10,72,030 18,854 August, 2020 19,82,375 28,722 September, 2020 26,04,518 33,028 October, 2020 19,11,356 24,144 November, 2020 12,94,572 15,498 December, 2020 8,34,983 11,599 January, 2021 4,79,509 5536 February, 2021 3,33,796 2664 March, 2021 10,69,356 5530 April, 2021 66,13,641 45,862 May, 2021 92,84,558 1,20,770 June, 2021 12,27,289 33,979 Total 2,92,74,823 3,62,661 Fig. 1 Total confirmed COVID-19 cases in India from March, 2020 to 8th June, 2021 Fig. 2 Total COVID-19 deaths in India from March, 2020 to 8th June, 2021 The trend of covid cases observed in Table 1 and Figs. 1 and 2 depict that from March, 2020 the number of covid cases started rising in India. During September, 2020, the covid cases were at peak and thereafter they started declining towards February, 2021. This period of twelve months can be considered as the first wave of the pandemic in India. Again, from March, 2021 the number of covid cases started increasing and during May, 2021 the number of cases were maximum. Eventually, the cases started decreasing by the onset of June, 2021. This time period of four months can be considered as the second wave of the pandemic in India. Although the duration of the first and the second wave are not same, the total number of cases and the peak observed during the second wave with 92,84,558 confirmed cases in the month of May, 2021 is much higher than that observed during the first wave. The second wave in India was more fatal as compared to the first wave. Analysis of COVID-19 Confirmed Cases and Deaths in the States and UTs of India Table 2 depicts the total COVID-19 confirmed cases and deaths in each state and UT of India during the first and the second wave. A trend of the same is depicted in Figs. 3, 4, 5 and 6.Table 2 COVID-19 confirmed cases and deaths in Indian states and UTs during first and second wave State/UT First wave Second wave Total confirmed cases Total deaths Total confirmed cases Total deaths AN 5018 62 2113 61 AP 8,89,799 7169 8,73,412 4383 AR 16,836 56 12,860 69 AS 2,17,527 1092 2,21,219 2603 BH 2,62,509 1541 4,51,370 3883 CH 21,719 351 38,988 423 CG 3,12,419 3833 6,69,441 9410 DNH 3406 2 7013 2 DL 6,39,092 10,909 7,90,383 13,718 GA 54,932 794 1,04,879 2046 GJ 2,69,482 4409 5,47,530 5535 HR 2,70,610 3047 4,92,321 5704 HP 58,598 995 1,37,157 2320 JK 1,26,383 1956 1,75,084 2134 JH 1,19,905 1088 2,21,671 3972 KA 9,50,730 12,326 17,56,751 19,594 KE 10,56,149 4182 15,86,246 5975 LD 9818 130 9440 65 LK 359 1 8416 40 MP 2,61,403 3863 5,24,364 4506 MH 21,46,777 52,092 36,95,223 48,378 MN 29,271 373 26,557 523 MG 13,961 148 25,195 521 MZ 4423 10 9573 45 NG 12,199 91 10,719 338 OD 3,37,104 1915 4,82,110 1120 PD 39,717 668 69,844 970 PJ 1,81,597 5825 3,99,232 9335 RJ 3,20,180 2787 6,26,795 5900 SK 6137 135 11,033 138 TN 8,51,063 12,493 14,05,618 14,863 TL 2,98,807 1634 2,98,006 1792 TR 33,417 391 22,752 181 UP 6,03,427 8725 10,95,656 12,608 UT 97,031 1692 2,37,388 5039 WB 5,74,926 10,266 8,57,093 6096 Fig. 3 COVID-19 confirmed cases in states of India during first and second wave Fig. 4 COVID-19 confirmed cases in union territories of India during first and second wave Fig. 5 COVID-19 deaths in states of India during first and second wave Fig. 6 COVID-19 deaths in union territories of India during first and second wave It is observed that among all the states and UTs, Maharashtra reported the highest number of COVID-19 cases and deaths both during the first and the second wave. All other states/UTs except Andaman and Nicobar (AN), Andhra Pradesh (AP), Arunachal Pradesh (AR), Ladakh (LD), Manipur (MN), Nagaland (NG) and Telangana (TL) showed a greater number of cases during the second wave as compared to the first wave. Lakshadweep reported its first COVID positive case in January, 2021. States Andhra Pradesh, Delhi, Karnataka, Kerala, Tamil Nadu, Uttar Pradesh and West Bengal reported more than 5 lakh cases during both the waves. COVID-19 Vaccination Status in India Looking into the severity of the second wave, the foremost priority of the government is to speed up the vaccination process among the residents. No vaccines were available almost during the first wave. The vaccination process started in India from 16th January, 2021 in which initially only the frontline workers were given two doses of the vaccine with a gap of 12–16 weeks using two DCGI [1] approved drugs by Oxford-AstraZeneca’s Covishield and Bharat Biotech’s Covaxin. From 1st March, 2021, the vaccines were given to the residents over the age of 45 and with the onset of the deadly second wave the vaccine is now available for all residents over the age of 18. Table 3 depicts the vaccination status of India as on 8th June, 2021 (Fig. 7).Table 3 Vaccination Status of India as on 8th June, 2021 Total residents receiving First Dose Total residents receiving Second Dose Age range (years) Percentage of total population receiving (%) 18–45 45–60 60 +  First Dose Second Dose 18,69,33,771 4,51,29,717 4,72,33,720 7,79,70,082 6,17,29,969 15.44% 3.73% Fig. 7 Vaccination status in India as on 8th June, 2021 It is observed from Table 3 that out of the total population of the country, 15.44% people have received the first dose whereas only 3.73% people of the total population has received both the doses. This majorly includes the frontline workers and the residents in the age groups of 45 and more. COVID-19 Vaccination Status in States and UTs of India Table 4 depicts the demographics and the vaccination status of each state and UT of India. The demographic details include the total population of the state/UT, its population density and the rural and urban population percentage (Figs. 8, 9).Table 4 Demographics and Vaccination status of Indian states and UTs as on 8th June, 2021 State/UT Total Population Density (/km2) Rural (%) Urban (%) First Dose Second Dose Percentage of total population receiving (%) First Dose (%) Second Dose (%) AN 3,80,581 46 62 38 1,12,507 3,80,581 29.56 4.01 AP 4,95,77,103 303 71 29 84,29,887 4,95,77,103 17.00 5.21 AR 13,83,727 17 77 23 3,06,022 13,83,727 22.12 5.69 AS 3,12,05,576 398 86 14 35,34,232 3,12,05,576 11.33 2.74 BH 10,40,99,452 1102 89 11 92,77,636 10,40,99,452 8.91 1.78 CH 10,55,450 9252 03 97 3,08,126 10,55,450 29.19 7.13 CG 2,55,45,198 189 77 23 51,55,182 2,55,45,198 20.18 4.45 DNH 5,85,764 970 42 58 2,03,171 5,85,764 34.68 4.45 DL 1,67,87,941 11,297 03 98 44,19,597 1,67,87,941 26.33 7.85 GA 14,58,545 394 38 62 4,85,171 14,58,545 33.26 6.62 GJ 6,04,39,692 308 57 43 1,43,59,541 6,04,39,692 23.76 7.16 HR 2,53,51,462 573 65 35 52,76,368 2,53,51,462 20.81 4.05 HP 68,64,602 123 90 10 21,02,102 68,64,602 30.62 6.33 JK 1,22,67,032 297 74 26 29,32,304 1,22,67,032 23.90 4.64 JH 3,29,88,134 414 76 24 38,64,177 3,29,88,134 11.71 2.27 KA 6,10,95,297 319 61 39 1,26,12,607 6,10,95,297 20.64 4.73 KE 3,34,06,061 859 52 48 83,02,066 3,34,06,061 24.85 6.50 LD 2,74,000 3 16 84 1,42,943 2,74,000 52.17 13.62 LK 64,473 2013 22 78 33,318 64,473 51.68 10.83 MP 7,26,26,809 236 72 28 1,12,99,196 7,26,26,809 15.56 2.55 MH 11,23,74,333 365 55 45 1,95,97,498 11,23,74,333 17.44 4.32 MN 25,70,390 122 70 30 4,33,599 25,70,390 16.87 2.76 MG 29,66,889 132 80 20 4,03,761 29,66,889 13.61 2.51 MZ 10,97,206 52 48 52 2,76,319 10,97,206 25.18 4.69 NG 19,78,502 119 71 29 2,39,568 19,78,502 12.11 2.63 OD 4,19,74,219 269 83 17 69,38,186 4,19,74,219 16.53 3.63 PD 12,47,953 2598 32 68 2,42,580 12,47,953 19.44 4.16 PJ 2,77,43,338 551 63 37 41,63,128 2,77,43,338 15.01 2.88 RJ 6,85,48,437 201 75 25 1,46,15,154 6,85,48,437 21.32 4.75 SK 6,10,577 86 75 25 1,80,310 6,10,577 29.53 9.78 TN 7,21,47,030 555 52 48 80,31,685 7,21,47,030 11.13 2.92 TL 3,50,03,674 312 61 39 55,54,284 3,50,03,674 15.87 3.75 TR 36,73,917 350 74 26 11,32,397 36,73,917 30.82 13.83 UP 19,98,12,341 828 78 22 1,70,79,924 19,98,12,341 8.55 1.83 UT 1,00,86,292 189 70 30 23,96,288 1,00,86,292 23.76 6.83 WB 9,12,76,115 1029 68 32 1,24,92,937 9,12,76,115 13.69 4.34 Fig. 8 Vaccination status in states of India as on 8th June, 2021 Fig. 9 Vaccination status in union territories of India as on 8th June, 2021 The following observations are made from Table 4:In states Assam, Bihar, Jharkhand, Meghalaya, Nagaland, Tamil Nadu, Uttar Pradesh and West Bengal out of the total population, less than 15% people have been vaccinated with the first dose The states/UTs Dadra and Nagar Haveli, Goa, Himachal Pradesh, Ladakh and Lakshadweep have recorded very good vaccination program having more than 30% vaccinated residents with first dose Cluster Analysis Cluster analysis is a statistical data mining technique [5] used for grouping the data set having similarities in their parameters. In the present study, two data mining clustering techniques namely, k-means clustering and hierarchical agglomerative clustering is applied on the COVID-19 dataset for grouping the states/UTs based on their demographics, number of COVID confirmed and death cases and the vaccination status. k-means Clustering k-means clustering [5] is an unsupervised clustering technique in which the dataset is partitioned into k clusters such that the variance between the dataset within the cluster is minimum. Each data from the dataset belongs to a cluster with the nearest mean. The k-means algorithm returns the average value of the parameters. In the present study, k-means clustering is applied to group the states/UTs based on three cases:Case A_kclust Clustering the states/UTs based on the total number of COVID-19 cases and deaths during the first and the second wave Case B_kclust Clustering of states/UTs to observe the vaccination status with respect to their population Case C_kclust Clustering the states/UTs to group them respective to the number of COVID-19 cases and deaths with their vaccination status The following steps are performed while implementing the k-means clustering algorithm:Determination of the parameters used for clustering the data set into groups Implementation of elbow method [2, 5] for determining the optimal number of clusters. The elbow method also known as knee of curve method is a heuristic approach used to determine the number of clusters in a dataset. Applying k-means clustering using the optimal number of clusters determined in the elbow method. Case A_kclust: Clustering the states/UTs based on the number of COVID-19 cases and deaths. Four parameters considered while performing the clustering operation are: total confirmed cases during first wave, total deaths during first wave, total confirmed cases during second wave and total deaths during second wave. Figure 10 depicts the result of the elbow method applied on the dataset.Fig. 10 Elbow method plot for obtaining optimal number of clusters for Case A_kclust It is observed from Fig. 10 that the total within the sum of squares value does not vary much after 3 clusters and so 3 is considered as the optimal number of clusters. By applying k-means algorithm with k = 3 gives cluster of sizes 28, 7 and 1. The result and the plotting of k-means clustering is tabulated in Table 5 and Fig. 11 respectively.Table 5 Result of k-means clustering algorithm for Case A_kclust Cluster First wave total cases First wave total deaths Second wave total cases Second wave total deaths 1 1,20,884 1388 2,08,681 2452 2 7,95,026 9438 11,95,022 11,033 3 21,46,777 52,092 36,95,223 48,378 Fig. 11 k-means cluster plot for Case A_kclust The states belonging to each cluster are depicted in Table 6:Table 6 States/ UTs belonging to Cluster 1, 2 and 3 for Case A_kclust Cluster 1 Cluster 2 Cluster 3 AN, AR, AS, BH, CH, CG, DNH, GA, GJ, HR, HP, JK, JH, LD, LK, MP, MN, MG, MZ, NG, OD, PD, PJ, RJ, SK, TL, TR, UT AP, DL, KA, KL, TN, UP, WB MH The following inferences are made from the result of k-means clustering depicted in Table 5 and 6:Maharashtra is the worst hit state with maximum number of COVID-19 confirmed cases and deaths during both the waves Although there is a substantial increase in the number of COVID-19 cases in the states belonging to cluster 2, overall, they are moderately affected The states belonging to cluster 1 have fewer number of cases as compared to those in cluster 2 Case B_kclust Clustering the states/UTs based on their vaccination status. The parameters considered while performing the clustering operation is the percentage of residents vaccinated by the first and the second dose out of the total population. The elbow method is used to determine the optimal number of clusters as depicted in Fig. 12.Fig. 12 Elbow method plot for obtaining optimal number of clusters for Case B_kclust The elbow method suggests 3 as the optimal number of clusters. k-means algorithm applied on the data set with k = 3 gives cluster of sizes 18, 4 and 14. Table 7 depicts the mean of the percentage of people vaccinated by first and second dose in each cluster. Figure 13 shows the plotting of k-means clustering for Case B_kclust.Table 7 Result of k-means clustering algorithm for Case B_kclust Cluster First dose (%) Second dose (%) 1 51.93 12.23 2 15.39 3.41 3 27.68 6.82 Fig. 13 k-means cluster plot for Case B_kclust The states belonging to each cluster are depicted in Table 8:Table 8 States/ UTs belonging to Cluster 1, 2 and 3 for Case B_kclust Cluster 1 Cluster 2 Cluster 3 LD, LK AP, AS, BH, CG, HR, JH, KA, MP, MH, MN, MG, NG, OD, PD, PJ, RJ, TN, TL, UP, WB AN, AR, CH, DNH, DL, GA, GJ, HP, JK, KL, MZ, SK, TR, UT The following observations are noted from the results derived in Tables 7 and 8.The states belonging to cluster 1 have more than 50% and 10% vaccinated residents with first and second dose respectively The states belonging to cluster 2 are the least vaccinated statesThe first dose vaccination rate of the states/UTs in this cluster is less than 20% which is quiet alarming The average vaccination rate of the states/UTs belonging to cluster 3 is moderate with 27% of first dose and 6% of second dose Case C_kclust Clustering the states/UTs based on their COVID-19 cases and deaths with their vaccination status. The parameters considered while applying k-means clustering are: total confirmed cases and deaths during the first and the second wave and percentage of residents receiving first and second dose of the vaccine. Similar to Case A_kclust and Case B_kclust, the elbow method shows 3 as the optimal number of clusters as depicted in Fig. 14. Applying k-means algorithm with k = 3, three cluster of sizes 7, 1and 28 are formed. The result and the cluster plot for Case C_kclust is depicted in Table 9 and Fig. 15.Fig. 14 Elbow method plot for obtaining optimal number of clusters for Case C_kclust Table 9 Result of k-means clustering algorithm for Case C_kclust Cluster First wave total cases First wave total deaths Second wave total cases Second wave total deaths First dose (%) Second dose (%) 1 7,95,026 9438 11,95,022 11,033 17.45 4.76 2 21,46,777 52,092 36,95,223 48,378 17.44 4.32 3 1,20,884 1388 2,08,681 2452 23.55 5.37 Fig. 15 k-means cluster plot for Case C_kclust The states belonging to each cluster are depicted in Table 10:Table 10 States/ UTs belonging to Cluster 1, 2 and 3 for Case C_kclust Cluster 1 Cluster 2 Cluster 3 AP, DL, KA, KL, TN, UP, WB MH AN, AR, AS, BH, CH, CG, DNH, GA, GJ, HR, HP, JK, JH, LD, LK, MP, MN, MG, MZ, NG, OD, PD, PJ, RJ, SK, TL, TR, UT The following observations are made considering Tables 9 and 10.Maharashtra the only state belonging to cluster 2, has highest number of COVID-19 cases and deaths in both waves with quiet a smaller number of residents getting vaccinated The states/UTs in cluster 2 are moderately affected with COVID-19 cases and deaths having less vaccination rate The states/UTs belonging to cluster 3 have least number of COVID-19 cases as compared to the other two clusters with highest vaccination rate Hierarchical Agglomerative Clustering An unsupervised data mining statistical approach [5] used for grouping data set with similar characteristics by building a hierarchy of clusters. Two types of hierarchical clustering can be performed; i.e., agglomerative and divisive. The type of hierarchical clustering performed in the present study is agglomerative which creates groups from bottom to top. In this method, each observation of the dataset is considered as a cluster which merges with other clusters while moving up the hierarchy. The squared Euclidean distance is used to find the similarities in the data set and average method is used to evaluate the distance between the clusters. Given two set of points p (p1, p2) and q (q1, q2), the Euclidean distance between points p and q is measured as:Dp,q=q1-p12+q2-p221/2 The algorithm is applied to group the states/UTs based on the following three cases:Case A_hclust Clustering the states/UTs hierarchically based on the total number of COVID-19 cases and deaths during the first and the second wave Case B_hclust Clustering of states/UTs to observe the vaccination status with respect to their population Case C_hclust Clustering the states/UTs to group them respective to the number of COVID-19 cases and deaths with their vaccination status The following steps are performed while implementing the hierarchical agglomerative clustering algorithm:Determination of the parameters used for clustering the data set into groups Implementation of elbow method [26] for determining the optimal number of clusters. Application of hierarchical agglomerative using the optimal number of clusters determined in the elbow method. Creating the cluster dendrograms and highlighting individual clusters Creating the phylogenetic tree representation for better understanding of the clusters Case A_hclust Hierarchical clustering is applied with parameters total confirmed cases and deaths during the first and the second wave. The dendrogram showing the clustering of states/UTs for Case A_hclust is depicted in Fig. 16.Fig. 16 Dendrograms showing clustering of states/UTs for Case A_hclust Each cluster is marked by the red border. The following observations are made from Fig. 16:Maharashtra is the only state belonging to cluster 1 with more than twenty lakh cases in both the waves. Twenty-eight states/UTs group together for cluster 2. Cluster 2 is formed by merging three sub-clusters.:The first sub-cluster contains eight states having less than 4 lakh cases during the first wave and less than 7 lakh cases during the second wave. The total cases considering both the waves is less than 10 lakhs The second sub-cluster contains 15 states having less than 90,000 cases during the first wave and less than 2 lakh cases during the second wave The third sub-cluster has 5 states having total cases less than 3 lakh during first wave but less than 6 lakh total cases considering both the waves Cluster 3 contains 7 states having more than 5 lakh confirmed cases and more than 4000 deaths during both the waves A phylogenetic tree for Case A_hclust using “Radial” representation is depicted in Fig. 17.Fig. 17 A phylogenetic tree showing clustering of states/UTs for Case A_hclust Case B_hclust The clustering of states/UTs to observe the vaccination status is done using the percentage of residents receiving the first and the second dose of the vaccine out of their total population. The dendrogram showing the results is depicted in Fig. 18.Fig. 18 Dendrogram showing clustering of states/UTs for Case B_hclust The following observations are made from the dendrogram representing the vaccination status of the depicted in Fig. 18:Union territories Ladakh and Lakshadweep belonging to cluster 1 has more than 50% first dose vaccinated residents The 15 states/UTs grouped into 7 sub-clusters merge to form cluster 2The first dose vaccination percentage in cluster 2 is less than 20% of their total population The states/UTs in this cluster represent least number of vaccinated residents Cluster 3 contains 19 states/UTs grouped by sub-clusters having vaccination percentage between 20 and 50% A radial representation of the phylogenetic tree for Case B_hclust is depicted in Fig. 19.Fig. 19 A phylogenetic tree showing clustering of states/UTs for Case B_hclust Case C_hclust The clustering of the states/UTs based on their COVID-19 cases and deaths with their vaccination status has the following parameters: total confirmed cases and deaths during the first and the second wave and the percentage of residents receiving first and second dose of the vaccine out of the total population. The dendrogram and radial representation of the phylogenetic tree showing clustering of states/UTs for Case C_hclust is depicted in Figs. 20 and 21 respectively.Fig. 20 Dendrogram showing clustering of states/UTs for Case C_hclust Fig. 21 A phylogenetic tree showing clustering of states/UTs for Case C_hclust The following observations are made from the dendrogram depicted in Fig. 20:Maharashtra is the only state belonging to cluster 1 with highest number of covid-19 cases during both the waves and less than 20% residents getting vaccinated with first dose 28 states/UTs grouped into sub-clusters merge to form cluster 2. The sub-clusters are formed by the total number of cases during both waves and their vaccination percentage.First 2 states in the sub-cluster have total cases between 3 and 7 lakhs with more than 20% vaccination Next 6 states/UTs have covid cases up to 3 lakhs during the first wave and more than 3 lakh cases during the second wave with more than 8% vaccination Sub-cluster 3 formed by grouping 15 states/UTs have less than 60,000 cases during the first wave and up to 1.5 lakh cases during the second wave with more than 10% vaccination Sub-cluster 4 comprises of 5 states with cases between 90,000 and 3 lakhs during both the waves and more than 10% vaccination The 7 states /UT belonging to cluster 3 have more than 6 lakh COVID-19 cases during both the waves with less than 30% vaccination. Research Findings and Future Scope The present study performs cluster analysis on the COVID-19 dataset of each state/UT of India from March, 2020 to 8th June, 2021. Two unsupervised clustering algorithms are applied to the COVID-19 and vaccination data set in order to group and monitor the states and the UTs based on their increase/decrease of covid cases, deaths and vaccination status. The situation in the states having maximum number of COVID-19 cases and deaths both during the first and the second wave with less than 20% vaccination is quiet alarming. Worst affected states during both the waves are Maharashtra, Andhra Pradesh, Delhi, Karnataka, Kerala, Tamil Nadu, Uttar Pradesh and West Bengal. Looking into the severity of the second wave, faster vaccination process in the densely populated states may help in reducing the rapid transmission of the infection. The vaccination drive in the rural part of the country is a major challenge as myths regarding the vaccines proves to be a major obstacle. The results of the analysis presented in this study will provide useful information regarding the pandemic and to the frontline workers combatting the spread of the infection in the country. The results can be used for pursuing further research for the betterment of government policies. The analysis can be further carried out at district level of each state/UT to explore and identify the useful information about the disease spread and the vaccination drive. Author’s contributions The only author. Funding Not Applicable. Data availability Not applicable. Code availability Not applicable. Declarations Conflict of interest Not applicable. Ethical Statements I hereby declare that this manuscript is the result of my independent creation under the reviewers’ comments. Except for the quoted contents, this manuscript does not contain any research achievements that have been published or written by other individuals or groups. I am the only author of this manuscript. The legal responsibility of this statement shall be borne by me. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ==== Refs References 1. Ministry of Health and Family Welfare, Government of India (2021). https://www.mohfw.gov.in. Accessed 20 June 2021 2. PRS Legislative Research (2021). https://prsindia.org/covid-19/cases. Accessed 20 June 2021 3. The Office of the Registrar General & Census Commissioner, India (2011). https://censusindia.gov.in. Accessed 20 June 2021 4. World Health Organization (2021). https://www.who.int/emergencies/diseases/novel-coronavirus. Accessed 20 June 2021 5. Han J Kamber M Pei J Data mining-concepts and techniques 2011 3 Morgan Kaufman Publishers 6. Olson DL Shi Y Introduction to business data mining 2007 New York McGraw-Hill/Irwin 7. Shi Y Tian YJ Kou G Peng Y Li JP Optimization based data mining: theory and applications 2011 Berlin Springer 8. Tien JM Internet of things, real-time decision making, and artificial intelligence Ann Data Sci 2017 4 2 149 178 10.1007/s40745-017-0112-5 9. COVID-19 India (2021). https://www.covid19india.org. Accessed 20 June 2021 10. Wang Y Grunewald M Pearlman S Corona viruses: an updated overview of their replication and pathogenesis Methods Mol Biol 2020 10.1007/978-1-0716-0900-2_1 11. Dehkordi A Alizadeh M Derakshan P Babazadeh P Jahandideh A Understanding epidemic data and statistics: a Case Study of COVID-19 J Med Virol 2020 10.1101/2020.03.15.20036418 12. Deng Y He F Li W Coronavirus disease 2019: What we know? J Med Virol 2020 10.1002/jmv.25766 13. Wang J, Tang K, Feng K, Lv W (2020) High temperature and high humidity reduce the transmission of covid-19. https://arxiv.org/abs/2003.05003. Accessed 25 June 2021 14. Gupta S (2020) Epidemic parameters for COVID-19 in several regions of India. https://arxiv.org/abs/2004.11677 Accessed 24 June 2021 15. Gupta S (2020) The age and sex distribution of COVID-19 cases and fatalities in India. https://www.medrxiv.org/content/10.1101/2020.07.14.20153957. Accessed 24 June 2021 16. Gupta S (2020) Inferring epidemic parameters for COVID-19 from fatality counts in Mumbai. https://arxiv.org/abs/2004.11677. Accessed 24 June 2021 17. Gupta S, Shankar R (2020) Estimating the number of COVID-19 infections in Indian hot-spots using fatality data. https://arxiv.org/abs/2004.04025. Accessed 24 June 2021 18. Kumar S Monitoring novel corona virus (COVID-19) infections in India by cluster analysis Ann Data Sci 2020 7 417 425 10.1007/s40745-020-00289-7 19. Li J Guo K Herrera Viedma E Lee H Liu J Zhong Z Gomes L Filip FG Fang SC Özdemir MS Liu XH Lu G Sh Y Culture vs policy: more global collaboration to effectively combat COVID-19 Innov 2020 10.1016/j.xinn.2020.100023 20. Liu Y Gu Z Xia S Shi B Zhou X Shi Y Liu J What are the underlying transmission patterns of COVID-19 outbreak? An age-specific social contact characterization EClincialMedicine 2020 22 100354 10.1016/j.eclinm.2020.100354 21. Temesgen A Gurmesa A Getchew Y Joint modeling of longitudinal CD4 count and time-to-death of HIV/TB co-infected patients: a case of jimma university specialized hospital Ann Data Sci 2018 5 659 678 10.1007/s40745-018-0157-0 22. Hussain A Bouachir O Turjman F Alooqaily M AI techniques for COVID-19 IEEE Access 2020 8 128776 128795 10.1109/ACCESS.2020.3007939 34976554 23. Gondauri D Mikautadze E Batiashvili M Research on covid-19 virus spreading statistics based on the examples of the cases from different countries Electron J Gen Med 2020 17 em209 10.29333/ejgm/7869 24. Kumar J, Agiwal V, Yau C (2021) Study of the trend pattern of COVID-19 using spline-based time series model: a Bayesian paradigm. Jpn J Stat Data Sci: 1–15 25. Pai C Bhaskar A Rawoot V Investigating the dynamics of COVID-19 pandemic in India under lockdown Chaos Solitons Fractals 2020 10.1016/j.chaos.2020.109988.Accessed20June2021 26. National Program on Technology Enhanced Learning (NPTEL) (2021). nptel.ac.in/ courses/106/106/106106179. Accessed 10 June 2021
PMC009xxxxxx/PMC9098920.txt
==== Front Curr Probl Cardiol Curr Probl Cardiol Current Problems in Cardiology 0146-2806 1535-6280 Elsevier S0146-2806(22)00147-5 10.1016/j.cpcardiol.2022.101250 101250 Article Molecular Determinants, Clinical Manifestations and Effects of Immunization on Cardiovascular Health During COVID-19 Pandemic Era - A Review Chatterjee Amrita a Saha Rajdeep a Mishra Arpita b Shilkar Deepak a Jayaprakash Venkatesan a Sharma Pawan c⁎ Sarkar Biswatrish a† a Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India b SLT Institute of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh, India c Center for Translational Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Jane & Leonard Korman Respiratory Institute, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA † Corresponding authors: Biswatrish Sarkar, PhD Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, 835215, Jharkhand, India. ⁎ Corresponding authors: Pawan Sharma, PhD Center for Translational Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Jane & Leonard Korman Respiratory Institute, Thomas Jefferson University, 1020 Locust St, Room 543, Philadelphia, PA 19107. 13 5 2022 8 2023 13 5 2022 48 8 101250101250 . 2022 Elsevier Inc. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has enveloped the world into an unprecedented pandemic since 2019. Significant damage to multiple organs, such as the lungs and heart, has been extensively reported. Cardiovascular injury by ACE2 downregulation, hypoxia-induced myocardial injury, and systemic inflammatory responses complicate the disease. This virus causes multisystem inflammatory syndrome in children with similar symptoms to adult SARS-CoV-2-induced myocarditis. While several treatment strategies and immunization programs have been implemented to control the menace of this disease, the risk of long-term cardiovascular damage associated with the disease has not been adequately assessed. In this review, we surveyed and summarized all the available information on the effects of COVID-19 on cardiovascular health as well as comorbidities. We also examined several case reports on post-immunization cardiovascular complications. ==== Body pmcIntroduction Coronavirus disease 2019 (COVID-19) is the first large pandemic after the 1918 Influenza pandemic that caused nearly 15 million deaths. 1 COVID-19 is caused by a novel beta coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus belongs to the coronaviridae family, members of which have caused similar respiratory diseases in the past.2 COVID-19 began as a respiratory disease outbreak in Wuhan city of Hubei province in Mainland China, with the index case being discovered in November 2019. The disease was declared as a pandemic by World Health Organization (WHO) on March 11, 2020, primarily due to its rapid community transmission.3 The COVID-19 etiologic agent, initially designated as 2019-nCoV, was later isolated and classified as a novel coronavirus. After genome sequencing, the virus was named severe acute respiratory syndrome coronavirus-2 by the International Committee for Virus Taxonomy due to its similarity to the virus that triggered the 2003 SARS outbreak.4 After sequencing 96% of the genome, the SARS-CoV-2 sequence was found to be identical to another coronavirus isolated from bat species (Bat-CoV-RaTG13) from Yunnan province, nearly 2000 km away from Wuhan.5 Thus, the origin and source of SARS-CoV-2 were suspected to be a horseshoe bat.6 According to WHO, fever, cough, tiredness, loss of taste or smell are the most typical signs and symptoms of this viral illness. Shortness of breath, loss of speech or movement, chest discomfort are all severe signs that require rapid medical attention. Sore throat, headache, bodyaches, diarrhoea, skin rash, and red or irritated eyes are some of the less usual symptoms.7 COVID-19 has rapidly emerged as a pandemic with over 513,955,910 cases with 6,249,700 deaths globally, as documented in WHO latest on May 06, 2022.8 The rapid contagion necessitated an immediate understanding of the pathogen and associated comorbidities to find an effective treatment regimen. Primarily affecting lung function, coronavirus infections impair multiple organ systems, including the cardiovascular system and gastrointestinal tract.9 COVID-19 infected patients have impaired cardiac functions leading to deleterious consequences like myocardial injury, arrhythmias, and heart failure (Fig 1 ). Further, patients with cardiovascular comorbidities reportedly had a higher mortality rate than non-comorbid patients suffering from COVID-19.10 Cardiovascular complications in COVID-19 patients include long-term consequences like heart palpitations, loss of breath, persistent cough, chest ache. In a study by Guo et al.11 35.3% of the total 187 COVID-19 positive patients had a history of cardiovascular comorbidities like hypertension and coronary heart disease, and 27.8% of patients had suffered a myocardial injury. Among a total of 187 patients, 144 patients were discharged from the hospital. In contrast, 43 patients succumbed to the disease. On average, 8%-12% of COVID-19 infected patients reportedly suffered a direct or indirect myocardial injury, systemic inflammation, and acute coronary arterial event.12 According to 1 report, of the 16.7% cases of arrhythmia in COVID-19 patients, 8.9% were mild, and 44.4% were severe, others were moderate. Abnormalities in glucose and lipid metabolism were also noted in a long-term assessment of COVID-19 patients.13 These irregularities necessitate a detailed evaluation of cardiovascular implications related to coronavirus infection. In this review, we have attempted to summarize available knowledge on the impact of SARS-CoV-2 viral infection on the human heart as well as the cardiovascular system through systematic research.FIG 1 Cardiovascular pathology due to SARS-CoV-2 infection (Color version of figure is available online.) FIG 1 Mechanism of Virus Entry SARS-CoV-2 exhibits a striking surface entry mechanism wherein spike glycoprotein (S) present on the external envelope of the virion facilitates its entry into the host cell. Biochemically, the structure of SARS-CoV-2 consists of an outsized ectodomain, a short C-terminal intercellular tail, and a single pass trans-membrane anchor. The large ectodomain of S protein of a coronavirion is composed of 2 parts: the S1 site, which binds to the receptor and is a measure of the capability of the virus to enter a host cell, and another part, the S2, which is the membrane fusion unit (Fig 2 ). Studies have revealed that SARS-CoV-2 can strongly bind to the human angiotensin-converting enzyme 2 (ACE2) receptor.14 Although both SARS-CoV and SARS-CoV-2 share a similar binding pattern with ACE2 receptor, minor molecular difference in the receptor-binding domain of the S-unit in SARS-CoV-2 increases its ACE2 binding affinity. Therefore, a quantum increase in pathogenicity and virulence is observed in SARS-CoV-2.15 , 16 FIG 2 Structural features of SARS-CoV-2 virus (Color version of figure is available online.) FIG 2 Cells with a high surface ACE2 expression [eg, type II alveolar cells (AT2) of the lungs] are more in the risk of SARS-CoV-2 infection.14 Evidence from single-cell RNA sequencing has suggested that organs like the bladder, esophagus, kidney, heart, and ileum are highly affected by SARS-CoV-2 infection due to the abundant expression of ACE2 receptors on the outer surface of these cells.17 The virus can enter the cells in 2 ways following cell contact, that is, either through endosomes or plasma membrane fusion (Fig 3 ). The entry of SARS-CoV-2 is facilitated by Spike proteins (S1 and S2) by mediating cell membrane attachment through ACE2 binding. As virions are endocytosed into endosomes, either cathepsin L or trans-membrane protease serine 2 (TMPRSS2) activates spike proteins close to the ACE2 receptor, which initiates viral membrane fusion with the plasma membrane. After endocytosis, the virus releases positive-sense single-stranded genomic RNA. Subsequently, the released RNA is translated into polyproteins.3 The genomic RNA of SARS-CoV-2 encodes nonstructural proteins that play a critical role in synthesizing viral RNA and structural proteins essential for assembling new virions. The process involves the translation of positive-sense single-stranded genomic RNA into nonstructural proteins 1a and 1ab, followed by cleavage of the nonstructural proteins into smaller components, such as RNA-dependent RNA polymerase complex (RdRp) or helicase with the help of 2 enzymes; papain-like protease (PIpro) and 3C-like protease (3CLpro).4 By both replication and transcription, this complex drives the development of negative-sense RNAs. The ribosomes of the rough endoplasmic reticulum (RER) translate a subset of around 9 subgenomic RNAs, including those that code for all structural proteins. They are transported to the RER surface for virion assembly. The nucleocapsids (N) are assembled with genomic RNA in the cytoplasm. The precursor of virions is then transferred from RER as vesicles via the Golgi apparatus to the cell surface. Lastly, Exocytosis releases virions from infected cells, kicking off a new replication cycle.3 FIG. 3 The life cycle of SARS-CoV-2. (1A) virus entry through endosomes, (1B) virus entry through plasma membrane fusion, (2) virions are endocytosed into endosomes, (3) virus releases RNA, (4) Genomic RNAs are then prepared to initiate translation, (5) polyproteins are translated to form polyproteins pp1a and ppab, (6) Proteolysis of polyproteins 1a and 1ab to form 16 non-structural proteins (7) formation of helicase and RdRp complex, (8) RdRp complex helps development of negative-sense RNAs, (9) Transcription of mRNAs and Ribosomes translate S-spike, M-membrane, N-nucleocapsid, and E-envelope encoding proteins, (10) The nucleocapsids are assembled along with genomic RNA, (11) The precursor of virions is then transferred by vesicles from the RER via the Golgi apparatus to the cell surface, (12) Virions are released by exocytosis, (13) Virus is released in the extracellular environment.3,4 FIG 3 Virus Mediated Pathogenesis The clinical course of SARS-CoV-2 infection can be divided into 2 clinical phases. The first phase involves replication of SARS-CoV-2, known as the replicative phase, during which the patient exhibits no symptoms to mild clinical manifestation of the disease. A significant difference between infection caused by old forms of coronaviruses and SARS-CoV-2 infection is the absence of upper respiratory tract infection (eg, Rhinorrhea) in the case of the latter.18 A study reported that nearly 18% of COVID-19 patients lacked any symptoms despite having the SARS-CoV-2 infection.19 The most common symptoms exhibited by most patients are- dry cough, shortness of breath, and fever. In addition to these, patients suffering from severe COVID-19 also exhibited pneumonia, and mild respiratory distress, requiring supportive maintenance such as oxygen supplementation. Besides these symptoms, patients suffering from SARS-CoV-2 infection displayed gastrointestinal abnormalities such as diarrhea, abdominal pain, and nausea,18 along with occasional cases of lymphopenia. The second phase involves the build-up of adaptive immunity by the body against the virus through an antibody response. This decreases the virus titers and resolution of symptoms in most patients. However, high mortality risk persist in a minority of patients who become critically ill, and around 10% of total patients succumb to the worsening symptoms arising from the support of intensive care for survival.20 The patients also develop other symptoms such as multiorgan failure, acute cardiac injury, acute respiratory distress, secondary bacterial infections, and viremia. Multiorgan failure is reportedly associated with a marked elevated immune-inflammatory response.21 The second phase of infection plays a vital role here as the severity of the infection depends on this phase. While most infected individuals remain asymptomatic or exhibit mild symptoms, patients with comorbidities or old adults with weak immune systems require hospitalization.19 Direct Impact of Coronavirus on the Heart and its Management We reviewed numerous studies that evaluated the micro- and macro-histopathological changes in the patients’ heart due to SARS-CoV-2 infection through tissue examination. All of them were either autopsies or post-mortem reports. However, only patients with the severe manifestation of the disease have been described here, along with the treatment approach. Mechanism of COVID-19 Related Cardiovascular Manifestations Out of the several theories speculating the probable mechanism of COVID-19 related cardiovascular manifestations, the following 5 mechanistic pathways of cardiac damage appear promising: (i) Direct injury; (ii) Cardiovascular injury by ACE2 downregulation, (iii) Hypoxia-induced myocardial injury, (iv) Systemic inflammatory response syndrome and (v) Psychological stress-induced cardiomyopathy. Direct Injury The presence of viral RNA in the blood is linked to the severity of COVID-19. As a result, SARS-CoV-2 infect cardiomyocytes directly through circulation. Direct SARS-CoV-2 infection can cause cardiomyocyte inflammation, apoptosis, and necrosis, leading to acute myocardial damage and myocarditis.22 Cardiovascular Injury by ACE2 Downregulation Cardiomyocytes reportedly sustain direct damage due to the binding of SARS-CoV-2 with the functional receptor ACE2, which is abundantly expressed in the heart and lungs. ACE2, a type 1 transmembrane protein receptor, acts as a regulator of the cardiovascular system by its essential functions like vasodilation, anti-hypertrophic, anti-fibrotic and antioxidant activity.23 Though ACE2 is homologous to ACE receptors, it can balance the renin-angiotensin-aldosterone system (RAAS) by converting angiotensin II into angiotensin. Downregulation of ACE2 induces systemic RAAS imbalance via angiotensin II overexpression. A cohort study of SARS-CoV-2 infected patients showed that angiotensin II expression was more remarkable among infected patients than normal. This condition results in RAAS imbalance inducing multiorgan failure.12 Hypoxia-Induced Myocardial Injury A direct attack on the pulmonary epithelial cells by the SARS-CoV-2 might play a potential role in developing acute respiratory distress syndrome (ARDS) and pneumonia.24 Additionally, patients suffering from ARDS and severe pneumonia experience hypoxia. The acute respiratory damage-induced severe hypoxia may give rise to oxidative stress and hence an overall increase in oxygen demand in the myocardial tissue (due to the existing acute lung injury). Apart from oxidative stress, intracellular acidosis and mitochondrial damage may lead to myocardial injury (Fig 4 ). This can further reduce oxygen saturation due to respiratory failure and systemic arterial hypotension, particularly among patients with low ischemic thresholds22 , 25 as described in a retrospective cohort study where 10% of total hospitalised COVID positive patients under cardiovascular treatment in ICU had severe respiratory failure leading to cardiac arrest due to ARDS and sudden pneumonia.FIG 4 The probable mechanism of COVID-19 induced cardiac manifestations: SARS-CoV-2 enters the cells through binding with ACE2 receptors and directly attacking the epithelial cells in the lungs and heart, leading to acute respiratory distress syndrome (ARDS) pneumonia. Along with that, these patients experience hypoxia, which also worsens myocardial damage, causing myocardial infarction, myocarditis, and ischemia (Color version of figure is available online.) FIG 4 Systemic Inflammatory Response Syndrome The SARS-CoV-2 infection leaves scope for deregulated immune response where an increase in neutrophil-lymphocyte ratio has been observed, in contrast to the lower concentration of both the T suppressor cells and T helper cells. There is an overall increase in the expression of pro-inflammatory cytokines, such as granulocyte-colony stimulating factor, tumor necrosis factor (TNF)-α, Interleukin (IL)-6, IL-2R, monocyte chemoattractant protein 1 along with interferon-γ inducible protein 10, chemokine (IL-8), macrophage inflammatory protein 1-α.26 These altered levels of immune mediators generate cytokine storm syndrome. This massive increase in the immune response leads to cardiac microvascular damage, hyperpermeability of blood vessels, and clot formation in the coronary arteries, resulting in acute coronary syndrome (ACS) (as illustrated in Fig 5 ). This systemic inflammatory response can also cause plaque rupture leading to epicardial coronary artery occlusions.27 FIG 5 Mechanisms implicated in the pathogenesis of myocardial injuries related to COVID-19 infection. (1) SARS-CoV-2 enter through the ACE2 receptors; (2) Viruses attack alveolar epithelial cells in lungs; (3) Viruses are then recognized by dendritic cells and macrophages followed by the release of large amounts of cytokines; (4) Increased level of proinflammatory cytokines like IL-1, IL-6, IL-8, TNF-α, NF-κB induce cytokine storm; (5) Cytokine storm stimulates the production of ROS in the cells; (6) ROS lead to lung injury, pulmonary edema and acute respiratory distress syndrome (ARDS); (7) Lung injury causes an imbalance between oxygen demand and supply resulting in arterial hypotension causing cardiovascular damage; (8) Cytokine storm-induced ROS causes systemic inflammation leading to cardiac microvascular damage and acute coronary syndrome. FIG 5 Psychological Stress-Induced Cardiomyopathy During SARS-CoV-2 infection, infected patients suffer from severe stress disorders like depression and anxiety. Physical and psychological stress stimulates sympathetic nerve activity and increases catecholamines release. This fear or stress causes several cardiac manifestations like hypertension due to coronary artery vasoconstriction, myocardial injury, and arrhythmia. These conditions might play a significant role in cardiovascular damage, causing vascular leakage with peripheral and pulmonary edema, direct cardiac toxicity, or rapid onset of severe cardiac dysfunction.27 Diagnostic Markers for Cardiac Manifestations To manage COVID-19 induced cardiac complications, the primary diagnosis is made by laboratory tests, echocardiography, and electrocardiography (ECG). Coronary angiogram by computerized tomography (CT) and magnetic resonance imaging (MRI) is a highly preferred diagnosis technique22 to identify the early manifestations of cardio dysfunction. Evaluation for cardiac biomarkers like N-terminal pro-B-type natriuretic peptide (NT-proBNP), cardiac troponin (cTn) is also equally essential to identify the cardiomyopathy in COVID-19 infections.28 NT-proBNP is secreted by the heart during myocardial wall stress, and the heart is working hard to pump. A higher level of NT-proBNP indicates the risk of cardiomyopathy.29 Frequently elevated blood troponin level is an interesting but common observation in COVID-19 patients. Elevated cTn levels can be widely connected with augmented severity of cardiovascular disease and consequent risk of death.30 The rise in cTn level in COVID-19 patients also be noted due to arrhythmia, heart failure, hypotension, hypoxemia and renal failure, and other common factors, which must be clinically evaluated.31 Myocardial infarction is characterized by an elevation of the cTn value above the 99th percentile, according to the fourth universal concept of myocardial infarction. If there is a rise and/or decline in cTn values, the injury is considered acute. In a retrospective single-center case series, Guo et al.11 analyzed that SARS-CoV-2 infected hospitalized patients with elevated cTn levels had more frequent malignant arrhythmias than normal patients. Reasons other than systemic inflammation, myocardial infarction, direct myocardial inflammation, plasma troponin concentration elevation can result due to SARS-CoV-2 infection associated thromboembolism leading to coronary microvascular ischemia. The myocardial zymogram, including the measurement of D-Dimer, C-reactive protein (CRP), IL-6, Creatine Kinase (CK), or more specifically creatine kinase-myocardial band (CK-MB) and lactate dehydrogenase (LDH) activities, was frequently described in COVID-19 cohort studies.24 , 32 , 33 CK-MB isoenzyme level signifies injured myocardial cell wall,30 and D-Dimer level indicates formation and dissolution of a clot in the body. CRP and LDH, inflammatory markers are associated with cardiac arteries inflammation.29 The rise of CK (≥200 U/L) and LDH (≥250 U/L) serum levels accounted for 13.7 % and 41 % respectively, in a large multicenter retrospective analysis involving 1099 COVID-19 confirmed patients from 552 hospitals throughout 31 Chinese regions. Critically ill patients had higher CK and LDH levels (19 % and 58.1 %, respectively) and those with significant composite endpoint events, such as admission in ICU, invasive mechanical ventilation, and death.24 Cardiovascular Manifestations COVID-19 and Myocardial Infarction and Myocarditis SARS-CoV-2 infection induces clinical manifestations of myocardial infarction, which can be diagnosed as ST-segment elevation myocardial infarction (STEMI), which helps in further treatment approach.34 An imbalance between myocardial oxygen demand and supply can cause myocardial infarction type 2.11 In our literature search, we also found that some authors have argued a direct connection between COVID-19 with myocardial infarction and myocarditis manifestations. In contrast, an autopsy of a patient who died of cardiac arrest and was simultaneously suffering from COVID-19 revealed no indication of involvement of any myocardial structure, suggesting no direct impact on cardiac tissue due to COVID-19.35 Contrastingly, another case study revealed low-grade inflammation of the myocardium along with localization of SARS-CoV-2 particles in the myocardium outside of cardiomyocytes (estimated by endomyocardial biopsy) indicate towards the direct deleterious consequence of COVID-19 on the myocardium.36 The presence of viral RNA and mild inflammation in the heart of patients suffering from COVID-19 was confirmed by autopsy reports. SARS-CoV-2 infection is known to cause systemic inflammation, which probably may, in turn, augment the excessive risk of developing myocardial infarction of type 1, by destabilizing the coronary atheromatous plaques, leading to an increase in aggregation of platelets and consequently posing a greater risk of stent thrombosis.12 In another study, 64 SARS-CoV-2 infected patients were assessed for left ventricular ejection fraction (LVEF). COVID-19 patients showed low LVEF leading to cardiac failure, which is scored by heart failure with preserved ejection fraction or HFA-PEFF. As a higher HFA-PEFF score signifies that patients are suffering from myocardial injury, it was observed that the score was higher in COVID-19 patients along with left ventricular diastolic dysfunction.28 Anticoagulation therapy with low-molecular-weight-heparin was used to treat myocarditis, but this therapy could not be continued in 1 patient due to profuse bleeding in the coronary artery.33 A tentative mechanism and effect on the myocardium have been summarized in Figure 6 .FIG 6 Detailed overview of the bidirectional correlation between COVID-19 and cardiovascular manifestations. Cardiovascular comorbidities in patients with COVID-19, like coronary artery disease and hypertension are associated with heart failure. COVID-19 is most commonly associated with viral pneumonia, but it can also cause cardiac damages like myocarditis, arrhythmias, acute coronary syndrome, and thromboembolism in the cardiovascular system. Finally, several of the drugs that have been recommended as COVID-19 therapies have pro-arrhythmic properties.22,27 (Color version of figure is available online.) FIG 6 Available clinical data suggest that progressive systemic inflammation caused by the SARS-CoV-2 may be attributed to myocardial injury, along with a direct infection of the myocardium, causing viral myocarditis, as evident in the fraction of patients already suffered from COVID-19. COVID-19 and Acute Coronary Syndrome (ACS) Initiation of acute coronary syndrome following COVID-19 might be attributed to microthrombi formation, which may arise due to the cytokine storm or systemic inflammation, coronary spasm, or rapture of concomitant plaque37 (Fig 6). In a case study in New York, 18 patients with COVID-19 infection and simultaneous elevation of ST-segment (suggestive of potential acute myocardial infarction), 5 out of a total of 6 patients suffering from myocardial infarction required urgent percutaneous coronary intervention.38 A case study from Portugal reported that though the number of ACS patients hospitalized was less, cases were severe with a larger acute STEMI, increased troponin level, and left ventricular systolic dysfunction.39 In another report from Italy, 24 patients out of 28 patients with COVID-19 had elevated ST-segment during myocardial infarction as the primary clinical manifestation. However, they were found to be negative in the COVID-19 test during coronary angiography.40 Salinas et al.41 reported a comparative cohort analysis where invasively managed ACS patients in 2020 were compared in the same time frame of 2019. This study analyzed the effect of SARS-CoV-2 infection on 30 days mortality rate in ACS patients. A total of 118 ACS patients were hospitalized, and 11% were COVID positive. Of these, 23.1% of COVID positive ACS patients and 5% COVID negative ACS patients died in 2020. This study showed that 30 days mortality rate in COVID positive ACS patients was greater than COVID negative ACS patients. A positive SARS-CoV-2 test was shown to be related with 30-day mortality in the multivariable analysis. These observations put forward substantial evidence on how COVID-19 may be a precedent cause for the ACS, even when no systemic inflammation occurred. On the other hand, the global pandemic has changed the ACS treatment approach, Morishita et al.42 observed a change in the ACS treatment of in-hospital patients in Japan, like reduction in primary percutaneous coronary intervention and increased in the use of fibrinolytic therapy (use of thrombolytic agent), and coronary artery bypass graft surgery had ceased. COVID-19 and Arrhythmia The 2 most common clinical manifestations of COVID-19 are sudden cardiac arrest and arrhythmias. In COVID-19 patients devoid of cough or fever, heart palpitations have emerged as the primary clinical symptom.43 In a study on a group of 138 COVID-19 patients from Wuhan, China, 17% of the patients (44% patients in the ICU) reportedly developed arrhythmia; however, no records have stated the type of arrhythmia.18 In another study from Wuhan, the cohort of 187 hospitalized patients suffering from COVID-19, found with raised levels of troponin T. They had a greater risk of developing malignant arrhythmias, like ventricular fibrillation and tachycardia, as compared to the population having normal plasma concentration of troponin T (12% vs 5%).11 Myocardial injuries or other systemic factors like sepsis, fever, electrolyte imbalance, and hypoxia can trigger arrhythmias, especially atrial as well as ventricular fibrillation and tachycardia.32 , 33 Generally, cardiac depolarization and repolarization time or QTc interval prolongation is directly related to a high risk of ventricular arrhythmias and cardiac failure (Fig 6). In a report, Guo et al.11 showed that QTc interval was prolonged in SARS-CoV-2 infected patients with preserved ejection fraction-like syndromes and leading to heart failure. During this pandemic, not only did the patients with a history of cardiovascular complications have experienced severe COVID-19 induced cardiac arrhythmia, but it has also been observed in patients without any pre-existing syndrome. Zylla et al.33 described a study where 34 patients were hospitalized due to arrhythmia, where atrial fibrillation was the most common type. In 10.2% of patients, arrhythmia was diagnosed before SARS-CoV-2 infection, where 16 patients had a history of atrial fibrillation, and 1 patient had bradycardia. In contrast, 13.3% of patients had new-onset arrhythmia, and 9.6% had no previous history before contracting COVID-19 and hospitalization. Four patients were administered amiodarone to manage the arrhythmic complications, and 3 received chronic antiarrhythmic therapy. Since many patients with atrial fibrillation type of arrhythmia have been found with new or previously diagnosed venous thrombosis or pulmonary embolism, they received anticoagulation therapy. To maintain oxygen supply in blood or support blood circulation in the body, patients receive oxygen, vasopressors, and noninvasive ventilation. In severe respiratory failure due to cardiac arrhythmia, patients require mechanical ventilation. Duration of mechanical ventilation was not related to new or previously diagnosed COVID-19 infected arrhythmic patients.33 In addition, the antibiotic and antiviral treatments (Hydroxychloroquine, Tocilizumab, Remdesivir, Favipiravir) were administered to patients suffering from advanced COVID-19 infections induce arrhythmias or other cardiotoxicities (Table 1 ) in a few patients.32 , 44 Ståhlberg et al.45 highlighted the presence of tachycardia within 4-12 weeks after a SARS-CoV-2 infection as a symptom of post-acute COVID-19 syndrome.TABLE 1 Updated drug therapies for cardiovascular complications in COVID-19 patients TABLE 1Class of drug Name Mechanism of action Role of the drug on COVID-19 infected patients Adverse effects or contraindications Antiviral drugs Remdesivir ■ It is a nucleotide prodrug of an adenosine analog; administered intravenously. ■ The drug inhibits viral replication as it terminates RNA transcription prematurely by binding to the viral RNA-dependent RNA polymerase.54 ■ Remdesivir shortened the recovery time of hospitalized patients, as the treated patients had reduced respiratory infection.58 ■ Patients who received at least 1 dose of remdesivir had improved oxygen support.54 ■ Hepatotoxicity, renal toxicity are common. ■ Cardiotoxicity has been reported in rare cases or in higher doses.54 Ritonavir/ Lopinavir ■ Binds and inhibits 3C-like proteinase enzyme and suppresses SARSCoV- 2 viral replication. ■ The proteinase enzyme cleaves a long protein chain during replication.59 The median time for clinical advancements in the lopinavir-ritonavir treatment group was 1 day less than the standard group in an open level randomized control trial conducted with 199 COVID positive patients, where 99 patients were allotted in the lopinavir-ritonavir group.60 ■ Cardiovascular risks have been reported for QT and PR interval prolongation in healthy adults, and there are rare reports of atrioventricular blockage in patients with pre-existing conduction abnormalities.54 ■ Hepatotoxicity, pancreatitis, and neurotoxicity are the main reported adverse effects.59 Favipiravir Inhibits RNA-dependent RNA polymerase enzyme, thus terminates viral replication.59,60 Favipiravir group have a shorter viral clearance median time and significantly improved chest CT compared with the ritonavir/ lopinavir group in a preliminary clinical study where 35 patients received favipiravir along with interferon (IFN)-α and 45 patients were treated with ritonavir/ lopinavir along with IFN-α.61 ■ Common adverse effects are increased hepatic enzymes, nausea, vomiting, tachycardia, and diarrhoea. ■ Severe adverse effects, mainly in men above 64 years of age, are blood and lymphatic disorders, cardiac disorders.62 Antiparasitic drug Ivermectin ■ Inhibits the nuclear import of proteins of virus and host as well. ■ It could bind to 3CL protease, RNA-dependent-RNA polymerase, and helicase, and nucleocapsid protein.27 ■ Ivermectin-treated patients had lower mortality and needed less ventilator support.63 ■ Patients on ivermectin treatment resolved all the symptoms of COVID-19 on the 21st day of infection.64 ■ Combining ivermectin and doxycycline increased viral clearance and recovery.65 , 66 ■ Headache, vomiting, diarrhoea, abdominal discomfort is common adverse effects.67 ■ Cardiovascular risk reports in COVID -19 patients showed tachycardia and PR interval prolongation in rare cases.54 Antibiotics Fluoroquinolones, Cephalosporins, Azithromycin, and Ornidazole. ■ Cephalosporins bind to the penicillin-binding protein and inhibit bacterial cell wall synthesis.68 ■ Azithromycin inhibits bacterial protein synthesis in bacterial coinfection associated with COVID-19 viral infection and stimulates human immune and epithelial cells.69 ■ Ornidazole acts via reduction of the nitro group, produces toxic derivatives and free radicals.70 ■ Fluoroquinolones act by inhibiting 2 enzymes involved in bacterial DNA synthesis.71 In a retrospective case-control study where 65 COVID positive patients with nosocomial infection were evaluated against 260 COVID positive non-nosocomial infection patients as control. In the univariate and multivariate analysis, significant positive associations between nosocomial infection and antibiotics were seen. These antibiotics significantly inhibited bacterial infection in patients with several comorbidities like hypertension, cardiovascular diseases, liver, and chronic kidney diseases, diabetes, and respiratory diseases.72 ■ Common adverse reactions are nausea, vomiting, lack of appetite, dry mouth. ■ Some reports showed Azithromycin as arrhythmogenic.68 , 73 Moxifloxacin, Ceftriaxone, Azithromycin were used to treat bacterial coinfection due to SARS-CoV-2 infection. ■ Ceftriaxone selectively binds to penicillin-binding protein and inhibits bacterial cell wall synthesis.74 ■ Moxifloxacin functions the same as Fluoroquinolones. Wang et al.18 described a retrospective, single-center case report from Wuhan, China, of 138 COVID positive hospitalized patients with confirmed pneumonia, and 46.4% among them had one or more comorbidities. 14.5% of the total comorbid patients with pneumonia were suffering from pre-existing cardiovascular diseases, and 31.2% had hypertension. Moxifloxacin was given to 64.4% patients; ceftriaxone to 24.6%; azithromycin to 18.1% of patients among total patients who received antibiotic therapy. These therapies significantly reduced the median hospital stay of patients by reducing disease severity. Common adverse reactions are nausea, vomiting, lack of appetite, headache, and dizziness. Acute thrombocytopenia with epistaxis and petechiae occurred during treatment with ceftriaxone, levofloxacin, and lopinavir/ritonavir in a COVID positive patient and recovered gradually with withdrawal.74,75 Immuno-modulatory regimens Tocilizumab ■ This anti-IL-6 receptor monoclonal antibody blocks IL-6 receptor-mediated signal transduction. ■ It prevents the cytokine storm syndromes caused due to the elevation of IL-6 during COVID-19.76 ■ Tocilizumab treatment among COVID-19 infected patients suffering from severe pneumonia showed a reduced risk of invasive mechanical ventilation or death.77 , 78 ■ Hospital mortality was less in the patients who received tocilizumab in the first 2 d of ICU admission.79 It may increase the severity of atherosclerotic cardiovascular disease as it increases serum LDL, cholesterol, and triglyceride levels.80 Hypolipidemic drug Statins Used for secondary prevention of coronary heart disease in COVID-19 infected patients.81 A retrospective cohort analysis of COVID-19 patients conducted on 1296 patients (648 statin users, 648 non-statin users) reported that antecedent statin use was associated with lower inpatient mortality.82 ■ Cause elevation in serum glucose level, CK, and liver enzymes. ■ Antiviral drugs Ritonavir/ Lopinavir may have serious side effects like rhabdomyolysis.81 Antihypertensive drugs Renin-angiotensin-aldosterone system inhibitors or RAAS inhibitors include ACE inhibitors (ACEIs) and Angiotensin II receptor blockers (ARBs) ■ Commonly used to treat hypertension, myocardial infarction, and heart failure. ■ In the COVID-19 treatment approach, the favourable action of RAAS inhibitors is blocking ACE2 receptors and preventing viral entry into the heart and lungs.83 ■ ACEIs or ARBs can reduce severity in COVID-19 patients with hypertension.84 ■ Also, decrease IL-6 and CRP levels in peripheral blood. ■ These drugs also reduce peak viral load by increasing CD3+ and CD8+ T cells.85 ■ There were some different opinions regarding the withdrawn of RAAS inhibitors for their negative impact on SARS-CoV-2 infected patients,86 but Chouchana et al.87 found no association between the use of RAAS inhibitors with in-hospital mortality. ■ Hypotension, hyperkalaemia, rash, angioedema, diarrhoea.83 β-blockers Act via slowing down conduction velocity and prolonging the refractory period, as it indirectly prevents calcium from entering into myocardial cells.88 β-blockers treatment reduced mortality in elderly patients with cardiovascular comorbidity.87 Bradycardia, hypotension, fatigue, nausea, and constipation.89 Calcium channel blockers (CCB) CCBs prevent calcium enter into the cells of the heart and arteries, leading to hypotension in the blood vessels.90 CCB treatment reduced mortality in elderly patients with cardiovascular comorbidity.87 Constipation, bradycardia, and headache.90 Antiplatelet blood-thinning agents Aspirin Prevent the formation of a blood clot, inhibiting platelet aggregation via blocking thromboxane A2 formation in platelets.91 ■ Combination therapy of enoxaparin injection, ivermectin solution, aspirin 250 mg tablets and dexamethasone 4-mg injection significantly lowered the overall mortality rate of the infected population in Argentina and did not allow the disease to progress from mild to moderate symptoms.92 ■ In another case, study patients over 60 years who received aspirin showed lower cumulative in-hospital death.93 Gastrointestinal ulcer, abdominal pain, stomach upset, and rash.94 Impact of COVID-19 on the Heart of Children The severity of SARS-CoV-2 infection is reportedly low among children with mild symptoms compared to adults. However, it reportedly has severe manifestations like pneumonia, acute injury in the kidney and heart leading to a multisystem inflammatory syndrome in children (MIS-C) in a few children.46 MIS-C reportedly affects children below 21 years of age, and half of the patients are above 10 years. Some symptoms of MIS-C are similar to Kawasaki disease, and some are with SARS-CoV-2 associated cardiovascular complications in adults due to the elevation of inflammatory markers. Symptoms like fever, abdominal pain, mucocutaneous diseases, and coronary artery dilation are similar to Kawasaki disease, where elevated cTn, acute systolic biventricular heart failure, cardiogenic shock, ST-segment elevation in ECG finding are the symptoms similar to adult SARS-CoV-2-induced myocarditis. Thrombocytopenia is another common symptom of MIS-C.47 Association for European Paediatric and Congenital Cardiologists had conducted a multicentre survey to document MIS-C associated cardiovascular clinical manifestations in 286 children with an average age of 8.4 years in 17 European countries from 55 centers. A majority had elevated cTn value and reduced LVEF with elevated inflammation markers like CRP, NT-proBNP, IL-6, serum ferritin, procalcitonin, and D-dimer in blood. Cardiovascular complications included were cardiogenic shock, arrhythmias, pericardial effusion, coronary artery dilatation.48 Another retrospective case report analyzed 4 children and adolescents 6-12 years of age admitted to the ICU with acute myocarditis. All patients were hospitalized within a week from the onset of initial symptoms of SARS-CoV-2 infection, that is, fever, gastric irritation, rash, conjunctivitis. Tachycardia, systolic dysfunction, and vasoplegia with low-normal LVEF were reported from ECG findings in most of these patients. Elevated brain natriuretic peptide (BNP), cTn, and CRP were also reported. Postinfectious diffuse myocardial edema was found in cardiac MRI. Intravenous immunoglobulin therapy was the treatment approach.49 In another meta-analysis of cardiac markers reported by Zhao et al.,50 in 1613 hospitalized children diagnosed with MIS-C, BNP level was significantly higher in patients with MIS-C than patients with mild or moderate symptoms. BNP is a protein made by heart and blood vessels, and a higher level of it indicates the risk of heart failure. In a retrospective single-center study reported by Theocharis et al.,51 20 patients of average age 10.6 ± 3.8 years were admitted at Evelina London Children's Hospital with MIS-C associated cardiovascular complications. All patients showed abnormality in the Doppler echocardography, and ejection fraction resulted in low-normal echocardiography in half of the patients. Uniform coronary artery dilation in CT and myocardial edema in MRI had been reported in 50% of patients. Similar to ECG findings in adults with myocardial infarction or arrhythmias, ST-segment elevation and QTc interval prolongation were seen in patients with MIS-C-associated cardiovascular manifestations.52 These findings suggest that though the percentage of infected children is very low, SARS-CoV-2 infection injures and alters the functions of vital organs, and the findings on the extent of cardiac involvement are increasing day by day from the initial reports. ACS, cardiac edema, and other cardiovascular changes can persist in the future despite the normalization of cardiac and inflammatory markers.51 There has been no WHO-approved vaccine available for children till now. So, detailed screening using advanced techniques on the changes in patients with infection and pharmacovigilance monitoring should be continued to manage this condition. Management of COVID-19 Induced Cardiovascular Complications For the treatment of COVID-19, no specific effective therapies have yet passed FDA screening in the United States. The World Health Organization's “Solidarity” international clinical trial aimed to recognize medicines with therapeutic promise for COVID-19 involves 14,200 hospitalized patients from 600 hospitals of 52 countries.53 Still the approach of medication has been towards “repurposing” or “repositioning” of other drugs for the treatment of COVID-19. The aim of “repurposing” or “repositioning” is to quickly assess the effectiveness of current antiviral, antiparasitic and immunomodulatory drugs that have not yet been registered for the treatment of COVID-19.54 Many drug candidates have been screened, and many are currently being investigated, including antiviral drugs (eg, remdesivir, ritonavir/lopinavir, Favipiravir), antibiotics (eg, fluoroquinolones, cephalosporins, azithromycin, ornidazole), antiparasitic drug (eg, ivermectin), immunomodulatory regimens (eg, tocilizumab), and supporting agents (vitamin B complex, C and D). For specific cardiac manifestations, symptomatic treatment approach has been considered like antihypertensive drugs (β-blockers, renin-angiotensin-aldosterone system inhibitors), hypolipidemic drug (statins), and antiplatelet blood-thinning agents (aspirin, warfarin, heparin, and clopidogrel).3 , 44 , 55 , 56 For different cardiovascular manifestations with COVID-19, possible anti-SARS-CoV-2 regimens have been summarized in Table 1. Recently, WHO has announced the start of next phase of the Solidarity trial where SARS-CoV-2 infected hospitalized patients will be tested for a new treatment approach with 3 new drug therapies. Artesunate, Imatinib, and Infliximab are the 3 new drugs of choice that will be tested for their efficacy in reducing severity and mortality in COVID-19 hospitalized patients. These drugs are already being used for other diseases like severe malaria, cancers, and immune disorders (Crohn's Disease, rheumatoid arthritis) respectively.57 Immunization and post-immunization cardiovascular complications COVID-19 vaccines are being produced faster than conventional vaccines and are being approved internationally through Emergency Use Authorization (EUA). According to a report published by WHO, as of May 06, 2022, there are 351 vaccines to be developed for COVID-19, 197 are in preclinical development, and almost 154 vaccines are under human clinical trials.95 There are 3 main approaches to vaccine design: (1) use a whole virus (inactivated virus, live-attenuated virus, and viral vector); (2) use a part of the viral particle to trigger the immune system; (3) use the virus genetic material (nucleic acid). These immunization processes are meant to boost the immune response by various mechanisms. Both T and B cells have an adaptive immune response to SARS-CoV-2. At about 10 days after viral infection, IgG and IgM antibodies appear in the infected host. The antibodies have neutralizing activity and are made against the virion's internal nucleoprotein and spike protein.96 Total 11,598,144,093 vaccine doses have been administered worldwide till May 07, 2022.8 Individuals receiving the influenza vaccine within a year of contracting the infection reportedly had significant protection and experienced mild clinical conditions, including the patients with various comorbidities who received this vaccine. Influenza vaccine activated natural killer cells within the body after viral entry. Thus influenza immunized patients had fewer hospitalization and ICU admission risks than non-vaccinated COVID infected patients.97 Behrouzi et al.98 have shown that influenza immunization could reduce cardiovascular manifestations in COVID-positive patients leading to a reduction in morbidity and mortality. Comirnaty and Covishield vaccines reportedly have mild side effects like- headache, fever, muscle pain, fatigue, joint pain and pain or redness or swelling at the injection site.99 Experiencing these side effects following vaccination is indicative of an active immune response. However, there are also some alarming cardiovascular complications during this process. Advisory Committee on Immunization Practices reviewed the safety data of Pfizer-BioNTech and Moderna mRNA-COVID-19 vaccine and observed that males were more prone to post-immunization myocarditis than females.100 Chest pain, dyspnea, or palpitations in infants, young adults, and adolescents were most common. They were diagnosed with myocarditis by the cardiac MRI result, elevated cTn, CRP levels, and abnormal ECG with ST-segment elevations along with abnormal echocardiogram report.101 According to a report, a 96-year-old female suffered myocardial infarction nearly 1 hour after her first Moderna COVID-19 vaccination, having no known cardiac history.102 Older adults and young people were equally prone to the cardiovascular effects post-immunization. A 24-years man experienced chest pain 4 days after his second dose of Moderna vaccine and was diagnosed with myocarditis via Cardiac MRI.103 Mouch et al.104 showed that 6 patients with a median age of 23 years were diagnosed with myocarditis, 5 patients received the second dose, and 1 received the first dose of BNT162b2-mRNA COVID-19 vaccine (Pfizer-BioNTech). Due to some symptoms like chest pain or discomfort, cardiac markers were checked, and cTn and CRP levels were found higher than normal. All of them were without any history of COVID-19 infection or cardiovascular problems. Similar symptoms with cardiac dysfunction and cardiac MRI evidencing myocarditis were found in a report by Kim et al.105 where 4 patients (23-36 years aged 3 younger males and a 70-year-old female) had experienced myocarditis 3-5 days after receiving the second dose of mRNA-COVID-19 vaccine (where 2 of them received BNT162b2-mRNA vaccine and other 2 received mRNA-1273 vaccine). In a case report from US Military Health System, 23 participants had acute myocarditis during their active duty, and 20 of them experienced it 4 days after receiving of mRNA COVID-19 vaccine.106 Supporting the observations of the Advisory Committee on Immunization Practices, Marshall et al.,107 reported that 7 males (14-19 year-old adolescents) experienced post-immunization myocarditis and myopericarditis after 4 days of receiving the BNT162b2-mRNA vaccine. After mRNA vaccines, another case of acute myocarditis in 28 years male patient came from the US after being vaccinated by EUA approved adenovirus vaccine (Johnson and Johnson). 5 days after vaccination, the subject experienced chest pain, and ST-segment elevation in the prostate ECG was found along with elevated cTn. In the same case series of 7 patients from US another report on mRNA vaccines by Moderna or Pfizer/BioNTech came where 6 patients had acute chest pain with biochemical evidence of myocardial injury 3-7 days after the second dose of vaccination. Cardiac MRI had no evidence of sustained arrhythmia.108 Another case report by Chamling et al.109 on another approved vaccine Covishield, showed that a 68-year-old lady experienced acute chest pain after her first dose of the vaccine. Elevated cardiac enzymes (cTn, CK, CK-MB) and cardiac MRI report suggested it as non-ischemic myocardial damage or vaccine-associated autoimmune myocarditis with active inflammation in basal and apical segments of the septal wall. In the same case series report, a healthy young man (25 years) had acute chest pain after 10 days of receiving the first dose of Pfizer–BioNTech mRNA vaccine. Elevated cTn, CK values, and ST-segment elevation in ECG finding along with cardiac MRI report evidenced it to be vaccination-associated non-ischemic autoimmune myocarditis. Similar clinical manifestations were reported in a 20-year-old, very healthy young police officer after 3 days of receiving his second dose of the Pfizer–BioNTech mRNA vaccine. Finding a direct link between myocarditis and COVID-19 vaccination remains challenging.105 However, the limited observations on cardiac complications suggest that despite the safety data for all the approved COVID-19 vaccines, critical observation and thorough worldwide pharmacovigilance will be required to manage post-immunization complications. Conclusion The SARS-CoV-2 induced novel COVID-19 has numerous similarities with other pre-existing beta coronavirus infections like middle east respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). However, the infection has been found to be more severe, along with the involvement of multiple organs, including the cardiovascular system, as reported in many autopsies of COVID-19 infected patients. A systemic inflammation triggered by the infection may have implications on the heart. Reports of viral particles being present in the heart suggest the spread and reach of the COVID-19 virus into the cardiovascular system. It has now been reported that the ACE2 receptor is the primary interacting site both for the SARS-CoV and SARS-CoV-2 in the host cell, with 6.5% of all the myocardial cells have been reported to express this ACE2 receptor.17 Various animals and human studies regarding hypertension and diabetes suggest that the concentration of ACE2 receptors increased in those receiving medication with angiotensin-converting enzyme 2 inhibitors or angiotensin receptor blockers. These treatments up-regulate ACE2 receptors in the body, which further assists the entry of SARS-CoV-2 into the target cells. In contrast, an increase in the number or sensitivity of ACE2 receptors decreases the SARS-CoV-2 binding affinity to that present on the membrane. The soluble ACE2 receptor, when up-regulated consecutively, facilitates a reduction in the activity of angiotensin II, exerting a protective effect against the inflammation, and thus vasoconstriction, caused by the COVID-19 infection. This available information can be further explored and researched to treat COVID-19 and concomitant cardiovascular manifestations associated with COVID-19 infection. Also, the advent of different immunization schedules and stringent pharmacovigilance worldwide may provide more insights into the cardiovascular effects of the vaccination. CRediT Authorship Contribution Statement Amrita Chatterjee: Literature Search, Writing-original draft; Writing -review & editing; Rajdeep Saha: Literature Search, Writing-original draft; Arpita Mishra: Conceptualization, Literature Search, Writing-original draft; Deepak Shilkar: Writing-review & editing; Editing and Revision; Venkatesan Jayaprakash: Conceptualization and Supervision; Biswatrish Sarkar: Conceptualization, Supervision, Writing -review & editing; Editing and Revision; Pawan Sharma: Supervision, Writing -review & editing. Acknowledgments The authors duly acknowledge DST-SERB, Government of India funded project [File No. EMR/2016/ 005695] to Dr. Biswatrish Sarkar and Junior Research Fellowship to Amrita Chatterjee and Institute Research Fellowship [Ref No. GO/SS/Extn-Institute-F/Ph.D/2021-22/3289; dated 13.08.21] to Rajdeep Saha by Birla Institute of Technology, Mesra, Ranchi. The authors have no conflicts of interest to disclose. ==== Refs References 1 Spreeuwenberg P Kroneman M Paget J Reassessing the global mortality burden of the 1918 influenza pandemic Am J Epidemiol 187 2018 2561 2567 10.1093/aje/kwy191 30202996 2 Jahangir MA Muheem A Rizvi MF Coronavirus [COVID-19]: history, current knowledge and pipeline medications Int J Pharm Pharmacol 4 2020 1 9 10.31531/2581-3080.1000140 3 Dos Santos WG Natural history of COVID-19 and current knowledge on treatment therapeutic options Biomed Pharmacother 129 2020 1 18 10.1016/j.biopha.2020.110493 4 Shereen MA Khan S Kazmi A COVID-19 infection: Origin, transmission, and characteristics of human coronaviruses J Adv Res 24 2020 91 98 10.1016%2Fj.jare.2020.03.005 32257431 5 Tan W Aboulhosn J The cardiovascular burden of coronavirus disease 2019 [COVID-19] with a focus on congenital heart disease Int J Cardiol 309 2020 70 77 10.1016/j.ijcard.2020.03.063 32248966 6 Zhou P Yang XL Wang XG A pneumonia outbreak associated with a new coronavirus of probable bat origin Nature 579 2020 270 273 10.1038/s41586-020-2012-7 32015507 7 World Health Organization [WHO]. Coronavirus disease [COVID-19]: Symptoms. https://www.who.int/health-topics/coronavirus#tab=tab_3. 8 World Health Organization WHO Coronavirus [COVID-19] Dashboard 2022 https://covid19.who.int/ 9 Booth CM Matukas LM Tomlinson GA Clinical features and short-term outcomes of 144 patients with SARS in the Greater Toronto area J Am Med Assoc 289 2003 2801 2809 10.1001/jama.289.21.JOC30885 10 Shi S Qin M Shen B Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan China. JAMA Cardiol 5 2020 802 810 10.1001/jamacardio.2020.0950 32211816 11 Guo T Fan Y Chen M Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 [COVID-19] JAMA Cardiol 5 2020 811 818 10.1001/jamacardio.2020.1017 32219356 12 Magadum A Kishore R Cardiovascular manifestations of COVID-19 infection Cells 9 2020 1 21 10.3390/cells9112508 13 Dan S Pant M Upadhyay SK The case fatality rate in covid-19 patients with cardiovascular disease: global health challenge and paradigm in the current pandemic Curr Pharmacol Rep 15 2020 1 10 10.1007/s40495-020-00239-0 14 Chen Y Guo Y Pan Y Structure analysis of the receptor binding of 2019 nCoV Biochem Biophys Res Commun 525 2020 135 140 10.1016/j.bbrc.2020.02.071 32081428 15 Li F Structure, function, and evolution of coronavirus spike proteins Annu Rev Virol 3 2016 237 261 10.1146/annurev-virology-110615-042301 27578435 16 Wan Y Shang J Graham R Receptor recognition by the novel corona virus from wuhan: an analysis based on decade-long structural studies of SARS coronavirus J Virol 94 2020 10.1128/JVI.00127-20 e00127-20 17 Zou X Chen K Zou J Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection Front Med 12 2020 1 8 10.1007/s11684-020-0754-0 18 Wang D Hu B Hu C Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan China. Jama. 323 2020 1061 1069 10.1001/jama.2020.1585 32031570 19 Mizumoto K Kagaya K Zarebski A Estimating the asymptomatic proportion of coronavirus disease 2019 [COVID-19] cases on board the Diamond Princess cruise ship, Yokohama, Japan EuroSurveill 25 2020 1 5 10.2807/1560-7917 2020 20 Li LQ Huang T Wang YQ COVID-19 patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis J Med Virol 92 2020 577 583 10.1002/jmv.25757 32162702 21 Qin C Zhou L Hu Z Dysregulation of immune response in patients with coronavirus 2019 [COVID-19] in Wuhan, China Clin Infect Dis 71 2020 762 768 10.1093/cid/ciaa248 32161940 22 Kim IC Kim HA Park JS Updates of cardiovascular manifestations in COVID-19: Korean experience to broaden worldwide perspectives Korean Circ J 50 2020 543 554 10.4070/kcj.2020.0205 32588565 23 Crackower MA Sarao R Oudit GY Angiotensin-converting enzyme 2 is an essential regulator of heart function Nature 417 2002 822 828 10.1038/nature00786 12075344 24 Guan WJ Ni ZY Hu Y Clinical characteristics of coronavirus disease 2019 in China N Engl J Med 382 2020 1708 1720 10.1056/NEJMoa2002032 32109013 25 Roedl K Söffker G Fischer D Effects of COVID-19 on in-hospital cardiac arrest: incidence, causes, and outcome–a retrospective cohort study Scand J Trauma Resusc Emerg Med 29 2021 1 11 10.1186/s13049-021-00846-w 33407690 26 Libby P Tabas I Fredman G Inflammation and its resolution as determinants of acute coronary syndromes Circ Res 114 2014 1867 1879 10.1161/CIRCRESAHA.114.302699 24902971 27 Luo J Zhu X Jian J Cardiovascular disease in patients with COVID-19: evidence from cardiovascular pathology to treatment Acta Biochim Biophys Sin 53 2021 273 282 10.1093/abbs/gmaa176 33428706 28 Hadzibegovic S Lena A Churchill TW Heart Failure with preserved ejection fraction according to the HFA-PEFF score in COVID-19 patients: clinical correlates and echocardiographic findings Eur J Heart Fail 23 2021 1891 1902 10.1002/ejhf.2210 33932255 29 Jacob R Khan M Cardiac biomarkers: what is and what can be Indian J cardiovasc dis women WINCARS 3 2018 240 244 10.1055/s-0039-1679104 31934672 30 Wu YW Ho SK Tseng WK Potential impacts of high-sensitivity creatine kinase-MB on long-term clinical outcomes in patients with stable coronary heart disease Sci Rep 10 2020 1 9 10.1038/s41598-020-61894-3 31913322 31 Hui H Zhang Y Yang X Clinical and radiographic features of cardiac injury in patients with 2019 novel coronavirus pneumonia MedRxiv 2020 10.1101/2020.02.24.20027052 32 Clerkin KJ Fried JA Raikhelkar J COVID-19 and cardiovascular disease Circulation 141 2020 1648 1655 10.1161/CIRCULATIONAHA.120.046941 32200663 33 Zylla MM Merle U Vey JA Predictors and prognostic implications of cardiac arrhythmias in patients hospitalized for COVID-19 J Clin Med 10 2021 1 14 10.3390/jcm10010133 34 Welt FG Shah PB Aronow HD Catheterization laboratory considerations during the coronavirus [COVID-19] pandemic: from the ACC's Interventional Council and SCAI J Am Coll Cardiol 75 2020 2372 2375 10.1016/j.jacc.2020.03.021 32199938 35 Xu Z Shi L Wang Y Pathological findings of COVID-19 associated with acute respiratory distress syndrome Lancet Respir Med 8 2020 420 422 10.1016/S2213-2600[20]30076-X 32085846 36 Tavazzi G Pellegrini C Maurelli M Myocardial localization of coronavirus in COVID-19 cardiogenic shock Eur J Heart Fail 22 2020 911 915 10.1002/ejhf.1828 32275347 37 Bentzon JF Otsuka F Virmani R Mechanisms of plaque formation and rupture Circ Res 114 2014 1852 1866 10.1161/CIRCRESAHA.114.302721 24902970 38 Bangalore S Sharma A Slotwiner A ST-segment elevation in patients with Covid-19—a case series N Engl J Med 382 2020 2478 2480 10.1056/NEJMc2009020 32302081 39 Calvão J Amador AF da Costa CM The impact of the COVID-19 pandemic on acute coronary syndrome admissions to a tertiary care hospital in Portugal Rev Port Cardiol 1-6 2021 10.1016/j.repc.2021.01.007 40 Stefanini GG Montorfano M Trabattoni D ST-elevation myocardial infarction in patients with COVID-19: clinical and angiographic outcomes Circulation 141 2020 2113 2116 10.1161/CIRCULATIONAHA.120.047525 32352306 41 Salinas P Travieso A Vergara-Uzcategui C Clinical profile and 30-day mortality of invasively managed patients with suspected acute coronary syndrome during the covid-19 outbreak Int Heart J 62 2021 274 281 10.1536/ihj.20-574 33731529 42 Morishita T Takada D Shin JH Trends, treatment approaches, and in-hospital mortality for acute coronary syndrome in japan during the coronavirus disease 2019 pandemic J Atheroscler Thromb 28 2021 1 11 10.5551/jat.62746 32493882 43 Liu K Fang YY Deng Y Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province Chin Med J 133 2020 1025 1031 10.1097%2FCM9.0000000000000744 32044814 44 Sanders JM Monogue ML Jodlowski TZ Pharmacologic treatments for coronavirus disease 2019 [COVID-19]: a review JAMA 323 2020 1824 1836 10.1001/jama.2020.6019 32282022 45 Ståhlberg M Reistam U Fedorowski A Post-Covid-19 tachycardia syndrome: a distinct phenotype of post-acute covid-19 syndrome Am J Med 134 2021 1451 1456 34390682 46 Ludvigsson JF Case report and systematic review suggest that children may experience similar long-term effects to adults after clinical COVID-19 Acta Paediatr 110 2021 914 921 10.1111/apa.15673 33205450 47 Most ZM Hendren N Drazner MH Striking similarities of multisystem inflammatory syndrome in children and a Myocarditis-Like syndrome in adults: overlapping manifestations of COVID-19 Circulation 143 2021 4 6 10.1161/CIRCULATIONAHA.120.050166 32787714 48 Valverde I Singh Y Sanchez-de-Toledo J Acute cardiovascular manifestations in 286 children with multisystem inflammatory syndrome associated with COVID-19 infection in Europe Circulation 143 2021 21 32 10.1161/CIRCULATIONAHA.120.050065 33166189 49 Blondiaux E Parisot P Redheuil A Cardiac MRI in children with multisystem inflammatory syndrome associated with COVID-19 Radiology 297 2020 E283 E288 10.1148/radiol.2020202288 32515676 50 Zhao Y Patel J Huang Y Cardiac markers of multisystem inflammatory syndrome in children [MIS-C] in COVID-19 patients: A meta-analysis Am J Emerg Med 49 2021 62 70 10.1016/j.ajem.2021.05.044 34082189 51 Theocharis P Wong J Pushparajah K Multimodality cardiac evaluation in children and young adults with multisystem inflammation associated with COVID-19 Eur Heart J Cardiovasc Imaging 22 2021 896 903 10.1093/ehjci/jeaa212 32766671 52 Minocha PK Phoon CK Verma S Cardiac findings in pediatric patients with multisystem inflammatory syndrome in children associated with COVID-19 Clin Pediatr 60 2021 119 126 10.1177%2F0009922820961771 53 World Health Organization. WHO COVID-19 Solidarity Therapeutics Trial.https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments. 54 Yu WL Toh HS Liao CT A double-edged sword-cardiovascular concern of potential anti-COVID-19 drugs Cardiovasc Drugs Ther 35 2020 205 214 10.1007/s10557-020-07024-7 32557011 55 Bhandari R Khanna G Kuhad A Pharmacological insight into potential therapeutic agents for the deadly Covid-19 pandemic Eur J Pharmacol 890 2021 173643 10.1016/j.ejphar.2020.173643 56 Bala A Sengupta A Matsabisa MG Covid-19: pathophysiology; mechanism of transmission and possible molecular drug target for management Curr Mol Pharmacol 14 2021 509 519 10.2174/1874467213999200831104324 32867666 57 World health organization. WHO's Solidarity clinical trial enters a new phase with three new candidate drugs. https://www.who.int/news/item/11-08-2021-who-s-solidarity-clinical-trial-enters-a-new-phase-with-three-new-candidate-drugs. 2021 58 Beigel JH Tomashek KM Dodd LE Remdesivir for the treatment of Covid-19—preliminary report New Eng J Med 383 2020 1813 1826 10.1056/NEJMoa2007764 32445440 59 Yu WL Toh HS Liao CT Cardiovascular complications of COVID-19 and associated concerns: a review Acta Cardiol Sin 37 2021 9 17 10.6515%2FACS.202101_37[1].20200913A 33488023 60 Cao B Wang Y Wen D A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19 N Engl J Med 382 2020 1787 1799 10.1056/NEJMoa2001282 32187464 61 Cai Q, Yang M, Liu D, et al: Experimental treatment with Favipiravir for COVID-19: an open-label control study. Engineering. 6: 1192-1198, 2020. doi:10.1016/j.eng.2020.03.007 62 Kaur RJ Charan J Dutta S Favipiravir use in covid-19: analysis of suspected adverse drug events reported in the WHO database Infect Drug Resist 13 2020 4427 4438 10.2147%2FIDR.S287934 33364790 63 Rajter JC Sherman MS Fatteh N Use of ivermectin is associated with lower mortality in hospitalized patients with coronavirus disease 2019: the ivermectin in COVID nineteen study Chest 159 2021 85 92 10.1016/j.chest.2020.10.009 33065103 64 López-Medina E López P Hurtado IC Effect of ivermectin on time to resolution of symptoms among adults with mild COVID-19: a randomized clinical trial Jama 325 2021 1426 1435 10.1001/jama.2021.3071 33662102 65 Alam MT Murshed R Bhiuyan E A case series of 100 COVID-19 positive patients treated with combination of ivermectin and doxycycline J Bangladesh Coll Phys Surg 12 2020 10 15 10.3329/jbcps.v38i0.47512 66 Mahmud R Rahman MM Alam I Ivermectin in combination with doxycycline for treating COVID-19 symptoms: a randomized trial J Int Med Res 49 2021 1 14 10.1177/03000605211013550 67 Chandler RE Serious neurological adverse events after ivermectin—do they occur beyond the indication of onchocerciasis? Am J Trop Med Hyg 98 2018 382 388 10.4269%2Fajtmh.17-0042 29210346 68 Bui T Preuss CV: Cephalosporins. [Updated 2021 Aug 31]. In: StatPearls [Internet] 2022 Treasure Island [FL]: StatPearls Publishing https://www.ncbi.nlm.nih.gov/books/NBK551517/ 69 Sultana J Cutroneo PM Crisafulli S Azithromycin in COVID-19 patients: pharmacological mechanism, clinical evidence and prescribing guidelines Drug Saf 43 2020 691 698 10.1007/s40264-020-00976-7 32696429 70 Chowdhury KH Chowdhury M Mahmud S Drug repurposing approach against novel coronavirus disease [COVID-19] through virtual screening targeting SARS-CoV-2 main protease Biology 10 2021 1 14 10.3390/biology10010002 71 Blondeau JM Fluoroquinolones: mechanism of action, classification, and development of resistance Surv Ophthalmol 49 2004 S73 S78 10.1016/j.survophthal.2004.01.005 15028482 72 He Y Li W Wang Z Nosocomial infection among patients with COVID-19: A retrospective data analysis of 918 cases from a single center in Wuhan China. Infect Control Hosp Epidemiol 41 2020 982 983 10.1017/ice.2020.126 32279676 73 Norrby SR Side-effects of quinolones: comparisons between quinolones and other antibiotics Eur J Clin Microbiol Infect Dis 10 1991 378 383 10.1007/BF01967014 1864300 74 Tulkens PM Arvis P Kruesmann F Moxifloxacin safety Drugs R D 12 2012 71 100 10.2165/11634300-000000000-00000 22715866 75 Nham E Ko JH Jeong BH Severe Thrombocytopenia in a Patient with COVID-19 Infect Chemother 52 2020 410 414 10.3947%2Fic.2020.52.3.410 32342677 76 Pelaia C Calabrese C Garofalo E Therapeutic role of tocilizumab in SARS-CoV-2-induced cytokine storm: rationale and current evidence Int J Mol Sci 22 2021 1 16 10.3390/ijms22063059 77 Guaraldi G Meschiari M Cozzi-Lepri A Tocilizumab in patients with severe COVID-19: a retrospective cohort study Lancet Rheumatol 2 2020 e474 e484 10.1016/S2665-9913[20]30173-9 32835257 78 Somers EC Eschenauer GA Troost JP Tocilizumab for treatment of mechanically ventilated patients with COVID-19 Clin Infect Dis 73 2021 e445 e454 10.1093/cid/ciaa954 32651997 79 Gupta S Wang W Hayek SS Association between early treatment with tocilizumab and mortality among critically ill patients with COVID-19 JAMA Intern Med 181 2021 41 51 10.1001/jamainternmed.2020.6252 33080002 80 Charan J Dutta S Kaur R Tocilizumab in COVID-19: a study of adverse drug events reported in the WHO database Expert Opin Drug Saf 8 2021 1 2 10.1080/14740338.2021.1946513 81 Pawlos A Niedzielski M Gorzelak-Pabiś P COVID-19: direct and indirect Mechanisms of statins Int J Mol Sci 22 2021 1 14 10.3390/ijms22084177 82 Gupta A Madhavan MV Poterucha TJ Association between antecedent statin use and decreased mortality in hospitalized patients with COVID-19 Nat Commun 12 2021 1 9 10.1038/s41467-021-21553-1 33397941 83 Wang Y Chen B Li Y The use of renin–angiotensin–aldosterone system [RAAS] inhibitors is associated with a lower risk of mortality in hypertensive COVID-19 patients: a systematic review and meta-analysis J Med Virol 93 2021 1370 1377 10.1002/jmv.26625 33095513 84 Meng J Xiao G Zhang J Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension Emerg Microbes Infect 9 2020 757 760 10.1080/22221751.2020.1746200 32228222 85 Zhang G Wu Y Xu R Effects of renin-angiotensin-aldosterone system inhibitors on disease severity and mortality in patients with COVID-19: A meta-analysis J Med Virol 93 2021 2287 2300 10.1002/jmv.26695 33231299 86 Kuster GM Pfister O Burkard T SARS-CoV2: Should inhibitors of the renin-angiotensin system be withdrawn in patients with COVID-19? Eur Heart J 41 2020 1801 1803 10.1093/eurheartj/ehaa235 32196087 87 Chouchana L Beeker N Garcelon N Association of antihypertensive agents with the risk of in-hospital death in patients with Covid-19 Cardiovasc Drugs Ther 17 2021 1 6 10.1007/s10557-021-07155-5 88 Wiysonge CS Bradley HA Volmink J Beta-blockers for hypertension Cochrane Database Syst Rev 2017 1 71 10.1002%2F14651858.CD002003.pub5 89 Farzam K Jan A Beta blockers. [Updated 2021 Jul 9] StatPearls [Internet]. Treasure Island [FL]: StatPearls Publishing 2021 https://www.ncbi.nlm.nih.gov/books/NBK532906/ 90 Rodriguez JB Alkhateeb H Beta-blockers, calcium channel blockers, and mortality in stable coronary artery disease Curr Cardiol Rep 22 2020 1 5 10.1007/s11886-020-1262-1 31932992 91 Undas A Brummel-Ziedins KE Mann KG Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions Blood 109 2007 2285 2292 10.1182/blood-2006-01-010645 17148593 92 Carvallo HE, Hirsch RR, Farinella ME: Safety and efficacy of the combined use of ivermectin, dexamethasone, enoxaparin and aspirin against COVID-19. medRxiv 1-10, 2020. doi:10.1101/2020.09.10.20191619. 93 Meizlish ML Goshua G Liu Y Intermediate-dose anticoagulation, aspirin, and in-hospital mortality in COVID-19: A propensity score-matched analysis Am J Hematol 96 2021 471 479 10.1002%2Fajh.26102 33476420 94 Sostres C Gargallo CJ Arroyo MT Adverse effects of non-steroidal anti-inflammatory drugs [NSAIDs, aspirin and coxibs] on upper gastrointestinal tract Best Pract Res Clin Gastroenterol 24 2010 121 132 10.1016/j.bpg.2009.11.005 20227026 95 World Health Organization. COVID-19 vaccine tracker and landscape. https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines. 2022 96 World Health Organization. The different types of COVID-19 vaccines.https://www.who.int/news-room/feature-stories/detail/the-race-for-a-covid-19-vaccine-explained. 2021 97 Yang MJ Rooks BJ Le TT Influenza vaccination and hospitalizations among COVID-19 infected adults J Am Board Fam Med 34 2021 S179 S182 10.3122/jabfm.2021.S1.200528 33622834 98 Behrouzi B Araujo Campoverde MV Liang K Influenza vaccination to reduce cardiovascular morbidity and mortality in patients with COVID-19: JACC state-of-the-art review J Am Coll Cardiol 76 2020 1777 1794 10.1016/j.jacc.2020.08.028 33032740 99 World Health Organization. Side Effects of COVID-19 Vaccines. https://www.who.int/news-room/feature-stories/detail/side-effects-of-covid-19-vaccines. 2021 100 Centers for Disease Control and Prevention. COVID-19 Vaccine safety updates. Advisory Committee on Immunization Practices [ACIP].https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-06/03-COVID-Shimabukuro-508.pdf. 2021 101 Bozkurt B Kamat I Hotez PJ Myocarditis with COVID-19 mRNA vaccines Circulation 144 2021 471 484 10.1161/CIRCULATIONAHA.121.056135 34281357 102 Boivin Z, Martin J: Untimely Myocardial Infarction or COVID-19 vaccine side effect. cureus 13: e13651, 2021. doi:10.7759%2Fcureus.13651. 103 Albert E Aurigemma G Saucedo J Myocarditis following COVID-19 vaccination Radiol Case Rep 16 2021 2142 2145 10.1016/j.radcr.2021.05.033 34025885 104 Mouch SA Roguin A Hellou E Myocarditis following COVID-19 mRNA vaccination vaccine 39 2021 3790 3793 10.1016/j.vaccine.2021.05.087 34092429 105 Kim HW Jenista ER Wendell DC Patients with acute myocarditis following mRNA COVID-19 vaccination JAMA Cardiol 6 2021 1196 1201 10.1001/jamacardio.2021.2828 34185046 106 Shay DK Shimabukuro TT DeStefano F Myocarditis occurring after immunization with mRNA-based COVID-19 vaccines JAMA cardiol 6 2021 1115 1117 10.1001/jamacardio.2021.2821 34185047 107 Marshall M Ferguson ID Lewis P Symptomatic acute myocarditis in seven adolescents following Pfizer-BioNTech COVID-19 vaccination Pediatrics 148 2021 1 11 10.1542/peds.2021-052478 108 Rosner CM Genovese L Tehrani BN Myocarditis temporally associated with COVID-19 vaccination Circulation 144 2021 502 505 10.1161/CIRCULATIONAHA.121.055891 34133885 109 Chamling B Vehof V Drakos S Occurrence of acute infarct-like myocarditis following COVID-19 vaccination: just an accidental co-incidence or rather vaccination-associated autoimmune myocarditis? Clin Res Cardiol 31 2021 1 5 10.1007/s00392-021-01916-w
PMC009xxxxxx/PMC9111942.txt
==== Front Journalism (Lond) Journalism (Lond) JOU spjou Journalism (London, England) 1464-8849 1741-3001 SAGE Publications Sage UK: London, England 10.1177/14648849221090744 10.1177_14648849221090744 Articles Avoiding real news, believing in fake news? Investigating pathways from information overload to misbelief https://orcid.org/0000-0002-8740-9313 Tandoc Edson C Jr Kim Hye Kyung Wee Kim Wee School of Communication and Information, Nanyang Technological University, Singapore Edson C Tandoc Jr., Wee Kim Wee School of Communication and Information Nanyang Technological University, 31 Nanyang Link, Singapore, 637718 Singapore. Email: edson@ntu.edu.sg 16 5 2022 6 2023 16 5 2022 24 6 11741192 © The Author(s) 2022 2022 SAGE Publications This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections. This study sought to examine the potential role of news avoidance in belief in COVID-19 misinformation. Using two-wave panel survey data in Singapore, we found that information overload is associated with news fatigue as well as with difficulty in analyzing information. News fatigue and analysis paralysis also subsequently led to news avoidance, which increased belief in COVID-19 misinformation. However, this link is present only among those who are frequently exposed to misinformation about COVID-19. COVID-19 fake news information overload misinformation news avoidance Singapore Ministry of Education Singapore Social Science Research Council MOE2018-SSRTG-022 typesetterts10 ==== Body pmcIntroduction Fake news has become a serious global concern that in the midst of the COVID-19 pandemic, the World Health Organization also declared an “infodemic” over the spread of fake news about the disease (Thomas, 2020). Inaccurate claims about the origin of the virus, home remedies to kill the virus, as well as about COVID-19 vaccination went viral on social media during the pandemic. A number of factors has been examined that may help explain why some individuals believe in misinformation, such as repeated exposure to the misinformation (Fazio et al., 2015; Pennycook et al., 2018) and confirmation bias, or when the fake news aligns with an individual’s pre-existing beliefs (Cha et al., 2020; Ling, 2020). An important factor that some studies have explored is information overload (Bawden and Robinson, 2020). For example, Apuke and Omar (2021) found in a study involving social media users in Nigeria that information overload was related to frequency of sharing fake news related to COVID-19. Lazer et al. (2017) also argued that information overload, coupled with limited individual attention, may prevent adequate assessment of information on social media, which may contribute to misinformation. However, the pathway between information overload and believing in wrong information has not been sufficiently explored. What many studies have examined and established is how experiencing information overload can increase news avoidance (Goyanes et al., 2021; Song et al., 2016), especially during the COVID-19 pandemic, when people across countries were exposed to a wealth of information about the COVID-19 (De Bruin et al., 2021; Ytre-Arne and Moe, 2021). News plays an important role in keeping the public informed about various issues and occurrences. By being informed, citizens can hopefully make better decisions, from whether they should bring an umbrella today to whether they should support a political party. This is why news is considered integral to a functioning democracy—people need regular access to accurate and reliable information to be able to responsibly participate in public affairs (Schudson, 2008). And yet, as fake news rose to buzzword status, news organizations in many parts of the world are seeing continuous decline in readership. While part of it comes from intense competition, part of it also comes from an increasing number of people actively avoiding the news. Studies have documented several reasons for news avoidance, from readers being turned off by negativity in the news to readers finding most news stories to be not relevant to their daily concerns (Pentina and Tarafdar, 2014). A recurring explanation, however, is information overload. News outlets no longer compete with one another for audience attention, but also with non-news outlets, such as social media platforms and messaging apps, that have become significant sources of information for an increasing number of people (Newman, 2019). But while studies have explored the antecedents of news avoidance, comparatively less scholarly attention has focused on the consequences of avoiding the news. Investigating consequences for news avoidance is particularly important in contexts where access to accurate information is critical, such as during the COVID-19 pandemic. Covered round the clock by news organizations around the world, the global health crisis also became a hotbed for misinformation. Against the backdrop of an abundant supply of COVID-19–related information and misinformation, a survey in the United Kingdom found that the initial increase in news consumption during the earlier stages of the COVID-19 outbreak was followed by a “significant increase in news avoidance” (Kalogeropoulos et al., 2020: para. 1). Similar findings were documented in other countries, such as in the Netherlands (De Bruin et al., 2021) and Norway (Ytre-Arne and Moe, 2021). What happens when individuals actively avoid the news about a timely and highly relevant topic that has also been the subject of a flurry of fake news and other types of misinformation? One potential but still unexplored possibility is that individuals who experience information overload and actively avoid real news might fall prey to misinformation instead, especially in a period when the supply of both accurate and inaccurate information about a rapidly evolving crisis is high. Information overload is particularly relevant to the small city-state of Singapore, which has universal internet access and high levels of internet and social media use (Statista, 2019). The Singapore Government also turned to social media platforms, such as the messaging app WhatsApp, on top of traditional news media, to update residents about number of COVID-19 cases and new regulations (Tandoc and Lee, 2020). While Singapore has a very small traditional news media market, dominated by one company that controls all newspapers and another company that controls all broadcast channels—both of which have strong ties with the government—Singapore residents also easily get their news from international sources, such as the BBC (Tandoc, 2021). Building on the growing body of work on information overload and news avoidance (e.g. Edgerly et al., 2017; Holton and Chyi, 2012; Park, 2019; Skovsgaard and Andersen, 2020; Song et al., 2016; Van Den Bulck, 2006), especially during the COVID-19 pandemic (De Bruin et al., 2021; Ytre-Arne and Moe, 2021), and using a two-wave national survey conducted in Singapore, a small nation that recorded among the highest number of COVID-19 cases in Asia, this current study revisits the link between information overload and news avoidance during the pandemic, and how this link may also affect belief in misinformation about COVID-19. Literature review Information overload Humans are said to be cognitive misers. Our capacity to process stimuli is limited, so our “basic tendency is to default to processing mechanisms of low computational expense” (Stanovich, 2018: 424). Such limited capacity becomes salient in the context of information abundance, which can make individuals feel overloaded with information, or what others referred to as information overload. This situation occurs “when information-processing demands on the individual exceed their capacity to process the information, rendering them unable to process all informational inputs” (Pentina and Tarafdar, 2014). Studies have explored potential causes of information overload, particularly in the context of news. For example, Pentina and Tarafdar (2014: 213) identified the following reasons for information overload in the context of online news: “the sheer number and variety of news sources, the limited time available to process them, and the increasingly un-organized and non-verified content that is available from peer-produced and peer-curated sources such as blogs and social networks.” Information overload is related to how individuals navigate the presence of multiple choices. While having options is often a positive experience, the presence of too many options at some point can become cognitively challenging for individuals. Edgerly (2017: 362) argued: “When presented with many options, individuals find it hard to actively compare and evaluate attributes across options and, as a result, will take themselves out of the decision-making process.” The negative impact of being confronted by an overload of choices, or what Scheibehenne et al. (2010: 409) referred to as the “choice overload hypothesis,” has been investigated across different contexts. For example, D’Angelo and Toma (2017) found that online daters who had chosen their respective dates from a set of 24 potential partners reported feeling less satisfied with their choice after a week compared with those who had chosen their dates from a set of only six options. Choosing places to travel or making decisions on online shopping were also found to be hampered by the presence of too many choices (Chen et al., 2009; Park and Jang, 2013). News consumption is also marked by making choices on what to read or watch. Thus, studies have also examined information overload within the specific context of news. Song et al. (2016) proposed a theoretical model to examine the consequences of news overload. Through an online survey of 1200 adults in South Korea, they found that the higher the level of perceived news overload an individual reports, the more likely the individual to also suffer from analysis paralysis and news-related fatigue (Song et al., 2016). Analysis paralysis refers to the “inability to make decisions” in the midst of too much information (White and Dorman, 2000: 160); Song et al. (2016) operationalized this in their model as an individual’s self-reported difficulty in processing information. News fatigue, on the other hand, refers to “the subjective, self-evaluated feeling of being tired of news consumption” (Song et al., 2016: 1179). They found that news overload led to news fatigue, but not to analysis paralysis; they also found that news fatigue is correlated with analysis paralysis (Song et al., 2016). However, the study focused on general news and not on a specific news topic, which could explain why it did not find a link between news overload and news paralysis. This current study thus adopts the theoretical model earlier proposed by Song et al. (2016) and examines it in the specific context of COVID-19–related news. Indeed, studies conducted during the COVID-19 pandemic have documented experiences of information overload due to the sheer volume of COVID-19–related information. For example, interviews with media consumers in Norway revealed how some experienced feeling that information about COVID-19 was “just too much” and that they found difficult to keep up (Ytre-Arne and Moe, 2021: 1748). Thus, guided by previous research on information overload during the COVID-19 pandemic (De Bruin et al., 2021; Ytre-Arne and Moe, 2021) and the framework earlier proposed by Song et al. (2016), we are focusing on COVID-19–related news and hypothesize that:H1. COVID-19 news overload will lead to a) analysis paralysis and b) news fatigue. News avoidance Information avoidance refers to “any behavior intended to prevent or delay the acquisition of available but potentially unwanted information” (Sweeny et al., 2010: 341). Of course, individuals might be unable to attend to information because of structural reasons, such as lack of access or even not knowing that information is available. Thus, Golman et al. (2017) also referred to active information avoidance, or when an individual knows that information is available and has access to the information but still decides to avoid that information. Information avoidance has also been studied in the context of news consumption, although Skovsgaard and Andersen (2020) correctly pointed out a lack of consensus in defining and operationalizing news avoidance. They observed that: “Despite increasing attention to the concept, scholars are far from reaching consensus on the extent of news avoidance” (Skovsgaard and Andersen, 2020: 460). An earlier iteration was “newscast avoidance” which was coined in the context of political activists shunning daily television newscasts because they are dissatisfied with the political developments being reported (Grupp, 1970). In a study of television news exposure of secondary school students in Belgium, Van den Bulck (2006) proposed four types of television news exposure that also brings in the element of intentionality: intentional news selection, unintentional news selection, intentional news avoidance, and unintentional news avoidance. While the unintentional news avoider “watches the news rarely, not because they do not want to but because structural factors pull them away from the news,” the intentional news avoider “does not like the news and consciously seeks to avoid watching it” (Van Den Bulck, 2006: 248). This distinction between intentional and unintentional news avoidance is important: “Understanding the underlying causes for these different types of news avoidance is crucial for understanding that they demand solutions at different levels” (Skovsgaard and Andersen, 2020: 460). This current study focuses on active or intentional news avoidance, consistent with Song et al. (2016) who had found that the consequences of information overload—analysis paralysis and news fatigue—lead individuals to actively avoid the news. We are extending work in this area by focusing on a specific news context, which is the COVID-19 outbreak, instead of operationalizing news avoidance as a general news usage pattern (Skovsgaard and Andersen, 2020). In proposing their model, Song et al. (2016: 1176) had also argued that individuals who cannot cope with information overload “are likely to avoid receiving more news,” hinting a potential direct link between information overload and news avoidance. Another study in South Korea also found that information overload directly led to news avoidance even in the context of social media (Park, 2019). This is also consistent with what other studies during the pandemic found, that information overload is linked with news avoidance (De Bruin et al., 2021; Ytre-Arne and Moe, 2021). Therefore, focusing on Singapore, we also hypothesize that:H2. Analysis paralysis will lead to news avoidance. H3. News fatigue will lead to news avoidance H4. Information overload will lead to news avoidance. Consequences of news avoidance Studies exploring news consumption as well as news avoidance are grounded on the assumption that exposure and attention to news exert important effects on the individual and the society at large. For example, numerous studies have focused on the impact of news consumption across various platforms on political knowledge across different age groups, finding that news consumption, in general, leads to higher political knowledge (Moeller and De Vreese, 2015; e.g. Beam et al., 2016; Ran et al., 2016; Park and Kaye, 2019), except for the use of social media for news (e.g. David et al., 2019). But what about the impact of active news avoidance? Studies on news avoidance have examined its effects on news curation and political participation. Song et al. (2016) found that those who actively avoid the news were more likely to engage in news curation, which refers to using news aggregators to select and limit the news stories they receive. Edgerly et al. (2017) also found that news avoiders tend to have the lowest levels of political participation. However, does avoiding the news, which contains factual reports, lead to belief in misinformation? A survey of students, faculty, and staff members in two universities in Bangladesh during the COVID-19 pandemic found that information overload was positively related to sharing of unverified information (Laato et al., 2020). Sharing an article, however, may not necessarily mean believing in the article (Tandoc et al., 2020). Therefore, this current study builds on these previous studies and examines whether news avoidance is also positively related to believing in COVID-19 misinformation. While studies have distinguished between misinformation and disinformation by defining the former as inadvertent dissemination of inaccurate information and the latter as the intentional creation and propagation of falsehoods (Tandoc et al., 2017; Wardle, 2017), we are using the general term of misinformation, since it is beyond the scope of our study to scrutinize the intention behind the dissemination of falsehoods during the COVID-19 pandemic. Fake news refers to a specific type of misinformation that uses the format and language of real news, but since in this study we showed participants summaries of fake news narratives, instead of the whole fake news story, we use the more general term misinformation. Thus, we also predict that:H5. News avoidance will lead to belief in misinformation about COVID-19. News outlets in Singapore, just like in many other countries, devoted much of their day-to-day coverage to reporting about the developments related to the COVID-19 pandemic. However, avoiding the news may not necessarily mean avoiding all information about COVID-19 altogether, including both accurate and inaccurate information about the pandemic. For example, interviews with young adults in Singapore at the earlier stages of the pandemic showed that while some participants said they actively avoided news related to the pandemic, they still heard about it from interpersonal discussions with friends and family, in person as well as online, like in their family groupchats, where some received inaccurate information forwarded by their parents (Tandoc et al., 2020). Such finding is consistent with the conceptualization of information avoidance as not referring to a successful complete avoidance of a particular information, but to very low levels of exposure due to intentional avoidance and potentially unintentional exposure (Skovsgaard and Andersen, 2020). When individuals actively avoid news about COVID-19, and yet still potentially get exposed to other types of information about COVID-19, what kinds of information these might be? Some may be getting exposed to misinformation instead, which may lead them to develop misbeliefs (see Drummond et al., 2020; Pennycook et al., 2018). We argue, therefore, that news avoidance may lead to belief in misinformation, but only among those who frequently get exposed to misinformation. Since this plausible moderated effect has not been explored, we propose the following question:RQ1. Does exposure to misinformation moderate the link between news avoidance and belief in misinformation? Method Participants and procedures This study is based on a two-wave panel survey involving Singaporean participants, aged 21 and above, recruited from an online panel managed by international survey company Qualtrics. Out of 827 respondents who had initiated the survey, 767 completed the Wave 1 survey in March 2020. The Wave 2 survey was conducted about a month later in April 2020, and 540 participants completed the survey (retention rate of 70.4%). The participants’ age ranged from 21 to 76 (MW1 = 44.26, SD = 12.31; MW2 = 44.91, SD = 12.26) and slightly more than half were male (Wave 1, 52.0%; Wave 2, 54.6%). The majority were ethnic Chinese (Wave 1, 84.5%; Wave 2, 86.3%), followed by Malay (Wave 1, 8.3%; Wave 2, 8.0%); this means our sample slightly overrepresents Chinese Singaporeans, which accounts for 75.9% of the population based on government census data (Singapore, 2020). For both waves, the median education attainment was university graduate, and the median monthly household income was in the range of SGD 6000–7999 (equivalent to USD 4211–5615). The survey was administered in English and took about 15 min to complete (see Table 1 for other demographic statistics and descriptive statistics for measures). Table 1. Sample profile and descriptive statistics. Wave 1 (n = 767) Wave 2 (n = 540) M (SD) or % M (SD) or % Age 44.26 (12.31) 44.91 (12.26) Gender (Male) 52% 54.6% Ethnicity (Chinese) 84.5% 86.3%  Malay 8.3% 8.0%  Indian 4.8% 4.1%  Eurasian 0.7% 0.6%  Other 1.7% 1.1% Education (Upper secondary or less) 12.3% 12.4%  Junior college, pre-university, polytechnic 30.2% 29.4%  University 45.9% 47.4%  Graduate/professional degree 11.6% 10.7% Income (SGD) (below 3999) 19.6% 17.6%  4000–7999 35.5% 35.9%  8000–11999 24.6% 25.6%  12000 and above 20.4% 20.9% Exposure to misinformation 1.97 (0.86) 2.12 (0.93) News overload 2.73 (0.74) 2.83 (0.81) Analysis paralysis 2.35 (0.91) 2.44 (0.96) News fatigue 2.46 (1.02) 2.63 (1.06) News avoidance 1.97 (0.98) 2.10 (0.92) Belief in misinformation 2.23 (0.87) 2.09 (0.79) Note. No significant differences were found across Wave 1 and Wave 2, except for exposure to misinformation, t (539) = –4.58, p < .01; news overload, t (539) = –2.87, p < .01; and belief in misinformation,t (539) = –3.50, p < .01. Wave 2 sample scored slightly higher in exposure to misinformation and news overload than Wave 1 sample, while Wave 1 sample scored higher belief in misinformation thanWave 2 sample. Measures Information overload While Song et al. (2016) assessed perceived overload focusing on news, our current study includes general information besides news. This is in consideration of the fact that information about COVID-19 did not only come from news sources, as the Singapore Government was also proactive in disseminating information to the public through its WhatsApp alert service and online sites (Ministry of Communications and Information, 2020). The news industry in Singapore is also relatively small, dominated by only two media companies. Therefore, we decided to measure information—and not just news—overload. We adapted eight items from the information overload scale from Jensen et al. (2014) and the Health Information National Trends Survey (HINTS) questionnaire in the United States to assess feelings about the overwhelming amount of information on COVID-19. We slightly modified the statements to contextualize them. On a 5-point Likert scale (1 = strongly disagree; 5 = strongly agree), participants reported their level of agreement with statements, including “There is not enough time to do all of the things recommended to prevent the COVID-19”; “No one could actually do all of the COVID-19 recommendations that are given”; “I forget most of the COVID-19 information right after I hear it”; and “It has gotten to the point where I don’t even care to hear new information about the COVID-19.” The scale is reliable (α = 0.87 at Wave 1, α = 0.89 at Wave 2) (Table 2). Table 2. Bivariate correlations between study variables. 1 2 3 4 5 6 7 8 9 10 1. Overload_W1 1 2. Paralysis_W1 0.519 *** 1 3. Fatigue_W1 0.574 *** 0.405 *** 1 4. Avoidance_W1 0.436 *** 0.412 *** 0.732 *** 1 5. Exposure_W1 0.197 *** 0.214 *** 0.147 *** 0.177 *** 1 6. Belief_W1 0.225 *** 0.237 *** 0.142 *** 0.165 *** 0.426 *** 1 7. Overload_W2 0.614 *** 0.456** 0.422** 0.308** 0.189** 0.240** 1 8. Paralysis_W2 0.509 *** 0.798 *** 0.440 *** 0.494 *** 0.204 *** 0.224 *** 0.544 *** 1 9. Fatigue_W2 0.493 *** 0.391 *** 0.540 *** 0.505 *** 0.071 0.110 ** 0.508 *** 0.501 *** 1 10. Avoidance_W2 0.424 *** 0.432 *** 0.469 *** 0.454 *** 0.180 *** 0.170 *** 0.422 *** 0.532 *** 0.735 *** 1 11. Exposure_W2 0.110 ** 0.126 ** 0.075 0.112 ** 0.472 *** 0.254 *** 0.208 *** 0.197 *** 0.018 0.118 ** 12. Belief_W2 0.216 *** 0.217 *** 0.174 *** 0.192 *** 0.401 *** 0.613 *** 0.264 *** 0.292 *** 0.140 *** 0.204 *** Note: Displayed values are Pearson correlation coefficients. Overload_W1/W2 = information overload at Wave 1 or 2; Paralysis_W1/W2 = analysis paralysis at Wave 1 or 2; Fatigue_W1/W2 = news fatigue at Wave 1 or 2; Avoidance_W1/W2 = news avoidance at Wave 1 or 2; Exposure_W1/W2 = exposure to misinformation at Wave 1 or 2; Belief_W1/W2 = belief in misinformation at Wave 1 or 2. **p < 0.01. ***p < 0.001. Analysis paralysis The participants also reported using a 5-point Likert scale (1 = strongly disagree; 5 = strongly agree) to what extent they agreed or disagreed with each of these three statements assessing perceived inability to appraise the COVID-19 situation described in the news, which we also adapted from previous studies (Song et al., 2016; Stanley and Clipsham, 1997): “I find it difficult to understand COVID-19 even after reading the news;” “I have a hard time in understanding news stories about COVID-19;” and “I feel like I still do not get the complete picture even after reading the news about COVID-19.” The scale is also reliable (α = 0.83 at Wave 1, α = 0.84 at Wave 2). News fatigue To assess the subjective feelings of being tired of news consumption, we used three items adopted from Oppenheim (1997) and also used by Song et al. (2016). On a 5-point Likert scale (1 = strongly disagree; 5 = strongly agree), participants reported their agreement with each of these three statements: “I feel tired of receiving and processing information about COVID-19;” “I feel exhausted due to too much news about COVID-19;” and “I am tired of hearing about COVID-19.” The scale is likewise reliable (α = 0.89 at Wave 1, α = 0.91 at Wave 2). News avoidance Recent studies measured news avoidance in different ways, such as by measuring usage of different news sources (e.g. Edgerly et al., 2017). However, Van den Bulck (2006: 236) argued, in the specific context of television news use, that “watching a program is not necessarily an expression of preference and not watching is not always an expression of avoidance.” Thus, other studies measure news avoidance by specifically asking the extent to which individuals actively avoid the news (e.g. Song et al., 2016). For our study, we adapted one item derived from prior research on information avoidance (Howell and Shepperd, 2016; Miles et al., 2008) to specifically focus on news about COVID-19. On a 5-point Likert scale (1 = strongly disagree; 5 = strongly agree), participants reported their agreement with the following statement: “I intentionally avoid news about COVID-19.” Exposure to misinformation Participants were presented with inaccurate claims about the COVID-19 outbreak that went viral in Singapore. They were asked to report how often they heard or came across each claim on a 5-point scale (1 = never; 5 = a lot of times). We selected three misinformation claims that circulated in Singapore during the data collection period (between Wave 1 and Wave 2) and were debunked as false by the Singapore Government (Ministry of Communications and Information, 2020): (1) Woodlands MRT was closed for disinfection due to a suspected case of COVID-19 infection; (2) Gargling with salt water can protect you from COVID-19; and (3) Scientists have confirmed that the COVID-19 virus originated from a biowarfare lab located in Wuhan. Responses were averaged to create an index of exposure to misinformation (α = 0.67 at Wave 1, α = 0.68 at Wave 2). Belief in misinformation Participants were presented with the same set of inaccurate claims about the COVID-19 outbreak and asked to indicate to what extent they think each claim is true or false on a 5-point scale (1= definitely false; 5 = definitely true). We averaged responses to create an index of belief in misinformation, so that a higher score means stronger belief in misinformation about COVID-19 (α = 0.67 at Wave 1, α = 0.69 at Wave 2). A possibility is that for some participants, being exposed to the misinformation claim via the Wave 1 questionnaire may have influenced their belief in it in Wave 2. Therefore, in our analysis, we also controlled for Wave 1 exposure in our model. Results We performed structural equation modeling (SEM; AMOS 25), an approach that accounts for measurement errors by using latent variables (Aiken et al., 1994). All constructs, except exposure, news avoidance, and belief in misinformation, were treated as latent variables with respective measurements. We used the full information maximum likelihood (FIML) method to address missing data in Wave 2 (Graham, 2009). The robustness check using the balanced samples of those who completed both waves found largely consistent results as those found when using the imputed data employing FIML estimation. For information overload, news fatigue and analysis paralysis, Wave 1 data were used, consistent with the model proposed by Song et al. (2016). However, to establish time order between news avoidance and its antecedents, we used news avoidance and belief in misinformation measured at Wave 2. For information overload with 8 items, we employed item parceling (random algorithm) to reduce theoretically unimportant noise (Matsunaga, 2008). In the structural model testing, we controlled for age, gender, education, and income. Taking advantage of our panel data, we also controlled for news avoidance, exposure to misinformation, and belief in misinformation assessed at Wave 1 in the structural model. Measurement model To validate the measurement model, we ran confirmatory factor analysis (CFA) with all latent factors in the proposed model. According to Hu and Bentler (1999), a good model has a root mean square error of approximation (RMSEA) ⩽0.06, a comparative fit index (CFI) ⩾0.95, and a standardized root mean square residual (SRMR) <0.08. The final CFA model fitted satisfactorily (χ2/df = 4.13, CFI = 0.98, RMSEA = 0.06, SRMR = 0.03). Standardized loadings of indicators were all above 0.60, ranging from 0.70 to 0.92 (Kline, 2011). The composite reliabilities (CRs) of latent variables ranged from 0.83 to 0.89 (>0.7) and the average variance extracted (AVE) values of the latent factors ranged from 0.63 to 0.73 (>0.5) (Hair et al., 2010). Also, the square root of each construct AVE was greater than its correlation with other latent factors (Hair et al., 2010). Thus, the CFA model had sufficient reliability, convergent and discriminant validity. Structural model The structural model, which incorporates all our hypotheses, has a good model fit adequately explaining the patterns of association between model constructs (χ2/df = 2.86, CFI = 0.951, RMSEA = 0.049; SRMR = 0.075) (Hu and Bentler, 1999). H1 expected that information overload will lead to a) analysis paralysis and b) news fatigue. As shown in Figure 1, the findings showed that consistent with our prediction, information overload was significantly associated with both analysis paralysis (β = 0.48, p < .001) and news fatigue (β = 0.58, p < .001). Thus, H1 is supported. Figure 1. A conceptual model of misbelief formation. Note: Displayed values are standardized coefficients. Controlled for age, gender, education, income, ethnicity, news avoidance at Wave 1, exposure to misinformation at Wave 1, and belief in misinformation at Wave 1. * denotes p < .05, **p < .01, ***p < .001. H2 predicted that analysis paralysis will lead to news avoidance. Similarly, H3 predicted that news fatigue with lead to news avoidance. Controlling for news avoidance at Wave 1, analysis paralysis (β = 0.17, p < .001) and news fatigue (β = 0.14, p = .008) at Wave 1 both increased news avoidance at Wave 2; this allows us to account for time order, where analysis paralysis and news fatigue were measured at an earlier timepoint, consistent with our prediction that they will subsequently lead to news avoidance. Thus, both H2 and H3 are supported. We also found that news fatigue was marginally associated with analysis paralysis (β = 0.087, p = .066). H4 predicted a direct link between information overload and news avoidance. The model also found that as predicted, information overload at Wave 1 increased news avoidance at Wave 2 (β = 0.20, p < .001). Thus, H4 is also supported. H5 predicted that news avoidance will lead to belief in misinformation. Controlling for belief at Wave 1 and exposure to misinformation at both waves, the analysis found that as predicted, news avoidance was positively associated with belief in misinformation (β = 0.067, p = .036). Thus, H5 is supported. We also found that news paralysis (p = .76) and news fatigue (p = .19) did not directly impact belief in misinformation at Wave 2. Finally, RQ1 asked about the moderating effect of exposure to misinformation on the relationship between news avoidance and belief in misinformation in Wave 2. While we predicted that the link between news avoidance and belief in misinformation will be significant only among those who get exposed to fake news, there is no literature on this moderating effect. Thus, we raised a question, instead. We ran another structural model by adding the interaction term between exposure to misinformation and news avoidance (mean centered). This model had an acceptable model fit (χ2/df = 2.79, CFI = 0.947, RMSEA = 0.048; SRMR = 0.074). There was a significant interaction between misinformation exposure and news avoidance on belief in misinformation (β = 0.10, p < .001). As presented in Figure 2, news avoidance increased belief in misinformation only among those who were more frequently exposed to the misinformation at Wave 2: (a) high exposure group, B = 0.11, 95% CI [0.06, 0.16], (b) average group, B = 0.056, 95% CI [0.01, 0.10] and (c) low exposure group, B = 0.001, 95% CI [−0.06, 0.06]. Figure 2. Effect of news avoidance on belief in misinformation by exposure level. Controlled for exposure to and belief in misinformation at Wave 1, * denotes p < .05, ***p < .001. Discussion and conclusion Using two-wave panel data that allows time-ordering of variables, we examined the potential role of information overload and news avoidance in explaining misbelief formation. This was carried out within the context of the COVID-19 pandemic in Singapore. This current study found that information overload was associated with news fatigue as well as with difficulty in analyzing and processing related information. News fatigue and analysis paralysis also subsequently led to news avoidance, which made individuals more likely to believe in misinformation. However, we also found that this link is only present among those who are frequently exposed to misinformation. In other words, news avoidance can lead to higher propensity to believe in misinformation among those who are frequently exposed to misinformation. The growing academic literature on news avoidance stems from the normative assumption that exposure and attention to news are important processes in a functioning democracy (Edgerly et al., 2017; Pentina and Tarafdar, 2014). We argue that this is more so in this era of misinformation. Individuals can fully and responsibly participate in social and political processes if they are sufficiently and correctly informed about issues and events related to public interest. In the context of a global health crisis, such as what the world witnessed with the COVID-19 pandemic, it is also important for individuals to know about important and accurate information that they can use to protect themselves and their loved ones. However, studies have documented that some individuals actively avoid the news (Edgerly et al., 2017; Pentina and Tarafdar, 2014). While the nature of news is partly to blame, such as its tendency to focus on negative stories, many studies have focused on the role of information overload (Pentina and Tarafdar, 2014). Exposed to an abundant supply of information, some individuals might feel overwhelmed, leading them to actively avoid news instead. This current study finds support for this hypothesis even in the context of COVID-19–related news, consistent with the literature on general news avoidance (Edgerly et al., 2017; Holton and Chyi, 2012; Van Den Bulck, 2006). Specifically, we find support for the earlier theoretical model proposed by Song et al. (2016), which they tested in an online cross-sectional survey in South Korea. Our study based on a two-wave panel survey found that information overload triggered news fatigue, which then led to news avoidance, consistent with what Song et al. (2016) had found. Our analysis also found a significant link from information overload to analysis paralysis to news avoidance, which Song et al. (2016) had hypothesized but did not find to be a statistically significant pathway. More importantly, we found a significant direct cross-lagged effect of information overload on subsequent news avoidance. These collectively emphasize the critical role of information overload in triggering news avoidance and demonstrate two important psychological mechanisms of such negative effect. This current study also sought to expand this theoretical model as well as research on news avoidance by examining its negative consequences. While previous studies focused on exploring the effect of news avoidance on using news aggregation services, employing social media filtering of news, as well as engaging in various form of political participation (Edgerly et al., 2017; Park, 2019; Pentina and Tarafdar, 2014; Song et al., 2016), our study explored the impact of news avoidance on belief in misinformation (Apuke and Omar, 2021; Laato et al., 2020). If news is about informing readers, are news avoiders less informed, if not misinformed? This is a timely and relevant question, given the rise of misinformation that competes with real journalism not just for audience attention but also for social legitimacy (Tandoc et al., 2017; Mourão and Robertson, 2019; Cabañes, 2020). Therefore, we explored the impact of news avoidance on belief in misinformation. We found that those who actively avoid the news about COVID-19 were more likely to believe in pieces of COVID-19 misinformation that went viral in Singapore—but only among those who are frequently exposed to misinformation. Our findings thus contribute to a growing body of work on the adverse effects of news avoidance (e.g. Edgerly et al., 2017; Song et al., 2016) by demonstrating its link to belief in misinformation. Our focus on this moderating effect, however, is exploratory; studies that examined the effects of news avoidance in the context of fake news only examined its direct impact on the frequency of sharing unverified information, not on the extent to which one believes in misinformation (Apuke and Omar, 2021; Laato et al., 2020). In our study, we specifically measured news avoidance—that is, news about COVID-19—instead of general information avoidance. Thus, it may be plausible that individuals who actively avoided news about COVID-19 may have still been exposed to other types of information about it, such as pieces of fake news online. Our study found that news avoidance leads to misbeliefs but only among those frequently exposed to misinformation. Future studies can build on the expanded model we have tested here to go beyond beliefs and examine the effects of news avoidance on misinformed behaviors as well. Future studies can also explore the underlying mechanisms that can explain the impact of news avoidance on belief in misinformation. For instance, when people actively avoid real news, do they then pay more attention to non-news sources to compensate for what they might be missing, thereby inadvertently exposing themselves to unreliable information? Alternatively, when people actively avoid the news in this age of misinformation, do they then potentially miss on the opportunity of being exposed to fact-checks conducted by, or disseminated through, news outlets? The findings of this study must be understood within the context of several limitations. First, we examined our proposed expanded model of the antecedents and consequences of news avoidance within the specific issue of COVID-19. While it is a timely and globally relevant issue, news avoidance has also been conceptualized as a type of general news behavior; for example, Skovsgaard and Andersen (2020: 463) defined news avoidance as “low news consumption over a continuous period of time caused either by a dislike for news (intentional) or a higher preference for other content (unintentional).” Thus, future studies should also test whether our expanded model also holds in the long-term and with regards to a general news behavior, not just on a specific issue. For example, an individual might shun health-related news but might religiously follow business news. Second, our expanded model builds on an earlier model proposed by Song et al. (2016) and focuses on information overload as a predictor of news avoidance; future studies might expand these models by also accounting for other factors that lead to news avoidance, such as perceiving news to be too negative or irrelevant. Third, we relied on a two-wave panel survey, which allowed us to measure our predictor variables at an earlier time than our dependent variables; and yet the survey method also relies heavily on the ability and willingness of respondents to accurately report their attitudes, beliefs, and behavior. Fourth, we believe that it is important to continue exploring the consequences of news avoidance in terms of what people know—news is a source of accurate information, and if they actively avoid the news, how does it affect what they know about the world around them? We tried to address this question by examining impact on belief in misinformation, but future studies can also examine impact on other forms of learning from the news, such as on subjective knowledge and even knowledge miscalibration. Finally, our study was conducted within the context of Singapore, a small but technologically advanced nation, as well as during the earlier stages of the COVID-19 pandemic. While these contexts allowed us to keep our investigation focused, future studies should revisit the patterns we have uncovered here across different socio-political and temporal contexts. Still, despite these limitations, we hope that our findings can contribute to expanding and deepening what we know about the causes and effects of news avoidance as well as the role it plays in the process of misinformation. Author biographies Edson C Tandoc Jr (Ph.D., University of Missouri) is an Associate Professor at the Wee Kim Wee School of Communication and Information at Nanyang Technological University in Singapore. His studies have focused on the impact of journalistic roles, new technologies, and audience feedback on the news gatekeeping process. He has also looked at how readers make sense of critical incidents in journalism and take part in reconsidering journalistic norms; and how changing news consumption patterns facilitate the spread of fake news. Hye Kyung Kim (Ph.D., Cornell University) is an Associate Professor at the Wee Kim Wee School of Communication and Information at Nanyang Technological University in Singapore. Her overarching research goal is to apply communication and social psychological theories to understand the processing and effects of communicative interactions in health. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Singapore Ministry of Education and Singapore Social Science Research Council (MOE2018-SSRTG-022). ORCID iD: Edson C Tandoc https://orcid.org/0000-0002-8740-9313 ==== Refs References Aiken LS Stein JA Bentler PM (1994) Structural equation analyses of clinical subpopulation differences and comparative treatment outcomes: Characterizing the daily lives of drug addicts. Journal of Consulting and Clinical Psychology 62 : 488–499.8063975 Apuke OD Omar B (2021) Social media affordances and information abundance: Enabling fake news sharing during the COVID-19 health crisis. Health Informatics Journal 27 (3 ): 14604582211021470.34250868 Bawden D Robinson L (2020) Information overload: an introduction. In: Oxford Research Encyclopedia of Politics. Oxford, UK: Oxford University Press. DOI: 10.1093/acrefore/9780190228637.013.1360. (accessed 2020-06-30). Beam MA Hutchens MJ Hmielowski JD (2016) Clicking vs. sharing: the relationship between online news behaviors and political knowledge. Computers in Human Behavior 59 : 215–220. Cabañes JVA (2020) Digital disinformation and the imaginative dimension of communication. Journalism & Mass Communication Quarterly 97 (2 ): 435–452. DOI: 10.1177/1077699020913799. Cha M Gao W Li C-T (2020) Detecting fake news in social media: an Asia-Pacific perspective. Commun. ACM 63 (4 ): 68–71. Chen Y-C Shang R-A Kao C-Y (2009) The effects of information overload on consumers’ subjective state towards buying decision in the internet shopping environment. Electronic Commerce Research and Applications 8 (1 ): 48–58. D’Angelo JD Toma CL (2017) There are plenty of fish in the sea: the effects of choice overload and reversibility on online daters’ satisfaction with selected partners. Media Psychology 20 (1 ): 1–27. David CC San Pascual MRS Torres MES (2019) Reliance on Facebook for news and its influence on political engagement. PloS one 14 (3 ): e0212263–e0212263.30889186 de Bruin K de Haan Y Vliegenthart R , et al . (2021) News avoidance during the Covid-19 crisis: understanding information overload. Digital Journalism 9 (9 ): 1286–1302. Drummond C Siegrist M Árvai J (2020) Limited effects of exposure to fake news about climate change. Environmental Research Communications 2 (8 ): 081003. Edgerly S (2017) Seeking out and avoiding the news media: young adults’ proposed strategies for obtaining current events information. Mass Communication and Society 20 (3 ): 358–377. Edgerly S Vraga EK Bode L , et al . (2017) New media, new relationship to participation? A closer look at youth news repertoires and political participation. Journalism & Mass Communication Quarterly 95 (1 ): 192–212. Fazio LK Brashier NM Payne BK , et al . (2015) Knowledge does not protect against illusory truth. Journal of Experimental Psychology: General 144 (5 ): 993–1002.26301795 Golman R Hagmann D Loewenstein G (2017) Information Avoidance. Journal of Economic Literature 55 (1 ): 96–135. Goyanes M Ardèvol-Abreu A Gil de Zúñiga H (2021) Antecedents of news avoidance: competing effects of political interest, news overload, trust in news media, and “news finds me” perception. Digital Journalism. DOI: 10.1080/21670811.2021.1990097. Graham JW (2009) Missing data analysis: making it work in the real world. Annual Review of Psychology 60 : 549–576. Grupp FW Jr (1970) Newscast avoidance among political activists. The Public Opinion Quarterly 34 (2 ): 262–266. Hair JF Black W Babin B , et al . (2010) Multivariate Data Analysis. 7th edition. Upper Saddle River, NJ: Prentice Hall. Holton AE Chyi HI (2012) News and the overloaded consumer: factors influencing information overload among news consumers. Cyberpsychology, Behavior & Social Networking 15 (11 ): 619–624.23020743 Howell JL Shepperd JA (2016) Establishing an information avoidance scale. Psychological Assessment 28 (12 ): 1695–1708.27099980 Hu LT Bentler PM (1999) Cutoff criteria for fit indexes in covariance structure analysis: conventional criteria versus new alternatives. Structural Equation Modeling: A Multidisciplinary Journal 6 (1 ): 1–55. Jensen JD Carcioppolo N King AJ , et al . (2014) The cancer information overload (CIO) scale: establishing predictive and discriminant validity. Patient Education and Counselling 94 (1 ): 90–96. Kalogeropoulos A Fletcher R Nielsen RK (2020) Initial Surge in News Use Around Coronavirus in the UK Has Been Followed by Significant Increase in News Avoidance. Rochester, NY: SSRN. (accessed on 6 June 2020). Kline RB (2011) Principles and Practice of Structural Equation Modeling. 3rd edition. New York, NY: Guilford Press. Laato S Islam AKMN Islam MN , et al . (2020) What drives unverified information sharing and cyberchondria during the COVID-19 pandemic? European Journal of Information Systems 29 (3 ): 288–305. Lazer D Baum M Grinberg N , et al . (2017) Combating Fake News: An Agenda for Research and Action. MA: Shorenstein Center on Media, Politics and Public Policy. Ling R (2020) Confirmation bias in the era of mobile news consumption: the social and psychological dimensions. Digital Journalism 8 (5 ): 596–604. Matsunaga M (2008) Item parceling in structural equation modeling: a primer. Communication Methods and Measures 2 (4 ): 260–293. Miles A Voorwinden S Chapman S , et al . (2008) Psychologic predictors of cancer information avoidance among older adults: the role of cancer fear and fatalism. Cancer Epidemiology and Prevention Biomarkers 17 (8 ): 1872–1879. Ministry of Communications and Information (2020) Clarifications: Misinformation, Rumours Regarding COVID-19. Singapore: Ministry of Communications and Information. Moeller J de Vreese C (2015) Spiral of political learning: the reciprocal relationship of news media use and political knowledge among adolescents. Communication Research 46 (8 ): 1078–1094. Mourão RR Robertson CT (2019) Fake news as discursive integration: an analysis of sites that publish false, misleading, hyperpartisan and sensational information. Journalism Studies 20 (14 ): 2077–2095. Newman N (2019) Executive Summary and Key Findings of the 2019 Report. Oxford, UK: Digital News Report (accessed on 1 November 2019). Oppenheim C (1997) Managers’ use and handling of information. International Journal of Information Management 17 : 239–248. Park CS (2019) Does too much news on social media discourage news seeking? Mediating role of news efficacy between perceived news overload and news avoidance on social media. Social Media + Society 5 (3 ): 2056305119872956. Park CS Kaye BK (2019) Mediating roles of news curation and news elaboration in the relationship between social media use for news and political knowledge. Journal of Broadcasting & Electronic Media 63 (3 ): 455–473. Park J-Y Jang S (2013) Confused by too many choices? Choice overload in tourism. Tourism Management 35 : 1–12. Pennycook G Cannon TD Rand DG (2018) Prior exposure increases perceived accuracy of fake news. Journal of Experimental Psychology: General 147 (12 ): 1865–1880.30247057 Pentina I Tarafdar M (2014) From “information” to “knowing”: Exploring the role of social media in contemporary news consumption. Computers in Human Behavior 35 : 211–223. Ran W Yamamoto M Xu S (2016) Media multitasking during political news consumption: a relationship with factual and subjective political knowledge. Computers in Human Behavior 56 : 352–359. Scheibehenne B Greifeneder R Todd PM (2010) Can there ever be too many options? A meta-analytic review of choice overload. Journal of Consumer Research 37 (3 ): 409–425. Schudson M (2008) Why Democracies Need an Unlovable Press. Cambridge, UK: Polity Press. Singapore (2020) Population in Brief 2020. Reportno. Report Number, Date. Place Published. Institution. Skovsgaard M Andersen K (2020) Conceptualizing news avoidance: towards a shared understanding of different causes and potential solutions. Journalism Studies 21 (4 ): 459–476. Song H Jung J Kim Y (2016) Perceived news overload and its cognitive and attitudinal consequences for news usage in South Korea. Journalism & Mass Communication Quarterly 94 (4 ): 1172–1190. Stanley AJ Clipsham PS (1997) Information overload—Myth or reality? IEE Colloquium (Digest) 97 (340 ): 1–4. Stanovich KE (2018) Miserliness in human cognition: the interaction of detection, override and mindware. Thinking & Reasoning 24 (4 ): 423–444. Statista (2019). Internet User Penetration in Singapore from 2017 to 2023. Hamburg, Germany: Statista. Available at: https://www.statista.com/statistics/975069/internet-penetration-rate-in-singapore/ Sweeny K Melnyk D Miller W , et al . (2010) Information avoidance: who, what, when, and why. Review of General Psychology 14 (4 ): 340–353. Tandoc E (2021) Singapore. Reuters Institute Digital News Report (accessed on 5 July 2021). Tandoc E Huang A Duffy A , et al . (2020) To share is to receive: news as social currency for social media reciprocity. Journal of Applied Journalism & Media Studies 9 (1 ): 3–20. Tandoc E Lee JCB (2020) When Viruses and Misinformation Spread: How Young Singaporeans Navigated Uncertainty in the Early Stages of the COVID-19 Outbreak. 24(3): 778-796. New Media & Society. DOI: 10.1177/1461444820968212. Tandoc E Lim ZW Ling R (2017) Defining “fake news:” A typology of scholarly definitions. Digital Journalism 6 (2 ): 137–153. Thomas Z (2020) WHO Says Fake Coronavirus Claims Causing 'Infodemic. London, UK: BBC. (accessed on 22 March 2020). Van den Bulck J (2006) Television news avoidance: exploratory results from a one-year follow-up study. Journal of Broadcasting & Electronic Media 50 (2 ): 231–252. Wardle C (2017) Fake News. It’s Complicated. https://firstdraftnews.org/articles/fake-news-complicated/ (accessed on 1 April 2017). White M Dorman SM (2000) Confronting information overload. Journal of School Health 70 (4 ): 160. Ytre-Arne B Moe H (2021) Doomscrolling, monitoring and avoiding: news use in COVID-19 pandemic lockdown. Journalism Studies 22 (13 ): 1739–1755.
PMC009xxxxxx/PMC9127449.txt
==== Front sppfe PFE Policy Futures in Education 1478-2103 SAGE Publications Sage UK: London, England 10.1177_14782103221095924 10.1177/14782103221095924 Special Issue: Higher Education Policy and Management in the Post-Pandemic COVID-19 and higher education in Vietnam: Systematically rethinking the quality assurance system and practices towards the ‘new normal’ in post-crisis era Ngo Ha N Faculty of Education, 8491 Victoria University of Wellington , Wellington, New Zealand https://orcid.org/0000-0001-9979-1321 Phan Anh NQ Faculty of Education and Social Work, 1415 The University of Auckland , Auckland, New Zealand Ha N Ngo, Faculty of Education, Victoria University of Wellington, Room 108, 15B Waiteata Road, Wellington 6012, New Zealand. Email: ha.ngo@vuw.ac.nz 5 2022 20 5 2022 20 5 2022 21 4 355371 © The Author(s) 2022 2022 SAGE Publications This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections. COVID-19 has spawned a critical shift in the landscape of higher education (HE) worldwide, entailing transformations of practices across the field, in which quality assurance (QA) for HE has also evolved to both reflect and stay adaptive to the ‘new normal’ formed during and beyond the pandemic. Against the COVID-19 context, this paper retells some of the existing debates for Vietnamese QA and accreditation activities, as well as identifies emerging challenges in QA practices in the post-pandemic era. Theoretically, the paper contributes a conceptual tool to examine the QA of the Vietnamese HE system, embracing three dimensions of teaching and learning, inputs and outputs. This further underpins our inquiry for QA practices in the Vietnamese HE context which has been scaffolded and developed accordingly. Drawn from a critical review and analysis of emerging policies and existing literature, practical implications and projections for the directions of Vietnamese QA in the future will be provided. This paper presents a timely insight for the process of policy-making and the implementation process of QA in Vietnamese HE during a time of uncertainties and looks towards building resilience to future crises. COVID-19 quality assurance higher education Vietnam crisis new normal post-pandemic typesetterts10 ==== Body pmcIntroduction The global spread of the novel coronavirus has had unprecedented impacts on every aspect of life, shifting the way we see the world and think of the society in which we are living. In the context of higher education (HE) in particular, the pandemic is causing a ‘tidal wave of disruption to the higher education sector’ (MacIntosh, 2020, n.p). Vietnam has experienced numerous waves of the COVID-19 outbreak since the first infection detected in January 2020, leading to constant switches between online and offline learning with significant effects on how teaching and learning occurred. Vietnam issued Government Decision 749 on the National Digital Transformation Program and from 3 May 2021, the Ministry of Education and Training (MoET) approved all higher education institutions (HEIs) to transfer up to 30% of their programs to online platforms (MoET, 2020c; 2020d). These critical transformations have led us to question the potential ramifications to QA and accreditation activities in Vietnamese HE during and post-COVID times. This study aims to explore the changing landscape of QA during this time of crisis. The paper begins with the conceptualization of QA before moving on to the presentation of the QA structure of Vietnamese HE. The following section expounds our discussion on extant literature on QA and accreditation and recent policy documents issued by the Government of Vietnam (GoV) and MoET in 2020 and 2021. Against the COVID-19 context, whilst we retell some of the existing debates on QA in Vietnam regarding external QA (EQA) and internal QA (IQA), we argue that these existing problems will be intensified when the entire HE system has been restructured during the global crisis. Based on the analysis, the paper provides implications for future policies and practices for the QA system and accreditation initiatives. Conceptualization of Quality Assurance in Higher Education Quality has long been an established theme in literature across disciplines including education. However, within HE, quality has always been identified as the most contestable notion due to the multi-layered, overlapping characteristics of the sector itself. Developed from the ideologies of total quality management and system approach (Tenner and DeToro, 1992), Cheng and Tam (1997: 1477) defined education quality as “the character of the set of elements in the input, process, and output of the education system that provides services that completely satisfy both internal and external strategic constituencies by meeting their explicit and implicit expectations”. Ellis (1993), however, equated quality to the standards needed to satisfy students-as-customers whilst standards are understood as the minimum threshold by which performance is evaluated (Ashcroft and Foreman‐Peck, 1996). According to Harvey (2002: 247), quality refers to areas such as ‘control, assurance, management, audit, assessment, policy and funding’ which can be investigated through five interrelated approaches: quality as exceptional, perfection, fitness for purpose, value for money, and transformation (Harvey and Green, 1993). Although it is subject to various interpretations which are ‘dependent largely on specific national circumstances, which change over time’ (Brockerhoff et al., 2015: 9), the discourse of quality has progressively gained a dominant role in the national development agenda of many institutions, countries, and educational settings, including Vietnam. Similar to quality, the conceptualization of QA has not yet been universally agreed upon. QA has long been employed as a collective phrase for monitoring, assessing or reviewing. It has been described as a ‘catch-all phrase’ (Williams, 2016: 97), which examines all associated policies, processes, and actions used to maintain and develop the quality of HE (Campbell and Rozsnyai, 2002). QA is also described as an ‘ongoing, continuous process’ of quality evaluation across HE systems, institutions, or programs (Vlăsceanu et al., 2004: 74). In other words, the ultimate goal of QA is to evaluate quality and measure the standards of teaching and learning outcomes (Harvey, 2002). Cheng and Tam (1997) proposed that QA incorporates an evaluation of inputs, processes, and outputs. In a similar vein, Boyle and Bowden (1997) presented QA for HE as an ongoing evolution and application of ethos, policies and processes intended to preserve and ameliorate quality according to articulated values and stakeholders’ demands. A recurring theme across QA discourses is quality values (e.g. academic, managerial, pedagogic, employment focused) and stakeholder-driven power that determine QA typologies, approaches and models for HE (Boyle and Bowden, 1997; Feigenbaum, 1951; Harvey and Knight, 1996; Srikanthan and Dalrymple, 2007). Regardless of the receptive nature of QA, there remains a long-standing controversy over the notion of QA for accountability (QA serves both as a response to the demands of external standards and as a foundation for enhancement) versus QA for improvement (continuous enhancement is placed at the heart of any QA activities or periodic oversight, internally derived from institutional needs to improve quality) (Wilger, 1997). These traits are found as the intrinsic and extrinsic functions that construct two integral components in any QA system: IQA, driven by the commitment for improvement of the institutions and EQA, underpinned by an accountability-oriented perception (Srikanthan and Dalrymple, 2007). IQA embraces a totality of all institutional processes in place to regularly monitor, reflect and enhance the quality of education provided by HEIs to students. Harvey (2002) and Mishra (2006) shared their viewpoint with Westerheijden et al. (2007) and categorized the focus of IQA in HE into three major aspects: Teaching and learning: this measure refers to factors that contribute to the quality of education delivery and reception of learners such as curriculum content and distribution, assessment/graduation evaluation, standards for learning outcomes and academic competence. Inputs: this includes resources fundamental to teaching and learning, for instance the issues of HEIs facility and infrastructure, human resources, and budget. Outputs: this examines the intensity and scope of knowledge and experience advancement. Lecturers’ performance and professional development, the outcomes of students / dropouts, and graduates’ employability are commonly adopted to analyse the quality of educational delivery. EQA, on the other hand, refers to the supra-institutional policies and practices of authorized governance at the national level whereby the participation of external bodies such as auditing and accrediting agencies plays a fundamental role in the monitoring and cross-checking of the implementation process (Dill, 2007). There is a wide array of approaches to external quality monitoring such as evaluation, accreditation, assessment, and audit (Harvey, 2002). It is noteworthy that both IQA and EQA establish stakeholders’ confidence in the attainment of qualities as stated in the educational goals and missions of the HE providers (Blackmur, 2007; Harvey, 2002; Stella, 2008). Some researchers also associate EQA with the perceptions of quality as fitness for purpose and value for money whilst the transformative characteristics of quality are entrenched in the locus of IQA (Fresen and Boyd, 2005; Harvey and Askling, 2003; Harvey and Knight, 1996; Welzant et al., 2011). In this paper, we pursue the conceptualization of QA by Harvey and Green (2002), Mishra (2006), and Dill (2007) to explore the QA of HE in Vietnam at external and internal levels as visualized in Figure 1. How this conceptualization is interpreted in the Vietnamese HE context will be further elaborated in the following sections of the paper.Figure 1. Conceptualization of the paper (configured by the first author based on Harvey and Green, 1993; Mishra, 2006; Dill, 2007). This conceptualization is designated because firstly, it is not our primary intention to explore QA variations, but other than that, we concentrate on what QA actually does and how it is implemented in practice. The stakeholder-driven nature of QA proposed by Harvey (2002) and Dill (2007) provide us with multi-dimensional insights to explore the HE system in Vietnam, one that has long been characterized as ‘complex and fragmented’ and involved multiple actors in the policy-making and policy-implementing processes (Pham and Nguyen, 2019:60). Secondly, COVID-19 has rapidly propelled Vietnamese HE into an advanced stage of development, which espouses two emergent characteristics of education as being open and life-long-oriented (Pham, 2021). Thus, quality itself will also have to evolve to adapt to this new shape and standard of education. This approach offers us a critical systematic tool to revisit both the multiple aspects of quality and the existing and emerging concerns of QA in Vietnam through the (re)configuration of new boundaries and transformability formed and intensified pre-, during and post-pandemic with relevant and practical implications to education governance and policy-making. An overview of Quality Assurance in Vietnamese Higher Education According to Vietnam Higher Education Law 2012 and the Revised Higher Education Law 2018 (National Assembly, 2012, National Assembly, 2018), Vietnam follows the American program and institution accreditation models (Pham and Nguyen, 2019). Accreditation, also known as EQA in the Vietnamese QA system, is a process by which ‘a (non)governmental or private body evaluates the quality of a higher education institution as a whole or of a specific educational programme in order to formally recognize it as having met certain pre-determined minimal criteria or standards’ (Vlăsceanu et al., 2004: 25). However, unlike the US model which operates voluntarily and independently, accreditation in Vietnam is under governmental oversight and is conducted in a mandatory manner (Pham and Nguyen, 2019). The Higher Education Law also stipulates that accreditation outcomes will determine quotas for student enrolment, and the level of state funding, recognition and eligibility for transfer of academic credits. Circular No. 62/2012/TTBGDĐT and Circular No. 38/2013/TTBGDĐT issued in 2012 and 2013 respectively provide four steps in the accreditation procedure, which are (1) self-review by HEIs, (2) registration with an accrediting agency for external review, (3) site visit to HEIs by an accrediting agency and (4) final recognition. The result is valid for 5 years (National Assembly, 2012, National Assembly, 2018). EQA and IQA activities have mutual influences within the national HE system (Do, 2019). EQA is grounded on the assessment and recognition of quality standards of an HEI whilst it is the role of IQA embedded in the HEI to provide a robust mechanism with adequate evidence for EQA to arrive at informed decisions and accurate accreditation outcomes. Hence, the contribution from each component impacts the practices of every other. In this paper, EQA activities and accreditation will be employed interchangeably as this is the sole EQA mechanism that has been legalized in Vietnam to date (Pham and Nguyen, 2019). Externally, the QA mechanism of Vietnamese HEIs consists of (1) state-control through the management of MoET and the Vietnam Education Quality Management Agency (VQA), and (2) the involvement of 10 accrediting agencies (international, public, and private) located across the country. Moet also advocates the employment of accrediting services administered by overseas agencies such as ASEAN University Network-Quality Assurance (AUN-QA) and Accreditation Board for Engineering and Technology (ABET). Internally, as of June 2021, almost every Vietnamese university has established and financially funded the operation of their own Quality Assurance Units (QAUs) (Ministry of Education and Training MoET, 2021a). GoV, MoET, employers and representatives of professional bodies are the key stakeholders involved in EQA whilst IQA driven individually by each HEI embraces the participation of their own managers, academic staff, QA specialist, and students. The Vietnamese HE system has been shaped by various reforms driven by both national and international drivers, which have exerted critical influences onto the QA system (Phan, 2022). Three major achievements of the Vietnamese HE system are (1) the progressive granting of autonomy to HEIs, (2) the socialization and privatization of HE in general and QA activities specifically, and (3) the promotion of online training and digital transformation in the university sector. In recent years, the eight-level National Qualifications Framework – from certificate (Levels 1–3) through to doctorate (Level 8) - that targets standardizing educational degrees and quality to attain regional and international recognition, was also introduced and enforced within the Vietnamese education system (MoET, 2021). In brief, the QA system of Vietnamese HE underpinned by EQA and IQA mechanisms has gone through stages of development over the last decades. How it has been challenged by the enormous impacts of COVID-19 will be discussed followingly. Methodology Based on the conceptualization above, we conducted document analysis on policy statements, statistical reports, consultation papers, legislations and information on websites produced by MoET and GoV. These cover recent guidelines and directives issued by MoET under the impacts of COVID-19, coupled with extant literature on QA of Vietnamese HE and QA and the COVID-19 effects. The policy documents include:Document No. 795/BGDĐT-GDĐH (2020): Guidelines for universities, academies, and colleges to actively implement distance learning and conduct teaching and learning activities through digital platforms. Document No. 988/BGDĐT-GDĐH (2020): A follow-up of Decree No. 795/BGDĐT-GDĐH offering instructions to unify the implementation of QA activities and recognize accumulated learning results (credit-based) in Vietnamese HEIs during the COVID-19 pandemic, on the basis of practical conditions. Document No. 707/BGDĐT-GDĐH (2021): Guidelines for evaluating graduation projects and theses delivered online during the COVID-19 pandemic. Document No. 2077/BGDĐT-GDĐH (2021): Guidelines for organizing teaching and learning activities, end-of-academic year and recruiting/enrolling students during the COVID-19 pandemic at HEIs. Moet also issued Circular No. 38/2020/TT-BGDĐT acknowledging blended/hybrid programs jointly delivered with foreign universities for Masters, and Doctoral degrees and Circular No. 39/2020/TT-BGDĐT fortifying standards for assessing quality of programs. Universities hold accountability for ratifying these guidelines and keeping them updated within their institutional quality review and program operation. The analysis was grounded on the conceptualization of QA presented in the previous section (Dill, 2007; Harvey and Green, 1993; Mishra, 2006). Accordingly, QA practices in Vietnamese HE in this paper are examined through EQA and IQA. Specifically, in terms of EQA, issues are investigated through the accreditation mechanism, policies and policy-making practices at the national level, all of which aim at ensuring accountability and conformity to stated quality standards (Dill, 2007; Harvey, 2002). Besides, as universities are obliged to operate within a national policy framework designated by the government (GoV and MoET in this case) to assure academic standards (Dill, 2007), the discussion also situates HEIs at the intersection of accreditation-related policy-making and planning process where they act as interrelated entities with their own governance and programs under the overarching management of MoET and GoV. Therefore, reviews will also draw on key existing and emerging challenges posed by accreditation as an EQA mechanism that has accompanied recent reforms in national policies and the issues they raise for HE. In terms of IQA, the operationalization of IQA of Vietnamese HE will be explored through three principles of quality monitoring developed by Harvey (2002) and Mishra (2006), including teaching and learning, inputs and outputs. We position HEIs as single IQA units with their (i) own systems of staff, programs, courses, etc. and (ii) unique characteristics and practices that can facilitate or hinder the development of quality and implementation of QA before and during crisis. IQA of HEIs hence will be discussed in relation to the social and political dynamics within the wider Vietnamese HE context. Existing debates on Vietnamese QA and the emerging issues against the context of the pandemic In this section, we will present the existing problems that the Vietnamese QA system has been confronting, and at the same time, argue how these problems became more challenging as the global crisis occurred. In light of the conceptualization of the paper, we will present the analysis in terms of EQA and IQA. External Quality Assurance After almost two decades of development, Vietnam still possesses an incomplete QA system. Its accreditation remains in ‘a nascent stage’ (Nguyen, 2019: 253). Even prior to the pandemic, Vietnamese QA was confronted by a number of obstacles. At the national level, the governance of Vietnamese HE itself is very ‘complex and fragmented’, with diverse involvement of entities ranging from specialised, small HEIs and big, multidisciplinary public universities to private institutions and international branch campuses ( Pham and Nguyen, 2019). A majority of HEIs are affiliated with their line ministry (e.g. Ministry of Health, Ministry of Finance), whilst only one-third of them report to MoET (Le et al., 2019). These HEIs are not entirely independent in terms of finance and management from their line ministries, as HEIs still need to seek permissions on decisive matters and report back to them as well as to MoET. Furthermore, despite MoET’s declaration of its long-term strategy of decentralizing the QA system, scepticism persists over the gap between policy and practice given the complete dependence of the operation of VQA on MoET (in terms of finance, human resources, staff quota and so on). Additionally, policies issued in Vietnam are constrained by a mandatory acknowledgement of the Communist Party’s guidelines and resolutions (Pham, 2019a). This justifies the centralized, top-down characteristics of Vietnamese QA with GoV promulgating core legal frameworks and MoET playing the central role in monitoring quality at the national level. MoET’s responsibilities range from setting up QA regulations, to supervising and authorizing accrediting agencies across the country. All in all, the overlapping roles of various actors in the system management, as well as the half-way decentralization of QA practices in the Vietnamese socio-political setting, can become a great hindrance for the timely response to imperative adaptations needed in times of crisis, such as the COVID-19 pandemic. In other words, Vietnamese QA, in its current state, was already vulnerable to crisis even prior to the advent of the crisis. Meanwhile, at the institutional level, ways of ensuring that QA is practised effectively during the pandemic remains a big concern to institutions. Since this process of institutional autonomy is unsettled, many QAUs belonging to HEIs are left with limited power in deciding what to do with their accreditation whilst being deterred from developing effective QA (Pham, 2018). At the program level, the pace of institutional and program accreditation was already being criticized for being slow and stagnant even before COVID-19 (Pham and Nguyen, 2019). The pandemic has arguably cast a heavier burden on the process, making it difficult to regularly review and update all programs. Lockdowns, as a result of COVID-19, have initiated a tremendous deviation in the way education and QA operate (Eaton, 2020). The relocation of accreditation activities, for instance physical site-visits to online site-visits, has recently sparked discussions and debates among MoET and scholars for it is deemed an overwhelming mission for many HEIs, especially HEIs with limited infrastructures, resources, and in rural areas where the Internet is not stable and the digitalization of teaching and learning and QA activities is still limited (Duong, 2021; Pham and Ho, 2020). Concerns also arise over the insufficient information technology resources as many QAUs are unprepared for quality online support structures and tools, including robust databases, document depositories, and advanced online meeting tools (Pham, 2021; Tran et al., 2020). Likewise, the overlapping roles of many stakeholders in the decision-making and governance process in the Vietnamese HE context as addressed by Le et al. (2019) might lead to ineffective communication among staff and leaders as they conduct institutional reviews pre and during the crisis. This may also hinder students from delivering informed evaluation of the quality of education they received. For Vietnamese students who are ‘latent stakeholders’ holding the least power in the QA process, their voices are only heard indirectly through surveys and occasional interviews in site-visits (Pham, 2019b: 155). They now may find themselves obstructed from authentically engaging in QA activities, given that they are stranded in their hometowns under social-distancing measures. Internal quality assurance The section below attempts to highlight the challenges posed by the pandemic to the IQA of Vietnamese HEIs following the conceptualization of quality (Harvey and Green, 1993; Mishra, 2006) that embodies three dimensions of teaching and learning, inputs and outputs. Existing obstacles and complications that emanated from the pandemic will be simultaneously analysed according to each dimension outlined in the framework. Teaching and learning The repercussions of the COVID-19 crisis on the quality of teaching and learning in Vietnamese HE is most explicitly manifested in the areas of curriculum, content delivery and assessment. Firstly, in terms of curriculum, it has been emphasized that in the challenging context of COVID-19, curriculum serves not purely as “a conveyor or product of a particular body of knowledge’”but also needs to be flexibly reinforced to accommodate an active course of substantive learning inquiry (Nan-Zhao, 2005: n.p). Whilst curriculum represents one key measure of educational quality and students’ learning outcomes that has been standing at the heart of national efforts in enhancing the quality of HE worldwide (UNESCO, 2004), the suspension of physical, in-person classes has induced Vietnamese HEIs to rethink their delivery approaches. Under Directive No. 795/BGDĐT-GDĐH issued in 2020, detailed guidelines for universities, academies and colleges were set out by MoET to encourage and instruct HEIs to actively embrace distance teaching and learning. However, ‘difficult’ and ‘challenges’ are the most frequently repeated phrases in the latest quick report from MoET on the implementation of online teaching and learning after the 2021 new school year commenced (Duong, 2021). Since this was the first-time online and blended learning was officially recognized and widely applied in Vietnam, these policy mandates were relatively generic, top-down structured rather than institutionally quality-focused. This swift transition which embraces the incorporation of a new fully online mode into university curricula raises concerns over the sustainability of quality itself in the long run. For some Vietnamese HEIs that have been intensively internationalizing their curriculum following the Higher Education Reform Agenda, the digitization of curriculum in the time of crisis presents implications for reshaping the competencies of the educators to adapt to new quality standards (Nguyen et al., 2019). These challenges and expected changes in educational practices in Vietnam echo the findings in studies carried out by Cunningham and Pardo (2019), Jones and Sharma (2020), and Famularsih (2020). Secondly, regarding content delivery, an exemplary issue is programmes that involve practicum. According to Pham and Ho (2020), the unplanned shift to online practicum in many institutions and disciplines undesirably turned many universities into submissive e-learning laboratories without properly updating their learning objectives, syllabuses, and content outlines. Furthermore, many HEIs have struggled during the crisis to maintain their quality and satisfy students’ needs due to a scarcity of e-learning materials (Dinh and Nguyen, 2020; Ho et al., 2020). In some specialised majors such as medical studies, although the theoretical components can be delivered online, it is not always possible to compensate for the practical and clinical training that students miss during lockdowns. Indeed, such a deficiency of interactions with peers and field work opportunities likely hinder students from developing cooperative and individualistic learning skills as well as attaining cognitive instructional objectives (Bloom, 1956). In terms of assessment, Document 707/BGDĐT-GDDH by MoET in 2021 provides guidelines for evaluating graduation projects and theses delivered online during the pandemic, and many universities have commenced to adopt various forms of online assessment. Accordingly, HEIs grant autonomy of organizing examinations to faculties and departments, who mostly rely on the learning outputs or standards of a particular module/discipline to decide the most appropriate methods of assessment. Assessment tools vary from online oral quizzes, and multiple choice exams to essay exams, and assignments (See Ministry of Education and Training, 2020a, Ministry of Education and Training, 2020b). However, many universities encountered critical hurdles during implementation; the most identifiable issues were administering test questions, organizing exams, ensuring reliability of academic results and addressing equality in accessing fair and transparent assessment (Pham, 2021; Tran et al., 2020). Findings from an online survey conducted across 225 undergraduate students at Ho Chi Minh City University of Technology and Education demonstrated that insufficient interactions and constraints in infrastructure are compelling drawbacks leading to inaccurate reflection of their actual performance in partaking of e-assessment during the pandemic (Lu and Nguyen, 2020). This calls for an evolution in evaluation practices that requires more holistic and flexible e-learning criteria for the purpose of quality assessment to ensure credibility of learning outcomes in a virtual world (Eaton, 2020). Implications of the process may include the construction of national academic test banks and complete online testing systems as well as innovation in strengthening quality culture across involved stakeholders. Inputs Regarding inputs for quality provision of HE, Vietnam has been confronted with underdeveloped resources, both physically and virtually in the areas of infrastructure, human resources and finance (Pham and Ho, 2020). These obstacles have been intensified under the enormous impacts of COVID-19 and critically challenged educational quality. The adoption of hybrid or online education during the COVID-19 pandemic obligates a process that is composed of collective efforts and procedures. These vary from developing a robust internal QA system for e-learning to incorporating perspectives from all stakeholders including students, academics, support staff, alumni, and employers. Empirical evidence from the case of Vietnamese social work educators and students (e.g. Dinh and Nguyen, 2020; Pham et al., 2021) demonstrates that restricted access to technology resources (e.g. disrupted Internet connection and low-quality sound of the lectures) has impeded effective participation in online courses during COVID-19. These studies indicated that the level of satisfaction of students and lecturers of educational quality was significantly lower than pre-COVID face-to-face instruction delivery. It is noteworthy that in some distant, isolated areas such as Dien Bien, Quang Nam, 70% of students do not have access to electronic devices, not to mention stable internet connection (Duong, 2021). The transformation to e-learning enacted by social-distancing mandates further widens the existing gap in resource accessibility between rural and urban regions, which almost seemed invisible prior to the pandemic thanks to the availability of physical classes (Ewing, 2021; Tran et al., 2020). Furthermore, a critical shortage in well-trained, qualified QA human capital as well as appropriate staff capacity building schemes has been identified as one of the long-term impediments to the development of the internal QA mechanism within HEIs (Nguyen, 2019; Pham, 2018). For active Vietnamese QA specialists working at QA Units of universities, their challenges comprise a deficiency of knowledge, skills, experience and low English command. This situation is ascribed to the existent Vietnamese HE context, which leaves little or no room for a sufficient, ongoing scheme of professional development for QA staff (either formally through intensive QA-focused education or informally through professional workshops and training), their irrelevant profiles prior to undertaking QA roles, as well as the growing involvement of inexperienced young professionals, who possess inadequate comprehension of HE operations. Meanwhile, the limited English competencies also hamper these personnel from profoundly engaging with the international QA community, reflecting on enhanced models of QA and accreditation globally, and strengthening their professional practices (Nguyen, 2021). In times of instability and disruption, the lack of competence and experience in implementing online QA practices may jeopardize the effectiveness of QA policy/guideline implementation. Their participation as professional interlocutor for national control and institutional governance will potentially bring pertinent implications for the post-pandemic realities that require Vietnamese HEIs to critically ‘re-evaluate, rethink, and retool approaches to instructional practices’ (Felix, 2021: 1) to maintain and enhance educational quality in preparation to stay more resilient to future crises. As to financial resources, despite repeated calls for fostering institutional autonomy in governmental documents over the years (Higher Education Law, 2012; Revised Higher Education Law, 2018; Fundamental and Comprehensive Education Reform, 2013), moderate progress has been recorded in HEIs in Vietnam. This is partially attributed to an absence of a homogeneous scheme for institutional financial management. In Vietnam, annual funds allocated to public HEIs are managed by the Ministry of Finance and not until reimbursement is made to them will an annual budget for QA activities be finalized and assigned by institutions themselves. As an indirect receiver of funding, many HEIs position themselves as being stranded in a half-way institutional autonomy, submissive and ‘exercise a little independence in the management of their own matters’ (Le et al., 2019: 7). During a time of crisis, inflexibility in finance management can impede many Vietnamese HEIs from settling budgets in response to urgent quality-improvement demands and high-cost services. Outputs In terms of output, staff performance, learning outcomes and employability are key quality outputs that have been substantially suppressed by the pandemic’s turbulence. One concern that emerged from the COVID-19 era for many HEIs is staff performance and professional development. For academics, the hasty transition from traditional ‘talk-and-chalk’ classrooms to virtual teaching without foundational IT-training or professional development activities has been reported as a frustrating experience. According to a large-scale survey conducted on the COVID-19 impacts in HEIs across 47 countries/territories including Vietnam, individual psychological and behavioural responses have been confirmed to be negatively influenced (Asian Pacific Quality Network, 2020). However, issues of mental health support have long been overlooked in the Vietnamese education system. As we have studied through all the related QA documents in Vietnam, teachers' mental health and well-being has never been acknowledged as a quality index in any QA measurements. At the crisis juncture, little attention has been paid to how pedagogically stressful it has been for teachers due to the switch of the instructional mode of delivery. Similarly, personal strains on lecturers resulting from the pandemic such as health concerns, emotional care, new family and domestic responsibilities, professional and personal plans, or household organisation are rarely put in the forefront, if at all considered. Studies have shown that Vietnamese teachers are undesirably pushed to stay more resilient to unexpected transformation in daily teaching routines caused by the pandemic (Pham and Phan, 2021; Pham et al., 2021). Indeed, despite the volume of work and additional training needed to adjust to online teaching and assessment during COVID-19, teacher remuneration paradoxically remains unchanged (Pham, 2021). That said, the pandemic has created a constant struggle of lecturers to balance between moral profession, cultural norms, teaching quality and the essentiality to financially sustain over a time of uncertainties. The extrinsic contextual and societal factors subsequently call for an ongoing ‘negotiation and reconstitution of values and identities’ (Phan and Phan, 2006: 136). It is hoped that this will indirectly mitigate adverse influences on the quality of academic outputs of teachers and learning outcomes of students throughout the pandemic compared to their pre-crisis teaching and learning. Besides, education systems and employability skills are two key determinants that have the most severe effects on the unemployment rate in Vietnam under the COVID-19 impacts (Nguyen et al., 2019). Investigations into the employability of Vietnamese students majoring in English education during the pandemic revealed that the switch to remote learning mode has had ‘significant impact on their employability capital’ and imposed restrictions on their post-study career plans as well as their career-related decision-making, with variations recorded among groups of various backgrounds (Vu et al., 2022). A post-COVID era: Implications for Vietnamese QA An overall picture that is clearly discernible in this article is that COVID-19 has provided the HE system in Vietnam with new challenges that need intense reworking and rethinking, as much as it has elsewhere in the world (Crawford et al., 2020; MacIntosh, 2020, n.p.). As Altbach and De Wit (2020) have asserted, although predicting a post-COVID future for universities is not an easy task, demand for higher education is still significant and will continue to grow. This means that QA cannot afford to lose its importance and may play an even more important role. It should be noted that keeping QA activities going is important also to ensure continually maintained trust in the quality of education provision within and between systems, especially with the inclusion of online education for the past year and in the future. As the Vietnamese HE system is moving from temporary measures to longer-term sustainable adjustments that hopefully can be the antidote to a future crisis on a global scale, some initial projections towards the future landscape of Vietnamese QA for HE as the result of the COVID-19 crisis are presented in this section. QA in a future where blended learning is the new trend What looms in the post-pandemic future is a new paradigm of teaching and learning that might depart from traditional and lecture-based activities and skew towards more digitally facilitated group activities, discussions and individual self-exploration of online educational resources in Vietnam (Pham and Ho, 2020; Pham and Phan, 2021). In that sense, QA policies and practices need to follow and follow-up these possible changes. As learning now happens far beyond a four-walled room and may occur anytime, anywhere, both synchronously and asynchronously, evidence-based criteria for QA purposes might be more difficult to achieve and collect (Eaton, 2020). Learning, predicted by Ewing (2021: 39), will become more oriented to ‘stackable segments’ whereby participants can receive ‘education which is primarily just-in-time not just-in-case’. However, we should be mindful that digital learning requires stable infrastructure and digital platforms, which might be unevenly distributed across Vietnam. The disruptions to traditional classrooms created by the conversion to online learning has only occurred in provinces or cities where there was an outbreak. This requires flexibility in QA policies and practices, and the criteria of QA should be refined in order to satisfactorily address the situation of combined online and offline learning and teaching. Furthermore, learning may be disrupted for particular groups of marginalized students such as those of ethnic minorities in Vietnam living in disadvantaged conditions. The challenge for QA here is to embrace a holistic approach to online learning and teaching that not only guarantees effectiveness and transparency of the QA process, but also minimizes any inequalities caused by this incoming shift in instruction delivery. In this case, we expect there will be training for teachers in terms of content development, as well as assessment in online learning, or the combination of both online and offline learning when possible so that students in less advantaged areas will not be further disadvantaged by the ongoing crisis. QA in a future where there is increasingly profound involvement of students in QA activities It has been recommended that seeking collaborative opportunities between students and staff academic representatives is necessary so that students can be involved in the conception, design, implementation and review of any future programmatic and institutional changes (Whelehan, 2020). This partnership with students, hopefully, can contribute to a more student-led approach in the post-digital learning era. Concurring with Whelehan (2020), we foresee a future in which both students and teachers are on a similar learning journey in a digital learning environment. If this is to happen, QA policies and practices are expected to get involved in feedback mechanisms at an institutional level. In Vietnam, QA is seen as a ‘ritualistic activity’ carried out in HEIs to fulfil requirements set by GoV’s regulations (Tran and Vu, 2019: 115), sometimes the discourse only exists between universities’ leaders and their QA staff. The role of students in QA processes is restricted to surveys on teaching quality, programs, libraries and services offered at the institutions. The culture of student partnership or students-as-partners, a practice adopted by other developed QA systems such as those in the UK, Scotland and New Zealand, remains a completely new concept in the Vietnamese HE context (New Zealand Academic Quality Agency, 2017, Student Partnerships in Quality Scotland, 2012). The new situation of COVID-19 can be an opportunity for a collaborative approach to QA at the programme and institutional level that may play an important role in ensuring students successfully attain a quality education. A future where QA is going hybrid Whilst QA traditionally relies on actual classrooms, physical infrastructure and physical teacher-student interactions in HEIs to assess the educational settings, now QA policies and practitioners including QA policy makers at national and institutional levels and QA officers at QA units may need to take the virtual environment into consideration. From the institutional perspective, it is crucial to envision a future where both IQA and EQA operate on a hybrid basis. Specifically, HEIs may need to prepare for online visits of QA practitioners by better equipping themselves with technological support structures and tools, such as databases, document depositories and well-established online meeting platforms so that institutions and programs going through an online review are not disadvantaged. Hybrid forms of QA that combine both online and offline assessment are possible and desirable in the future. It should be noted that online QA practices require rigorous examination of numbers, documents from experts, maintenance of confidentiality, professionality and non-conflict of interest, as well as acknowledgement of the specific challenges from the online environment (Kelo, 2020). We propose that online QA practices and/or hybrid QA practices are not only a ‘fire-fighting strategy’ to be used during the COVID-19 outbreak but can actually serve a longer-term purpose in Vietnamese HE for several reasons. Firstly, online visits offer the possibility to engage experts of QA from abroad with less additional cost and to interact with more stakeholders, which Vietnam has needed for the implementation and improvement of its QA system. Going online can save travel time for practitioners and allow them to focus more on what matters most in the QA process, especially for EQA. Secondly, as expected and specified in the QA regulations of MoET, institutions will gradually bear the cost of QA by themselves. Hybrid QA practices can facilitate initial stages of EQA procedures such as initial accreditation, initial fact collection and fact checking. This will not only reduce the estimated cost of QA but also bring benefits such as timesaving, efficiency and wider participation of stakeholders (such as employers, policy makers, teachers, students and parents). Physical visits can be reserved for activities such as verification and feedback, which are critical for the improvement of QA in Vietnam due to great discrepancies among institutions of different geographical areas in the country. The predicted rise of transnational higher education in Vietnam and challenges for QA Global mobility has been stalled and international education, though still enticing for many students, may be negatively affected in the future (Yang, 2020). The hit of the novel virus has been detrimental to global economies and, henceforth, parents and students will need to take monetary expenditures into more serious consideration. Students may choose to stay in their home country rather than travel abroad for international education. Foreign students may also be denied study visas under the COVID-19 rules (as in the cases of border closures in Australia and New Zealand), and international travel may be more expensive and subject to more restrictions than before. The precarity and fear induced by the global outbreak of COVID-19 and the resultant restrictions on movement may lead students to opt for alternative to gain an international education experience other than physical mobility, such as transnational higher education (TNHE), or international education at home. This educational provision is offered through different variations of modalities such as joint-degree, twinning or articulation programs (e.g. 2+2, 3+1) and international branch campuses. In the former model, students pursue their degrees being co-delivered by a Vietnamese university and a foreign institution through which they spend the first phase (2 or 3 years) in Vietnam and the remainder overseas. The latter model requires the physical presence of a foreign institution in Vietnam that offers its programs offshore (e.g. RMIT University with their branch campuses based in Hanoi and Ho Chi Minh City). Other modes of TNHE (e.g. online courses) are excluded from the scope this paper covers. The nature of TNHE practices is complex and diverse (Knight and McNamara 2015) Hence, during the time of crisis, QA for TNHE programmes will draw more attention from policy makers and practitioners. This area of QA is still the least monitored in Vietnam (Nhan and Nguyen, 2018) and also the most challenging aspect because, as Ziguras and McBurnie (2014) specify, the nature of transnational partnerships in education entails difficulty in regulating and ensuring the quality of programs delivered whilst ensuring the quality of joint programs is one of the most important issues in implementing transnational education (Hou et al., 2016; Kallo and Semchenko, 2016). With the post-pandemic increasing interest in this form of education from students and parents, we expect the demand for QA practices of joint programmes and transnational higher education will also increase so that students can gain the actual benefits of international education. Conclusion All in all, COVID-19 is a crisis that brings about danger, but also possible changes and transformations. This paper has outlined the status quo of the Vietnamese QA for HE, what we think will be problems emerging out of the pandemic context in Vietnam and how its QA system will need to evolve to respond to the ‘new normal’. After years of development, Vietnam has worked to establish a QA system for HE that consists of both IQA and EQA (accreditation) components and involves various actors in the monitoring of quality at institutional and program levels. These range from GoV, MoET, line ministries, and domestic and international accrediting agencies at the external and macro-management level to higher education institutions including QA specialists, academics and students at the internal level. Based on the conceptualization of QA (Dill, 2007; Harvey and Green, 1993; Mishra, 2006), we position Vietnamese HE as a case study and QA at the epicentre of systematically rethinking educational policies and practices in this time of uncertainties and strive to present a holistic picture with emerging challenges and practical considerations for the quality of HE at the external and internal levels. Such an assortment of challenges posed by COVID-19, if examined through a positive lens, can intersect with the ongoing motion of Vietnamese HE and become the country’s opportunity to rethink and restructure its accreditation and QA evolution. Our arguments from the unique perspective of Vietnam may also help enrich the ongoing debates on the quality of education delivery through the digitalization of HE in a post-pandemic climate which involves the evolution of hybrid and online teaching formats. As one among the first papers to initiate the discussion on the post-pandemic HE landscapes in Vietnam, we acknowledge several limitations of our work. These include the scope of review and the restricted availability of publications in the research areas, especially those with empirical evidence investigating Vietnamese HE in general and QA in particular due to the contemporary nature of the crisis. Future scholars are encouraged to develop this discussion to a larger extent of audience across HE in order to craft guidelines on good practices of specific quality dimensions such as pedagogical innovation or professional development in delivering remote teaching and learning. A comparative study in QA across regional and national contexts is also potentially beneficial to depict the impacts of cultural variations of stakeholders’ responses in times of uncertainties. Ha Ngo is a PhD candidate in International Education, Victoria University of Wellington. Prior to her doctoral study, she was involved in academic exchange in Uppsala University, Sweden through the Erasmus Mundus scholarship and obtained her Master of Education from Australia before becoming a university lecturer in Vietnam. Her research interests include quality assurance, transnational higher education, international education, transnationalism and educational technology. Anh Ngoc Quynh Phan is currently a doctoral student at University of Auckland. Her research interests involve transnationalism, mobility, migration, sense of belonging, doctoral education, higher education, auto-ethnography and poetic inquiry ORCID iDs Ha N Ngo https://orcid.org/0000-0002-4275-3620 Anh NQ Phan https://orcid.org/0000-0001-9979-1321 The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding: The author(s) received no financial support for the research, authorship and/or publication of this article. ==== Refs References Altbach P de Wit H (2020) Post pandemic outlook for HE is bleakest for the poorest. University World News. April 4. Ashcroft K Foreman‐Peck L (1996) Quality standards and the reflective tutor. Quality Assurance in Education 4 (4 ): 17–25. doi: 10.1108/09684889610146154. Asian Pacific Quality Network (APQN) (2020) APQN Survey Research on the COVID-19 Impact in Higher Education Institutions (HEIs). Shanghai, China: APQN. Blackmur D (2007) The public regulation of higher education qualities: Rationale, processes, and outcomes. In: Quality Assurance in Higher Education. Berlin, Germany: Springer, pp. 15–45. Bloom BS (1956). Taxonomy of educational objectives. Vol. 1: cognitive domain. New York, NY: McKay 20 (24 ): 1. Boyle P Bowden JA (1997) Educational quality assurance in universities: an enhanced model. Assessment & Evaluation in Higher Education 22 (2 ): 111–121. Brockerhoff L Huisman J Laufer M (2015) Quality in Higher Education: A Literature Review. Ghent, Belgium: Centre for Higher Education Governance, Ghent University. Campbell C Rozsnyai C (2002) Quality Assurance and the Development of Course Programmes. Papers on Higher Education. Bucharest, Romania: UNESCO‐CEPES. Cheng YC Tam WM (1997) Multi‐models of quality in education. Quality Assurance in Education. Cunningham P Pardo GA (2019) Editorial note. The shifting mind set of the higher education internationalization landscape. ObIES 3 : 23–25. Dill D (2007) Quality assurance in higher education: practices and issues. In-Chief Barry McGaw, Eva Baker and Penelope P. Peterson. Amsterdam, Netherlands: Elsevier Publications. Dinh LP Nguyen TT (2020) Pandemic, social distancing, and social work education: students’ satisfaction with online education in Vietnam. Social Work Education 39 (8 ): 1074–1083. Do QTN (2019) Quality assurance and accreditation as a mechanism for accountability. In: Nguyen CH Shah M (eds) Quality Assurance in Vietnamese Higher Education: Policy and Practice in the 21st Century. Berlin, Germany: Springer Nature, 81–96. Duong T (2021) MoET expressed no optimistim for online teaching. Thanhnien News. Ellis R (1993) Quality Assurance for University Teaching. Buckingham, UK: SRHE & Open University Press. Eaton J (2020) Taking Initial Steps: A Path for Rethinking Accreditation and Quality Assurance. Inside Accreditation. Washington, DC: Council for Higher Education Accreditation / CHEA International Quality Group. Ewing L-A (2021) Rethinking higher education post COVID-19. The Future of Service Post-COVID-19 Pandemic 137 . Famularsih S (2020) Students’ experiences in using online learning applications due to COVID-19 in English classroom. Studies in Learning and Teaching 1 (2 ): 112–121. Felix JJ (2021) Higher education in times of instability and disruption: rethinking notions of values, value creation and instructional practices in Vietnam and beyond. Frontiers in Communication 6 : 22. Fresen JW Boyd LG (2005) Caught in the web of quality. International Journal of Educational Development 25 (3 ): 317–331. Harvey L (2002) Evaluation for what? Teaching in Higher Education 7 (3 ): 245–263. Harvey L Askling B (2003) Quality in higher education. In: Begg R (ed) The Dialogue between Higher Education Research and Practice. Berlin, Germany: Springer, 69–83. Harvey L Green D (1993) Defining quality. Assessment & Evaluation in Higher Education 18 (1 ): 9–34. Harvey L Knight PT (1996) Transforming Higher Education. London, UK: Open University Press and SRHE. Ho NTT Sivapalan S Pham HH , et al. (2020) Students’ adoption of e-learning in emergency situation: the case of a Vietnamese university during COVID-19. Interactive Technology and Smart Education. Hou Y-C Ince M Tsai S , et al. (2016) Quality assurance of joint degree programs from the perspective of quality assurance agencies: experience in East Asia. Higher Education Research & Development 35 (3 ): 473–487. Kallo J Semchenko A (2016) Translation of the UNESCO/OECD guidelines for quality provision in cross-border higher education into local policy contexts: a comparative study of Finland and Russia. Quality in HigHer Education 22 (1 ): 20–35. Jones K Sharma R (2020) On reimagining a future for online learning in the post-COVID era. In: Kevin Jones and Ravi Sharma (2020). Reimagining A Future for Online Learning in the Post-COVID Era. First Posted on medium.com. Amsterdam, Netherlands: Elsevier. Kelo Mnd (2020) European Quality Assurance Agencies’ Response to the COVID-19 Pandemic - from Fire-Fighting to Re-thinking External Quality Assurance. Strasbourg, France: Council of Europe. Knight J McNamara J (2015) The Impact of Transnational Education in Receiving Countries. International Higher Education 82 : 3–5. Le KAT Hayden M Nhan TT (2019) Development of the higher education sector in Vietnam. In: Nguyen HC Shah M (eds) Quality Assurance in Vietnamese Higher Education. Berlin, Germany: Springer, 1–23. Lu TMO Nguyen TNT (2020) Assessing the effectiveness of students’ online learning amid the COVID-19 epidemic. VNU Journal of Science: Education Research 37 (1 ). Ministry of Education and Training (MoET) (2020a) Document 795/BGDĐT-GDĐH: Guidelines for Universities in Implementing Distance Learning during COVID-19. Hanoi, Vietnam: MOET. Ministry of Education and Training (MoET) (2020b) Công Văn 988/BGDĐT-GDĐH Về Đảm Bảo Chất Lượng Đào Tạo Từ Xa Trong Thời Gian Phòng Chống Dịch COVID-19 [Document 988/BGDĐT-GDĐH on Quality Assurance of Distance Education in COVID-19 ]. Hanoi, Vietnam: MoET. Ministry of Education and Training (MoET) (2020c) Quyết Định 749/QĐ-TTg Phê Duyệt “Chương Trình Chuyển Đổi Số Quốc Gia Đến Năm 2025, Định Hướng Đến Năm 2030” [Decision No. 749/QD-TTg: Approval for National Digital Transformation Program to 2025, with Orientation to 2030]. Hanoi, Vietnam: MoET. Ministry of Education and Training (MoET) (2020d) Thông Tư 38/2020/TT-BGDĐT Quy Định Về Liên Kết Đào Tạo Với Nước Ngoài Trình Độ Đại Học, Thạc Sĩ, Tiến Sĩ Theo Hình Thức Trực Tuyến Và Hình Thức Trực Tiếp Kết Hợp Trực Tuyến [Circular No. 38/2020/TT-BGDDT on Regulations of Joint Training with Foreign Universities, Masters and Doctoral Degrees in Online and Hybrid Modes]. Hanoi, Vietnam: MoET. Ministry of Education and Training (MoET) (2021a) Danh Sách Các Cơ Sở Giáo Dục Được Công Nhận Đạt Tiêu Chuẩn Chất Lượng Giáo Dục (Cập Nhật Đến Ngày 30/6/2021) [List of Higher Education Institutions Recognized to Have Met Educational Quality Standards (Updated to June 30 , 2021)]. Hanoi,Vietnam: MoET. Ministry of Education and Training (MoET) (2021b) Triền Khai Khung Trình Độ Quốc Gia Việt Nam cho Giáo Dục Đại Học [Implement National Qualifications Framework for Vietnamese Higher Education. Hanoi, Vietnam: MOE. Mishra S (2006) Quality Assurance in Higher Education: An Introduction. Padi, India: National Printing Press. MacIntosh R (2020) Leadership intelligence: how to manage in unchartered territory. Available at: https://charteredabs.org/leadership-intelligence-how-to-manage-in-unchartered-territory/ Nan-Zhao Z (2005) Four ‘Pillars of Learning’ for the Reorientation and Reorganization of Curriculum: Reflections and Discussions. Geneva, Switzerland: International Bureau of Education‐UNESCO. National Assembly (2012) Higher Education Law. Hanoi, Vietnam: National Assembly. National Assembly (2018) Law Amending and Supplementing a Number of the Higher Education Law. Hanoi, Vietnam: National Assembly. Nhan TT Nguyen HC (2018) Quality challenges in transnational higher education under profit-driven motives: the Vietnamese experience. Issues in Educational Research 28 (1 ): 138–152. New Zealand Academic Quality Agency (2017) Memorandum of Understanding - AQA & NZUSA . [online] Available at: < https://aqa.ac.nz/memorandum > [Accessed 3 May 2022]. Nguyen CH (2019) Building national capacity for quality assurance. In: Nguyen HC Shah M (eds) Quality Assurance in Vietnamese Higher Education. Berlin, Germany: Springer, 241–260. Nguyen HC (2021) Exploring internal challenges for quality assurance staff in Vietnam: voice of insiders. Quality Assurance in Education 29 (2/3 ): 70–83. doi: 10.1108/QAE-07-2020-0080. Nguyen NT Tran LT Le TTT (2019) Work-integrated learning for enhancing graduate employability: moving from the periphery to the centre of the curriculum. In: Nguyen NT Tran LT (eds) Reforming Vietnamese Higher Education. Berlin, Germany: Springer, 113–132. Pham DNT (2021) Bảo đảm và kiểm định chất lượng giáo dục đại học trong bối cảnh đại dịch Covid 19: Tác động và vấn đề [Assuring and accrediting educational quality of higher education in the COVID-19 context: issues and Impacts]. Tạp Chí Khoa Học Và Giáo Dục Việt Nam [Journal of Educational Science] 37 . Pham H-H Ho T-T-H (2020) Toward a ‘new normal’ with e-learning in Vietnamese higher education during the post COVID-19 pandemic. Higher Education Research & Development 39 (7 ): 1327–1331. Pham HT (2018) Impacts of higher education quality accreditation: a case study in Vietnam. Quality in Higher Education 24 (2 ): 168–185. Pham HT (2019a) Limited legitimacy among academics of centrally driven approaches to internal quality assurance in Vietnam. Journal of Higher Education Policy and Management 41 (2 ): 172–185. Pham HT (2019b) Stakeholders’ engagement in quality assurance in Vietnam. In: Nguyen HC Shah M (eds) Quality Assurance in Vietnamese Higher Education. Berlin, Germany: Springer, 137–161. Pham HT Nguyen CH (2019) History of quality assurance in Vietnamese higher education. In: Nguyen HC Shah M (eds) Quality Assurance in Vietnamese Higher Education. Berlin, Germany: Springer, 59–80. Pham LTT Phan ANQ (2021) “Let’s accept it”: Vietnamese university language teachers’ emotions in online synchronous teaching in response to COVID-19. Educational and Developmental Psychologist. Ahead-of-print. DOI: 10.1080/20590776.2021.2000321. Pham PT Phan TT Nguyen YC , et al. (2021) Factor associated with teacher satisfaction and online teaching effectiveness under adversity situations: a case of Vietnamese teachers during COVID-19. Journal of Education: 00220574211039483. Ahead-of-print. DOI: 10.1177/2F00220574211039483. Phan LH Phan VQ (2006) Vietnamese educational morality and the discursive construction of English language teacher identity. Journal of Multicultural Discourses 1 (2 ): 136–151. Phan ANQ (2022) Quality assurance of higher education from the glonacal agency heuristic: an example From Vietnam. In: Hesham M Siraj Kariyilaparambu K (eds) Global Perspectives on Quality Assurance and Accreditation in Higher Education Institutions. Hershey, PA: IGI Global, 136–155. Srikanthan G Dalrymple JF (2007) A conceptual overview of a holistic model for quality in higher education. The International Journal of Educational Management 21 (3 ): 173–193. Stella A (2008) Quality Assurance Arrangements in Higher Education in the Broader Asia-Pacific Region. Australia: Asia-Pacific Quality Network Inc. Student Partnerships in Quality Scotland (2012) A Student Engagement Framework for Scotland. Edinburgh, Scotland: SPARQS. Tenner AR DeToro IJ (1992) Total Quality Management: Three Steps to Continuous Improvement. Boston, MA: Addison Wesley Publishing Company. Tran NT Vu PAT (2019) Fifteen years of accreditation in Vietnam. In: Nguyen HC Shah M (eds) Quality Assurance in Vietnamese Higher Education. Berlin, Germany: Springer, 97–120. Tran TVH Pham TH Nguyen QH (2020) Đại dịch Covid-19: cơ hội và thách thức cho giáo dục đại học Việt Nam [Covid-19 pandemic: opportunities and challenges for Vietnamese higher education]. Kinh Tế Và Phát Triển [Journal of Economics and Development] 274 : 64–74. UNESCO (2004) EFA Global Monitoring Report 2005. Paris, France: UNESCO Press. Vu NT Nguyen TTT Hoang H (2022) English-majoring student teacher response to employability in light of a transition to online learning. International Journal of Teacher Education and Professional Development (IJTEPD) 5 (1 ): 1–16. Williams J (2016) Quality assurance and quality enhancement: is there a relationship? Quality in Higher Education 22 (2 ): 97–102. Welzant H Schindler L Puls-Elvidge S , et al. (2011) Definitions of quality in higher education: a synthesis of the literature. Higher Learning Research Communications 5 (3 ): 2. Westerheijden DF Stensaker B Rosa MJ (2007) Quality Assurance in Higher Education: Trends in Regulation, Translation and Transformation. Berlin, Germany: Springer Science & Business Media. Whelehan DF (2020) Students as partners: a model to promote student engagement in post-COVID-19 teaching and learning. All Ireland Journal of Higher Education 12 (3 ). Wilger A (1997) Quality assurance in higher education: a literature review. National Center for Postsecondary Improvement, Stanford University 10 . Vlăsceanu L Grünberg L Pârlea D (2004) Quality Assurance and Accreditation: A Glossary of Basic Terms and Definitions. Bucharest, Romania: Unesco-Cepes Bucharest. Yang P (2020) China in the global field of international student mobility: an analysis of economic, human and symbolic capitals. Compare: A Journal of Comparative and International Education. Epub ahead of print 13 May 2020. DOI: 10.1080/03057925.2020.1764334. Ziguras C McBurnie G (2014) Governing Cross-Border Higher Education. London, UK: Routledge.
PMC009xxxxxx/PMC9128631.txt
==== Front Inn Med (Heidelb) Inn Med (Heidelb) Innere Medizin (Heidelberg, Germany) 2731-7080 2731-7099 Springer Medizin Heidelberg 35608636 1337 10.1007/s00108-022-01337-5 Erratum Erratum zu: Praktische Empfehlungen zum Screening und Management von Funktionsstörungen der Nebennierenrinde bei einer akuten SARS-CoV-2-Infektion Erratum to: Practical recommendations for screening and management of functional disorders of the adrenal cortex in cases of SARS-CoV-2 infectionsMasjkur Jimmy jimmyrusdian.masjkur@uniklinikum-dresden.de 12 Barthel Andreas 13 Kanczkowski Waldemar 1 Müller Gregor 1 Bornstein Stefan R. 1 1 grid.412282.f 0000 0001 1091 2917 Medizinische Klinik und Poliklinik III, Universitätsklinikum Carl Gustav Carus Dresden, Fetscherstraße 74, 01307 Dresden, Deutschland 2 grid.412282.f 0000 0001 1091 2917 Else Kröner-Fresenius-Stiftung (EKFS) Clinician Scientist-Programm, UniversitätsCentrum für Seltene Erkrankungen (USE) am Universitätsklinikum Dresden, Dresden, Deutschland 3 Medicover Bochum MVZ, Bochum, Deutschland 28 4 2022 2023 64 Suppl 2 149149 © The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2022 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. issue-copyright-statement© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2023 ==== Body pmc Erratum zu: Internist 2021 10.1007/s00108-021-01236-1 Der Artikel „Praktische Empfehlungen zum Screening und Management von Funktionsstörungen der Nebennierenrinde bei einer akuten SARS-CoV-2-Infektion“ von Jimmy Masjkur, Andreas Barthel, Waldemar Kanczkowski, Gregor Müller, Stefan R. Bornstein wurde ursprünglich am 20 December 2021 mit „Open Access“ online auf der Internetplattform des Verlags unter der CC BY (German language version) 4.0 veröffentlicht. Nach der Veröffentlichung in Band 63 Heft 1 pp. 4–11 entschieden sich die Autoren den „Open Access“ zu stornieren. Das Urheberrecht des Artikels wurde deshalb am 7. April 2022 to © The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2021 unter Vorbehalt aller Rechte geändert.
PMC009xxxxxx/PMC9163654.txt
==== Front Illn Crises Loss Illn Crises Loss ICL spicl Illness, Crises, and Loss 1054-1373 1552-6968 SAGE Publications Sage CA: Los Angeles, CA 10.1177/10541373221105815 10.1177_10541373221105815 Articles Finding Strength in Times of Crisis? Post-Traumatic Growth During the Covid-19 Pandemic: A Saudi Arabian Perspective https://orcid.org/0000-0002-4129-8814 Winkel Carmen 1 McNally Beverley 1 Omari Razan Al 2 1 125898 Prince Mohammad Bin Fahd University , Kingdom of Saudi Arabia 2 1234 University of Amsterdam , Netherlands Carmen Winkel, Core Curriculum Department, College of Sciences & Human Studies, Prince Mohammad Bin Fahd University, Al-Khobar, Saudi Arabia. Email: cwinkel_79@outlook.com 1 6 2022 7 2023 1 6 2022 31 3 592607 © The Author(s) 2022 2022 SAGE Publications This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections. This paper contributes to the Covid-19 literature by exploring the concept of post-traumatic growth (PTG) utilizing a mixed methods approach. The study examines to what extent the participants experienced positive growth and renewal arising from the prolonged period of lockdowns and emergency online learning. Exploring the experiences of 552 female undergraduate students in a private Saudi Arabian university, an online survey was utilized to gather the data. All the students had experienced online education as a result of the pandemic. The findings indicate the participants underwent a diversity of personal growth experiences. In addition, they also developed different coping mechanisms. The study provides insights into the responses of the students to the issues they were facing during the pandemic. It identifies ways in which participants experienced personal growth as well as a shift in perspective about their lives. There are implications for educators, counselors and policymakers emerging from this study. posttraumatic growth higher education Saudi Arabia COVID-19 trauma typesetterts19 ==== Body pmcIntroduction For many people, the outbreak of Covid-19 pandemic, now in its second year, has produced quantum shifts in their lives. Recognized as contributing to psychological trauma, because of the pandemic, are the loss of loved ones, jobs or changes in employment, enforced isolation and online learning, the cancellation of festivities such as weddings, birthdays, and graduation ceremonies (Lonsdorf, 2022). Miller (2020) describes the pandemic as one of the greatest crises since the outbreak of World War II. Yet the long-term social, economic and societal consequences of the pandemic are still not foreseeable, nor is an end to the pandemic. Moreover, a Generation Corona has been identified (Rudolph & Zacher, 2020). A term referring those who will have to deal with the long-term social and economic consequences of the pandemic. Specifically, young people who will be disadvantaged compared to prior generations (Rudolph & Zacher, 2020). Consequently, they may suffer from noticeable psychological hurt (Masiero et al., 2020). While, there are ongoing discussions related to the use of the term trauma and its application to Covid-19, mental health issues are on the rise worldwide. The ongoing pandemic has people experiencing high level of uncertainties, anxiety and stress, - symptoms consistent with trauma (Lonsdorf, 2022). For the purposes of this study trauma is defined as a “complex emotional response to a stressful event, that overwhelms the individual’s capacity to cope” (Masiero et al., 2020, p. 514). A collective trauma defined by Hirschberger (2018) as:The psychological reactions to a traumatic event that affect an entire society; it does not merely reflect an historical fact, the recollection of a terrible event that happened to a group of people (2018, p. 1). As such, collective trauma stimulates a collective sentiment and often leads to cultural changes. However, there is minimal research examining what, if any, positive aspects have emerged from this pandemic which may lead to societal changes (Sun et al., 2021). This includes an exploration of the coping mechanisms developed in response to longevity of Covid-19. Post Traumatic Growth Theory (PTG) posits that people can grow personally through traumatic events and learn to overcome adversity because of this growth (Davis et al., 1998; Tedeschi & Calhoun, 1996, 2004). Since the advent of Covid-19 a more widespread discussion of PTG has occurred (Northfield & Johnston, 2021; Waters et al., 2021; Weir, 2020, June). Acknowledging the phenomenon of PTG recognizes that while victims of traumatic events may experience losses they also report personal development and a sense of renewal and growth (Weir, 2020, June). Acccordingly, this paper aims to determine: What, if any, positive outcomes the research participants experienced during the pandemic? How coping mechanisms developed in response to the enforced restrictions to the pandemic? How these outcomes manifested themselves as growth and renewal experiences? Literature Studies have shown that when individuals experience trauma there is a possibility this can lead to a sense of personal growth and the development of a new perspective on life (Davis & Nolen-Hoeksema, 2001). People who experienced traumatic situations and events reported that their relationships subsequently became closer and more authentic. They perceived a greater awareness of their own strength and that life is full of possibilities. Equally, they may simply be happy to be alive. During the various lockdowns, it became evident that a number of individuals generated a new sense of purpose in life. This included a sense of humbleness and gratitude in the face of the uncertainties (Dominick et al., 2021; Okafor et al., 2022). An awareness specifically demonstrated in recent studies of Covid-19 survivors (Sun et al., 2021). PTG describes the positive psychological change occurring in people who experience personal trauma or very stressful life situations (Tedeschi & Calhoun, 2004). Whereas mainstream psychology focuses on illness, positive psychology seeks to identify how an individual utilizes resources during traumatic experiences for healing and health (Park et al., 1996; Tedeschi & Calhoun, 1996). The concept of trauma causing people to mature and grow was first posited by (Tedeschi & Calhoun, 1996) Tedeschi and Calhoun (2004) contended that positive psychological change was possible as a result of directly confronting challenging life circumstances. As clinical psychologists, they observed a phenomenon of positive renewal occurring because of traumatic incidents experienced by their test subjects, a group of psychology students. All the students had survived a traumatic event: these experiences included death, an accident or the divorce of parents. The participants stated that while these experiences had burdened them, subsequently they had come to value their lives more than before. They felt stronger and more spiritual, their social relationships had deepened, and their priorities had shifted. This concept has grown in popularity (Gable & Haidt, 2005; Sheldon & King, 2001). However, the theoretical approach was not without its critics. The initial criticisms focused on the measurement of growth in the various studies. The more common PTG questionnaires, required the subjects to ask themselves a series of questions: to assess how they are doing psychologically at the moment; recall how they were doing before the traumatic event; assess how their psychological well-being has changed and, in the end, assess whether the traumatic event itself caused the change (Jayawickreme & Blackie, 2014; Taylor & Armor, 1996). There were expressions of concern that such a complex cognitive process is highly prone to error of interpretation. The subjects of such studies may often be wrong in their self-assessment – that people only believe they are growing after traumas and crises (Frazier et al., 2009). Referred to ‘positive illusion’ this phenomenon describes where, in stressful situations, most people respond with optimistically distorted perceptions (Taylor & Armor, 1996). This is also true in social comparison with others. Subjects who were asked to assess their own personality and that of their acquaintances before a stressful event tended to describe their former self as more immature than their acquaintances presumably, according to the interpretation, in order to be able to attest they had matured (McFarland & Alvaro, 2000). Moreover, there is a paucity of longitudinal studies examining how affected persons felt prior to the traumatic event and then several years later. In order to measure a meaningful improvement a control group would be required. One where the group had not experienced a traumatic event. The lack of this control group led some authors to assume that the trauma is the decisive reason for the personality change. Other possible explanations not considered for example, the possibility that the measured change is simply a coping strategy. An alternative argument is that people do well for themselves after a trauma and try to build themselves up in order not to appear as victims (Prati & Pietrantoni, 2009; Tamiolaki & Kalaitzaki, 2020). While there is an increasing body of literature covering this concept, researchers still face the dilemma that growth after a crisis can never be definitively proven. Primarily, because the subjects of the studies were usually only interviewed after a personal crisis, rarely prior and then usually only by chance (Frazier et al., 2009). In regard to the pandemic the phenomenon of PTG has been primarily studied with reference to first responders, for example, nurses, doctors, emergency personal (Chen et al., 2021; Finstad et al., 2021). Yet, there a few studies examining the occurrence of PTG in secondary or third level groups, for example, how university students have experienced the phenomenon (Jin et al., 2021; Kutza & Cornell, 2021; Zeng et al., 2021). Method The mixed methods approach as outlined by (Creswell & Plano-Clark, 2011) was employed for two reasons. First, the deductive approach as it was important to develop a level of understanding as to the incidence of PTG in the sample population. Second, we were aware the study was examining people’s lived experiences, behaviors, emotions and feelings, and cultural phenomena (Bhattacherjee, 2012; Strauss & Corbin, 1990). Therefore, it was important to acknowledge this by applying an interpretive lens. Participants/Sampling Participants came from the female campus of a private university in Saudi Arabia. The researchers contacted the students via email and on-line conversation; hence, the sample technique was convenience sampling. If they were interested, students were encouraged to forward the survey link to their peers. Thereby, using snowball sampling to build the sample size. Table 1 lists the characteristics of the sample. This study's participation was entirely voluntary and without remuneration. Table 1. Participants (N = 552). Gender Female 100% Age Younger than 20 37.9 Between 20-24 56.6 Older than 24 5.5 Academic Year Freshman 57 Sophomore 20.2 Junior 15.7 Senior 7.1 Major Interior Design 12.1 HR 9.4 Architecture 8.9 Graphic Design 4.6 Electrical Engineering 2.5 Mechanical Engineering 5.2 Civil Engineering 1.3 Information Technology 3.94.8 Computer Science 5.1 Software Engineering 8.5 Accounting 4 Finance 14.3 Law 11.6 MIS 6.6 Data Collection The data for this study was gathered in November/December 2021. We collected the participants’ written reflections, via an online survey. The first section of the survey was used to collect demographic data (such as age, college year, and major), as shown in Table 1. The purpose of the second section was to encourage student reflections. Students were supplied with basic instructions to assist them in their responses. That is, the reflection should be at least 400 words long and focus on how the student experienced the Covid-19 Pandemic. A total of 647 surveys were distributed, 552 responses were received. A response rate of 85%. All reflections were anonymized, and all participants gave their consent to participate in the study. Data Analysis The data analysis was conducted in two stages. In a first step, deductive thematic analysis was undertaken by applying the five PTG Scale Inventory Items as predefined set of codes to the dataset. The PTG inventory scale was designed by Tedeschi and Calhoun (1996) to measure positive effects for people who had experienced traumatic events. The original scale consisted of 21 items on a 6-point Likert scale. For our purposes, we used the five domains that the scale is exploring as codes (see Table 2). The analysis identified 225 of the 552 reflections as PTG items. Initially, each author applied the pre-defined codes were applied to the dataset, separately and then discussed to resolve discrepancies. Table 2. Posttraumatic Growth Inventory Items (PTGI). Item Number Personal Strength 90 Relating to others 79 Appreciation of Life 48 Openness to new possibilities 6 Spiritual change 2 Second, the inductive approach. In the initial stages, we entered the responses into the NVivo software program to derive the initial codes. The researchers then simultaneously discussed and compared these codes and organized them into themes. Themes are understood as patterns in the dataset that help us to analyze and interpret the data (Rivas, 2013). In this study thematic analysis was carried out in accordance with Braun and Clarke (2006) six-step procedure: Familiarization with the information Creation of preliminary codes The search for a theme, as well as the examination of a theme Identifying and defining the theme The creation of reports The use of NVivo played a beneficial and critical part in the initial analysis and supported the retrieval of information. However, manual thematic analysis helped the researcher achieve a more in-depth appreciation of the richness of the data and cultural nuances that may have been missed by the software analysis. Utilizing both approaches concurrently enabled a more holistic appreciation of the research data rather than relying solely upon one form. In addition to the five PTG items, seven additional themes were identified (see Table 3). Table 3. Additional Themes 1 . Additional Themes Subthemes Increased confidence and new values Changes in personality Shift in priorities and goals Improved relationships with family Changes in friendships Changes in forms of social interactions Appreciation of being alive Appreciation of staying healthy Appreciation of family health Acquiring new skills New plans and goals New opportunities Acceptance of Fate Focusing on God’s guidance Strengthen religious/spiritual beliefs 1 Number of themes does not add up to total number of participants because in some interviews multiple themes were mentioned. Findings The initial coding using the PTGI scale indicated in 225 cases students expressed PTG by stating positive influences the pandemic had on their personal growth and development. The most predominant response was personal strength, followed by relating to others and appreciation of life. Openness to new possibilities was less frequent and lastly spiritual change mentioned by two participants. Figure 1. Figure 1. PTG items. Personal Strength More than 40 percent of participants reported they felt a growth in personal strength. In the following quote the participant reflects how the lockdowns and isolation resulting from enforced on-line learning facilitated her ability to rely upon and trust her own judgement. Thereby enhancing both intellectual and personal maturity.When we stopped social gatherings and physical communication, I started to pay more attention to me. The normal life pattern we engage, can unconsciously distract us from our own self. It distracted me from my own self as a result in focusing on the outside more than the inside. By spending a lot of time with others, socializing, gathering, communicating and reacting, and sometimes overreacting to please others. My life was fully occupied with my own relationships with people. “what do they say? how would they react? etc. I can say that being locked down with my own self for two years in a raw, extremely developed my psychological experience and improved my own way of thinking. And most importantly, it played a huge rule in bringing my true-self to the surface rather than the false-self and egocentrism that we are all by nature filled with. Relating to Others Family relationships are important in Saudi Arabia, families are usually larger than those found in western society (Winkel et al., 2021). The importance of family was at the forefront of several of the comments especially during the strict lockdowns and curfews. The advantage of technology became evident as even virtual meetings with extended family provided great joy and made life more interesting.The pandemic days it really showed me what is the essence of my life, I learned the important things in my life is my family, and well-being. Even though it was really difficult to be separated from people that we love, and we couldn’t visit them, having the chance to call them virtually it was so interesting and fun we shared our memories through video calls and it was best days of my life. Appreciation of Life A deeper appreciation of life was referred to by 21 percent of the participants. The pandemic was described as a humbling experience for these students. While the death and hospitalization rate in Saudi Arabia was low relative to other countries, the pandemic still manifested itself as a frightening experience. One that had the potential to create fear and uncertainty and lack of direction for the future. Yet as per the comment below – one that provided a sense of renewal and optimism.The pandemic has taught me a lot, gave me many reasons to appreciate life and to appreciate my loved ones even more. Standing here today, in my dream college and dream major, and the cases decreasing and knowing that I have not lost any family members, makes me realize that life is much bigger than being sad and crying over a graduation ceremony while others were fighting for their lives. I think the pandemic taught me so much and made me realize the worth of many valuable aspects of my life. Openness to New Possibilities Approximately 3 percent of the participants reported a greater openness to new opportunities. The following commentary refers to the experiences during Covid-19 resulted in new experience and broadened her horizon. It resulted in reflection on prior lifestyle and life choices.The Corona period made me learn many things, including the use of time, and attention to my mental and physical health, period. Corona allowed me to try studying remotely, and relying more on myself, the period of Corona polished me, changed me, opened up horizons and experiences for me, and achieved my goals, made me think about the meaning of living and life, also a crisis. Corona made me reflect on my wasted energies and money in normal days. Spiritual Change The responses to the Covid-19 pandemic, for example, school-closures, curfews, lockdowns and prolonged online education are recognized as having significant impact on students worldwide. Alghamdi (2021) contended that while students were negatively impacted there was evidence of spiritual changes and higher level of spiritual awareness. While there were only two explicit references to religion and spiritual concepts, when reading the responses there was evidence that the spiritual dimension did underpin many of the other responses. It showed me my true friends and found my spiritual peace, as I was able to appreciate these times and give thanks to them. Also, I found myself thanking God. As for the academic level, the Corona epidemic allowed me to think with a clear mind to determine my future in a way that suits what I wish, and thanks to it. I can say that the Corona epidemic was a blessing from God because it showed me something in myself that I did not know existed. The thematic analysis revealed several additional subthemes related to PTG (see Table 3). The majority of these referring to positive changes that participants experienced like increased relationships with family and friends, reappraisal of life and a shift in priorities and goals. Increased Confidence and New Values The experience of lockdowns and the sudden shut down of normal life lead participants to focus on themselves and explore different copying strategies. Similar studies have indicated that participants develop a broad variety of coping mechanisms to deal with crisis such as the pandemic (Northfield & Johnston, 2021). Self-exploration and focus on their own strengths and capabilities are often the main elements of PTG. Participants expressed, in diverse ways, the discovery of new inner strengths and the ability to overcome different problems.The pandemic taught me a lot about myself, my strengths and weaknesses, how to improve and develop my abilities, who is my support, how to be happy, and how to deal with toxic people. Taking advantage of the time I had before I graduated to act in a comprehensible way is something I am grateful for. Improved Relationships with Family Many participants experienced an increased bond with their families; due to the prolonged time spend together during the lockdowns. Prior studies have pointed out that better relationships with family members and friends are often a result of traumatic events (Calhoun & Tedeschi, 2014; Dominick et al., 2021; Okafor et al., 2022).The pandemic days it really showed me what is the essence of my life, I learned the important things in my life is my faith, family, and well-being. I learned how to love myself… and my flaws. I explored many aspects of myself that I was not aware of due to the busy days of socialising and keeping up with the routine. Appreciation of Being Alive Covid-19 brought uncertainty to many peoples’ lives (Sun et al., 2021). Even without contracting the virus, our participants experienced a new appreciation for life and appreciated being healthy and alive.COVID taught me a lot of lessons. One of them is that life is shorter than we know. For that reason, we should treat ourselves and our loved ones with love and respect, because we might not live another day. I always believed in a saying in Arabic, "Nothing is forever" which is true. I am not the same person that I was, nor is the world the same after COVID. The lesson I learned is to enjoy the small moments because they are what life is all about. Acquiring New Skills Participants in prior studies reported changes in priorities and attitudes towards life (Sun et al., 2021). In this study the long period of online classes resulted in the students seeking to acquire new skills while trying to stay busy.The pandemic gave me the opportunity to explore myself and learning about new capabilities and developing my energies more than ever before. At the same time, we follow up on our daily life and commitments, whether it is work, study, or family life in a new way. Since the beginning of this crisis, I have been searching through the Internet more than ever, learning about different topics, the most important of which is business, and improving my drawing skills I keep studying to catch up on university subjects. Keeping busy and trying to improve oneself during a time of crisis is a coping mechanism (Gan & Flores, 2021). Participants tried to use the time at home to find meaningful ways to spend their time and used various instruments (online courses, apps, videos) that would help them to improve.COVID-19 changed a lot in my lifestyle because during the pandemic I have been more focused in myself without any distraction. First, I started to attend a lot of online courses which effected on my skills as interior designer, also I became more managed on my time, and I work effectively in a short time which also impacted the amount of work I am able to do now. Acceptance of Fate Participants expressed the influence of religion and faith on an ongoing basis. This is unsurprising given the fact that Saudi Arabia is a, hierarchical conservative-religious country. Participants mentioned their faith in God as important during the pandemic and that they accepted their situation as something that was God-given. This is in keeping with prior studies with participants who are from a strong faith-based context. Religion may play an important role as a coping strategy when dealing with traumatic events such as Covid-19 (Okafor et al., 2022).Covid-19 made me focus on what is laid out for us in life by god. It also made us understand how blessed we were, and now I am sure that each one of us knows this blessing and how to thank god for it. Discussion In keeping with prior studies (Davis et al., 1998; Davis & Nolen-Hoeksema, 2001; Dominick et al., 2021; Son et al., 2020), the participants reported experiencing PTG and viewed the consequences of the pandemic as period of change and renewal, both of their worldviews and of personal growth. The young women strived to find meaning in the losses they had experienced, reporting undergoing positive changes. This was evident even if they did not experience major losses such as the death of family members While personal growth is not only experienced after traumatic events or existential crisis, whenever it occurs it can make people shift their focus to things that seem more meaningful and important. For example, like friendships, family relations or lifestyle changes (Weir, 2020, June). While the majority of the participants experienced the pandemic as a stressful and traumatic event, they were able to develop different coping strategies to improve their psychological health and overall well-being. As reported in similar studies, developing new hobbies and interests as well as spending more time with family members and spending time on social media were named as coping strategies. Similarly as reported by Dominick et al. (2021) the participants in our study reexamined core beliefs and values and focused on their own strength and capabilities. Saudi Arabia is recognized as a devoted Islamic society therefore it is unsurprising the role of religion played a greater role in our participants’ experience than has been reported by college student in some other contexts (Gan & Flores, 2021). Whether by strengthening social relationships or focusing on new values and goals, the participants in this study responded to the individual stresses of lockdowns, social distancing, and the multiple uncertainties with an appreciation of individual growth based on spirituality. The sense of having grown and become stronger as a result of the pandemic was expressed by many of our participants, but also the simple realization that one has survived the crisis and is now open to new opportunities. Prior studies (Agbing et al., 2020; Son et al., 2020) have indicated that supportive, highly positive environment and social relationships play a major role in the enhanced ability to cope with traumatic experiences and regain an improved quality of life. Our students particularly valued the close bond with family and the additional time spent with them. As was the support of friends. However, there was an identified shift in perspective. With the sweeping changes brought about by the pandemic in addition to family there was also a recognition of the significance of meeting their own needs. This change in perspective was perceived as an expression of their own strength. As a tribal collective society, this is a significant shift. This change supporting the findings of Sun et al. (2021) as it revealed the development of insights into their own actions and thinking. Conclusion and Limitations The consequences of the Corona crisis are far too disparate to speak of a collective trauma without further research. Different social groups experience the pandemic differently (Weir, 2020, June). For some, the pandemic means deceleration and self-discovery; for others, distress and the loss of jobs and homes. However, the notion of personal growth ameliorates the view of harsh social and economic realities – shifting the focus to each person’s individual responsibility. Personal strengths were the most reported element of PTG in this study and indicated that students experienced the pandemic as a life-changing event. Many participants re-focused on positive things like learning a new skill or using the time to change their diets and taking up new hobbies. There are implications for educators, counselors and policy makers when working with these young people. This would necessitate the development of positive psychological principles and emphasizing the PTG coping strategies identified in this study. The study's limitations arose from Saudi Arabia's hard-lockdown restrictions. We were unable to conduct face-to-face interviews with our participants and effected the study completely online. Ease of access resulted in only female students participants in this study. It is recommended further research with male students be conducted prior to applying the findings to other groups. Our participants were all young females from middle to upper class families who are able to pay for their education at a private university. In addition, the study was conducted in the Eastern Region of Saudi Arabia, a more developed and affluent region than other parts of the country. Further research is required before generalizing these findings to the wider Saudi Arabian population. Acknowledgments We would like to thank Shahad Alaradi for her valuable support and all the participants for sharing their experiences and stories with us. Author Biographies Carmen Winkel is a Historian and earned her PhD from the University of Potsdam (Germany), researching the 18th century Prussian Army and Nobility. University positions in Germany and China, preceded her current post as Assistant Professor at Prince Mohammad Bin Fahd University(PMU) in Saudi Arabia. Her research interests are in the area of early modern history, oral history, digital humanities and middle eastern history. Beverley McNally is an experienced educator working in both the contact and distance tertiary environments. She earned her PhD from Victoria University of Wellington. Prior to working in Saudi Arabia, she has worked for over 20 years in the tertiary education sector in New Zealand. Prior to entering the education profession, she spent a number of years in HR and management roles in the insurance and finance and NGO sectors. Her research interests are in the area of leadership, entrepreneurship specifically CEO leadership and human resource development. Razan Al Omari is a student of Sociology at the University of Amsterdam. After graduating with a degree in Interior Architecture she decided to pursue a degree in social sciences. Her research interests include criminology, migration, gender and social justice. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. ORCID iD: Carmen Winkel https://orcid.org/0000-0002-4129-8814 ==== Refs References Agbing L. U. Agapito J. D. Baradi A. M. A. Bernadette C. Guzman M. Ligon C. M. Lozano A. T. (2020). COVID-19: In the eyes of a filipino child. Illness, Crisis & Loss, 0 (0 ), 1054137320966846. 10.1177/1054137320966846 Alghamdi A. A. (2021). Impact of the COVID-19 pandemic on the social and educational aspects of Saudi university students’ lives. PLoS ONE, 16 (4 ), e0250026. 10.1371/journal.pone.0250026 33852627 Bhattacherjee A. (2012). Social science research: Principles, methods, and practices. Global Text Project. http://scholarcommons.usf.edu/oa_textbooks/3. Braun V. Clarke V. (2006). Using thematic analysis in psychology. Qualitative Research in Psychology, 3 (2 ), 77–101. 10.1191/1478088706qp063oa Calhoun L. G. Tedeschi R. G. (2014). Handbook of posttraumatic growth: Research and practice. Routledge. Chen R. Sun C. Chen J.-J. Jen H.-J. Kang X. L. Kao C.-C. Chou K.-R. (2021). A large-scale survey on trauma, burnout, and posttraumatic growth among nurses during the COVID-19 pandemic. International Journal of Mental Health Nursing, 30 (1 ), 102–116. 10.1111/inm.12796 33107677 Creswell J. W. Plano-Clark V. L. (2011). Designing and conducting mixed methods research (2nd ed., pp. 19–53). Sage Publications. Davis C. G. Nolen-Hoeksema S. (2001). Loss and meaning: How do people make sense of loss? American Behavioral Scientist, 44 (5 ), 726–741. 10.1177/0002764201044005003 Davis C. G. Nolen-Hoeksema S. Larson J. (1998). Making sense of loss and benefiting from the experience: Two construals of meaning. Journal of Personality and Social Psychology, 75 (2 ), 561–574. 10.1037/0022-3514.75.2.561 9731325 Dominick W. Elam T. Fraus K. Taku K. (2021). Nontraditional social support, core belief disruption, and posttraumatic growth during COVID-19. Journal of Loss and Trauma, 27 (3 ), 1–13. 10.1080/15325024.2021.1932968 Finstad G. L. Giorgi G. Lulli L. G. Pandolfi C. Foti G. León-Perez J. M. Cantero-Sánchez F. J. Mucci N. (2021). Resilience, coping strategies and posttraumatic growth in the workplace following COVID-19: A narrative review on the positive aspects of trauma. International Journal of Environmental Research and Public Health, 18 (18 ), 9453. https://www.mdpi.com/1660-4601/18/18/9453 34574378 Frazier P. Tennen H. Gavian M. Park C. Tomich P. Tashiro T. (2009). Does self-reported posttraumatic growth reflect genuine positive change? Psychological Science, 20 (7 ), 912–919. 10.1111/j.1467-9280.2009.02381.x 19515115 Gable S. L. Haidt J. (2005). What (and why) is positive psychology? Review of General Psychology, 9 (2 ), 103–110. 10.1037/1089-2680.9.2.103 Gan I. Flores K. M. (2021). What have college students lost as they Cope with the COVID-19 pandemic? Journal of Loss and Trauma, 1–2. 10.1080/15325024.2021.1970962 Hirschberger G. (2018). Collective trauma and the social construction of meaning [review]. Frontiers in Psychology, 9 , 1–14. 10.3389/fpsyg.2018.01441 29410639 Jayawickreme E. Blackie L. E. R. (2014). Post–traumatic growth as positive personality change: Evidence, controversies and future directions. European Journal of Personality, 28 (4 ), 312–331. 10.1002/per.1963 Jin M. Zhang X. He H. Zeng L. Yuan Z. Xie W. Wang J. (2021). Psychological symptoms and posttraumatic growth among the general population in Wuhan, China during the COVID-19 pandemic: A cross-sectional study. Journal of Psychosocial Nursing and Mental Health Services, 60 (4 ), 39–46. 10.3928/02793695-20211118-03 34846228 Kutza D. Cornell K. (2021). Fostering post-traumatic growth in college classrooms during COVID-19. Journal of Teaching and Learning With Technology, 10 (1 ), 12–22. 10.14434/jotlt.v10i1.31381 Lonsdorf K. (2022). People are developing trauma-like symptoms as the pandemic wears on. [National Public Radio]. https://www.npr.org/2022/04/07/1087195915/covid-pandemic-trauma-mentalhealth. Masiero M. Mazzocco K. Harnois C. Cropley M. Pravettoni G. (2020). From individual to social trauma: Sources of everyday trauma in Italy, the US and UK during the COVID-19 pandemic. Journal of Trauma & Dissociation, 21 (5 ), 513–519. 10.1080/15299732.2020.1787296 32654633 McFarland C. Alvaro C. (2000). The impact of motivation on temporal comparisons: Coping with traumatic events by perceiving personal growth. Journal of Personality and Social Psychology, 79 (3 ), 327–343. 10.1037/0022-3514.79.3.327 10981837 Miller E. D. (2020). The COVID-19 pandemic crisis: The loss and trauma event of our time. Journal of Loss and Trauma, 25 (6-7 ), 560–572. 10.1080/15325024.2020.1759217 Northfield E.-L. Johnston K. L. (2021). “I get by with a little help from my friends”: Posttraumatic growth in the COVID-19 pandemic. Traumatology, 28 (1 ), 195–201. 10.1037/trm0000321 Okafor C. N. Bautista K. J. Asare M. Opara I. (2022). Coping in the time of COVID-19: Buffering stressors with coping strategies. Journal of Loss and Trauma, 27 (1 ), 83–91. 10.1080/15325024.2021.1914987 35173557 Park C. L. Cohen L. H. Murch R. L. (1996). Assessment and prediction of stress-related growth. Journal of Personality, 64 (1 ), 71–105. 10.1111/j.1467-6494.1996.tb00815.x 8656319 Prati G. Pietrantoni L. (2009). Optimism, social support, and coping strategies as factors contributing to posttraumatic growth: A meta-analysis. Journal of Loss and Trauma, 14 (5 ), 364–388. 10.1080/15325020902724271 Rivas M. F. (2013). An experiment on corruption and gender. Bulletin of Economic Research, 65 (1 ), 10–42. 10.1111/j.1467-8586.2012.00450.x Rudolph C. W. Zacher H. (2020). “The COVID-19 generation”: A cautionary note. Work, Aging and Retirement, 6 (3 ), 139–145. 10.1093/workar/waaa009 Sheldon K. M. King L. (2001). Why positive psychology is necessary. American Psychologist, 56 (3 ), 216–217. 10.1037/0003-066X.56.3.216 11315247 Son C. Hegde S. Smith A. Wang X. Sasangohar F. (2020). Effects of COVID-19 on college Students’ mental health in the United States: Interview survey study. Journal of Medical Internet Research, 22 (9 ), e21279. 10.2196/21279 32805704 Strauss A. L. Corbin J. M. (1990). Basics of qualitative research: Grounded theory procedures and techniques. Sage Publications. Sun W. Chen W.-T. Zhang Q. Ma S. Huang F. Zhang L. Lu H. (2021). Post-Traumatic growth experiences among COVID-19 confirmed cases in China: A qualitative study. Clinical Nursing Research, 30 (7 ), 1079–1087. 10.1177/10547738211016951 34018405 Tamiolaki A. Kalaitzaki A. E. (2020). "That which does not kill us, makes us stronger": COVID-19 and posttraumatic growth. Psychiatry Research (289 ), 113044. 10.1016/j.psychres.2020.113044 32388177 Taylor S. E. Armor D. A. (1996). Positive illusions and coping with adversity. Journal of Personality, 64 (4 ), 873–898. 10.1111/j.1467-6494.1996.tb00947.x 8956516 Tedeschi R. G. Calhoun L. G. (1996). The posttraumatic growth inventory: Measuring the positive legacy of trauma. Journal of Traumatic Stress, 9 (3 ), 455–471. 10.1002/jts.2490090305 8827649 Tedeschi R. G. Calhoun L. G. (2004). Posttraumatic growth: Conceptual foundations and empirical evidence. Psychological Inquiry, 15 (1 ), 1–18. 10.1207/s15327965pli1501_01 Waters L. Cameron K. Nelson-Coffey S. K. Crone D. L. Kern M. L. Lomas T. Oades L. Owens R. L. Pawelski J. O. Rashid T. Warren M. A. White M. A. Williams P. (2021). Collective wellbeing and posttraumatic growth during COVID-19: How positive psychology can help families, schools, workplaces and marginalized communities. The Journal of Positive Psychology, 1–29. 10.1080/17439760.2021.1940251 Weir K. (2020, June). Life after COVID-19: Making space for growth. Monitor on Psychology, 51 (4 ), https://www.apa.org/monitor/2020/06/covid-life-after. Winkel C. McNally B. Aamir S. (2021). Narratives of crisis: Female Saudi students and the COVID-19 pandemic. Illness, Crisis & Loss, 105413732110290. 10.1177/10541373211029079 Zeng W. Zeng Y. Xu Y. Huang D. Shao J. Wu J. Wu X. (2021). The influence of post-traumatic growth on college students’ creativity during the COVID-19 pandemic: The mediating role of general self-efficacy and the moderating role of deliberate rumination [original research]. Frontiers in Psychology, 12 , 1–13. 10.3389/fpsyg.2021.665973
PMC009xxxxxx/PMC9166169.txt
==== Front Qual Quant Qual Quant Quality & Quantity 0033-5177 1573-7845 Springer Netherlands Dordrecht 35694112 1453 10.1007/s11135-022-01453-2 Article Bibliometric network analysis of thirty years of islamic banking and finance scholarly research http://orcid.org/0000-0001-6295-9362 Hassanein Ahmed Hassanein.a@gust.edu.kw Ahmeda1@mans.edu.eg 12 Mostafa Mohamed M. Moustafa.m@gust.edu.kw 2 1 grid.448933.1 0000 0004 0622 6131 Gulf University for Science and Technology, Mubarak Al-Abdullah, Kuwait 2 grid.10251.37 0000000103426662 Faculty of Commerce, Mansoura University, Mansoura, Egypt 4 6 2022 2023 57 3 19611989 23 2 2022 4 5 2022 25 5 2022 © The Author(s), under exclusive licence to Springer Nature B.V. 2022 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. This study utilizes bibliometric analyses to map and visualize the development, conceptual structure, and thematic evolution of the Islamic Banking and Finance (IB&F) scholarly research. It analyses 464 WoS IB&F research publications of 921 authors comprising 58 countries published over three decades from 1990 to 2019. The results reveal that (i) collaboration among countries is limited and institutional collaboration can be described as a “locally concentrated and globally isolated,“ (ii) the IB&F research is a type of “small-world-network” where few authors and journals dominate the networks and play a central role in the diffusion of knowledge and the “homophily impact” is present among the leading authors of the IB&F research, (iii) the networks in IB&F research reflects the “Matthew Effect,“ implying that few authors have a more significant number of networks compared to the rest of authors. The study has also identified the conceptual structure and thematic trends in the IB&F research and provides avenues for future research. Keywords Islamic Banking and Finance Bibliometric analysis Co-citation networks Keyword co-occurrence networks Conceptual structure maps Thematic maps issue-copyright-statement© Springer Nature B.V. 2023 ==== Body pmcIntroduction The Islamic Banking and Finance (hereafter, IB&F) system is established on the concept of abolishing interest and unfair facets of the economy to comply with the principles of Islamic Shariah (Islamic jurisprudence). Besides, it is escorted by Islamic doctrine principles supporting risk sharing. Thus, lending, borrowing, and investment functions are likely to be conducted based on risk-sharing. In addition, IB&F is accompanied by social activities, including distributing social dividends. Hence, it can be seen as a value-based system aiming to ensure the substantial well-being of people and sustainable economic growth (Aydin 2020; Musa et al. 2020). The IB&F covers different sectors, including Islamic banks, financial markets, and financial intermediation. The principles of IB&F have been applied since the 1970s in the Middle East, leading to the establishment of Islamic banks1. At a later stage, the Western banks (e.g., Citibank & HSBC) have begun establishing their Islamic windows, which provide Islamic banking services to attract deposits from Muslims in Middle Eastern countries. The IB&F system grows through seeking innovation and diversity of services, customers, and markets. The Islamic services cover many areas such as Islamic Bonds (i.e., Sukuk), Islamic Insurance (i.e., Takaful), investments funds, and Islamic Stock Exchange (e.g., Dow Jones Islamic Index). The Banker’s report in 2015 declares that the Islamic assets have increased rapidly with a growth rate of 12.7% annually. The European Union countries were in the top 20 major countries that complied with Islamic Shariah in providing their Islamic services. Furthermore, the Islamic Financial Services Board report published in 2019 indicated that the IB&F industry worth is $2.19 trillion as of the second quarter of 2018, compared to the $2.05 trillion recorded at the end of 2017. Islamic banking represents 71.7% of the IB&F industry, while the Islamic capital market represents 27% of the global IF&B asset. The Takaful (Islamic Insurance) services represent 1.3% of the IB&F services, with an annual growth rate of 4.3%. IB&F research has received significant attention in recent years. Nevertheless, Narayan and Phan (2017) argue that research in this area is still evolving. Prior research on IB&F has focused mainly on investigating the performance of Islamic banks (e.g., Mobarek and Kalonov 2014; Saraç and Zeren 2015; Kabir et al. 2015; Mollah et al. 2017; Grira et al. 2016). Another stream of research has examined the corporate governance system of Islamic banks (Hayat and Hassan 2017; Elnahas et al. 2017; Jan et al. 2021). Previous studies have also explored the features of Islamic bond markets (Naifar and Hammoudeh 2016) and the Islamic Insurance system (Raza et al. 2019). Furthermore, research has explored some ethical issues related to IB&F. For instance, Al-Suhaibani and Naifar (2014) explore the ethical framework of Islamic financial institutions (IFIs) and Platonova et al. (2018) examine the social responsibility roles of IFIs. The evolution of research in a field of study induces scholars to quantitatively review its scientific production to understand its “intellectual structure” (Rivera and Pizam 2015). This helps develop a knowledge base for this field, identify its research trends, understand its theories and methodologies, determine the contributions and suggest potential avenues for future research (Ferreira et al. 2014). The bibliometric analysis is an innovative methodology aiming to reveal the development and structure and visualize the scientific production in a field of study (Mostafa 2020; Qi et al. 2018). It is applied to explore the knowledge structure in different fields of research, such as Halal food (Mostafa 2020), circular economy (Alnajem et al. 2021), operational research (Argoubi et al. 2020), innovation (Yahaya et al. 2020), and corporate governance (Zheng and Kouwenberg 2019). Nonetheless, there is a lack of research analyzing the intellectual structure of IB&F research. Therefore, the current study fills this gap and uses bibliometric networks to investigate IB&F scholarly publications. This technique helps identify the development, conceptual structure, and thematic evolution of the IB&F. The current study aims to answer the following research questions. First, how the research on IB&F has been evolved since its emergence? Second, what are the influential authors, journals, and countries in the IB&F field? Third, what are the collaborative networks among authors, institutions, and countries in the IB&F research? Fourth, what are the intellectual structure and thematic trends of IB&F research? Finally, what are the key hotspots in the IB&F research? The study analyses 464 World of Science (WoS) IB&F research publications of 921 comprising 58 countries published over three decades from 1990 to 2019. This helps to understand the development, intellectual structure, and contribution of the IB&F research and identify challenges and areas for future research in this field of study. The study contributes to the extent of literature in several ways. First, it is the first to employ the bibliometric analysis to review IB&F knowledge structure which adds an innovative way to show the thematic evolution of the key research themes in IB&F. Bibliometric networks methodology objectively, rather than subjectively, produces findings that show a joint view expressed by actual data (Linnenluecke et al. 2020). This helps to build knowledge, gain an understanding, and show the future direction in this research area. Second, the study also adds to the theoretical development of IB&F research as it helps scholars discover potential opportunities and define the significant intellectual structure and research themes in the field of IB&F. Third, the study focuses solely on examining Islamic rather than conventional banking and finance, which enriches the body of knowledge of this underrepresented field of study. The paper is structured as follows. Section 2 provides a review of IB&F literature. Section 3 describes the research design. Section 4 presents the descriptive statistics pertaining to the IB&F scientific production. Section 5 reports the network analyses. Section 6 presents the intellectual structure maps. Finally, the concluding remarks and directions for future research are provided in Sect. 7. IB&F literature: an overview The research on IB&F is fast growing due to innovative Islamic products, including Islamic bonds, insurance, and stock exchange (Zaher and Hassan, 2001). However, limited research has attempted to review the research about IB&F. For instance, Narayana and Phan (2019) surveyed the academic research on IB&F. They focused on 112 research papers from 1983 to 2017. The results suggest that examining bank performance is the most popular topic in IB&F, representing 44% of the research papers, followed by research on the equity market (24%) and market interactions (16%). Nonetheless, the research on Islamic bonds has received less attention from academics. The analysis of prior studies also reveals that they focus on several aspects of IB&F, including the performance of IFIs, their governance system, and ethical issues in IB&F. Substantial research has focused on the performances of Islamic compared to conventional (non-Islamic) banks. For instance, some studies (e.g., Olson and Zoubi 2011 & Beck et al. 2010) have explored how Islamic banks are cost-efficient compared to conventional banks. They find that conventional banks utilize their costs less efficiently than Islamic banks. However, Kabir et al. (2015) find that the credit risk is higher in conventional banks than in Islamic banks. Besides, Baele et al. (2014) and Pappas et al. (2017) suggest that the rate of loan default in conventional banks is higher than that of the Islamic banks. Mobarek and Kalonov (2014) confirm that Islamic banks are more likely to be financially secure than conventional banks. A group of prior studies reports mixed findings regarding the efficiency of Islamic relative to conventional banks. Some research reports the same efficiency level in conventional and Islamic banks (Johnes et al. 2014). However, other research reports that the efficiency of Islamic banks is either higher (Wanke et al. 2016) or lower (Belanès et al. 2015) relative to conventional banks’ efficiency. Research also has found that drivers of Islamic banking performance are the degree of capital adequacy, quality of management, and diversification of Islamic products (Sun et al. 2017). There is growing research on the performance of Islamic equity markets, though it reports mixed findings. It finds that the profitability of Islamic markets is better than conventional markets (Narayan et al. 2017; Dewandaru et al. 2015). Nevertheless, research suggests that Islamic stocks are less successful than conventional stocks (Rahim and Masih 2016; Narayan and Bannigidadmath 2017) examine how Islamic stocks respond to market news. They find that positive news has more substantial effects than negative news in Islamic and conventional banks. Azmat et al. (2014) examine the Islamic bonds and find differences in the characteristics of Islamic compared to conventional banks. Besides, Naifar and Hammoudeh (2016) find that spillover effects of Islamic bonds and stocks and the yields of Islamic bonds are more significantly associated with the conventional than Islamic stock markets. In support, Alexakis et al. (2016) and Alaoui et al. (2015) provide evidence that Islamic markets are co-moving with conventional markets. Research also explores the Shariah compliance issue and the corporate governance system of IFIs. Notably, the corporate governance system in IFIs is different from conventional counterparts in that it must be undertaken based on Islamic Shariah. Hence, non-compliance with Islamic Shariah can lead to financial turmoil (Grassa and Matoussi 2014). Besides, Shariah’s supervisory board is a crucial element in the governance system of IFIs. Grassa and Matoussi (2014) report significant variations in the structure of governance systems among Islamic banks, requiring more improvements and standardizations. Empirically, Mollah and Zaman (2015) find that Islamic banks’ performance is positively affected by the presence of the Shariah supervisory board. However, it is negatively associated with board structure and CEO duality. Mollah et al. (2017) confirm that Islamic banks’ governance structure facilitates risk-taking achievement of better performance. Apart from governance structure, Mallin et al. (2014) indicate that Islamic banks are aware of the mandatory disclosure requirements of the Accounting and Auditing Organization of Islamic Financial Institution (AAOIFI)2. However, they give less consideration to voluntary disclosure. The research area investigating the ethical issues in IB&F is still evolving. Limited research has investigated the effect of ethics and religion on either performance or reporting of Islamic banks. Ashraf (2016) examines whether the Islamic Shariah screening criteria influence the performance of the Islamic equity funds (IEFs). The findings reveal no significant variations between the performance of IEFs and conventional funds. Baele et al. (2014) examine whether religion affects the default rate of bank loans. Their results reveal that the rate of loan default in Islamic banks is less than that of the Islamic banks, suggesting that the religion from either individual piousness or network significantly influences the loan default. Likewise, Belal et al. (2015) examine the ethical reporting of Islamic banks. They find an increase in ethical information disseminated by Islamic banks. Besides, Islamic banks are likely to provide more clarity and community-related disclosures. Prior studies also explore the corporate social responsibility role of IB&F. Hassan et al. (2010) find that Islamic banks respond to society’s welfare needs and comply with the Islamic business ethics framework. Furthermore, Platonova et al. (2018) find that Islamic banks’ corporate social responsibility activities positively affect the current and future performance of Islamic banks. Finally, few studies also examine the nexus between IB&F and small-medium enterprises (SMEs). These studies suggest that Islamic banks are likely to provide different kinds of finance to SMEs (Aysan et al. 2016). Limited research focuses on the IB&F from a macro-economic perspective. It finds that IB&F leads to development in the banking sector (Gheeraert 2014) and contributes significantly to economic growth and welfare (Abedifar et al. 2016). Despite the significant research on IB&F, there is a lack of comprehensive evaluation of the scientific publication in this area. Hence, this study aims to fill this gap by comprehensively evaluating the research of IB&F. Research design Method The current study employs the “Scientometrics” method to analyze the IB&F research. It analyses various aspects of the field of study, including journals and their impacts, influential authors, countries, institutions, and thematic groups in the field of study. It involves developing “bibliometric network analyses” to examine all publications to identify the various networks, productivity, quality, and citations in a particular research field and evaluate its intellectual development. It has more advantages than the traditional state-of-the-art review in that it can investigate more relevant themes and provides an extra point of reference (Argoubi et al. 2020; Ronda-Pupo 2017) suggests that outputs of a specific field of study help understand its development and structure. Nonetheless, Block et al. (2020) indicate that research restricted to analyzing parameters such as influential authors, journals, and countries is not qualified to be bibliographic analysis. Besides, they argue that bibliometric analyses should aim to evaluate the development and thematic structure of the research field. In response, this study has followed Mostafa (2020) to conduct a thorough bibliometric analysis that evaluates the evolution, structure, and thematic of the IB&F scholarly research. This helps understand the development, intellectual formation, and contribution of the IB&F research and identify challenges and areas for future research in this field of study (Shi and Li 2019). We have used the VoSviewer software and the R statistical computing version 4.1 to develop citation and co-citation analyses. The influential authors are identified based on the number of articles and total citations. Lotka’s law is used to measure the authorship concentration. The citation analysis identifies the most cited articles in the IB&F research. The VoSviewer software and the R statistical computing also develop visualized network maps for chronological IB&F citations (i.e., historiographic network), keyword co-occurrence, conceptual structure, and thematic contents. These methods ensure concluding a comprehensive evaluation of the IB&F research. The VoSviewer and R statistical computing are dominant software instruments for building visualized maps for objects of interest. It is common in bibliometric studies such as Halal food (Mostafa 2020), operational research (Argoubi et al. 2020), innovation (Yahaya et al. 2020), and circular economy (Alnajem et al. 2021). Data The data was collected based on the WoS database. The WoS is a leading database covering high-quality information on multidisciplinary subjects (Argoubi et al. 2020), and it is a substantial source for research abstracts and citations (Amrutha and Geetha 2020). In addition, it permits scholars to download a database including the bibliographic information of a particular research area, such as journals, citations, and affiliations. In this study, we have reviewed IB&F publications, definitions, and categories of IB&F to develop a central theme search string. We have searched all articles, books, and editorial reviews that include the following terms, “Islamic Banking, “Islamic Banks,“ and “Islamic Finance,“ in the research papers’ titles, keywords, and abstracts. We limited our search to include only research papers written in the English language. The year 1990 is considered the date of reference as there are virtually no significant studies regarding IB&F studies published earlier. Table (1) shows that the search has produced 464 documents published from 1990 to 2019 in the WoS database comprising journal articles, book reviews, editorial materials, and proceeding papers. It also reveals that 921 authors wrote these documents. The average number of documents per author is 0.504, and on average, there are approximately1.98 authors per document. The average citation per document is 7.524 times. The collaboration index was 2.33, suggesting the non-dominance of single-authored papers, as per prior research (e.g., Alnajem et al. 2021). Table 1 Data No. [%] Article 248 [53.45] Article, early access 3 [0.65] Article, proceedings paper 3 [0.65] Book review 33 [7.11] Editorial material 4 [0.86] Proceeding’s paper 168 [36.21] Review 5 [1.08] Total documents 464 Period 1990–2019 No. of sources 229 No. of keywords 535 No. of author’s keywords 1003 Average citations per document 7.524 No. of authors 921 Author appearances 1165 No. of authors of single-authored documents 107 No. of authors of multi-authored documents 814 No. of single-authored documents 114 No. of documents per author 0.504 No. of authors per document 1.98 No. of co-authors per documents 2.51 Collaboration Index 2.33 Scientific production To answer the first research question, we traced the evolution of the scientific production of IB&F literature. Figure (1) presents the development and trend of IB&F research production. The graph shows that the IB&F research has witnessed exponential growth at an average rate of 5.6% annually. Nevertheless, this rate of growth is not equally dispersed over the years. The first decade of IB&F research starts from 1990 to 2000. During this decade, the IB&F literature seems to be relatively rare, representing a maximum of four annual research documents. This decade can be seen as the early application of IB&F principles as different nations began to develop their Islamic financial institutions. The second decade of the IB&F research starts from 2001 to 2010. This period has witnessed substantial interest in research in IB&F, as evidenced by the significant growth in IB&F publications, with a peak of 12 documents published per year. Therefore, the second decade can be called the “initial growth stage” in Islamic financial institutions. The third decade of IB&F research starts from 2011 to 2015, and it has a significant boost by scholars in the IB&F field of study, representing on average 30 annual research publications. Thus, it can be called the “swift growth stage” in the IB&F. The last decade of the IB&F research is from 2016 to 2019. It is observable that IB&F research has reached maturity during this decade, evidenced by the publication, on average, of 60 annual research documents. Hence, this decade can be called the “maturity stage” in the IB&F. Eventually, there has been an exponential increase in IB&F research since 2008. Fig. 1 Development of IB&F research production The large number of countries involved in IB&F research provides shreds of evidence for the significant growth of the IB&F research outputs. Table (2) shows the total citations, % of citations, and average article citations of the top 20 active countries in the IB&F research. It reveals that the USA led the publication in IB&F, with approximately 674 citations representing 20% of the total citations in this field. The United Kingdom contributes approximately 561 citations (17%), followed by Netherland (10%). There is no substantial contribution from other countries, including Egypt (0.74), South Africa (0.74), and Brazil (0.68). Table 2 Top active countries Country Total Citations % of citations Average Article Citations USA 674 19.99% 19.26 United Kingdom 561 16.64% 14.03 Netherlands 333 9.88% 83.25 France 269 7.98% 17.93 Malaysia 267 7.92% 2.54 New Zealand 222 6.58% 111.00 Pakistan 173 5.13% 5.97 Saudi Arabia 146 4.33% 9.12 Australia 129 3.83% 7.59 Jordan 123 3.65% 20.50 Sweden 101 3.00% 33.67 United Arab Emirates 63 1.87% 3.94 Canada 52 1.54% 7.43 Belgium 48 1.42% 8.00 Turkey 45 1.33% 3.00 Indonesia 42 1.25% 0.75 Lebanon 26 0.77% 13.00 Egypt 25 0.74% 6.25 South Africa 25 0.74% 12.50 Brazil 23 0.68% 23.00 Nonetheless, in Table (3), we have calculated the single-country publications (SCP) and the multiple country publications (MCP). The Table indicates that Malaysia ranks first in both SCP and MCP, followed by Indonesia and the United Kingdom. Malaysia has produced 82 single publications and 23 joint publications with other nations. The SCP and MCP of Indonesia are 50 and 6, respectively. The United Kingdom has produced 26 (14) SCP (MCP). In addition, there are a limited contribution of other countries such as Egypt (SCP = 2, MCP = 2) and the Netherland (SCP = 1, MCP = 3). Table 3 SCP & MCP Country Articles Freq SCP MCP MCP_ Ratio Malaysia 105 0.23702 82 23 0.219 Indonesia 56 0.12641 50 6 0.107 United Kingdom 40 0.09029 26 14 0.350 USA 35 0.07901 15 20 0.571 Pakistan 29 0.06546 23 6 0.207 Australia 17 0.03837 6 11 0.647 Saudi Arabia 16 0.03612 7 9 0.562 United Arab Emirates 16 0.03612 6 10 0.625 France 15 0.03386 9 6 0.400 Turkey 15 0.03386 11 4 0.267 China 10 0.02257 5 5 0.500 Canada 7 0.01580 1 6 0.857 Belgium 6 0.01354 2 4 0.667 Iran 6 0.01354 4 2 0.333 Jordan 6 0.01354 5 1 0.167 Bahrain 5 0.01129 1 4 0.800 Spain 5 0.01129 4 1 0.200 Tunisia 5 0.01129 4 1 0.200 Egypt 4 0.00903 2 2 0.500 Netherlands 4 0.00903 1 3 0.750 The substantial growth in the IB&F research is evident in the significant number of authors involved in this field of study. The top 20 influential authors in the IB&F research are shown in Table (4). The Table shows that the leading author in this field is Kabir Hassan [Hassan, M. K], with 14 research publications, followed by Sanaullah Ansari [Ansari, S], with seven publications. Besides, Ahmet Faruk Aysan [Aysan, A. F], Abdoulkarim Idi Cheffou [Cheffou, A. I], Fredj Jawadi [Jawadi, F], and Huseyin Ozturk [Ozturk, H] contribute by six publication each. Other IB&F leading authors include Ahmad Baehaqi [Ahmad, A], Mohammad Bitar [Bitar, M], Mustafa Disli [ Disli, M], Mansor H Ibrahim [Ibrahim, M. H], Nabila Jawadi [Jawadi, N], Kashif-Ur-Rehman [Kashif-Ur-Rehman, K. R], Ismah Osman [Osman, I], and Amine Tarazi [Tarazi, A] who provides five research publication each in the IB&F field. Other influential authors provide four IB&F research publications, including Khaliq Ahmad [Ahmad, K], Faisal Alqahtani [Alqahtani, F], Kym Brown [Brown, K], Sri Rahayu Hijrah Hati [Hati, S. R], Marwan Izzeldin [Izzeldin, M], and Abul Mansur M. Masih [Masih, M]. Table 4 Top influential authors Authors Articles Authors Articles Fractionalized Hassan, M. K 14 Hassan, M. K 4.50 Ansari, S 7 Ansari, S 3.83 Aysan, A. F 6 Cebeci, I 3.00 Cheffou, A. I 6 Ibrahim, M. H 3.00 Jawadi, F 6 Wilson, R 3.00 Ozturk, H 6 Hati, S. R 2.00 Ahmad, A 5 Khan, F 2.00 Bitar, M 5 Masih, M 2.00 Disli, M 5 Toksoez, M 2.00 Ibrahim, M. H 5 Wahyuni, S 2.00 Jawadi, N 5 Aysan, A. F 1.83 Kashif-Ur-Rehman, K. R 5 Ozturk, H 1.83 Osman, I 5 Ahmad, K 1.78 Tarazi, A 5 Bitar, M 1.75 Ahmad, K 4 Kashif-UR-Rehman, K. R 1.75 Alqahtani, F 4 Tarazi, A 1.75 Brown, K 4 Ahmad, A 1.58 Hati, S. R 4 Cheffou, A. I 1.57 Izzeldin, M 4 Jawadi, F 1.57 Masih, M 4 Abduh, M 1.50 The dominance of the IB&F influential authors varied over time. Figure (2) presents the dominance of the top ten IB&F influential authors from 1990 to 2019. The varying sizes of circles and their colours in the Figure suggest the authors’ dominance in terms of the number of articles and total citations, respectively, during a particular time. The Figure reveals that Sanaullah Ansari [Ansari, S] had the highest number of publications and total citations from 2010 to 2014, suggesting that this author was the most influential author from 2010 to 2014. Then, Kabir Hassan [Hassan, M. K] took the lead and became the most influential author from 2014 till now. It is also observable that Ahmet Faruk Aysan [Aysan, A. F], Huseyin Ozturk [Ozturk, H], Mustafa Disli [ Disli, M], and Mansor H Ibrahim [Ibrahim, M. H] were influential from 2015 to 2018. Other authors had also dominated for shorter periods, including Abdoulkarim Idi Cheffou [Cheffou, A. I] and Fredj Jawadi [Jawadi, F] for the period of 2016–2017, and Mohammad Bitar [Bitar, M] for the period of 2017–2019. Fig. 2 Dominance of influential authors over time It is argued that the consistency and concentration of the contributions of the authors in a field of study is an essential feature in bibliometric studies (Merediz-Solà and Bariviera 2019). Literature suggests that Lotka’s law, developed by Lotka (1926), is a widely used measure in bibliometric studies to measure the authorship concentration in a particular field of study (Corbet et al. 2019). To the best of our knowledge, this study provides the first application of Lotka’s law in the field of IB&F. Figure (3) presents the distributions of the observed and the fitted Lotka’s. The results of the Kolmogorov-Smirnov two-sample test show a β coefficient of 2.7 with a p-value of 0.27 and a goodness of fit of 0.92. These statistics imply no significant differences between the theoretical and the empirical distributions of the IB&F research, suggesting that authors contribute to both theoretical and practical aspects. Besides, Lotka’s law holds in the IB&F research at a 5% significance level. Fig. 3 Lotka’s law in IB&F research The citation analysis is utilized to determine the most popular articles in the IB&F research. It counts the frequency of citations that other research articles have cited a particular research paper for recognizing the impact of a research article in a specific field of study (Kumar et al. 2019). Table (5) presents the ten most cited research articles in IB&F. The first top-cited article was conducted by Thorsten Beck, Asli Demirguc-Kunt, and Ouarda Merrouche in 2013. It has 325 citations and was published in the “Journal of Banking and Finance.“ This article investigated how Islamic banks are different from conventional banking regarding business models, bank efficiency, and stability. Beng Chong and Ming-Hua Liu conducted the second most widely cited article in 2009. It was published in the “Pacific-Basin Finance Journal” with 200 citations. It focuses on the paradigm of distributing profit/ loss in the Islamic banking sector. The third most cited article was performed by Martin Cihak and Heiko Hesse in 2010, published in the “Journal of Finance Service Research,“ and has 170 citations. It aims to investigate the financial stability issue in Islamic banks. Feisal Khan did the fourth most cited article in 2010, published in the “Journal of Economic Behavior & Organization,“ and has 150 citations. It explores the practices that differentiate Islamic banks from conventional ones. The fifth most cited research paper was performed by Pejman Abedifar, Philip Molyneux, and Amine Tarazi in 2013. It was published in the “Review of Finance” with 121 citations. It examines the risk issue in Islamic banks. Finally, other research articles are considered influential in the field of IB&F, including Aggarwal and Yousef (2000), Maali et al. (2006), Haniffa and Hudaib (2007), Pollard and Samers (2007), and Johnes et al. (2014). Table 5 Top 10 cited manuscripts Author/s, (year) Title Journal TC TC per Year Thorsten Beck, Asli Demirguc-Kunt and Ouarda Merrouche, (2013) Islamic vs. conventional banking: Business model, efficiency and stability Journal of Banking and Finance 325 46.43 Beng Chong and Ming-Hua Liu, (2009) Islamic banking: Interest-free or interest-based? Pacific-Basin Finance Journal 200 18.18 Martin Cihak and Heiko Hesse, (2010) Islamic Banks and Financial Stability: An Empirical Analysis Journal of finance service research 170 17.00 Feisal Khan, (2010) How ‘Islamic’ is Islamic Banking? Journal of Economic Behavior & Organization 150 15.00 Pejman Abedifar, Philip Molyneux and Amine Tarazi, (2013) Risk in Islamic Banking Review of Finance 121 17.29 Rajesh Aggarwal and Tarik Yousef, (2000) Islamic Banks and Investment Financing Journal of Money, Credit and Banking 119 5.95 Bassam Maali, Peter Casson, Christopher Napier, (2006) Social reporting by Islamic banks ABACUS 118 8.43 Roszaini Haniffa and Mohammad Hudaib, (2007) Exploring the Ethical Identity of Islamic Banks via Communication in Annual Reports Journal of Business Ethics 115 8.85 Jane Pollard, and Michael Samers, (2007) Islamic banking and finance: postcolonial political economy and the decentring of economic geography Transactions of the Institute of British Geographers 84 6.46 Jill Johnes, Marwan Izzeldin, and Vasileios Pappas. (2014) A comparison of the performance of Islamic and conventional banks 2004–2009 Journal of Economic Behavior & Organization 72 12.00 Network analyses Historiographic and co-citation networks The historiographic network is utilized to identify the temporal direct citation flow of highly cited research papers to trace the intellectual history of the IB&F field. It has been employed in myriad fields of studies, including the circular economy (Alnajem et al. 2021), Halal food (Mostafa 2020), and service networks (da Silva et al. 2017). The Historiographic network of the IB&F research is shown in Fig. (4). The Figure indicates a presence of various distinct IB&F research with, to some extent, joint clusters. The primary subnetwork was initiated in 2000 through a research paper conducted by Aggarwal and Yousef (2000). This paper was published in the “Journal of Money Credit and Banking” and investigated Islamic banks’ financial instruments. It has remained influential in the IB&F field until 2016. Besides, it has gained a substantial impact over time because Abdul-Majid first cited it in 2010, which was cited by Beck et al. (2010). Subsequently, several authors have cited this article leading to a complicated citation network of this research paper. Considerably, it becomes a central research paper in IB&F after several years. A research paper by Maali B. (2006) developed another cluster of citations, which was cited by Mallin c. (2014) and Elnahass M. (2014), followed by a large number of citations. Fig. 4 IB&F historiographic network The influential authors can distribute the knowledge through their networks because they are in a good position to initiate interactions and seek comments on a particular research area. Hence, they are more likely to stimulate the flow of ideas and information in a field of study. The co-citation network of authors helps identify the leading authors in an area of research (Alnajem et al. 2021). The IB&F co-citation network of authors is shown in Fig. (5). Several meaningful insights are observable from examining the Figure. For instance, the nodes’ sizes suggest that Kabir Hassan (Hassan MK) dominates a key node spot in the network, suggesting his central role in the diffusion of knowledge in the IB&F research (i.e., a leading author in the IB&F author co-citation network). It is also observable that several spots of nodes are relatively close. This suggests a presence of a “homophily impact” among authors of the IB&F research. In IB&F, authors have common research interests, leading to a high level of coordination among authors. The “homophily impact” can be identified in the co-citations networks through the authors’ thematic similarity of the research agenda (Jiang et al. 2019). The Figure also shows that the node spot representing Thorsten Beck (Beck, T) is close to the node spot representing Allen N. Berger (Berger, A. N), suggesting that they share common research interests (i.e., homophily impact). Furthermore, the red-coloured nodes on the right side of the Figure represent, to some extent, virtually separate nodes. This suggests a presence of structural holes (Mostafa 2020), meaning that some authors develop research articles that may act as bridges to link between different separate nodes and are subsequently cited by authors in different clusters. Fig. 5 IB&F co-citation network of authors Likewise, Fig. (6) presents the IB&F co-citation network of academic Journals. It reveals four distinct Journal co-citation nodes presented in four different colours. Each coloured node combines journals that publish a particular theme of IB&F research. The Figure also depicts a low connection among the four coloured nodes. The Journals within each coloured node can be described as a core-periphery pattern (Dobusch and Kapeller 2012). The core journals are shown in the central spot within each node, which are considered the primary academic Journals of a particular thematic area of the IB&F research. The periphery journals are presented around the core journals of each node. It is observable that few core journals dominate the publication of IB&F research on a specific theme of research. The red nodes present academic Journals that focus on the financial performance and instruments of Islamic financial institutions. The “Journal of Banking and Finance” is considered the core journal in this thematic area. While the periphery journals include the “Journal of Finance,“ “Pacific-Basin Finance Journal,“ and “Journal of Corporate Finance.“ The green nodes deal with Shariah-compliance issues, ethical values, and social responsibility duties of Islamic financial institutions. It includes the “Journal of Business Ethics” and the “International Journal of Islamic and Middle Eastern Finance and Management” as core journals. However, this node’s periphery journals include the “Managerial Auditing Journal” and the “International Journal of Social Economics.“ The blue cluster focuses on journals dealing with marketing aspects and customer preferences in IB&F. It includes the “International Journal of Bank Marketing” as a core journal and the “Journal of Applied Psychology” and “Emerging Market Business Research” as periphery journals. Finally, the yellow cluster focuses on managerial and administrative issues of Islamic financial institutions. It includes the “Academy Management Journal” and the “Academy Management Review.“ Fig. 6 IB&F co-citation network of journals Keyword, Sankey diagram, and co-occurrence network analyses Analyzing keywords of a field of study is essential in bibliometric analysis (Mostafa 2020). The keyword co-occurrence analysis identifies the main topics, domains, contents, and thematic structure in a particular field of study (Su and Lee 2010). The tag cloud is a visual figure depicting a specific word’s frequency of occurrence in a research article. Words with higher (lower) frequency are more (less) likely to be present in the tag could. The tag cloud of the keywords in the abstracts of the IB&F research is presented in Fig. (7). It is observable that the most repetitive keywords were “Islamic,“ “banks,“ “banking,“ “conventional,“ “performance,“ and “financial.“ This suggests that IB&F research mainly focuses on examining the financial performance of Islamic relative to conventional banks. This is consistent with the significant research that examines this issue (e.g., Narayan et al. 2017; Dewandaru et al. 2015; Wanke et al. 2016; Belanès et al. 2015; Baele et al. 2014; Pappas et al., 2016; Mobarek and Kalonov 2014). Fig. 7 IB&F tag cloud of keywords Moreover, Colicchia et al. (2019) argue that knowledge of a field of study includes topics and themes that are more likely to be investigated and attain particular research interest from scholars but then become less attractive to scholars and disappear eventually. Therefore, Fig. (8) presents the temporal occurrence of keywords with a sharp rise in frequency over time in the IB&F research. It reveals that keywords such as “performance,“ “efficiency,“ “risk,“ and “stability” have received more attention in IB&F research in recent years and may be seen as essential research fronts or hotspots in the future studies. It is also worth mentioning that methodological advancement was introduced recently, evidenced by the keyword “model.“ Thus, it is expected to see advanced models such as structural equation modelling and the generalized method of moments (GMM) model in the future research of IB&F. Fig. 8 IB&F temporal evolution of keyword The Sankey diagram presents the flow of parameters among two or more groups (Sankey 1898). For example, the Sankey diagram is presented in three field plots in bibliometric analysis. The left side represents the keywords in the field of study, the middle side represents the authors, and the right side reflects the cited publications in this field. Figure (9) presents the Sankey diagram, which illustrates the flow among keywords, authors, and research publications in the field of IB&F. It is observable that “Islamic banks” and “Islamic banking” keywords have the most significant edge widths. That is, these keywords are dominant and highly searched by scholars in the field of IB&F. Also, authors including Kabir Hassan [Hassan, M.K], Marwan Izzeldin [Izzeldin, M.], David Geoffrey Mayes [Mayes G. D], Ahmet Faruk Aysan [Aysan, A. F], Amine Tarazi [Tarazi, A], Huseyin Ozturk [Ozturk, H], Faisal Alqahtani [Alqahtani, F], Kym Brown [Brown, K], and Mohammad Bitar [Bitar, M.] have used relatively more keywords relative to other authors. This implies that their research publications covered numerous themes and topics in the field of IB&F, which is evidenced by their publications in diversifiable academic journals such as “Journal of Banking and Finance,“ “Journal of Finance Service Research,“ “Journal of Economic Behavior & Organization,“ “Review of Finance,“ and “Pacific-Basin Finance Journal.“ Fig. 9 IB&F Sankey diagram The keywords provided by authors in the abstracts of their research papers are used to develop the “keyword co-occurrence network.“ This network helps further probe the frequency that keywords appear in the research articles. Figure (10) presents the IB&F keyword co-occurrence network. The node’s size represents the frequency of each keyword, and the link thickness is the number of times a pair of keywords appears together in a research article. The large nodes close to the center of the network present research “hotspots” in the study field (Van Eck and Waltman 2014). The Figure reveals that IB&F deals mainly with five main clusters of topics, including “Islamic and conventional banking,“ “performance and corporate governance system,“ “risks and competition in Islamic and conventional banks,“ “efficiency of Islamic banking,“ and “service quality and consumer loyalty in Islamic and conventional banks.“ These topics can be considered core trends for current and future research in IB&F. Fig. 10 IB&F keywords co-occurrence network Collaboration networks The authors’ collaboration network identifies the frequency of their joint research publications in a particular area. Figure (11) presents the author’s collaboration network in the IB&F field. The node’s size represents each author’s research, and the link thickness is to the frequency of joint research articles. The coloured nodes in the Figure represent 12 research groups of authors, suggesting a limited collaboration between authors in the IB&F research field. There is also a limited and dispersed collaboration network, such as the network of Marwan Izzeldin [Izzelldin, M.] and Vasileios Pappas [Pappas, V.]. The Figure also suggests that most of the networks are somewhat disjointed. This indicates rare cooperation among authors in the IB&F research field. This phenomenon could be explained on the basis that leading authors in IB&F are more likely to develop collaboration with authors from different research fields. Fig. 11 IB&F authors’ collaboration network Likewise, Fig. (12) presents the IB&F research institutions’ collaboration network. It shows that the institutions are categorized into three groups based on the colour used. The first group is shown in green and represents the largest institutions’ collaboration group. It consists of ten institutions located in different countries, such as the International Islamic University Malaysia [Malaysia], the King Abdulaziz University [Saudi Arabia], and the Universiti Teknologi Malaysia [Malaysia]. These institutions develop collaborations with other institutions such as the University of Durham [UK] and the Shariah Advisory Council [Malaysia]. The second cluster is blue and includes nine institutions, such as the Institute of Islamic Banking and Finance and Kuala Lumpur University in Malaysia. They initiate collaboration with the association of Islamic banking and financial institution of Malaysia. The final cluster shows isolated and limited collaboration and includes only one institution: the University of New Orleans in the USA. The IB&F research institutions’ collaboration network is a “locally concentrated and globally isolated” collaboration. This is observable from the high level of collaboration among universities and research institutions in Malaysia and the limited collaboration between Malaysian and international institutions. Furthermore, there is limited collaboration among institutions in developed and developing countries. For example, the University of New Orleans has not developed collaboration with other institutions in developed countries. Henceforth, the institution’s collaboration network in the IB&F field denotes its scattered nature, leading to limited knowledge sharing among scholars and institutions. Fig. 12 IB&F institution’s collaboration network Furthermore, Fig. (13) shows the IB&F research countries’ collaboration. It reveals that Malaysia is the most productive in IB&F research, and it is highly collaborating with some other countries such as New Zealand, Indonesia, the USA, and the UK. Besides, it has some bit collaborations with Turkey, Nigeria, Belgium, and Egypt. The countries’ collaboration network is denser than the collaboration networks of authors (Fig. 11) and institutions (Fig. 12). However, this represents only 5% of countries’ collaboration with a few isolated countries such as Israel and Slovakia. Besides, the countries’ collaboration is more likely to be attributable to collaboration among authors from different countries rather than direct official collaboration between institutions from the countries. Overall, the collaborations of institutions and countries are driven by their Islamic culture, geographical area, and degree of economic development. Fig. 14 IB&F countries’ collaboration network Intellectual structure maps Conceptual structure map The current study utilizes the multiple correspondence analysis (MCA) to detect the conceptual structure and different dimensions of research in the IB&F field. The MCA has extensively been employed in prior studies (e.g., Mostafa 2020; Alnajem et al. 2021). Figure (14) is a mapping of the conceptual structure of the keywords that appeared in the IB&F research during the last 30-years. It categorizes the conceptual structure of IB&F research into four mutually interrelated clusters. It is observable that the core cluster is shown in red and incorporates keywords that are concerned with the performance of Islamic banks, such as “performance,“ “efficiency,“ “productivity,“ “liquidity,“ “stability,“ “diversification,“ “return” and “equity.“ This cluster may include, but is not limited to, research articles that explore the performance of Islamic compared to conventional banks concerning profitability (Narayan et al. 2017; Dewandaru et al. 2015), bank efficiency (Johnes et al. 2014; Wanke et al. 2016; Belanès et al. 2015), cost efficiency (Beck et al., 2013; Olson and Zoubi 2011), a default rate of loans (Baele et al. 2014; Pappas et al. 2017), and financial stability (Mobarek and Kalonov 2014). The second cluster is blue and deals with Islamic banks’ ethics, corporate governance system, and social responsibility. It includes keywords such as “ethics’, “management”, “quality”, “disclosure”, “corporate social responsibility” and “audit committee”. The authors within this cluster examine the efficiency of Islamic banks’ corporate governance system and how social responsibility affects the performance of Islamic financial institutions. Representative research articles include Mollah and Zaman (2015), who examine whether Shariah’s supervisory board and corporate governance system influence Islamic banks’ performance. Also, they include Mollah et al. (2016), who explore the impact of governance structures on risk-taking and financial performance of Islamic relative to conventional banks, and Baele et al. (2014), who investigate religion’s effect on the default rate of bank loans. Other representative articles of this cluster include Belal et al. (2015), who analyze the ethical reporting of Islamic banks, Hassan et al. (2010), and Platonova et al. (2016), who investigate the social responsibility behaviour of Islamic banks and its consequences on the future performance of bank banks. The third cluster is green and seems to deal with service quality and consumer perceptions of Islamic banks. It includes keywords such as “service quality”, “behavior”, “consumer perception”, “satisfaction”, and “culture”. Representative research includes Taap et al. (2011), who investigate the quality of services in Islamic banks relative to conventional ones, and Haron et al. (2020), who examine the customers’ satisfaction, loyalty, and trust in Islamic banks. The last cluster is shown in purple, and it seems to deal with behavioural and social finance in Islamic banking. It includes keywords such as “adoption,“ planned behaviour,“ perceptions,“ and “image.“ Representative research includes Hoque et al. (2019), who explores the drivers of customers’ intention to follow a variety of products and services of Islamic banks. Fig. 14 IB&F conceptual structure map Thematic map The thematic map is a clustering algorithm used to identify the concentration of different themes related to a specific field of study. It is divided into four quadrants based on the levels of density and centrality. The first one is the “well-developed” theme with high density and centrality. The second one is the “highly-developed-and-isolated” theme which can be identified by a high density and a low centrality. The third one is the “emerging-or-declining” theme with low density and centrality. The final them is termed “basic-and-transversal” and is described by low density and high centrality. The size of the theme bubble is prorated to the frequency of research publications that include particular keywords. Figure (15) presents the thematic map of IB&F research. It shows that the well-developed theme includes “corporate governance,“ “finance,“ and ‘management,‘ while the highly developed and isolated theme includes “performance,“ “impact’ and “financial institutions.“ The emerging or declining theme in IB&F research includes the “determinants,“ “conventional banks” and “panel data.“ However, the primary and transversal theme includes “efficiency,“ “risk” and “stability.“ The Figure also shows some issues that occupy a hybrid positions (present in two quadrants) including “model,“ ‘behaviour” and “customer satisfaction.“ These can be seen as highly total citations implying impactful themes in the IB&F field (Mostafa 2020). Fig. 15 IB&F thematic map Concluding remarks and future research directions The IB&F is a value-based system aiming to ensure the substantial well-being of people and sustainable economic growth of a country. The research on IB&F has witnessed exponential growth at an average rate of 5.6% annually during the last three decades. Besides, scholars are interested in examining the roles of Islamic financial institutions in the COVID-19 pandemic (Hassan et al. 2021), suggesting future research in this area. This study is motivated by a research interest in mapping IB&F scholarly research. It adds to the literature by utilizing bibliometric analyses–an innovative way to map and visualize the development, conceptual structure, and thematic evolution of the IB&F field. The study analyses 464 WoS IB&F research publications of 921 authors comprising 58 countries published over three decades from 1990 to 2019. It presents a “big picture” of IB&F research that identifies the temporal chronological IB&F citations to trace the intellectual history of the IB&F. It also builds different networks between authors, research publications, academic journals, institutions, and countries to understand the sources and flow of knowledge in IB&F filed. In addition, it utilizes the MCA to detect the conceptual structure and different dimensions of research in the IB&F field. Furthermore, it develops a thematic clustering algorithm map to identify the concentration of different themes in IB&F research. The results suggest the following insights and implications for scholars. First, there has been an exponential increase in IB&F research since 2008, evidenced by a significant number of authors and countries involved alongside total citations in this field of study. Malaysia is the most productive in IB&F research, and it is ranked first in both SCP and MCP, followed by Indonesia and the United Kingdom. The collaboration among countries is limited and influenced by the culture (Islamic vs. non-Islamic countries), economic development (developed vs. developing countries), and geographical area. Besides, the countries’ collaboration is more likely to be attributable to collaboration among authors from different countries rather than direct official collaboration between institutions from these countries. The results also suggest that the collaboration among institutions can be described as a “locally concentrated and globally isolated” collaboration. This is evidenced by the high collaboration among universities and research institutions in Malaysia and their limited global collaboration. This scattered nature of institutions and countries’ collaborations is likely to lead to limited knowledge sharing among scholars and institutions. Second, the co-citations networks of authors and academic journals reveal that the IB&F research can be seen as a type of “small-world network.“ Few authors and journals dominate the networks and play a central role in the diffusion of knowledge in the IB&F research. Besides, there is a “homophily impact” among the leading authors of the IB&F research, meaning that they have common research interests, leading to a high level of coordination. Furthermore, there are structural holes in IB&F research, meaning that some authors develop research articles that may act as bridges to link different research themes. Thus, the networks in IB&F research reflect the “Matthew Effect” (described in sociology), meaning that few authors have a more significant number of networks than the rest of the authors. Third, the conceptual structure of IB&F research can be classified into four mutually interrelated clusters, including (i) performance of Islamic banks, (ii) Islamic banks’ ethics, corporate governance system, and social responsibility, (iii) service quality and consumer perceptions of Islamic banks, and (iv) behavioural and social finance in Islamic banking. This conceptual structure is essential in developing agenda for future research in the IB&F field. Finally, thematic development suggests a promising research trend in this field of study, especially in analyzing the performance of Islamic and conventional banks using longitudinal panel data techniques. The study has some limitations that can be suggested as avenues for future research. First, data is collected from only the WoS database, covering high-quality peer-reviewed research publications. Thus, the results of our search may not cover all publications of the IB&F research. Future research can use multiple data sources. Besides, we focus on English IB&F research publications, limiting the scope of research coverage. Future research can consider different languages (e.g., Arabic and Malay) alongside the English language to be able to generalize the results. Second, the current study follows prior research and uses the co-citations networks (Mostafa 2020; Argoubi et al. 2020; Yahaya et al. 2020; Alnajem et al. 2021). However, other methods, including self-organization- maps and continuous space (Skupin 2004), can be used for future research. Finally, based on our keyword network analyses, future research can employ methodological advancements such as structural equation modelling and the generalized method of moments (GMM) model. Besides, future research can explore several research aspects of Islamic institutions which are ignored in IB&F research, including Islamic banks’ level of cash holdings (Hassanein and Kokel 2022), voluntary disclosure (Alm El-Din et al. 2022), social responsibility (Alazzani et al. 2017), market reaction (Hassanein et al. 2021), earning management (Zalata et al. 2019), and future-oriented information (Hassanein and Hussainey 2015; Hassanein et al. 2019; Benameur et al. 2022). 1 In 1970s, many Islamic banks have been established such as Nasser Social Bank Cairo (1972, Egypt), Islamic Development Bank (1975, Saudi Arabia), Dubai Islamic Bank (1975, United Arab Emirates), Kuwait Finance House (1977, Kuwait), Faisal Islamic Bank of Sudan (1977, Sudan). 2 AAOIFI was created in 1990 to ensure that IFIs are complying with the Islamic jurisprudence. It develops standards for IFIs throughout the world and its standards focus on different areas including Shariah, accounting, auditing, governance, and codes of ethics. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Change history 8/11/2022 A Correction to this paper has been published: 10.1007/s11135-022-01491-w ==== Refs References Abedifar P Hasan I Tarazi A Finance-growth nexus and dual-banking systems: Relative importance of Islamic banks J. Econ. Behav. Organ. 2016 132 198 215 Aggarwal, R.K., Yousef, T.: Islamic banks and investment financing.Journal of money, credit and banking,93–120. (2000) Alaoui A Dewandaru G Rosly S Masih M Linkages and co-movement between international stock market returns: case of Dow Jones Islamic Dubai Financial Market index J. Int. Financ. Mark. Inst. Money 2015 36 53 70 Alazzani A Hassanein A Aljanadi Y Impact of gender diversity on social and environmental performance: evidence from Malaysia Corp. Gov. 2017 17 2 266 283 Alexakis, C., Pappas, V., Tsikouras, A.: Hidden cointegration reveals hidden values in Islamic investments.Journal of International Financial Markets, Institutions and Money,70–83(2016) Alm El-Din MM El-Awam AM Ibrahim FM Hassanein A Voluntary disclosure and complexity of reporting in Egypt: the roles of profitability and earnings management J. Appl. Acc. Res. 2022 23 2 480 508 Alnajem M Mostafa M ElMelegy A Mapping the first decade of circular economy research: a bibliometric network analysis J. Industrial Prod. Eng. 2021 38 1 29 50 Al-Suhaibani M Naifar N Islamic corporate governance: risk-sharing and Islamic preferred shares J. Bus. Ethics 2014 124 4 623 632 Amrutha VN Geetha SN A systematic review on green human resource management: Implications for social sustainability J. Clean. Prod. 2020 247 119131 Argoubi, M., Ammari, E., Masri, H.: A scientometric analysis of Operations Research and Management Science research in Africa.Operational Research,1–17. (2020) Ashraf D Does Shari’ah screening cause abnormal returns? Empirical evidence from Islamic equity indices J. Bus. Ethics 2016 134 2 209 228 Aydin N Paradigmatic foundation and moral axioms of ihsan ethics in Islamic economics and business J. Islamic Acc. Bus. Res. 2020 11 2 288 308 Aysan AF Disli M Ng A Ozturk H Is small the new big? Islamic banking for SMEs in Turkey Econ. Model. 2016 54 187 194 Azmat S Skully M Brown K Issuer’s choice of Islamic bond type Pac.-Basin Financ. J. 2014 28 122 135 Baele L Farooq M Ongena S Of religion and redemption: Evidence from default on Islamic loans J. Banking Finance 2014 44 141 159 Beck T Demirgüç-Kunt A Merrouche O Islamic vs. conventional banking: Business model, efficiency and stability J. Banking Finance 2010 37 433 447 Belal AR Abdelsalam O Nizamee SS Ethical reporting in Islami bank Bangladesh limited (1983–2010) J. Bus. Ethics 2015 129 4 769 784 Belanès A Ftiti Z Regaïeg R What can we learn about Islamic banks efficiency under the subprime crisis? Evidence from GCC Region Pac.-Basin Financ. J. 2015 33 81 92 Benameur K Hassanein A Azzam MEAY Elzahar H Future-oriented disclosure and corporate value: the role of an emerging economy corporate governance J. Appl. Acc. Res. 2022 10.1108/JAAR-01-2021-0002 Block J Fisch C Rehan F Religion and entrepreneurship: a map of the field and a bibliometric analysis Manage. Rev. Q. 2020 70 4 591 627 Colicchia C Creazza A Noè C Strozzi F Information sharing in supply chains: a review of risks and opportunities using the systematic literature network analysis (SLNA) Supply Chain Management: An International Journal 2019 24 5 21 Corbet S Dowling M Gao X Huang S Lucey B Vigne SA An analysis of the intellectual structure of research on the financial economics of precious metals Resour. Policy 2019 63 101416 da Silva SV Antonio N de Carvalho JC Analysis of the service dominant logic network, authors, and articles Serv. Ind. J. 2017 37 2 125 152 Dewandaru G Masih R Bacha OI Masih AMM Combining momentum, value, and quality for the Islamic equity portfolio: Multi-style rotation strategies using augmented Black Litterman factor model Pac.-Basin Financ. J. 2015 34 205 232 Dobusch L Kapeller J A guide to paradigmatic self-marginalization: Lessons for post-Keynesian economists Rev. Political Econ. 2012 24 469 487 Elnahas AM Hassan MK Ismail GM Religion and ratio analysis: Towards an Islamic corporate liquidity measure Emerg. Markets Rev. 2017 30 42 65 Ferreira MP Pinto CF Serra FR The transaction costs theory in international business research: a bibliometric study over three decades Scientometrics 2014 98 3 1899 1922 Gheeraert L Does Islamic finance spur banking sector development? J. Econ. Behav. Organ. 2014 103 S4 S20 Grassa R Matoussi H Corporate governance of Islamic banks Int. J. Islamic Middle East. Finance Manage. 2014 7 3 346 362 Grira J Hassan MK Soumaré I Pricing beliefs: Empirical evidence from the implied cost of deposit insurance for Islamic banks Econ. Model. 2016 55 152 168 Haniffa, R., Hudaib, M.: Exploring the ethical identity of Islamic banks via communication in annual reports. Journal of business Ethics, 76(1), 97–116. (2007) Haron R Subar NA Ibrahim K Service quality of Islamic banks: satisfaction, loyalty and the mediating role of trust Islamic Economic Studies 2020 28 1 3 23 Hassan MK Khan ANF Ngow T Is faith-based investing rewarding? The case for Malaysian Islamic unit trust funds J. Islamic Acc. Bus. Res. 2010 1 2 148 171 Hassan, M.K., Muneeza, A., Sarea, A.M.: COVID-19 and Islamic Social Finance. Routledge. (2021) Hassanein A Hussainey K Is forward-looking financial disclosure really informative? Evidence from UK narrative statements Int. Rev. Financial Anal. 2015 41 52 61 Hassanein A Kokel A Corporate cash hoarding and corporate governance mechanisms: evidence from Borsa Istanbul Asia-Pacific J. Acc. Econ. 2022 29 3 831 848 Hassanein A Mostafa M Benameur K Al- Khasawneh J How do big markets react to investors’ sentiments on firm tweets? J. Sustainable Finance Invest. 2021 10.1080/20430795.2021.1949198 Hassanein A Zalata A Hussainey K Do forward-looking narratives affect investors’ valuation of UK FTSE all-shares firms? Rev. Quant. Financ. Acc. 2019 52 2 493 519 Hayat R Hassan MK Does an Islamic label indicate good corporate governance? J. Corp. Finance 2017 43 159 174 Hoque ME Hassan MK Hashim NMHN Zaher T Factors affecting Islamic banking behavioral intention: the moderating effects of customer marketing practices and financial considerations J. Financial Serv. Mark. 2019 24 1 44 58 Jan, A.A., Lai, F.W., Draz, M.U., Tahir, M., Ali, S.E.A., Zahid, M., Shad, M.K.: Integrating sustainability practices into islamic corporate governance for sustainable firm performance: from the lens of agency and stakeholder theories.Quality & Quantity,1–24. (2021) Jiang Y Ritchie B Benckendorff P Bibliometric visualization: An application to tourism crisis and disaster research Curr. Issues Tourism 2019 22 1925 1957 Johnes J Izzeldin M Pappas V A comparison of performance of Islamic and conventional banks 2004–2009 J. Econ. Behav. Organ. 2014 103 S93 S107 Kabir MN Worthington A Gupta R Comparative credit risk in Islamic and conventional bank Pac.-Basin Financ. J. 2015 34 327 353 Kumar, S., Sureka, R., Colombage, S.: Capital structure of SMEs: a systematic literature review and bibliometric analysis.Management Review Quarterly,1–31. (2019) Linnenluecke MK Marrone M Singh AK Conducting systematic literature reviews and bibliometric analyses Aust. J. Manage. 2020 45 2 175 194 Lotka AJ The frequency distribution of scientific productivity J. Wash. Acad. Sci. 1926 16 12 317 323 Maali B Casson P Napier C Social reporting by Islamic banks Abacus 2006 42 2 266 289 Mallin C Farag H Ow-Yong K Corporate social responsibility and financial performance in Islamic banks J. Econ. Behav. Organ. 2014 103 S21 S38 Merediz-Solà I Bariviera AF A bibliometric analysis of bitcoin scientific production Res. Int. Bus. Finance 2019 50 294 305 Mobarek A Kalonov A Comparative performance analysis between conventional and Islamic banks: empirical evidence from OIC countries Appl. Econ. 2014 46 3 253 270 Mollah S Zaman M Shari’ah supervision, corporate governance and performance: Conventional vs. Islamic banks J. Banking Finance 2015 58 418 435 Mollah S Hassan MK Farooque A Mobarek A The governance, risk-taking, and performance of Islamic banks J. Financial Serv. Res. 2017 51 2 195 219 Mostafa MM A knowledge domain visualization review of thirty years of halal food research: themes, trends and knowledge structure Trends Food Sci. Technol. 2020 99 660 677 Musa MA Abd Sukor ME Ismail MN Elias MRF Islamic business ethics and practices of Islamic banks: Perceptions of Islamic bank employees in Gulf cooperation countries and Malaysia J. Islamic Acc. Bus. Res. 2020 11 5 1009 1031 Naifar N Hammoudeh S Dependence structure between sukuk (Islamic bonds) and stock market conditions: An empirical analysis with Archimedean copulas J. Int. Financ. Mark. Inst. Money 2016 44 148 165 Narayan PK Bannigidadmath D Does financial news predict stock returns? New evidence from Islamic and non-Islamic stocks Pac.-Basin Financ. J. 2017 42 24 45 Narayan PK Phan DHB Momentum strategies for Islamic stocks Pac.-Basin Financ. J. 2017 42 96 112 Narayan PK Narayan S Phan DHB Thuraisamy KS Tran VT Credit quality implied momentum profits for Islamic stocks Pac.-Basin Financ. J. 2017 42 11 23 Olson D Zoubi TA Efficiency and bank profitability in MENA countries Emerg. markets Rev. 2011 12 2 94 110 Pappas V Ongena S Izzeldin M Fuertes AM A survival analysis of Islamic and conventional banks J. Financial Serv. Res. 2017 51 2 221 256 Platonova E Asutay M Dixon R Mohammad S The impact of corporate social responsibility disclosure on financial performance: Evidence from the GCC Islamic banking sector J. Bus. Ethics 2018 151 2 451 471 Pollard J Samers M Islamic banking and finance: postcolonial political economy and the decentring of economic geography Trans. Inst. Br. Geogr. 2007 32 3 313 330 Qi T Wang T Ma Y Zhang W Zhu Y A scientometric analysis of e-participation research Int. J. Crowd Sci. 2018 2 136 148 Rahim AM Masih M Portfolio diversification benefits of Islamic investors with their major trading partners: Evidence from Malaysia based on MGARCH-DCC and wavelet approaches Econ. Model. 2016 54 425 438 Raza SA Ahmed R Ali M Qureshi MA Influential factors of Islamic insurance adoption: an extension of theory of planned behavior J. Islamic Mark. 2019 11 6 1497 1515 Rivera MA Pizam A Advances in hospitality research: from Rodney Dangerfield to Aretha Franklin Int. J. Contemp. Hospitality Manage. 2015 27 362 378 Ronda-Pupo GA The effect of document types and sizes on the scaling relationship between citations and co-authorship patterns in management journals Scientometrics 2017 110 3 1191 1207 Sankey, M.H.P.R.: Introductory note on the thermal efficiency of steam-engines. In Minutes of Proceedings of the Institution of Civil Engineers,134, 1897-98. (1898) Saraç M Zeren F The dependency of Islamic bank rates on conventional bank interest rates: further evidence from Turkey Appl. Econ. 2015 47 7 669 679 Shi, Y., Li, X.: A bibliometric study on intelligent techniques of bankruptcy prediction for corporate firms.Heliyon, 5(12), e02997. (2019) Skupin, A.: The world of geography: Visualizing a knowledge domain with cartographic means. Proceedings of the National Academy of Sciences, 101(suppl 1), 5274–5278. (2004) Su HN Lee PC Mapping knowledge structure by keyword co-occurrence: a first look at journal papers in Technology Foresight Scientometrics 2010 85 1 65 79 Sun PH Mohamad S Ariff M Determinants driving bank performance: A comparison of two types of banks in the OIC Pac.-Basin Financ. J. 2017 42 193 203 Taap MA Chong SC Kumar M Fong TK Measuring service quality of conventional and Islamic banks: a comparative analysis Int. J. Qual. Reliab. Manage. 2011 28 8 822 840 Van Eck NJ Waltman L Visualizing bibliometric networks Measuring scholarly impact 2014 Cham Springer Wanke P Azad MAK Barros CP Hassan MK Predicting efficiency in Islamic banks: An integrated multicriteria decision making (MCDM) approach J. Int. Financ. Mark. Inst. Money 2016 45 126 141 Yahaya IS Amat A Maryam S Khatib SFA Sabo AU Bibliometric analysis trend on business model innovation J. Crit. Rev. 2020 7 09 2391 2407 Zaher TS Kabir Hassan M A comparative literature survey of Islamic finance and banking Financial Markets, Institutions & Instruments 2001 10 4 155 199 Zalata AM Ntim CG Choudhry T Hassanein A Elzahar H Female directors and managerial opportunism: Monitoring versus advisory female directors Leadersh. Q. 2019 30 5 101309 Zheng C Kouwenberg R A bibliometric review of global research on corporate governance and board attributes Sustainability 2019 11 12 3428
PMC009xxxxxx/PMC9170589.txt
==== Front Genes Dis Genes Dis Genes & Diseases 2352-4820 2352-3042 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. S2352-3042(22)00162-3 10.1016/j.gendis.2022.05.027 Rapid Communication Two human monoclonal SARS-CoV-2 antibodies that maintain neutralizing potency against the SARS-CoV-2 Omicron BA.1 and BA.2 variants Zheng Qianqian ab1 Duan Liangwei ab∗1 Jiang Zhihua c1 Gu Tingxuan de1 Zhang Bojie ab Li Jiaoyang ab Zhang Yang ab Zhang Shiyu ab Liang Yinming ab Wang Hui ab∗∗ a Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan 453003, China b Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan 453003, China c KMD Bioscience (Tianjin) Company Limited, Tianjin 301723, China d Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, Henan 450001, China e China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan 450008, China ∗ Corresponding author. School of Laboratory Medicine, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, Henan 453003, China. Fax/Tel.: +86 373 3831203. ∗∗ Corresponding author. School of Laboratory Medicine, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, Henan 453003, China. Fax/Tel.: +86 373 3831203. 1 These authors contributed equally to this work. 7 6 2022 5 2023 7 6 2022 10 3 664667 8 3 2022 7 5 2022 21 5 2022 © 2022 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. 2022 Chongqing Medical University Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcThe pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to sweep the globe with devastating consequences on human lives and world economy. As an RNA virus, SARS-CoV-2 has a relatively high mutation rate and is rapidly evolving. Thus, new SARS-CoV-2 variants continued to emerge, 5 of which were designated by the World Health Organization (WHO) as variants of concern (VOCs), Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and, recently, Omicron (B.1.1.529).1 First identified in Botswana and South Africa in November 2021, the original Omicron, BA.1, then spread to every corner of the world and quickly replaced the previously dominant Delta strain to become the most prevalent SARS-CoV-2 circulating variant across the world. BA.1 is reported to escape most therapeutic monoclonal antibodies against SARS-CoV-2.2 Consistently, sera from convalescent donors and vaccinated individuals contain very low to undetectable levels of neutralizing antibodies against BA.1.3 Therefore, new therapeutic agents are urgently needed. By phage display technique, antibody libraries generated from RNAs extracted from peripheral lymphocytes of fully or booster-vaccinated individuals in our research group were constructed. The recombinant wild-type (WT) receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) glycoprotein was used as the target protein to screen the phage antibody library for potential hits. A panel of high-affinity binders to the RBD in single chain variable fragment (scFv) format were identified and two high-affinity candidate scFvs were converted into and expressed as two full-size IgG1 antibodies, XK01 and XK02. XK01 and XK02 bound strongly to the WT SARS-CoV-2 RBD with half-maximal effective concentration (EC50) values of 0.012 and 0.018 μg/mL, respectively, as measured by enzyme-linked immunosorbent assay (ELISA), suggesting both monoclonal antibodies have a higher binding avidity than that of ACE2 (EC50 = 0.048 μg/mL) (Fig. 1 A–C). To verify this result and further evaluate the binding affinity, we monitored real–time association and dissociation of XK01 and XK02 binding to the WT SARS-CoV-2 RBD (RBDWT) by surface plasmon resonance (SPR). XK01 and XK02 exhibited tight binding to RBDWT with equilibrium dissociation constants (K D) of 93 nM for XK01 and of 109 nM for XK02, respectively, both of which are superior to that of ACE2 with RBDWT (K D = 348 nM) (Fig. 1D–F).Figure 1 Binding and neutralization activities of XK01 and XK02 against SARS-CoV-2 wild-type (WT) and Omicron variants. (A–C) Binding curve of XK01 (A), XK02 (B) and ACE2-hFc (C) to the WT SARS-CoV-2 RBD (RBDWT) measured by ELISA. (D–F) Binding kinetic of XK01 (D), XK02 (E) and ACE2-hFc (F) with immobilized RBDWT, measured by SPR. The experiments were performed in duplicate with similar results and a representative experiment is shown. (G, H) WT SARS-CoV-2 S pseudovirus neutralizing activities of XK01 (G) and XK02 (H). (I–K) Binding kinetic of XK01 (I), XK02 (J) and ACE2-hFc (K) with immobilized RBDBA.1, measured by SPR. The experiments were performed in duplicate with similar results and a representative experiment is shown. (L, M) Potent neutralization of Omiron BA.1 S pseudovirus by XK01 (L) and XK02 (M). (N, O) Potent neutralization of Omiron BA.2 S pseudovirus by XK01 (N) and XK02 (O). Fig. 1 Based on the data obtained by ELISA and SPR, both XK01 and XK02 monoclonal antibodies probably have potential neutralization efficacy against SARS-CoV-2. As expected, both antibodies showed potent neutralizing activities against virus pseudotyped with the WT SARS-CoV-2 S with half-maximal inhibitory concentration (IC50) values of 0.098 μg/mL for XK01 and 0.072 μg/mL for XK02, respectively (Fig. 1G, H). In the case of BA.1, the binding kinetics of the Omicron SARS-CoV-2 RBD (RBDBA.1) to the ACE2 receptor was measured by SPR, which showed that RBDBA.1 bound potently to ACE2. The K D values of RBDBA.1 with ACE2 were 245 nM for XK01 and 438 nM for XK02, respectively (Fig. 1I, J), indicating the binding affinity of both antibodies for RBDBA.1 was higher than that of the ACE2 receptor (K D = 527 nM) (Fig. 1K). Notably, this observation is very similar to that is observed for RBDWT. Unexpectedly, both monoclonal antibodies showed no loss but increased potency of neutralization against BA.1 S pseudotyped virus with IC50 values of 0.011 μg/mL for XK01 and 0.024 μg/mL for XK02, respectively (Fig. 1L, M). Soon after the emergence and global spread of BA.1, BA.2 has initiated outcompeting BA.1 and has become the dominant Omicron subvariant circulating worldwide, which prompts us to evaluate the ability of XK01 and XK02 monoclonal antibodies to neutralize the BA.2 subvariant. Still, both monoclonal antibodies maintained high neutralizing potency against virus pseudotyped with BA.2 S with IC50 values of 0.025 μg/mL for XK01 and 0.015 μg/mL for XK02, respectively (Fig. 1N, O), despite there are as many as 20 different mutations between BA.2 and BA.1 S proteins. Unfortunately, XK01 and XK02 did not function synergistically with each other to enhance neutralization activities against WT and Omicron BA.1 SARS-CoV-2 (data not shown). Furthermore, both XK01 and XK02 exhibited little neutralizing potency against SARS-CoV S pseudovirus (data not shown) at the highest tested concentration (15.0 μg/mL). Structural studies clearly revealed that the RBD of SARS-CoV-2 is composed of a core subdomain and an external subdomain also known as receptor binding motif (RBM) which loops out of the core subdomain to directly engage ACE2.4 The amino acid sequence identity of the RBD core subdomain and RBM between SARS-CoV and SARS-CoV-2 is more than 85% and less than 50%, respectively.4 Almost all isolated neutralizing antibodies recognizing epitopes in the conserved core subdomain can cross-neutralize SARS-CoV-2 and SARS-CoV infections and are thought to maintain neutralizing potency against previous SARS-CoV-2 VOCs, while those targeting the RBM region with high sequence variations always exhibit no or limited cross–neutralization activity against both viruses. Based on these observations, it can be speculated that both XK01 and XK02 monoclonal antibodies neutralize WT and Omicron SARS-CoV-2 infections by competing with the ACE2 receptor for binding to the RBM and thus blocking attachment of the virus to the host cell surface, although the exact mechanisms of action of both neutralizing antibodies remain to be defined. Universal vaccine and broadly neutralizing antibodies and/or variant-specific vaccines and neutralizating antibodies are urgently needed to counteract the emerging SARS-CoV-2 variants of immune escape.5 S proteins of the Omicron BA.1 and BA.2 variants have approximately 37 and 31 mutations compared with the ancestral SARS-CoV-2 virus. The RBDs alone have 15 and 16 mutations, respectively, of which 5 and 8 lie in the conserved core domains, respectively, and the rests are in the RBM regions, enabling both Omicron subvariants to escape the majority of existing RBD-targeted neutralizing antibodies. Furthermore, use and development of broadly neutralizing antibodies may be challenged by the emergence of growing mutations in the conserved core of current and future emerging variants under the immune pressure exerted by vaccines or previous infections. For example, Sotrovimab (VIR-7831), the prototypic member of a canonical class of broadly neutralizing antibodies, has markedly reduced efficacy against BA.2 while maintaining much of it's neutralizating activity against BA.1 in pseudovirus neutralization assays, and thus its emergency use authorization has been withdrawn. Therefore, discovering variant-specific neutralizing antibodies is a more feasible strategy. Here, we isolated two such neutralizing antibodies, for which affinity maturation can be used to further improve their affinity and increase the virus neutralization potency. In conclusion, two SARS-CoV-2 neutralizing antibodies selected from vaccine recipients by phage display are successfully isolated. Importantly, these two monoclonal antibodies maintain high neutralizing potency against both BA.1 and BA.2, the two most common subvariants of Omicron. The identification of these two neutralizing antibodies in this study provides promising starting points to be added to the limited list of antibodies with a high potential to effectively counteract the dominant circulating SARS-CoV-2 Omicron VOCs. Author contributions L.D. and H.W. conceived the study and designed the experiments; Q.Z., L.D., Z.J. and T.G. performed the experiments with the assistance of B.Z., J.L., Y.Z., and S.Z.; Q.Z., L.D., Q.Z., L.D., L.Y., and H.W. analyzed the data; L.D., and H.W. wrote the manuscript with input from all authors. All authors read and approved the final version of the manuscript. Conflict of interests L.D., Z.J. and H.W. are listed as inventors on pending patent applications for XK01 and XK02. Z.J. is an employee of KMD Bioscience (Tianjin) Co, Ltd. The other authors declare that they have no competing interests. Funding This work was supported by 10.13039/501100001809 The National Natural Science Foundation of China (No. 81871312), the Key Scientific and Technological Project of Henan Province (No. 222102310025), The International Joint Research Laboratory for Recombinant Pharmaceutical Protein Expression System of Henan (KFKTYB202210), and the 111 Project (No. D20036). Appendix A Supplementary data The following is the Supplementary data to this article:Multimedia component 1 Multimedia component 1 Acknowledgements We would like to thank all study participants who donated blood to our research. We would like to thank Zhenlin Fan, Duan Li, Yunwei Lou, Chunlei Guo, Mengchao Cui, Ting Zhuang and Xin Li and for valuable advice and helpful discussions. Peer review under responsibility of Chongqing Medical University. Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.gendis.2022.05.027. ==== Refs References 1 He X. Hong W. Pan X. SARS-CoV-2 Omicron variant: characteristics and prevention MedComm 2 4 2021 838 845 34957469 2 Cao Y. Wang J. Jian F. Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies Nature 602 7898 2022 657 663 35016194 3 Planas D. Saunders N. Maes P. Considerable escape of SARS-CoV-2 Omicron to antibody neutralization Nature 602 7898 2022 671 675 35016199 4 Duan L. Zheng Q. Zhang H. The SARS-CoV-2 spike glycoprotein biosynthesis, structure, function, and antigenicity: implications for the design of spike-based vaccine immunogens Front Immunol 11 2020 576622 33117378 5 Cameroni E. Bowen J.E. Rosen L.E. Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift Nature 602 7898 2022 664 670 35016195
PMC009xxxxxx/PMC9174062.txt
==== Front Genes Dis Genes Dis Genes & Diseases 2352-4820 2352-3042 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. S2352-3042(22)00163-5 10.1016/j.gendis.2022.05.028 Rapid Communication 3′-UTR of the SARS-CoV-2 genome as a possible source of piRNAs Hernández-Huerta María Teresa a1 Pérez-Campos Mayoral Laura b1 Matias-Cervantes Carlos Alberto a1 Romero Díaz Carlos a∗∗ Cruz Parada Eli c Pérez-Campos Mayoral Eduardo b Baltiérrez-Hoyos Rafael a Martínez Cruz Margarito c Mayoral Andrade Gabriel b Pérez-Campos Eduardo c∗ a CONACyT, Faculty of Medicine and Surgery, Autonomous University “Benito Juárez” of Oaxaca (UABJO), Oaxaca 68020, Mexico b Research Center, Faculty of Medicine UNAM-UABJO, Autonomous University “Benito Juárez” of Oaxaca (UABJO), Oaxaca 8020, Mexico c National Technology of Mexico/IT Oaxaca, Oaxaca de Juárez, Oaxaca 68030, Mexico ∗ Corresponding author. ∗∗ Corresponding author. 1 These authors contributed equally to this work. 8 6 2022 5 2023 8 6 2022 10 3 668670 18 1 2022 18 5 2022 21 5 2022 © 2022 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. 2022 Chongqing Medical University Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. ==== Body pmcSARS-CoV-2 is the causal agent of the COVID-19 pandemic. This is a single-stranded RNA beta-coronavirus that is comprised of a 5′ and 3′-untranslated region (UTR) in its non-coding RNA (ncRNA) region. The P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are ncRNA sequences that bind to transposons and interfere with the translation of new genes. Here, we search for short sequences in the non-coding regions, corresponding to 28 nucleotides (nt). These start from a uracil and have a conserved region of at least 10 nt of homology with the previously reported piRNAs. The aim of this work was to identify piRNA-like sequences in the 3′-UTR of SARS-CoV-2 from the reported Wuhan Patient's genome sequence (GenBank: MN908947.3). As a first analysis, we performed alignments of 32,286 piRNAs from piRBase (http://bigdata.ibp.ac.cn/piRBase/, release V2.0), 27,700 from piRNAdb (https://www.pirnadb.org/download/archive), and 51,509 from piRNAQuest (http://bicresources.jcbose.ac.in/zhumur/pirnaquest/), using the 3′-UTR of the SARS-CoV-2 Wuhan patient's genome as a reference. Since we found no homologies within the piRNAs using BLAST (https://blast.ncbi.nlm.nih.gov/Blast.cgi), we used a text editor manually. Some authors consider piRNAs to be sequences constituting 21 to 35 nt long, while others expect them to have approximately 26–31 nt long. We analyzed piRBase, piRNAdb, and piRNAQuest as shown in the flow diagram (Fig. 1 A) and found that, on average, the number of nucleotides corresponds to 28 nt. Zhang et al1 found that piRNAs, like miRNAs, have a 7 nt “seed region” which needs to interact with their complementary nucleotides. Therefore, there is no consensus criterion to identify a piRNA sequence; nevertheless, it is known that 78%–94% of piRNAs begin with a uracil at their 5′-UTR (position +1),2 most piRNAs have an A at position +4, and an A or G at position −1.3 Based on the above, we used the following criteria to identify the possible piRNAs: 1) 28 nt sequences that shared at least 10 consecutive nucleotides with the piRNAs previously reported in databases, 2) a uracil in its 5’ (in position +1),2 3) an adenine (A) in position +4, 4) an adenine (A) or guanine (G) at position −1.3 Figure 1 3′-UTR of the SARS-CoV-2 genome as a possible source of piRNAs. (A) Flow diagram for identification of piRNAs in 3′-UTR of SARS-CoV-2. (B) Localization of piRNA-like sequences in the predicted secondary structure of 3′-UTR of SARS-CoV-2 through LinearFold. The sequence 29,682–29709 (blue), 29,684–29711 (green), 29,688–29717 (red) and 29,692–29719 (brown) are spliced in a common region, while the sequences 29,757–29784 (purple) and 29,775–29802 (cyan) are in a distant region. Fig. 1 In addition, for ensuring that the selected sequences were piRNAs, we used the 2L-piRNA server (http://bioinformatics.hitsz.edu.cn/2L-piRNA/#). Furthermore, we looked for 2′-OH methylated sites at the 3′-UTR end using the NmSEER V2.0 server (http://www.rnanut.net/nmseer-v2/). Also, we used the turbofold server to predict the 3′-UTR RNA secondary structure (http://linearfold.org/linearturbofold). By last, we evaluated the identity percentage, E-value, and the Waterman-Eggert scores between the sequences proposed as piRNAs in the 3′-UTR of SARS-COV-2, and their homologous sequences through LALIGN (https://fasta.bioch.virginia.edu/fasta_www2/fasta_www.cgi), using +5/-4 scoring matrix and changing the gap penalty, to obtain an approximation of similarities and biological relevance. To confirm that 3′-UTR is a conserved region, we made alignments of the 3′-UTR of the SARS-CoV-2 from alpha, gamma, delta, lambda, mu, and omicron variants, comparing them with the original sequence of the Wuhan patient's genome using Clustal X. Sequences were obtained from GISAID (https://www.gisaid.org/). Of the fifteen sequences that had 28 nt and matched the characteristics indicated above, two sequences, 29,792–29819 (hsa_piRNA_23,430) and 29,757–29784 (hsa_pRNA_25,334) meet all four criteria, twelve of them showed an A or G at position −1. And only two had an A at position +4, 29,792–29819 and 29,757–29784. Using the 2L-piRNA server, we found six sequences that were positive for piRNAs. Moreover, the server predicted that such sequences have a deadenylation function. Sequence alignment showed more than 10 nt of identity. The following scores were measured between the piRNA sequences in the database and the sequences found of the 3′-UTR of SARS-CoV-2; Waterman-Eggert score: more than 52, E-value: less than 0.1, and identity: between 54.3% and 87.5%. Taking into consideration of the % identity, E-value and Waterman-Eggert scores, all sequences selected showed high homology with the piRNAs in the databases (Supplementary data). In addition, RNA secondary structure showed four piRNA-like sequences overlapped in a region and two intersecting in another region, as illustrated in Figure 1B. The NmSEER V2.0 server predicted four methylation sites at positions 29,719 (C), 29,759 (T), 29,761 (T), and 29,766 (T). However, only one of the piRNA sequences reported here (29,692–29719 homolog to hsa_pRNA_1752) has a 2′-OH methylated site in its penultimate Cytosine (GTAACATTAGGGAGGACTTGAAAGAGCC). Relating to the alignments comparing the 3′-UTR from Wuhan's SARS-CoV-2 sequence (MN908947) versus the alpha, gamma, delta, lambda, mu, and omicron variants, we found that this entire region is highly conserved. We observed various random mutations in each one of the SARS-CoV-2 variants. However, these mutations do not affect the identification of piRNAs by the 2L-piRNA server. This is the first report describing the presence of homologous to known piRNA sequences in the 3′-UTR region. We have identified 6 sequences with a high probability of functioning as piRNAs in the 3′-UTR of SARS-CoV-2 from the Wuhan patient sequence. All of them are 28 nt long and have ten or more consecutive nucleotides that are contained in piRNAs already mentioned in different databases such as piRBase, piRNAQuest, and pirnaDB. In addition, they have homologous nucleotides in upstream or downstream positions. Due to piRNAs could be associated with different pathologies, such as the promotion of tumorigenesis, we suggest that if these sequences are present in high amounts in the human cell after exposure to SARS-CoV-2, as in the case of severe COVID-19; there is a high probability of a mismatch occurring in the homeostasis of the piRNAs already present in the cell, as in carcinomas. We should note that this is a theoretical study, with no experimental evidence. Another limitation to mention is that the LinearFold server is used to predict the secondary structure, and this depends on the beam size and the number of base pairs, of which only the 3′-UTR was predicted. We found six piRNA-like sequences in the 3′-UTR of SARS-CoV-2. These meet the criteria indicated above. Their identification has been verified by the 2L-piRNA server and by the similarities in sequences. Further research is needed to verify this finding. Author contributions C.R.D. and E.P.C.: conceptualization. M.T.H.H., L.P.C.M., C.A.M.C., C.R.D. and E.P.C.: formal analysis, investigation, methodology, data curation, software, figure preparation, writing original draft, review and editing. E.C.P., E.P.C.M., I.C.M., R.B.H., M.M.C., G.M.A. and M.E.A.V.: investigation, review and editing. Conflict of interests The authors declare that they have no conflict of interests. Funding This work was supported by Faculty of Medicine of the Autonomous University Benito Juarez of Oaxaca, Mexico, the National Technology of Mexico (TecNM)/IT Oaxaca, and CONACYT. Appendix A Supplementary data The following are the Supplementary data to this article:figs1 Multimedia component 2 Multimedia component 2 Acknowledgements The authors would like to thank the support throughout the work, to the Faculty of Medicine of the Autonomous University Benito Juarez of Oaxaca, Mexico; to the National Technology of Mexico (TecNM)/IT Oaxaca CONACYT- BP-PA-2021050723-4900732-959110 for financial support, and also to Charlotte Grundy for technical review. Peer review under responsibility of Chongqing Medical University. Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.gendis.2022.05.028. ==== Refs References 1 Zhang D. Tu S. Stubna M. The piRNA targeting rules and the resistance to piRNA silencing in endogenous genes Science 359 6375 2018 587 592 29420292 2 Betel D. Sheridan R. Marks D.S. Computational analysis of mouse piRNA sequence and biogenesis PLoS Comput Biol 3 11 2007 e222 3 Brayet J. Zehraoui F. Jeanson-Leh L. Towards a piRNA prediction using multiple kernel fusion and support vector machine Bioinformatics 30 17 2014 i364 i370 25161221
PMC009xxxxxx/PMC9206426.txt
==== Front Qual Quant Qual Quant Quality & Quantity 0033-5177 1573-7845 Springer Netherlands Dordrecht 35756089 1451 10.1007/s11135-022-01451-4 Article Modelling the lexical complexity of homogenous texts: a time series approach Zhang Yanhui Yanhui.Zhang@nottingham.edu.cn grid.50971.3a 0000 0000 8947 0594 School of Humanities and Social Sciences, University of Nottingham Ningbo China, Ningbo, China 18 6 2022 2023 57 3 20332052 25 5 2022 © The Author(s), under exclusive licence to Springer Nature B.V. 2022 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. Lexical complexity of homogeneous texts, especially when produced by an institutional author over time, exhibits a generally observed increasing trend with local random fluctuations. Such an irreversible entropic process fits very cogently into the dynamical complexity system theory, where the social, economic, and cultural missions such texts set to serve constitute the underlying driving momentum for the texts to adapt themselves from low to high complexity. Structural equations have been shown effective in modeling such macroscopic behavior of the entropic process of the homogeneous texts. The current work formulates the problem from a time series modeling approach applied to a large sociolinguistic corpus in written Chinese. The findings show that such an alternative approach not only produces as valid models with strong goodness of fit as the structural equation approach, but also exhibits, by design, additional benefits in explaining the entropic process of homogeneous texts in the dynamical complexity system framework. Some technical challenges, such as phase change in model calibration, are also solved with less cost using the newly proposed approach. Further directions are pointed out to more fully compare these approaches in the setup of the current study and corpus linguistics in general. Keywords Homogeneous texts Dynamical complexity Entropy Time series ARIMA model issue-copyright-statement© Springer Nature B.V. 2023 ==== Body pmcIntroduction Homogeneity provides a natural classification criterion to otherwise highly randomized organisms in various systems. In the context of linguistic studies, particularly corpus linguistics, homogeneous texts refer to a collection of texts profiling much enough in common in one or more linguistic characteristics that an underlying homogeneity is believed to be present to account for such observed commonness. The production mechanism of the texts is often, although not always, the source of homogeneity (Lai et al. 2020; Zhang, 2016; Boyd and Fraurud, 2010). From quantitative modeling and empirical analysis perspectives, homogeneity may help filter potential confounding factors and random noises in the observed realization of the response variables, increasing the validity and explaining the power of the model constructed. For instance, Mu and Dooley (2015) implicitly relied on the homogeneity in the first language (L1) background in both experiment and model design and ANOVA analysis in demonstrating how household background contributed to the literacy development among heritage Chinese learners in Australia. Such dichotomy of homogeneity and heterogeneity served as a critical methodological defense for many studies, explicitly or implicitly, in assessing how relatively effective the different L1 backgrounds or the different designs of learning and instructional schemes may affect the L2 literacy development (Maxwell et al. 2018; Li et al. 2019; Paap et al. 2014; Komachali and Khodareza, 2012; Zhou et al. 2019). More examples illustrate how homogeneity plays an essential role in the theoretical formulation or experiment design. Such instances include the cross corpora analysis (Kilgarriff, 2001; Kilgarriff and Grefenstette, 2003; Denoual, 2005; Smith and Kelly, 2002), topical dispersion analysis (Sahlgren and Karlgren, 2005), second language (L2) writing classification (Crossley and McNamara, 2011), and language assessment validations (Yao and Chen, 2020; Jang et al. 2015). A critical dimension of homogeneous texts is lexical complexity, especially when the exact linguistic production mechanism generates the texts at different times. According to the dynamic complex system theory (Larsen-Freeman and Cameron, 2008; Verspoor et al. 2011), the corpus of homogenous texts can be viewed as an entropy system. In the system, the texts perform the communicative functions, constituting the propelling force to fuel the evolution of the corpus’ entropic process. The dynamically complex nature of the corpus is compellingly exhibited in several aspects, including the expansive linguistic dimensions, such as semantic, syntactic, discourse, the infinite combinatory patterns of the constituents, the nonlinear or even chaotic interactions, and the potential self-organizational mechanisms. Such dynamic complexity is reinforced when the system allows information or energy to exchange between the system and its sustaining environment. In the case of institutional writings such as government work reports, the external environment is broadly made up of various socio-economic and cultural resources of the society, which provide but also constrain the government’s capacity in achieving its policy agenda. In other words, these reports are both socially conditioned and socially constitutive in that the collective mentalities of the society regulate their linguistic norms and styles. An essential example is the annual China Government Work Report (CGWR), delivered in the high profile “Two Sessions” – the annual plenary meetings of the Chinese National People’s Congress and the Chinese People’s Political Consultative Conference (CPPCC). As such, the CGWR is a dominantly important public document laying out the government’s policy priorities for the following year or years to come and encapsulating the achievements and tasks accomplished in the previous year. Given the above shown interacting relationship between language and society, an analysis on the evolution of the lexical complexity of the CGWR texts, which is the focus of the current study, is highly relevant for an insightful understanding of how the socio-economic and cultural milieu are linguistically manifested from a dynamical sociolinguistic perspective. One major challenge for dynamical complexity approaches to linguistics is the quantifiability of the theory with conceptually justified and computationally rigorous models. As a recent development, Zhang (2016) proposed a structural equation model describing the global entropic pattern of CGWR at a macroscopic level. One limitation of the structural equation modeling, however, is its time-invariance, making it intuitively less consistent with the dynamic complexity theory, where the system’s entropy is essentially assumed as irreversible in time. The current work attempts to model the lexical complexity process of CGWR with time series models which are generically more consistent with the dynamical and ever-increasing nature, at least in an average sense, of the entropic process of homogeneous texts. Accordingly, the nonstationarity of a time series foretells the emerging state or unsaturatedness of a dynamic complexity system. The interconnectedness and interacting nature of the dynamical complexity system are also naturally explained by the autocovariance of the process at different times. What is further, but not least, is that time series modeling can easily handle jumps, phase changes, and other nonlinear phenomena in a dynamic system. Time series methods and modeling (Shin, 2017; Box-Steffensmeier et al., 2014; Lameli, 2018) had been developed in the early 1980s, mostly for analyzing highly randomized socioeconomic data. An early example of time series approach in language studies goes back to Pawłowski (1997) for quantifying the underlying basis of rhythms in coded Latin hemameter syllables, but applications of time series analysis in humanity and social sciences, particularly in linguistic studies, are comparatively scarce. One major reason for the relatively scarce application of time series analysis in the linguistic field is the lack of datasets with high regularity and large sample size. But such a hurdle was gradually overcome with the ever-faster advancement in corpora development, automated testing, natural language processing, data mining, and machine learning technologies. Time series analysis approaches were recently applied, for instance, by research studies regarding word formation (Lameli, 2018) and the adoption and propagation of linguistic innovation (Blytheand Croft, 2021). Michel et al. (2011) conducted a time series analysis on cultural trends historically reflected in English books by drawing insights from diverse perspectives such as the adoption of technology, lexicography, and grammar evolution. Tarnish (2018) applied time series analysis to study how the use of modals and semi-modals in British and American English has evolved differently in the past 200 years. Koplenig (2017) applied the method to identify the correlated changes in chronological corpora. The significance of the current study is two-fold. First, the present study empirically demonstrates a unique angle to understand the interconnectedness between the linguistic features such as lexical complexity of institutional writings and the physical, socio-economic environment by which such writings are conditioned. Specifically, the results show that the lexical complexity of the CGWR, to date, is not a stationary process, implying that the texts are still in their initial states from entropic production and evolution point of view. Thus, the study evinces the ongoing ever-increasing complexity of China’s social, cultural, and economic realities, despite the dramatic changes and reformations undergone in recent decades. Methodologically, the current study provides a long-wished quantitative and analytical support to the theorists in dynamic complexity research by demonstrating that time series analysis is a conceptually valid and computationally rigorous approach to model the dynamic complexity phenomena in the homogeneous texts of institutional writings. Compared to the structural equations, the currently proposed approach is less challenged with variable identification problems and more robust in capturing the structural changes or other irregular patterns that could be more of an unexceptional occurrence with more incoming data of CGGR in the future. In sum, the approach and findings posit a methodological baseline to the corpus linguistics modeling in general where the datasets are of time series nature. In the following section Two, a more detailed literature review focuses on the pertinence to entropic modeling of the homogenous text of CGWR. Section Three focuses on the data description of the CGWR texts and the methods for successful modeling purported in the current study. Section Four provides the primary analysis, results, and discussions on the model validity and comparison with existing models. Finally, section Five presents the concluding remarks and future directions. Related literature Homogeneity analysis Homogeneity is a multi-field concept, the reference of which could be context-dependent. For instance, in music, homogeneity could mean how musical scores are stylistically similar from the music composition and appreciation perspective. But it could also tell how equal the opportunities in the music production industry are to the different backgrounds of musicians concerning, for instance, social class, gender, and ableism (Li et al. 2010). In ecology, species homogeneity is used, in duality with species richness, to measure how diversified an environment encompasses and sustains different species (Newbold et al. 2015). In corpus linguistics, homogeneity refers to the extent to which a group of texts shares much enough in common in one or more linguistic features, e.g., genre, prosody, lexical spectrum, and lexical distance at macroscopic level; or the choice of word, punctuation, tense, directness or indirectness, or the use of questions at local levels (Scott and Tribble, 2006; Nielbo et al., 2019; Kilgarriff, 2001; Kilgarriff and Grefenstette, 2003; Denoual, 2005; Sahlgren and Karlgren, 2005). As such, texts produced by the same author at different times could be reasonably rated as homogenous from a stylometry analysis point of view, even though the writing styles of the same author may still show variations over time. With such definition, the writings by Thomas Hardy are homogeneous when the authorship of texts is underscored. However, the writings of Thomas Hardy, Jane Austin, Charles Dickens, Virgina Wolf, and Mary Shelley, are also collectively homogeneous when highlighting that these writings are all of the same genres of classical English fiction. Homogeneity is essential for text classification. But perhaps more importantly, it accredits the models and analysis adopted in corpus linguistic research by filtering out the disturbing or even distorted information from the raw data and increases the probability and reliability of any proper pattern under seeking. For instance, from a statistical regression perspective, the challenges usually arise less from exploring new variables but more often from the confounding effects of many potential factors. Consequently, the non-homogeneity of factors is empirically demonstrated as one of the most frequent reasons leading to weak explaining powers of the conclusions made in linguistic and other social researches (Aguinis, 2003; Jang et al. 2015). With this rationale, homogeneity has increasingly attracted scholarly attention in linguistic practices. For instance, Kilgarriff and Grefenstette (2003) and Sahlgren and Karlgren (2005) relied on homogeneity to devise the metric of text distance for cross-corpora comparison studies. Denoual (2005) heavily highlighted the homogeneity of participants in the experiment to support the validity of the modeling results. Additionally, many research studies in frequency-based corpus studies premised their analysis on the homogeneity of the texts under review (Johansson, 2008; Voleti et al. 2019). Level of lexical complexity One of the core properties of homogeneous texts that may evolve is the level of complexity – lexical complexity in particular, as focused in the current study. From the information filtration and processing perspective, quantitatively primarily by entropy, lexical complexity refers to the degree of complicatedness the lexises are organized under various linguistic constraints (Hales, 2016; Lowder et al. 2018; Zhang, 2016). However, the notion of “complexity” in linguistic studies, particularly from the language acquisition and language proficiency perspectives, is somewhat complex and much-debated in its own right. According to Crossley et al. (2011) and Jarvis (2013), lexical complexity and lexical sophistication bear the same meaning to some extent. In contrast, the latter possesses more tinge of the high usage of advanced or more words but less of the combinatorial and configurational complexity as focused by the current study. On the other hand, research studies such as Housen et al. (2012) umbrellaed lexical complexity under the concept of linguistic complexity, including syntactic complexity, mainly referring to the organization of the text at phrasal, sentential, and clausal levels. Such taxonomy of linguistic complexity has also been echoed by research from cognitive tasks and assessment designs (Robinson, 2007; Housen et al. 2012). Another important contrast to draw is between lexical complexity and lexical richness (LR) or lexical diversity (Malvern and Richard, 2012; Daller and Xue, 2007), where LR entails a broader notion of a language user’s lexical proficiency. Such proficiency is hypothesized to symbolize how skillful the user is in maneuvering or manipulating different words (e.g., synonyms) when expressing the meaning with subtle differences. More specifically, lexical richness refers to the variability of word use profiled by a speaker or writer (Jarvis, 2013; Zhang and Wu, 2021). Under this umbrella, a variety of lexical richness measures was invented—each with pros and cons in assessing the level of LR of a text quantitatively, typically using frequency-based calculations. One of the oldest and most widely used LR measures is the Type to Token Ratio (TTR), where type refers to the number of unique words used in a text, while token refers to the total running words of the text. While simple, TTR has been demonstrated by substantial empirical studies to outperform many sophisticated LR measures, such as Sichel, Honor, or Yule (Zhang and Wu, 2021). There have been modifications and improvements over TTR, namely, LogTTR (Herdan 1960), rootTTR (Guiraud, 1960), D (Malvern and Richard, 2012), for instance. These attempts were invested mainly to overcome the length effect of TTR. In particular, several studies have shown D as more potent in describing and predicting the LR of speakers, although the computing of D, especially the simulation-based computation as required by the original definition of D, is more costly. Given the marginal benefit of the obvious more tedious and less intuitive formulas, it is a question whether highly algebraically sophisticated formulas yield a more insightful understanding of LR. Zhang and Wu (2021) recently reported a performance ranking of eighteen known LR measures for lexical differentiation of L1 and L2 speakers. Although not the best, TTR is shown as a reliable predictor for lexical proficiency. Instead of deep exploration of frequency-based formulas, some emerging LR studies are trying to leverage the configurational notion of diversity to enrich the understanding of LR, as hinted by diversity phenomena in ecology and biology (Javis, 2013). In contrast to the lexical manipulation skills of language users, lexical complexity focuses on how complex the words are produced and aligned in the text. In other words, how unpredictable are the next word or string of words given the known lexical information up to the current word in the text. From cognitive information retrieval and transmission perspective, the more unpredictable a system is, the more randomly organized its constituents, and hence the higher level of complexity of the system. Accordingly, the higher level of complexity of a text, the more memory and information processing capacity are required to store, retrieve, and process the information contained in the text. Thus, the major difference between a simple and a complex text is the probability of accurate prediction. Given a simple text, it is easier to predict the contents and meaning when an initial segment of the text is known, whereas, for a complex text, such prediction is more complicated and less accurate. Entropy measure of complexity Entropy, a total frequency spectrum accounted measure, has been shown as a natural and robust measure for the level of complexity of any close or open system with interconnected and interactive constituents. Let the system be composed of T different components out of N components in total, where each of the ith components shares pi percentage in the total constituents, then the entropy of the system is defined as1 EntropyS=-∑i=1Tpilnpi where the negative sign is to ensure the positivity of the quantity. In the context of corpus linguistics, T corresponds to the number of types, and N corresponds to the number of tokens of a text. The seminal introduction of the above entropy formulation goes to Shannon (1951). The entropy was initially introduced to measure the information load from the information processing perspective. For this reason, the entropy defined as such is called Shannon-entropy, in contrast to other versions of entropies that have been developed ever since. Nevertheless, the notion of entropy was widely used in the science community quite long before Shannon. Notably, entropy was originated from thermosdynamics as a metric defining the level disorderedness of a system; in particular, how the degree of disorderedness of all the molecules in a closed space will change over time as the temperature of the space increases or decreases (Ramshaw, 2018). The higher the entropy of a system, the less likely to predict with precision the state of positions or velocities of all the particles in the system. Because it includes all component information in one compact format and its easy computation, entropy since then has been adopted in many other fields, including the well-known Shannon entropy form information communications. In the list of other applications, environmental entropy refers to species richness and balance, thus the sustainability of an ecological system. Furthermore, entropy is an essential notion in cell biology, defining the degree of variability or uncertainty, and therefore the differentiation potency towards diversified biological forms in cellular dynamics (Gros, 2011; Sethna, 2006). One crucial remark is that a more generalized version of entropy has been developed, namely, Renyi entropy, which includes Shannon entropy as a particular case (Acharya et al. 2017). Specifically, Renyi entropy introduced a parameter alpha in the definition that2 RenyiEntropyS=11-αln∑i=1Tpiα where pi has the same definition as that for Shannon entropy. It is easily seen that when α=0, Renyi entropy reduces to Shannon entropy. Recent researches show that, in some scenarios, Renyi entropy of nonzero order could become desirable when the sample size becomes large. Dynamical complexity theory for linguistics The theory of dynamic complex system (Byrne and Callaghan, 2013; Larsen-Freeman and Cameron, 2008; Guastello et al. 2008; Gros, 2011) is one of the most ontologically important modern treatises of any physical or social system, aiming at understanding the movement or behavioral pattern of the system in both spatial and time domain, most often from a macroscopic perspective. Such treatise is fundamentally different from classical sciences, symbolized by a small number of components with limited dependent variables and free of external influence. Even facilitated with the ever-increasing computing technologies, a complete depiction of the whole microscopic structure and movement of a dynamic complexity system is yet not possible, so probabilistic modeling and data fitting are widely adopted to uncover the evolutionary patterns a statistical sense of the system at large. The system is admittedly dynamic and complex because the number of composite entities is often enormous. Secondly, the system is complex because of the interaction between the components. Even a pair-wise interaction between two components in the system may result in an incomprehensively high number of evolution routes momentarily due to the effect of combinatorics. Additionally, the dynamical complexity is naturally associated with the nonlinear changes allowed by the system. Many natural entities may behave nonlinearly and chaotically given sufficient time and external influences, starting from a simple linear rule at a local level. Last but not least, the reason for the dynamical complexity is the almost ubiquitous self–organization phenomena widely observed at both the cosmos level and the microscopic level. Putting together, dynamic complexity is a fundamental mechanism governing any system, where the components of subordinate entities are significant in number, allowing for spontaneous interactions, self-organization, nonlinear changes in time, and exchange of energy or substances or information in between and with external enrivonment. Dynamic complexity theory has been well elaborated in language and linguistic research, and empirically tested by numerous studies spanned from L1 and L2 acquisition to corpus linguistics. According to Larsen-Freeman and Cameron (2008), for instance, language entities such as lexical units, grammatical rules, language input from daily life, and so on, are all interactive components of a linguistic system when a proper context or environment is referred. These linguistic constituents, analogous to biological cells in life sciences, are interconnected, constantly interacting, subject to external sociolinguistic influences and functional constraints, and may also reshape their evolution through spontaneous self-organization. Such a framework has been applied to explain lexical skill development (Verspoor et al. 2011), language attrition in German (Hopp and Schmid, 2013), and English dialect variation across different regions (Clopper and Smiljanic, 2011). A distinct lineage of research motivated by dynamic complexity is framed as evolutionary linguistics, underscoring the self-adaptive nature of languages (Lee and Schumann, 2003; Croft, 2008; Steffensen and Fill, 2014). Method and procedure The corpus used for the current study is the CGWR from 1954, when the first report was delivered, to 2000, excluding the years when the report was not delivered. CGWR has always drawn wide attention from various perspectives, including academics and businesses, due to its significant socio-economic importance, as indicated in the Introduction section. The archives of CGWR texts are publicly available at the website www.gov.cn. Table 1 lists the main tags of the texts as a time series, the basic lexical statistics, and the main characteristics from a functional discourse point of view. To have a further glimpse of the data, Fig. 1 plots the types and tokens of each CGWR text up to 2020, which corresponds to a sample size of 546,015 Chinese words in total.Table 1 Descriptive statistics of the CGWR texts in the current study Time series tags Total number of texts 52 Frequency of delivery Annual Serial correlation Yes Type 2212 Average lexical statistics (in Chinese words) Token 10,500 Entropy 6.621 Genre Institutional writing Domain Socio-economic, public, world affairs Dicourse paramters Medium Public archive, internet Register High formal Fig. 1 Types and tokens in words for the corpus under study A quantitative analysis of word frequency may further illustrate patterns of keywords of each CGWR text at different times. Zhang (2016) provides a diagram of the first three most frequently appeared content words to demonstrate the word frequency changes in CGWR as a dynamic complexity system. A more visual aiding plot of word cloud could be drawn for similar purposes. Figure 2 is such a plot displaying the key content words in proportion to their frequencies in the CGWR texts of 2007 and 2008, where one may sense the topical continuation and variation through the frequency changes in the top-ranking nouns such as “development” and “system” or verbs “improve” and “promote”, hence an inkling to the evolution of the lexicial networks therein profiled. The dynamicity of such a complex system as visualized is more rigorously evaluated using Shannon entropy. As discussed in Literature Review, entropy is a proper and effective measure of the level of information complexity of a dynamic system, although probably not necessarily an optimal choice for lexical richness when the focus is lexical proficiency.Fig. 2 Word cloud example of the CGWR for the years 2007–2008 Zhang (2016) used the CGWR texts up to 2011 to construct an exponential structural equation model to explain the macroscopic entropic pattern CGWR. As pointed out in the concluding remark of the paper, the model fitting and forecasting accuracy will be substantially affected if the entropic process undergoes phase change phenomena. To potentially harness such drawback of the structural equation approach, among other methodological considerations, the current study uses times series analysis approach to model the entropic process of the CGWR texts using the updated data (1954–2000). The setup of the time series analysis, assuming that the text’s entropic value at the current time is a lagged function of the entropic values at previous times, does not allow for reversibility of time in the definition. To run a time series model, an initial value of the process should be specified before the following sequence of the series can be recursively determined. To highlight the major steps for time series analysis, stationary should be examined upfront. Technically there are also non-time-series approaches for handling nonstationary data, which is not the scope of the current study. Fortunately, there are methods in the time-series domain to transform a large class of nonstationary processes into stationary, notably by detrending or difference operation, for instance. Once the dataset is given, several tests are available to test the stationarity condition. They could be done through autocorrelation function (ACF) and partial autocorrelation function (PACF) plots for a gross graphical check. Stationarity could also be quantitatively assessed by statistical tests, including the augmented Dicky-Fuller (ADF) test, Phillips-Perron (PP) test, and Kwiatkowski-Phillips-Shin (KPSS) test. Some research studies also use Ljung-Box (LB) test for an additional measure convincing the stationarity, although LB is used primarily for testing autocorrelations. Once a process is proved stationary, the next step is to choose a specific model, such as an ARMA model with an adequate number of lags and proper coefficient parameters for each lag. There could be multiple ways to determine the best model depending on the research context. The minimization of information statistics, including Akaike information criterion (AIC) and Bayesian Information Criterion (BIC), is often a widely used metric to determine the optimal model, again usually in the ARMA class. After model selection, the next major task will be model diagnostics in terms of well-established statistics such as MSE, F-statistic, p-value, and R-squared values. Lastly, the validity of a time series model usually scrutinizes an out-sample forecasting analysis. The specific procedure typically involves splitting the available data into two sets—a training set for model fitting and the other as a “pseudo-future” set to benchmark how much the model forecasted values would deviate from these “pseudo-future” values at hand. Lastly, a word frequency analysis tool is needed for computing the raw frequency distributions of characters and words in each text of the CGWR corpus. The task was mainly carried out using The Computerized Language Analysis Program (CLAN) — a publicly available word frequency analyzer developed and maintained at Carnegie Mellon University (CMU)’s Child Language Data Exchange System (CHILDES). It is increasingly recognized by various research studies such as second language acquisition (SLA) and corpus linguistics. One may refer to MacWhinney (2007a, b), for instance, to get familiar with the tool. In contrast, there are similar tools capable of Chinese word segmentation and frequency analysis, including those developed at Stanford University and Tsinghua University. After the raw frequency distributions for all types and tokens of each text are obtained, model estimation and diagnostics can be conducted in programming languages, such as Python. Results and analysis As underscored in the Method and Procedure section, stationarity should be examined upfront in the data analysis and model selection. But for better contextualization, the time series of the entropy is first plotted by the following Fig. 3, shown together with which are the linear fit and the confidence interval (the light blue band) for the mean response at a significance level alpha = 0.01. In addition, the cubic-spline interpolation of the data is also plotted, showing an irregular cyclic pattern with heteroscedastic variances. The Discussion section provides a more detailed discussion from a dynamical sociolinguistic perspective. Finally, Fig. 4 gives a graphical check of stationarity using the ACF plot. The series is concluded as nonstationary because the ACF values decay rather slowly at a roughly linear rate than a geometric rate characterized by a stationary process.Fig. 3 Plot of the CGWR entropic process and the linear trend fitting Fig. 4 ACF plot of the CGWR entropic process Consistent with the graphic judgment, the following Tables 2 and 3 report the ADF statistics of the data for the three different significance levels and various choices of the characteristic formulation of the unit roots. The maximum number of lags included in the test is set as 12 (larger than what the ADF test conventionally requires for the current context, where such a conventional threshold is usually set as twelve multiplied by the fourth root of the one-hundredth of the number of the observations). Minimization of AIC information is set as the default criterion to choose the optimal number of lags to be included. Given the testing power of ADF may be biased by the sampling context and sampling size, a further comparison of unit root test using more influential statistics are provided by the following Table 2. As shown, there is no statistical evidence to reject that null hypothesis, at a significance level of 0.01, that unit root is present in the process under study. The test was conducted with constant not assumed for stationarity. On the other hand, the other choice of such condition, i.e., constant allowed for stationary, does not change the conclusion with ADF statistic = -1.4300, p-value = 0.5678, and corresponding critical values (CV) = -3.5689, -2.9214, -2.5987 to reject the null hypothesis, respectively for significance levels of 0.01, 0.05, and 0.10 under AIC information characterization for unit root. Test with BIC information characterization for unit root pointed to the same conclusion.Table 2 Unit root test statistics to the entropic process in original series (maximum number of lags included: 12; test mode: nc) Unit root criterion ADF statistic p-value CV (significance level 0.01) CV (significance level 0.05) CV (significance level 0.10) AIC 1.9491 0.9887 – 2.6150 – 1.9479 – 1.6122 BIC 0.7414 0.8746 – 2.6119 – 1.9475 – 1.6124 Table 3 Unit root test statistics to the first order differenced entropy series (maximum number of lags included: 12; test mode: c) Unit root characterization ADF statistic p-value CV (significance level 0.01) CV (significance level 0.05) CV (significance level 0.10) AIC – 5.7360 6.4348e-07 – 3.5778 – 2.9253 – 2.6008 BIC – 12.4612 3.4024e-23 – 3.5685 – 2.9214 – 2.5987 Table 2 and the above summary show that the series has unit roots unless a hidden trend, linear or nonlinear irrespectively, is allowed. Correspondingly, the process, at optimality, is intrinsically an integrated autoregressive moving average process (ARIMA) with the minimum integration order of one. Thus the process is not possibly modeled by a stationary ARMA model of any finite orders with a reasonable fit. In other words, the entropic process of the CGWR texts is not stationary, consistent with the fundamental assumption of the dynamic complex system point of view, where the lexical complexity of institutional writings, at emerging stages, is an entropic increasing process. A better understanding of the upward entropic pattern of CGWR texts should go beyond language use in itself as, from a dynamic sociolinguistic perspective, language and society are inseparable. Specifically, the observed entropy-increasing pattern of the CGWR texts manifests, in duality, the dramatic social and economic transformations and reformations at both macro and mundane aspects of China in the past many decades. In such interconnectedness between the linguistic domain and various exogenous sociocultural factors, coupled with probabilistically infinite reformations of such connections, other evolutionary phenomena, including possibly phase changes or irregular cyclic patterns, are linguistically observed in CGWR. Next, a difference operation was applied to the original data hoping that a stationary time series could be attained with such transformations. Let Δyt=yt-yt-1, the first-order difference of the entropy process of yt, for t = 2, 3, …, T, be presumably modeled by an ARMA (p,q) model in the form of3 Δyt=β0+β1Δyt-1+⋯+βpΔyt-p+γ1ϵt-1+⋯+γqϵt-q+ϵt ∈tN(0,σt2) where ϵt is assumed to follow a normal distribution with a mean of 0 and a variance of σt2. Accordingly, a stationarity check was performed on the Δyt series and the numeric statistics of the test are reported in the following Table 2, in addition to the ACF and PACF plots presented in Fig. 5. The geometrically fast decay pattern in the ADF and PACF plots and the significant enough absolute values of ADF statistics (< -3.5778 in real values) tend to affirm the stationarity of the Δyt process at a significance level of 0.01. The test was conducted with constant mode for a stationary check. However, lifting the constant assumption does not change the conclusion with ADF statistic = -12.4857 (far lower than the CV = -2.6119 at significance levels of 0.01), and corresponding p-value = 8.8206e-23, with AIC set as the information criterion for unit root characterization. The test statistic is significant enough to reject the null hypothesis of the existence of unit root. The conclusion remains the same when the BIC information criterion is used.Fig. 5 ACF and PACF plots of the first-order difference of the entropic process Following the rule of thumb for empirically determining the optimal orders for the ARMA process (Box-Steffensmeier et al. 2014), one may select p = 2 and q = 3 for the model as stated in the above Eq. (1).To double confirm the optimality of the order of the model decided firstly by the empirical rule of thumb based on ACF and PACF plots, we run the same optimization algorithm for all the possible combinations of (p, q) for 0≤p≤15,0≤q≤15 against the AIC values. Indeed the minimum of the AIC function is reached at roughly p = 2 and q = 3. A maximum likelihood procedure was carried outto fit the Δyt series with the specified ARMA(2, 3) model to estimate the parameters for the model using a maximum number of iterations set at 100,000. The fitted curve of the Δyt and the original series of Δyt are comparatively plotted in the following Fig. 6. The estimated parameter values and the in-sample goodness of fit were tabulated in Table 4. To make it a fair comparison in terms of in-sample forecasting accuracy, we use Eq. (1) to convert the differenced series back to the original entropic values, noting that yt+1=yt+Δyt and y^t+1=yt+Δy^t+1. The corresponding statistics and significance for the overall model and each parameter are provided in Table 4. As demonstrated, the p-values for the model and each coefficient parameter are significant, validating the choice of ARMA type of model and the order of the model. Overall, the optimized ARMA(2,3) model has a satisfactory fit with F-statistic = -7.0117, p-value = 6.8959e-10. MSE = 0.0168 and R-squared = 0.6830 further show the goodness of fit. Given the high nonlinearity of the entropic dynamics of CGWR texts over time, such R-squared value is at a reasonable and acceptable level of model fitting (see Shin, 2017; Wittink, 1988, for discussions on a reasonable benchmark of R-squared values in social sciences studies).Fig. 6 First-order difference process and the fitted curve Table 4 ARMAmodel estimation and significance (max iteration 100,000) Model and parameters Regression value p value Model (in F-test statistic) – 7.0117 6.8959e-10 β0 0.0128 1.1696e-26 β1 – 1.5310 2.9077e-29 β2 – 0.8100 1.4995e-14 β3 0.6561 1.6017e-09 γ1 – 0.6561 4.6939e-07 γ2 – 0.9999 4.7785e-21 In addition to the above in-sample forecasting performance assessment, we also conducted the out-sample forecasting evolution based on the empirical rule of thumb of model validation using three to one split of the full sample into the training and prediction sets. Four prominent measures of out-sample forecast performance, namely, MSE, MAE, MAPE, and Theil-statistics (Theil), were calculated for the 1-step, 2-step, and 3-step forward prediction. The selected ARMA(2,3) model has demonstrated sufficient out-sample forecasting power, as demonstrated in Table 5. At the same time, it might be intuitive to conjecture that the longer steps into the future, the less accurate the prediction, there could be local inconsistencies to such notion. However, as demonstrated, the foresting accuracy for the 2-step forward prediction is higher than that for both 1-step forward and 3-step forward predictions.Table 5 Out-sample forecasting statistics MSE MAE MAPE Theil 1-step-ahead forecast 0.0243 0.1195 0.0172 0.5283 2-step-ahead forecast 0.009 0.0629 0.0091 0.2955 3-step-ahead forecast 0.0107 0.0816 0.0118 0.3148 Lastly, a normality check was conducted to evaluate how well the residuals between the fitted values and the sample values of the differenced entropic process fit the normal distribution as part of the module assumptions. Figure 7 presents the QQ plot of residuals, where the normal quantiles were well followed overall with very scarce discrepancies at the extremely low or high quantiles on tails. It is again consistent with the assumption of the potential phase changes and other nonlinear phenomena in the entropic process of CGWR texts, despite the fact highlighted by the current study that ARIMA models are comparatively more robust in fitting such dynamical processes. Normality may also be demonstrated with several pertinent test statistics, notably Shapiro–Wilk (SW) test, the Liffiefore test, and Anderson–Darling (AD) test. Specifically, the residuals’ SW, Lilliefore, and AD statistics are 0.9877, 0.0639, and 0.2636, respectively. The corresponding p-values for these statistics are 0.8748, 0.8702, and 0.7026, all confirming the normality of residuals at the significance level of 0.05.Fig. 7 QQ normality plot Overall, the entropic process of the CGWR texts exhibits ARIMA type of nonstationarity with integration order one. An ARMA(2,3) model has been estimated and demonstrated to best bit the first-order difference of the original entropic process using the data by 2020. The validity and effectiveness of the proposed model have been consistently justified by the pertinent statistical procedure and results, including the reported unit root test, ACF and PACF plots, information test, and the in-sample and out-sample forecasting accuracies. Discussion The first discussion concerns the cyclic pattern, although irregular in a sense, of the entropic process as observed along with the linear trend. First, we would like to remark that cyclicity is not a new language phenomenon. For instance, Bouzouita et al. (2019) documented a wide range of cyclical styles such as diachronic connections with different typological probabilities regarding, for example, markers of sentential negation and tense inflection on verbs. In the context of the current study, however, we argue that one should appeal to a broader socio-economic context, instead of focusing on language use alone, to explain better the trend-surrounding cyclic pattern of the lexical complexity in the CGWR texts. From a dynamic complexity system perspective, the mechanism of the pattern is generically associated with the interdependence and interconnectedness between the texts and the external resources, where the present level complexity depends critically on the previous levels. One particularly influential factor having a cyclical feature, by design, goes to the so-called Five-Year Plan, a comprehensive blueprint outlining the government’s policy priorities, together with specific or qualitative evaluation metrics. The identified social, economic, and cultural significance initiatives are reviewed and possibly adjusted in the annual CGWR. The physical cycles of such topically significant projects, from inception to implementation and completion, likely affect the configurations of the linguistic counterparts of the CGWR, hence the observed quasi-cyclic pattern in the evolution of the lexical complexity. Not surprisingly, apart from the prominent cyclic elements inherited from the socio-economic world, other latent variables possibly contribute to lexical complexity dynamics, making exact cycles unattainable. Unforeseeable environmental or natural events may also cause changes to the overall pattern. The most recent impactful example goes to COVID-19, the main reason that caused the postponed delivery of the CGWR as of the year 2020, and possibly also the substantial decrease in the length of the report. The following discussion concerns comparing the current approach and the structural equation approach. As mentioned in the Introduction section, the structural equations are usually invariant in the time direction. In contrast, the ARIMA model introduced in the current study is timely irreversible by design, a property naturally consistent with the irreversible nature of the entropic evolution of dynamic complex systems. For comparison, we reran the model selection and estimation for the exponential model in Zhang (2016) using the updated CGWR data up to 2020. First, the empirical results demonstrated that the difference between the two models’ statistics in terms of goodness of fit is slight. Second, from the nuanced difference between the model statistics, it is generally observed that the structural exponential model tended to perform better for the in-sample fit. In contrast, the ARMA model provided a better out-sample fit when the number of prediction steps is not significant. Notwithstanding, we do not wish to generalize such observations regarding the relative accuracy of the exponential and the AMRA models. A resolute conclusion to such generalization is likely not realistic as it may largely depend on the research context and the data-generating mechanisms. Another comparison is between the currently proposed ARMA model and a possible GARCH type model. Although sampling autocorrelations does not make specific the choice of GARCH models, trials are worthwhile if one is concerned by whether this may imply further heteroscedasticity and variance clustering phenomena, which was confirmed with a formal arch effect test based on Lagrange multiplier statistics. Thus Garch type models are also potentially suitable for the differenced data, although cautions should be added in terms of the data’s low frequency and small size. To this end, a series of model selections and comparisons were done for the GARCH type models as for the ARMA (p, q) model selection explained in the above section. Then the corresponding time series were generated using simulations methods, with the selection criterion being to minimize the MSE. Setting the maximum simulations being 100,000, we derived the optimal GARCH model as GARCH (3, 1), and the corresponding R-squared value is 0.403, which is lower than that of the ARMA(2,3). This result demonstrated that a GARH model focusing on modeling the variance clustering does not yield better performance in fitting the up-to-date data of the CGWR. Finally, of course, one may further explore the possibility of ARMA-GARCH combined models. However, we opt to leave it for further directions given the concerns of the overfitting and interpretability of the parameters with the limited sample size. Conclusion Homogeneous texts, particularly those of the same individual or institutional authorship produced over different times, provide uniquely helpful resources for various linguistic research, particularly from a sociolinguistic perspective, as the discourse of such institutional writings are both socially conditioned and constitutive. The dynamical complexity theory offers a well-fit framework to analyze such homogeneous texts to unveil prominent linguistic patterns and insights with potent socio-economic implications. The current work analyzed the stylish features of the lexical profiles of the CGWR published from 1954 to 2000 using the Box-Jenkin approach. The results show that the entropic process of CGWR texts is not stationary from time series analysis perspective. Instead, an ARIMA process characterizes it, the stationarity of which requires an order one difference operation on the actual process. Further noticeable entropic features, such as the irregular cyclic pattern around the increasing linear trend, have also been characterized and explained in the dynamical complex sociolinguistic perspective. In particular, the government’s strategic socio-economic initiatives, such as education enhancement or countryside preservation, are inseparable factors to account for the stylish features exhibited in the CGWR texts. As such, the current study provides a unique angle for researchers interested in understanding the social dynamics of China from sociolinguistic text analysis. Theoretically significant, the dynamical complexity narrative is often challenged with the lack of pertinent and quantifiable models for the diversified field research in corpus linguistics. Despite emerging research studies with elements of structural equations and time series models as surveyed in the Introduction and Related Literature sections, such quantitative treatise specific to dynamic complexity theory is still scarce. With a rigorous implementation of time series modeling, the current study has exemplified the possibility of making the dynamical complexity a methodologically well-equipped framework instead of a hypothetical fad. More concretely, a thorough ARIMA modeling, including model identification, estimation, diagnostics, and assessment, was conducted based on the updated texts of CGWR. The validity and effectiveness of the currently proposed model were positively demonstrated, together with the pros and cons analysis compared to the more classical structural equation approaches. The overall goodness of the proposed mode of ARMA (2, 3) in particular is equivalent or slightly more substantial than the structural models of exponential type depending on the context of statistics. The current approach is strongly advocated with the extended horizon model fitting performance yet to be tested with future data. It naturally fits the dynamics complexity setting of the homogeneous texts’ entropic or information evolution process. With various toolkits of time series analysis facilitated with upgraded computing technologies, the current approach appears robust enough to accommodate the potentially high complexities of the incoming data. As noticed in the Discussion section, whether removing hidden irregular cyclic trends may produce a better model, in general, remains an open question. Similarly, the GARCH type models, designed to model variance clustering in the process, in particular, are not extensively explored by the current study. Although there are noticeable autocorrelations in the series, variance heteroscedasticity and variance clustering are not critically apparent. Hence, GARCH type modeling does not yield a better model fit. Among others, overfitting and interpretability are the main concerns. Moreover, given the so far limited sample size of the CGWR texts, the usefulness regarding GARCH models–typically applicable to high frequency and extensive sample data–could be inconclusive. However, these value-adding directions are worthwhile for future explorations. Another recommendable research direction is to apply the models of the current study to other types of homogeneous texts. This would generate more empirical verifications to the current modeling and provide more complete mappings in terms of the universality of the dynamical complexity system theory. Acknowledgements The author is grateful to the anonymous referees and the journal editors for the valuable comments and suggestions in improving the earlier manuscript. Funding The authors have not disclosed any funding. Declarations Conflict of interest The author has no competing interests to declare related to this article. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ==== Refs References Acharya J Orlitsky A Suresh AT Tyagi H Estimating renyi entropy of discrete distributions IEEE Trans. Inf. Theory 2017 63 1 38 56 Aguinis H Regression analysis for categorical moderators 2003 Guilford Press Blythe RA Croft W S-curves and the mechanisms of propagation in language change Language 2012 88 2 269 304 Bouzouita M Breitbart A Witzenhausen E Cycles in language change 2019 Oxford University Press Box-Steffensmeier JM Freeman JR Hitt MP Time series analysis for the social sciences 2014 Cambridge University Press Boyd S Fraurud K Auer P Schmidt JE Challenging the homogeneity assumption in language variation analysis: Findings from a study of multilingual urban spaces language and space: an international handbook of linguistic variation 2010 Mouton De Gruyter 686 706 Byrne D Callaghan G Complexity theory and the social sciences : the state of the art 2013 Taylor and Francis Clopper CG Smiljanic R Effects of gender and regional dialect on prosodic patterns in American English J. Phon. 2011 39 2 237 245 21686317 Croft W Evolutionary linguistics Annu. Rev. Anthropol. 2008 37 219 234 Crossley SA McNamara DS Shared features of L2 writing: intergroup homogeneity and text classification J. Second. Lang. Writ. 2011 20 4 271 285 Crossley SA Salsbury TL McNamara D Jarvis S Predicting lexical proficiency in language learner texts using computational indices Lang. Test. 2011 28 4 561 580 Daller H Xue H Daller H Milton J Treffers-Daller J Lexical richness and the oral proficiency of Chinese EFL students Modelling and assessing vocabulary knowledge 2007 Cambridge University Press 150 164 Denoual, E.: The influence of example-data homogeneity on EBMT quality, in Proceedings of the Second Workshop on Example-Based Machine Translation, pp. 35–42, Phuket, Thailand (2005) Gros C Complex and adaptive dynamical systems: a primer 2011 Springer Guastello SJ Koopmans M Pincus D Chaos and complexity in psychology: the theory of nonlinear dynamical systems 2008 Cambridge University Press Hale J Information-theoretical complexity metrics Language Linguistics Compass 2016 10 9 397 412 Herdan G Quantitative linguistics 1960 Butterworth Hopp H Schmid MS Perceived foreign accent in first language attrition and second language acquisition: the impact of age of acquisition and bilingualism Appl. Psycholinguist. 2013 34 2 361 394 Housen A Kuiken F Vedder I Dimensions of L2 performance and proficiency: complexity, accuracy and fluency in SLA 2012 John Benjamins Publishing Jang EE Cummins J Wagner M Stille S Dunlop M Investigating the homogeneity and distinguishability of STEP proficiency descriptors in assessing english language learners in Ontario Schools Lang. Assess. Q. 2015 12 1 87 109 Jarvis S Capturing diversity in lexical diversity Lang. Learn. 2013 63 87 106 Kilgarriff A Comparing corpora, International J. Corpus Linguistics 2001 6 1 1 37 Kilgarriff A Grefenstette G Introduction to the special issue on the web as corpus Comput. Linguist. 2003 29 3 333 348 Komachali ME Khodareza M The effect of using vocabulary flash card on iranian pre-university students’ vocabulary knowledge Int. Educ. Stud. 2012 5 3 134 147 Koplenig A A data-driven method to identify (correlated) changes in chronological corpora J. Quant. Linguistics 2017 24 4 289 318 Lai, Y. A., Zhu, X., Zhang, Y., and Diab, M. T.: Diversity, Density, and Homogeneity: Quantitative Characteristic Metrics for Text Collections. In Proceedings of The 12th Language Resources and Evaluation Conference, 1739–1746 (2020) Lameli A The replacement of diminutive suffixes in the New High German period: a time series analysis in word formation J. Historical Linguistics 2018 8 2 273 316 Larsen-Freeman D Cameron L Complex systems and applied linguistics 2008 Oxford University Press Lee, N., and Schumann, J. H.: The evolution of language and the symbolosphere as complex adaptive system, paper presented at the American Association of Applied Linguistics Conference, VA (2003) Li S Ellis R Zhu Y The associations between cognitive ability and L2 development under five different instructional conditions Appl. Psychol. 2019 40 3 693 722 Liu, Z., Wang, C., Guo, L., Bai, Y., and Wang, J.: LyDAR: A Lyrics Density based Approach to Non-homogeneous Music Resizing. In 2010 IEEE International Conference on Multimedia and Expo, 310–315 (2010) Lowder MW Choi W Ferreira F Henderson JM Lexical predictability during natural reading: effects of surprisal and entropy reduction Cogn. Sci. 2018 42 1166 1183 29442360 MacWhinney, B.: A unified model, in P. Robinson and N. Ellis, editors, Handbook of Cognitive Linguistics and Second Language Acquisition, Lawrence Erlbaum Associates, Mahwah, NJ (2007a) MacWhinney B Beal JC Corrigan KP Moisl HL The talkbank project Creating and digitizing language corpora: synchronic databases 2007 UK Palgrave-Macmillan Malvern DD Richards B Chapelle C Measures of lexical richness Theencyclopedia of applied linguistics 2012 Blackwell Wiley Maxwell, O., Payne, E., and Billington, R.: Homogeneity vs heterogeneity in Indian English: Investigating influences of L1 on f0 range. In 19th Annual Conference of the International Speech Communication Association: Speech Research for Emerging Markets in Multilingual Societies, 2191–2195 (2018) Michel JB Kui Shen Y Presser Aiden A Veres A Gray MK Pickett JP Aiden EL Quantitative analysis of culture using millions of digitized books Science 2011 331 6014 176 182 21163965 Mu GM Dooley K Coming into an inheritance: family support and Chinese Heritage Language learning Int. J. Biling. Educ. Biling. 2015 18 4 501 515 Newbold T Hudson LN Hill SLL Contu S Lysenko I Senior RA Collen B Global effects of land use on local terrestrial biodiversity Nature 2015 520 7545 45 50 25832402 Nielbo KL Baunvig KF Liu B Gao J A curious case of entropic decay: persistent complexity in textual cultural heritage Digital Scholarship Humanities 2019 34 3 542 557 Paap KR Johnson HA Sawi O Are bilingual advantages dependent upon specific tasks or specific bilingual experiences? J. Cogn. Psychol. 2014 26 6 615 639 Pawłowski A Time-Series analysis in linguistics: application of the ARIMA method to cases of spoken Polish J. Quant. Linguistics 1997 4 1–3 203 221 Ramshaw JD Statistical foundations of entropy 2018 World Scientific Publishing Robinson P Task complexity, theory of mind, and intentional reasoning: effects on L2 speech production, interaction, uptake and perceptions of task difficulty Int. Rev. Appl. Linguistics Language Teach. 2007 45 3 193 213 Sahlgren, M., and Karlgren, J.: Counting lumps in word space: density as a measure of corpus homogeneity, in Proceedings of 12th Symposium on String Processing and Information Retrieval, pp. 124–132, Argentina (2005) Scott, M., and Tribble, C.: Textual Patterns: Key words and corpus analysis in language education. Second Language Development: Methods and Techniques, 25–38, John Benjamins, Amsterdam (2006) Sethna JP Statistical mechanics: entropy 2006 Oxford University Press Shannon CE Prediction and entropy of printed English Bell Syst. Tech. J. 1951 30 50 64 Shin Y Time series analysis in the social sciences: the fundamentals 2017 University of California Press Smith JA Kelly C Stylistic constancy and change across literary corpora: using measures of lexical richness to date works Comput. Humanit. 2002 36 411 430 Steffensen S Fill A Ecolinguistics: the state of the art and future horizons Lang. Sci. 2014 41 6 6 25 Tarnish AH A corpus analysis of changes in the use of British and American English modals and semi-modals Int. J. English Cul. Stud. 2018 1 1 1 22 Verspoor MH Bot K Lowie W A Dynamic approach to second language development: methods and techniques 2011 John Benjamins Voleti, R., Woolridge, S., Liss, J. M., Milanovic, M., Bowie, C. R., andBerisha, V.: Objective assessment of social skills using automated language analysis for identification of schizophrenia and bipolar disorder. In 20th Annual Conference of the International Speech Communication Association: Crossroads of Speech and Language, 1433–1437 (2019) Wittink DR The application of regression analysis 1988 Allyn and Bacon Yao D Chen K Gender-related Differential Item Functioning Analysis on an ESL Test J. Language Test. Assess. 2020 3 1 5 19 Zhang Y Entropic evolution of lexical richness of homogeneous texts over time: a dynamic complexity perspective J. Language Modell. 2016 3 2 569 599 Zhang Y Wu W How effective are lexical richness measures for differentiations of vocabulary proficiency? a comprehensive examination with clustering analysis Language Test. Asia 2021 11 1 1 19 Zhou B Tan Y Pan DL Investigating the validity of different peer groupings in the assessment of english writings Int. Educ. Stud. 2019 12 12 55 61
PMC009xxxxxx/PMC9208354.txt
==== Front Qual Quant Qual Quant Quality & Quantity 0033-5177 1573-7845 Springer Netherlands Dordrecht 35756087 1429 10.1007/s11135-022-01429-2 Article Risk capacity and investment priority as moderators in the relationship between big-five personality factors and investment behavior: a conditional moderated moderated-mediation model Rajasekar Arvindh research.arvindh@outlook.com 1 Pillai Arul Ramanatha arulfriends2005@gmail.com 1 Elangovan Rajesh rajeshthamil654@gmail.com 2 http://orcid.org/0000-0001-5565-4413 Parayitam Satyanarayana sparayitam@umassd.edu 3 1 grid.411678.d 0000 0001 0941 7660 PG and Research Department of Commerce, St Joseph’s College (Autonomous), Affiliated to Bharathidasan University, Tiruchirappalli, Tamil Nadu India 2 grid.411678.d 0000 0001 0941 7660 Department of Commerce, Bishop Heber College (Autonomous), Affiliated to Bharathidasan University, Tiruchirappalli, Tamil Nadu India 3 grid.266686.a 0000000102217463 Department of Management and Marketing, Charlton College of Business, University of Massachusetts Dartmouth, 285 Old Westport Road, North Dartmouth, MA 02747 USA 20 6 2022 2023 57 3 20912123 6 5 2022 © The Author(s), under exclusive licence to Springer Nature B.V. 2022 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. This paper aims to explore the relationship between big-five personality traits and investment behavior, particularly in the Indian context. Riding on the theory of planned behavior (TPB), we built a multi-layered moderated moderated-mediation model exploring the complex relationships between personality traits, investment attitude, and investment strategy. We collected data from 934 respondents from the southern part of India and analyzed using the Hayes (2018) PROCESS macros to test the hypotheses. The results indicate that (i) Personality traits (extraversion, emotional stability, conscientiousness, agreeableness, and openness to experience) are positively related to investment attitude and investment strategy, (ii) Investment attitude is positively related to investment strategy, (iii) Risk capacity moderates the relationship between personality traits and investment attitude, and (iv) Investment priority (second moderator) moderates the moderated relationship between personality traits, risk capacity (first moderator), and investment strategy mediated through investment attitude. Finally, the implications for behavioral finance and practicing managers are discussed. Keywords Big-Five personality traits Investment attitude Investment strategy Risk capacity Investment priority Moderated-mediation model issue-copyright-statement© Springer Nature B.V. 2023 ==== Body pmcIntroduction This paper aims to shed light on the relationship between personality factors and investment behavior. Investment decisions are crucial for managing the present needs and future goals, and individuals and families spend a considerable amount of time and resources in financial planning (Baker et al. 2021; Barber and Odean 2013; Nadeem et al. 2020), and a plethora of research has been documented about the importance of such decisions (Aydemir and Aren 2017; Aydin and Selcuk 2019; Saurabh and Nandan 2018) The literature on the portfolio of choices and risk attitudes has been exhaustive (Barasinska et al. 2012; Friend and Blume 1975; Heo et al. 2021; Kapteyn and Teppa 2011; Kimball et al. 2008; Riley and Chow 1992). For the last two decades, researchers in behavioral finance have been studying how the cognitive thinking process of individuals affects their investment decisions: saving, spending, borrowing, lending, and short term versus long term investments (Belsky and Gilovich 1999). There is growing consensus among the researchers in psychology, economics, and finance that investors behave irrationally and do not follow rational decision-making processes, thus resulting in making monumental mistakes in their decisions (Dam 2017), and some researchers documented there are significant differences in the behavior of investors (Riitsalu and Murakas 2019; Wood and Zaickowsky 2004). Often these differences depend on the personality of individuals, socio-economic background, risk tolerance, risk-seeking, and risk-avoidance and risk capacity, and hence researchers focus on studying these variables (Bhoj 2019; Kansal and Singh 2013; Shtudiner 2018). The financial tsunami that engulfed the world sometime between 2007–2008, the researchers have switched their gears from traditional finance where investors’ decisions are rational to argue that decisions are irrational most of the time. The underlying assumption of behavioral finance scholars is that a complex combination of psychological factors influences investment decisions. As opposed to the belief of rational decision-making of investors according to traditional finance theories, behavioral scholars argue that investor behavior is irrational (Chiang et al. 2010; Tekce and Yılmaz 2015). There is consensus among the researchers in the field of economics and finance that it is important to consider psychological, sociological, demographic, and personality factors that may have a profound influence on investment decisions (Fung and Durand 2014; Zhang and Zheng 2015). The objective of this research is to explore the impact of personality factors in influencing the investment decisions. Motivation and justification for this study In response to the call by behavioral finance scholars to add a new dimension of research focusing on exploring the effect of the psychological and personality of individuals on investment decisions, several studies were conducted in that direction (Jain et al. 2015; Mak and Ip 2017). Subsequently, researchers in behavioral finance have examined the personality factors, risk-taking, financial attitude, and financial decisions (Filbeck et al. 2009; Mayfield et al. 2008). However, the extant research on the relationship between personality traits and investment decisions revealed mixed results (Belcher 2010). For example, Baddeley et al. (2010) found that extraverted individuals tend to follow others and exhibit herd behavior investments, Rzeszutek et al. (2015) found that extraverted individuals make rational decisions by taking into account the sunk costs, uncertainty, biases, etc. Paradoxically, the research by Belcher (2010) revealed that personality does not have any effect on investment decisions. Further, some researchers contend that personality traits such as extraversion and openness to experience are related to risk-taking behavior (Mayfield et al. 2008), and some others argue that behavioral biases, risk profile, and cognitive ability are the significant factors influencing the risk-taking behavior, in addition to personality traits (Mandal and Roe 2014; Verma and Verma 2018). Amid these controversial findings, the present study aims to bridge the gap by exploring the relationship between personality factors, investment attitude, and investors’ investment strategies. Most importantly, the research examines the moderating role of risk capacity and investment priority in the decision-making process. To achieve this objective, we develop a double-layered conceptual model (moderated-mediation), which is not done by previous research to the best of our knowledge, by exploring the complex relationships between personality factors and investment strategy. The outline of the paper is as follows. The following section briefly explains the relevance of Big-Five personality traits, followed by the theoretical framework and hypotheses development. Section 3 discusses methodology, and Sect. 4 provides the analysis of the results. In the final section, we discuss the effects, contribution of the research, theoretical and practical implications, limitations, and suggestions for future research. Big-Five personality traits An individual’s thoughts, actions, and behaviors are guided by their personality traits (Allport and Vernon 1930). Though there are several theories of personalities, there is consensus among the researchers that personality represents a whole system of characteristics an individual possesses and individuals differ in their thoughts, processes, feelings, emotions, and resultant behavior; and personality is one of the strongest predictors of the emotional and physical well-being of individuals (Manner 2017). The Big-Five personality traits (called FFM i. e five-factor model) of McCrae and Costa (1997) has been one of the widely used taxonomies of traits in organizational behavior and personnel psychology. This study incorporates Big Five personality traits as the primary independent variable that affects an individual’s investment behavior. These traits are openness to experience, conscientiousness, extraversion, agreeableness, and emotional stability. Briefly stated, individuals who are high on (i) Agreeableness tend to be reliable, generous, and well-mannered, (ii) Conscientiousness tend to be trustworthy, time-conscious, and well-organized, (iii) Extraversion tend to be active, social, and talkative, (iv) Emotional stability tend to be vigilant, stable, and balanced, and (v) Openness to experience tend to be versatile, dynamic, original, unique, and imaginative (McCrae and Costa 1997; John et al. 2008). Extant reported a close relationship of these personality traits with various outcomes: stress, burnout, self-efficacy, turnover, job satisfaction, sales performance, academic success, and financial decision making among others (Fernandes et al. 2014; Greenberg and Shtudiner 2016; Furnham and Fudge 2008; Shi et al. 2018; Soldz and Vaillant 1999). Particularly concerning behavioral finance, personality characteristics were linked to short–term and long–term investment choices (Mayfield et al. 2008; Durand et al. 2008) and investment in mutual funds (Chang et al. 2016). It was also found that individuals who are high on extraversion and openness to experience tend to have a high-risk tolerance. In contrast, individuals high on neuroticism tend to be risk-averse (Oehler et al. 2018). The investment strategy consists of the investor’s short-term and long-term investments. Short-term investments include setting aside some money for use shortly, and long-term investments may consist of setting aside money for the long term, post-retirement requirements, medical necessities, etc. Investment attitude refers to how individuals are motivated to save and invest rather than immediate consumption. Investment attitudes are also concerned with Individuals who keep watching how their investments are performing and periodically changing their portfolios. The risk capacity, another critical variable in this study, refers to the extent to which individuals can take the risk of investment, which is different from their willingness to take the risk. For example, a reasonably well-to-do investor with a substantial amount in fixed, tangible, and intangible assets has more risk capacity than an individual with a lower income and assets. Investment priority deals with the list of prioritized items in individual investments. For example, some individuals prioritize investment to meet their children’s educational requirements, weddings, healthcare or such necessities. Finally, individuals chalk out their strategies and choose their investment portfolio. This study explores the interrelationships between personality traits, investment priority, investment attitude, risk capacity, and investment strategy. Investigating the relationship between big-five personality traits and investment decisions is essential for at least three reasons. First, the relationship between personality traits and investment strategies and investment priorities explains the differences among individuals and sheds light on inconsistent findings and behavioral biases among single studies that ignored personality factors (Charles and Kasilingam 2014; Pompain and Longo 2004; Moitto and Parente 2015 Mushinada and Veluri 2019). Psychological characteristics determine individual financial behavior and the self-control individuals possess to avoid bad financial decisions (Baker et al. 2021; Strömbäck et al. 2017). Personality traits are central to understanding an individual (Parks-Leduc et al. 2015) and explain how the individuals receive, process, and act on the information. Second, the five-factor personality trait model provides a convenient nomological network of exploring the effect of individual characteristics on risk capacity, risk aversion, and risk-taking behavior in investment decisions. Most importantly, by using the five-factor personality, we avoid the jingle-jangle fallacy: using different constructs with the same name (jingle fallacy) and the same constructs with other names (jangle fallacy) because each of the traits is different and well supported by extensive research. Third, understanding how personality traits affect the complex relationships between risk capacity, investment priorities, and investment strategies are indispensable and affect individuals’ financial well-being. Theoretical background and hypotheses development The theory of planned behavior (TPB) (Ajzen 1991) provides a theoretical platform for the present study. The basic tenet of the TPB is that the attitudes of individuals drive their behavior. Behavioral intentions are influenced by perceived behavioral control, subjective norms, and attitudes. Therefore, the TPB is helpful in understanding and predicting investors’ behavior in choosing their investment portfolios. Individuals evaluate their behavior depending on the perceived control. Favorable evaluation results in solid intention to perform that behavior, and unfavorable evaluation would prevent an individual from exhibiting that behavior (Ajzen and Driver 1992). Several researchers in behavioral finance have employed TPB to explain investor behavior. For example, Yen et al. (2016) used TPB to explore earnings management of accountants by using ‘attitude’ as a construct, stating that attitude leads to the resultant behavior. The perceived behavioral control, which depends on the personality characteristics, plays a vital role in investment behavior (Elliott and Ainsworth 2012). Therefore, TPB is applicable in this study because the investment attitude depends on personality, chalking out investment strategy. Further, the extroverts and individuals high on openness to experience tend to follow. Hence, subjective norms arising from peers and family members would affect the investment behavior, which may motivate the investors towards socially responsible investments (Adam and Shauki 2014). Therefore, in line with the other researchers, we firmly believe that TPB is an appropriate theoretical platform for the present study. Hypotheses development Direct hypotheses We would begin by explaining how each of the big-five personality traits relates to financial decision-making before offering the direct hypotheses. Individuals high on extraversion tend to be active, optimistic, and socialize with others (Leary et al. 2009; McCrae and Costa 1997). As a result, extroverted individuals tend to receive positive information and assess their probability of success in investment decisions; and sometimes they tend to exhibit overconfidence in investments in risky ventures (Brown and Taylor 2014; Mayfield et al. 2008; Pan and Statman 2013). Therefore, the extant research reported a positive association between extraversion and investment attitude. Agreeableness trait is concerned with altruism, personal warmth, helpful and forgiving attitude, avoiding conflicts, and using inoffensive language (Costa and McCrae 1992). Most of the time, individuals high on agreeableness have a positive and optimistic view of human nature; they receive information from others positively and accept it without critically examining it (Mayfield et al. 2008). Individuals who are high on agreeableness tend to follow the suggestions given by the investment brokers and have a positive attitude towards financial investments (Pak and Mahmood 2015). Openness to experience is concerned with creativity, novelty, variety, and interest in travel and adventure. Individuals high on openness to experience tend to accept new thoughts and are more likely to have long-term investments (Mayfield et al. 2008) and embrace new investing methods (Nga and Yien 2013). The trait of openness to experience is also related to exhibiting intellectual curiosity, self-awareness, and individualism. Hence, individuals high on openness to experience tend to take risky investment decisions (Gunkel et al. 2009; Nandan and Saurabh 2016). The conscientiousness trait concerns planning, quality-consciousness, achievement-orientation, persistence, and self-discipline (Ali 2019). Some researchers found individuals high on conscientiousness tend to exhibit a positive attitude towards investment and are also actively involved in the decision-making process (Durand et al. 2013; Gunkel et al. 2010; Sadi et al. 2011). In addition, some researchers documented that individuals who are high on conscientiousness tend to believe that their investment decisions are better than others (Jamshidinavid et al. 2012) as they have a high level of discipline and show carefulness in decision-making. Emotional stability (opposite of neuroticism) trait is concerned with the balanced approach, stability, high self-esteem, optimistic attitude of individuals Costa and McCrae (1992). Individuals who are high on emotional stability (low on neuroticism) have high levels of cognitive skills, conceptual understanding, and the ability to think analytically and critically. Therefore, emotionally stable individuals are not afraid of investing in risky ventures (Young et al. 2012). On the other hand, some researchers reported that individuals characterized by high neuroticism tend to be risk-averse, shy away from investment decisions, and avoid uncertainty (Gambetti and Giusberti 2012). Thus, high individuals in these five traits tend to make rational investment decisions and exhibit a positive attitude towards financial investments—both short and long run. While the five-factor theory is applicable in explaining the attitude of individuals towards investment decisions, researchers found a positive association of investment attitude to the investment strategies (Sadiq and Khan 2019). In a study conducted on 534 university students from Brazil, it was found that investment attitude is positively associated with financial behavior (Potrich et al. 2016). From the literature on financial literacy, extant research provided empirical evidence about the positive relationship between financial attitude, investment strategy, and investment behavior of individuals (Lusardi et al. 2010; Parrotta and Johnson 1998). In a recently conducted study in Pakistan, researchers found that investment criteria were positively related to investment behavior (Saleem et al. 2021). Based on the available empirical evidence and logs, we offer the following hypotheses: H1 Personality is positively related to investment strategy H2 Personality is positively associated with investment attitude H3 Investment attitude is positively associated with investment strategy Investment attitude as mediator We argue in this research that the personality traits, in addition, to having direct influence, have an indirect effect through investment attitude. While the immediate impacts of five personality traits: extraversion, emotional stability, agreeableness, openness to experience, and conscientiousness, have been documented in the literature, as discussed in previous sections, the indirect effect of the personality traits through investment attitude has not been examined by earlier researchers to the best of our knowledge. Following the relatively recent approach and call by Nigam et al. (2018) who emphasized the role of mediators in the studies involved in behavioral finance, we argue that investment attitude is one of the potential mediators. The previous research established that personality traits directly positively affect investment attitude (Isidore and Christie 2017; Sadiq and Khan 2019). In addition, there is empirical evidence that investment is a precursor to investment strategy (Lusardi and Mitchell 2008; Mak and Ip 2017). Based on the above and available empirical evidence, we offer the following exploratory mediation hypothesis: H4 Investment attitude mediates the relationship between personality and investmentstrategy Risk capacity as a first moderator As the risk component, in different degrees, is embedded in all investments, it is essential to consider the risk tolerance and risk capacity of the individuals. Risk consists of two major components in behavioral finance: risk appetite and risk tolerance. An individual’s willingness to take risks determines the risk appetite, whereas the amount of risk an individual can handle refers to risk tolerance (Corter and Chen 2005; Grable and Roszkowski 2008; Moreschi 2004). While some individuals are risk-averse, irrespective of whether they have risk capacity, some are active risk-seekers even though they do not possess the requisite risk capacity to survive the loss of money in their investments. Investors calculate the anticipated returns and associated risks (Sindhu and Kumar 2014). Risk capacity is different from risk tolerance. Risk tolerance is concerned with an individual’s willingness to trade off potential future outcomes, whereas risk capacity is the cushion an individual has in the event of investment failure. Risk tolerance deals with an individual’s willingness to take risk whereas risk capacity is concerned with how much risk an individual can take. Risk capacity refers to the extent to which an individual has financial ability to take investment risk, the higher the ability the greater the capacity. The amount of risk an individual is comfortable taking may differ from the capacity, which depends on the financial position. A wealthy person may have risk capacity (i.e., the ability to withstand investments loss). In contrast, an individual with fewer financial holdings may have enough capacity to bear the loss from an investment. Furthermore, some researchers documented the positive association between risk capacity and investment decisions of post-graduate students in the Indian context (Ananthan et al. 2017). Therefore, it is more likely that individuals with high-risk capacity may choose risky investment strategies than those with low-risk capacity. Based on the intuitive logic and available sparse empirical evidence, we offer the following exploratory hypothesis: H2a Risk capacity moderates the relationship between personality and investment strategy mediated through investment attitude Investment priority as a second moderator The most important part of this research is to examine the role of investment priority as a second moderator in the relationship between personality and investment attitude. The behavioral finance scholars have been trying to assess the influence of personality traits on financial decisions, taking into account the risk involved in the economic and investment decisions (Charness et al. 2013; Goulart et al. 2013, 2015; Mandal and Roe 2014). As the risk capacity determines the behavior of investors under the conditions of uncertainty, the investment priorities of these individuals influence their attitude of investment. Furthermore, when personality traits help individuals gain access to information from the public domain and change their relationship to risk, it may affect their investment attitude and investment priorities in decision making (De Bortoli et al. 2019). While the direct relationship between investment priority and investment attitude has been examined by previous researchers, exploring the moderating role of investment priority is under-studied. We argue that investment priority (second moderator) moderates the moderated relationship between personality characteristics and risk capacity (first moderator) and investment attitude. We, therefore, propose the following exploratory moderated moderated-mediation hypothesis: H2b Investment priority positively moderates the moderation effect of risk capacity on the investment strategy from personality via investment attitude as mediator. The conceptual model is presented in Fig. 1.Fig. 1 Conceptual model Method Sample The sample for this study consisted of respondents from the southern part of India. A carefully structured survey instrument was prepared and distributed among the individuals in Tiruchirappalli, a big city in Tamil Nadu. We collected data using convenience non-random sampling. In all, we distributed surveys online because of COVID-19 restrictions and periodical lockdowns. This is consistent with the other studies conducted during the global pandemic period. Using google drive, we collected data, and we received 934 respondents. First, we secured email ids from the respective institutions to contact the respondents. Then, we administered the survey instrument and asked the respondents to fill out the instrument. Google form does not allow the respondents to proceed further if they do not answer any of the questions. We sent surveys in mid-December 2020, and it took four months to get responses from 934 respondents. Based on the population, according to the sample size tables by Krejcie and Morgan (1970), the minimum required sample size is 384. According to Comrey and Lee (1992) sample size of over 500 is very good (100 = poor, 200 = fair, 300 = good, 500 = very good, 1000 or more = excellent). To check the non-response bias, we compared the first one hundred observations with the last one hundred observations and found no significant differences between these two subsamples. Demographics The demographics of the respondents were mentioned in Table 1.Table 1 Demographic profile of respondents Category Profile Total number Percentage Gender Male 509 54.5 Female 425 45.5 Age (in years) 18–31 246 26.3 32–45 418 44.8 46–59 222 23.8 60 and above 48 5.1 Types of investors Adventurous investor 132 14.1 Cautious investors 314 33.6 Balanced investors 399 42.7 Prudent investors 89 9.5 Annual income Below Rs.300,000 ($4000) 329 35.2 Rs 300,000 – Rs. 600,000 ($4000—$8000) 314 33.6 Rs.600,000 – Rs. 900,000 ($8000—$12,000) 181 19.4 Rs. 900,000 – Rs. 1,200,000 ($12,000—$16,000) 70 7.5 Over Rs. 1,200,000($ 16,000—$20,000) 40 4.3 Over Rs. Rs. 12,50,000($20,000) 329 35.2 Preferred investment Periods Short term (less than 1 year 225 24.1 Medium term (1–3 years 381 40.8 Long term (more than 3 years) 276 29.6 Intraday 52 5.6 Experience in investments (in years) Less than 1 year 233 24.9 1–3 years 252 27.0 4– 6 years 274 29.3 7– 9 years 113 12.1 More than 10 years 62 6.6 Measures After reviewing the literature on behavioral finance, we designed a self-administered survey using the scale items adapted from the established and validated measures. Since most of the measures were developed and used in the context of Western countries, we had to adapt the measures to suit the Indian context. Before adapting the measures to suit the requirements of the context of individuals and families interested in investment and consulted five faculty members to make sure that the indicators tap the intended constructs. We used Likert-type 5-point scale (‘1″ representing ‘strongly disagree’ and ‘5 representing ‘strongly agree’). The term ‘personality’ is used here to represent the aggregation of five personality traits (from the Five Factor Theory of McCrae and Costa (1997). The Big-Five personality variables were adapted from John and Srivastava (1999) and used by Mayfield et al. (2008): extraversion (4 items: Cronbach’s alpha = 0.71), agreeableness (4, Cronbach’s alpha = 0.81), conscientiousness (5: Cronbach’s alpha = 0.82), emotional stability (5 items: Cronbach’s alpha = 0.81), and openness to experience (5 items: Cronbach’s alpha = 0.87). The Cronbach’s alpha for personality, for all the 23 items taken together, was 0.92. Risk capacity was measured using ten items adapted from Filbeck et al. (2009) and Global Asset Management (GAM 2019), and the reliability coefficient Cronbach’s alpha was = 0.88. Investment attitude was measured using 9 items out of which 4 items were adapted from Lai (2019), and five items self-developed, and the reliability coefficient Cronbach’s alpha was = 0.83. Investment priority was measured with 8 items adapted from the literature and self-developed to suit the Indian context because the priority of Indian investors are radically different from the individuals in Western countries, and the reliability coefficient Cronbach’s alpha was = 0.0.89. Investment strategy, consisting of strategies regarding the short-term investments (5 items) and long-term investments (5 items) was measured using 10 items adapted from Mayfield et al. (2008) and the reliability coefficient Cronbach’s alpha was = 0.92. Results Descriptive statistics Before testing the hypotheses it is essential to check the measurement properties of the instrument and observe the correlations between the variables. Table 2 captures the descriptive statistics – means, standard deviations, and correlations.Table 2 Descriptive Statistics: Means, Standard deviations, and zero-order correlations Variable Mean Standard Deviation 1 2 3 4 5 6 7 8 9 1.Extraversion 3.33 0.69 1 2.Agreeableness 3.22 0.68 0.68*** 1 3.Conscientiousness 3.24 0.68 0.62*** 0.65*** 1 4.Emotional Stability 3.16 0.71 0.57*** 0.59*** 0.69*** 1 5.Openness to Experience 3.36 0.70 0.50*** .051*** 0.52*** 0.52*** 1 6.Risk Capacity 3.22 0.74 0.47*** 0.47*** 0.53*** 0.53*** 0.37*** 1 7.Investment Attitude 3.37 0.70 0.51*** 0.47*** 0.48*** 0.39*** 0.49*** 0.53*** 1 8.Investment Priority 3.28 0.81 0.46*** 0.44*** 0.42*** 0.34*** 0.44*** 0.48*** 0.70*** 1 9.Investment Strategy 3.18 0.85 0.47*** 0.46*** 0.47*** 0.43*** 0.46*** 0.59*** 0.65*** 0.61*** 1 *** Correlation is significant at the 0.01 level (2-tailed) We also tested for multicollinearity by observing correlations between the variables. As can be seen in Table 2, the correlations were less than 0.75. As suggested by Tsui et al. (1995), correlations of less than 0.75 suggest multicollinearity is not a problem. Furthermore, to double-check the presence of multicollinearity we observed the variance inflation factor (VIF) and found that the VIF values were less than 5, thus reiterating that multicollinearity is not a problem with the data (Hair et al. 2019). Common Method Bias and measurement properties We followed the recommendations of Podsakoff et al. (2003) to check common method bias and performed Harman’s single-factor analysis. The results showed that the single factor accounted for 32.46 percent variance, which is far less than the cut-off value of 0.50, and hence common method bias is not a problem with the data. We also tested the measurement properties of the instrument. All the factor loadings for the constructs were over 0.7, and the Average Extracted Estimates were over the threshold values of 0.50. Further, the composite reliability (CR) are over the acceptable values. The summary of the measures and measurement properties (Confirmatory Factor Analysis) were presented in Appendix 1. Hypotheses Testing To test the hypotheses 1,2,3 and 4 we used model number 4 in Hayes (2018) PROCESS macros, and the results of hypotheses testing are presented in Table 3. First, we tested the effect of control variables (age, gender, income, and education) and found that none of these control variables were significant. So, we did not include these demographic variables in the PROCESS analysis. Therefore, Table 3 shows the effect of main independent variables on dependent variable and the mediator.Table 3 Testing H1, H2, H3, and H4 (Mediation Hypothesis) DV = Investment strategy DV = Investment attitude H2 DV = Investment strategy Step 1 Step 2 Step 3 Coeff se t p Coeff se t p Coeff se t p Constant 0.4348 0.1349 3.2221 0.0013 1.0550 0.1105 9.5482 0.0000  − 0.1934 0.1235  − 1.5656 0.1178 Personality H1 0.8399 0.0408 20.6080 0.0000 0.7100 0.0334 21.2756 0.0000 0.4171 0.0434 9.6126 0.0000 Investment attitude H3 0.5954 0.0349 17.0381 0.0000 R-square 0.313 0.327 0.477 F 424.68 452.65 423.40 df1 1 1 2 df2 932 932 931 p .000 .000 .000 Total effect Total effect se t p LLCI ULCI 0.8399 0.0408 20.6080 0.0000 0.7599 0.9198 Direct effect Direct Effect se t p LLCI ULCI Personality investment strategy 0.4171 0.0434 9.6126 0.0000 0.3320 0.5023 Bootstrapping indirect effect: H4 Indirect Effect BOOT se BOOT LLCI BOOT ULCI Personality investment attitude investment strategy 0.4227 (0.5954 × 0.7100) 0.0465 0.3286 0.5126 N = 934. Boot LLCI refers to the lower bound bootstrapping confidence intervals. Boot ULCL refers to the upper bound bootstrapping confidence intervals. Number of bootstrapping samples for this bias corrected bootstrapping confidence intervals are 20,000. The level of confidence for all confidence intervals in output was 0.95. We have four decimal digits for bootstrap results because some values may be very close to zero Step 1 from Table 3 shows the effect of personality on investment strategy. The regression coefficient of personality was positive and significant (β = 0.84, t = 20.60; p < 0.001). The 95 percent bias-corrected confidence interval (BCCI) was 0.7599 (LLCI) and 0.9198 (ULCI). The model was significant and explains 31.3 percent variance in the investment strategy [R2 = 0.313; F (1,932) = 424.68; p < 0.001]. These results support H1 that personality is positively associated with investment strategy. Hypothesis 2 proposes that personality will have a positive effect on investment attitude. As shown in the step 2 of Table 2, the regression coefficient of personality on investment attitude was positive and significant (β = 0.71; t = 21.75; p < 0.001). The 95 percent (BCCI) LLCI and ULCI were 0.6445 and 0.7754 respectively. The model was significant and explains 32.7 percent variance in the purchase intention because of social adjustive function [R2 = 0.327; F (1,932) = 452.65; p < 0.001]. These results support H2. Step 3 (Table 2) shows the results of the effects of investment attitude on investment strategy. The regression coefficient of investment attitude on investment strategy was positive and significant (β = 0.59; t = 17.03; p < 0.001). The model explains 47.7 percent of variance in investment strategy and the magnitude is statistically significant [R2 = 0.477; F (2,931) = 423.40; p < 0.001]. These results render support to H3 that investment attitude is positively associated with investment strategy. The hypothesis 4 is concerned with the mediation of investment attitude between personality and investment strategy. To test this hypothesis, we had to check the indirect effect. As shown in Table 3, the total effect (0.839) was consisting of direct effect of personality on investment strategy (0.417) and indirect effect through investment attitude (0.422). The indirect effect was calculated as the multiplication of regression coefficient of personality on investment attitude (0.7100) and the regression coefficient of investment attitude on investment strategy (0.5954) [i.e. 0.7100 × 0.5954 = 0.422]. The total effect of personality on investment strategy was 0.417 + 0.422 = 0.839. In order to check mediation effect of investment attitude, it is important to see whether the indirect effect is significant or not. The indirect effect of personality investment attitude investment strategy was significant (β = 0.4227; Boot s. e = 0.0465), and the bootstrapping results based on 20,000 bootstrap samples in Hayes (2018) PROCESS macros, show that 95 percent bias-corrected confidence interval (BCCI) are between 0.3286 and 0.5126. Because zero was not contained in CIs, investment attitude does mediate the relationship between personality and investment strategy, thus supporting the H4. Testing the first order moderation of risk capacity One of the most important segment of the model is testing the first order moderation i.e. risk capacity as a moderator between personality and investment attitude. To test this model, we used model number 7 of Hayes (2018) PROCESS Macros. We presented the results of regression in Table 4.Table 4 Testing of Hypothesis 2a (Model number 7 of Hayes PROCESS) (Results of two-way interaction) DV = Investment strategy mediator = Investment attitude; Moderator: Risk capacity; IV = Personality Step 1 Step 2 DV = Investment attitude DV = Investment strategy Coeff se t p LLCI ULCI LLCI ULCI Constant 0.0839 0.2504 0.3350 0.7377  − 0.4075 0.5752  − 0.1934 0.1235  − 1.5656 0.1178  − 0.4358 0.0490 Personality 0.7699 0.0810 9.5054 0.0000 0.6109 0.9288 0.4171 0.0434 9.6126 0.0000 0.3320 0.5023 Risk capacity 0.5238 0.0916 5.7180 0.0000 0.3440 0.7035 Personality x Risk capacity H2a  − 0.0840 0.0265  − 3.1676 0.0016  − 0.1361  − 0.0320 Investment attitude 0.5954 0.0349 17.0381 0.0000 0.5268 0.6640 R-square 0.402 0.476 F 233.26 423.40 df1 3 2 df2 930 931 P value .000 .000 Index of moderated moderated-mediation Index BOOT SE BOOT LLCI BOOT ULCI − 0.0507 0.0226 − 0.0959 − 0.0065 Conditional effects of the focal predictor (Investment attitude) at the value of the moderator (Risk Capacity) Risk capacity Effect se t p LLCI ULCI 2.5000 (Low) 0.5598 0.0375 14.9139 0.0000 0.4861 0.6334 3.3000 (Medium) 0.4925 0.0402 12.2407 0.0000 0.4136 0.5715 3.9000 (High) 0.4421 0.0487 9.0849 0.0000 0.3466 0.5376 Conditional effects of the focal predictor (Investment Attitude) at values of moderator (Risk Capacity) Risk Capacity Effect se t p LLCI ULCI 1.0000 0.6858 0.0587 11.6876 0.0000 0.5707 0.8010 1.2000 0.6690 0.0547 12.2369 0.0000 0.5617 0.7763 1.4000 0.6522 0.0509 12.8130 0.0000 0.5523 0.7521 1.6000 0.6354 0.0474 13.3974 0.0000 0.5423 0.7285 1.8000 0.6186 0.0443 13.9585 0.0000 0.5316 0.7055 2.0000 0.6018 0.0417 14.4478 0.0000 0.5200 0.6835 2.2000 0.5850 0.0395 14.8003 0.0000 0.5074 0.6625 2.4000 0.5682 0.0380 14.9425 0.0000 0.4936 0.6428 2.6000 0.5514 0.0372 14.8114 0.0000 0.4783 0.6244 2.8000 0.5345 0.0372 14.3793 0.0000 0.4616 0.6075 3.0000 0.5177 0.0379 13.6696 0.0000 0.4434 0.5921 3.2000 0.5009 0.0393 12.7507 0.0000 0.4238 0.5780 3.4000 0.4841 0.0413 11.7119 0.0000 0.4030 0.5652 3.6000 0.4673 0.0439 10.6367 0.0000 0.3811 0.5535 3.8000 0.4505 0.0470 9.5872 0.0000 0.3583 0.5427 4.0000 0.4337 0.0504 8.6015 0.0000 0.3348 0.5326 4.2000 0.4169 0.0542 7.6980 0.0000 0.3106 0.5231 4.4000 0.4001 0.0581 6.8819 0.0000 0.2860 0.5141 4.6000 0.3833 0.0623 6.1508 0.0000 0.2610 0.5055 4.8000 0.3664 0.0666 5.4982 0.0000 0.2357 0.4972 5.0000 0.3496 0.0711 4.9163 0.0000 0.2101 0.4892 Indirect effect (Personality Investment Attitude Investment Behavior) Risk capacity Effect Boot SE Boot LLCI Boot ULCI 2.5000 (Low) 0.3378 0.0408 0.2594 0.4207 3.3000 (Medium) 0.2972 0.0354 0.2285 0.3677 3.9000 (High) 0.2668 0.0370 0.1940 0.3389 The moderation hypothesis suggests that risk capacity moderates the relationship between personality and investment attitude. The regression coefficient of the multiplicative term (personality x risk capacity) was significant (β =− 0.084; t = − 3.167; p < 0.01; Boot LLCI (− 0.1361; Boot ULCI (− 0.0320). The index of moderated-mediation, as shown in the Table 3, was − 0.0507 with Boot SE (0.0226) and Boot LLCI (− 0.0959); Boot ULCI (− 0.0065), thus rendering support to H2a. The conditional effects of the focal predictor (Investment Attitude) at the value of the moderator (Risk Capacity) were presented at the bottom of the Table 3. The indirect effect shown in the bottom part also corroborate the moderation hypothesis. The interaction effect is presented in Fig. 2.Fig. 2 Risk Capacity as a moderator in the relationship between personality and investment attitude As shown in Fig. 2, the relationship personality and investment strategy was stronger under the high-risk capacity than at the medium and lower levels of risk capacity. As individuals move from lower scores on personality to higher levels, the higher risk capacity is associated with higher investment strategy than at lower and middle levels of risk capacity These results corroborate the support for moderation hypothesis 2a. Testing the second-order moderation effect Hypothesis 2b posits that risk capacity (first moderator) and investment priority (second moderator) interact with personality to affect investment strategy mediated through investment attitude. To test this moderated moderated-mediation hypothesis, we used model number 11 of Hayes (2018) PROCESS macros and presented the results in Table 5.Table 5 Testing of Hypothesis 2b (three-way interaction) (Results of moderated moderated-mediation model) DV = Investment strategy; Mediator = Investment attitude; Moderators: Risk capacity (first Moderator) and Investment priority (Second Moderator); IV = Personality DV = Investment attitude DV = Investment strategy Coeff se t p LLCI ULCI Coeff se t p LLCI ULCI Constant  − 1.3137 0.5197  − 2.5279 0.0116  − 2.3335  − 0.2938  − 0.1934 0.1235  − 1.5656 0.1178  − 0.4358 0.0490 Personality 0.6123 0.1686 3.6327 0.0003 0.2815 0.9431 0.4171 0.0434 9.6126 0.0000 0.3320 0.5023 Risk capacity 0.9410 0.2259 4.1650 0.0000 0.4976 1.3843 Investment priority 1.4070 0.2450 5.7426 0.0000 0.9262 1.8878 Personality x Risk capacity  − 0.1536 0.0662  − 2.3201 0.0206  − 0.2836  − 0.0237 Personality x Investment priority  − 0.2111 0.0706  − 2.9895 0.0029  − 0.3497  − 0.0725 Risk capacity x investment priority  − 0.3579 0.0798  − 4.4847 0.0000  − 0.5145  − 0.2013 Personality x Risk capacity x Investment priority H2b 0.0785 0.0215 3.6411 0.0003 0.0362 0.1208 Investment Attitude 0.5954 0.0349 17.0381 0.0000 0.5268 0.6640 R-square 0.572 0.476 F 176.62 423.40 df1 7 2 df2 926 931 P value .000 .000 Index of moderated moderated-mediation Index BOOT SE BOOT LLCI BOOT ULCI 0.0467 0.0141 0.0214 0.0769 Indices of conditional moderated mediation by Risk capacity Investment priority Index BOOT SE BOOT LLCI BOOT ULCI 2.7333 (Low) 0.0362 0.0394  − 0.0358 0.1198 3.4000 (Medium) 0.0674 0.0406  − 0.0067 0.1540 4.0000 (High) 0.0954 0.0434 0.0171 0.1891 Conditional effects of the focal predictor (Investment Attitude) at values of moderators (Risk capacity x Investment priority) Risk capacity Investment priority Effect se t p LLCI ULCI Low Low 0.1874 0.0419 4.4783 0.0000 0.1053 0.2696 Low Medium 0.1775 0.0518 3.4259 0.0006 0.0758 0.2792 Low High 0.1685 0.0666 2.5316 0.0115 0.0379 0.2992 Medium Low 0.2361 0.0432 5.4612 0.0000 0.1513 0.3209 Medium Medium 0.2680 0.0393 6.8109 0.0000 0.1908 0.3452 Medium High 0.2967 0.0467 6.3574 0.0000 0.2051 0.3883 High Low 0.2726 0.0577 4.7205 0.0000 0.1593 0.3859 High Medium 0.3359 0.0490 6.8613 0.0000 0.2398 0.432 High High 0.3928 0.0527 7.4583 0.0000 0.2895 0.4962 As shown in the first column of Table 5, the regression coefficient of the three-way interaction (personality x risk capacity x investment priority) was significant (β = − 0.0785; t = 3.64; p < 0.001). This is labeled as testing the ‘moderated moderated-mediation’. Most importantly, as shown in Table 4, the index of moderated moderated-mediation was (0.0467) and Boot SE (0.0141) and Boot LLCI (0.0214) and BOOT UL (0.0769). As zero was not contained in the 95 percent bias-corrected confidence interval (BCCI) Lower and Upper limits, the moderated moderated-mediation hypothesis was supported. The indices of conditional moderated mediation by Risk Capacity, as shown in the bottom of the Table 4, reveal that at higher levels of investment priority the index was significant [Index, 0.954; BOOT SE, 0.0434; BOOT LLCI, 0.0171; BOOT ULCI, 0.1891]. The conditional effects of the focal predictor (Investment Attitude) at values of moderators (Risk Capacity x Investment Priority) were presented in the bottom of the Table 4, also corroborate the results. Most importantly, the indirect effect of personality on investment strategy, (Personality Investment AttitudeInvestment Strategy) as shown in Table 6 also show the support for moderated moderated-mediation hypothesis.Table 6 Indirect Effect (Personality Investment Attitude Investment Strategy) Risk capacity Investment priority Effect Boot SE Boot LLCI Boot ULCI 2.5000(Low) 2.7333 (Low) 0.1116 0.0430 0.0333 0.2025 2.5000 (Low) 3.4000(Medium) 0.1057 0.0486 0.0092 0.1991 2.5000 (Low) 4.0000 (High) 0.1003 0.0624 − 0.0283 0.2166 3.3000(Medium) 2.7333 (Low) 0.1406 0.0390 0.0727 0.2246 3.3000 (Medium) 3.4000(Medium) 0.1596 0.0323 0.0994 0.2263 3.3000(Medium) 4.0000 (High) 0.1767 0.0401 0.0994 0.2554 3.9000 (High) 2.7333 (Low) 0.1623 0.0507 0.0752 0.2754 3.9000( High) 3.4000(Medium) 0.2000 0.0379 0.1319 0.2841 3.9000 (High) 4.0000 (High) 0.2339 0.0384 0.1622 0.3136 The three-way interaction was shown in Fig. 3 in two panels.Fig. 3 The moderating effect of Investment Priority and Low and High levels on the relationship between Personality and Investment Attitude moderated by Risk Capacity Panel A (Fig. 3) shows the effect of different levels of risk capacity the relationship between personality and investment attitude, under the conditions of lower level of investment priority. As can be seen, when individuals have high risk capacity, the relationship between personality and investment attitude is stronger than at lower levels of risk capacity. As individuals move from lower levels of personality to higher levels, the relationship between personality and investment attitude becomes much stronger (as the slope is greater relative the slope of the curve at lower levels of risk capacity). When we consider the panel B, represented by higher levels of investment priority, the relationship between personality and investment attitude becomes much stronger (as the curve becomes steeper at higher levels of personality), though at lower levels the relationships is not strong. The intersecting curves represent a strong three-way interaction effect at higher levels of investment priority. These graphs render support to three-way interaction hypothesis 2b. Summary of hypotheses were captured in Table 7.Table 7 Summary of the results of hypotheses testing Number Hypothesis Result H1 Personality is positively related to investment strategy Supported H2 Personality is positively associated with investment attitude Supported H3 Investment attitude is positively associated with investment strategy Supported H4 Investment attitude mediates the relationship between personality and investment strategy Supported H2a Risk capacity moderates the relationship between personality and investment strategy mediated through investment attitude Supported H2b Investment priority positively moderates the moderation effect of risk capacity on the investment strategy from personality via investment attitude as mediator Supported Discussion The empirical findings of this study support the multi-layered moderated-moderated-mediation conceptual model mentioned in Fig. 1. We analyzed the data collected from 934 respondents and analyzed the data using Hayes (2018) PROCESS macros to test the hypotheses. All the hypotheses found support in this study. To begin with, big-five personality traits, collectively, are positively associated with investment strategy (hypothesis 1), and this finding is consistent with the previous studies from the literature (Mayfield et al. 2008; Durand et al. 2008; Sadiq and Khan, 2019). The positive relationship between personality traits and investment attitude (hypothesis 2) was demonstrated in this study, which adds to the results from the earlier studies and is consistent with the TPB theory. The direct relationship between investment attitude and investment strategy is also observed in this study (hypothesis 3). These relationships are compatible with the previous studies conducted in various parts of the world, including India (Isidore and Christie 2017; Saleem et al. 2021; Sultana 2010). The results also support that personality traits influence the investment strategy through investment attitude (hypothesis 4). However, earlier researchers did not test the relationship, and they could not vouch for the connection. Another interesting finding from this study is the role of risk capacity in changing the strength of the relationship between personality traits and investment attitude (hypothesis 2a). This result is consistent with the previous studies that showed the positive effect of the individual’s risk capacity on their investment decisions (Ananthan et al. 2017). Finally, the investment priority further moderates the relationship between personality and investment strategy mediated by investment attitude by risk capacity (hypothesis 2b). Again, no previous studies were available to vouch for this finding. However, the finding has intuitive appeal as the positive interaction between risk capacity, and investment priority is expected to influence the relationship between personality traits and investment attitude. Overall, the results support the theoretical assertions of TPB that investment behavior of individuals is led by the attitudinal evaluations about risk factors involved in financial decisions and perceived control individuals have, depending on their personality traits. The perceived behavioral control, though we did not measure in this study, largely depends on individuals’ personality traits and thus provides a convenient platform for this study. Our results, therefore, are supported by TPB. Theoretical implications This research has proposed a multi-layered conceptual model for exploring the relationship between five-factor personality traits (extraversion, openness to experience, emotional stability, conscientiousness, and agreeableness) and investor behavior, contributing to the growing body of knowledge in the field of behavioral finance in several ways. First, to be consistent with most of the earlier studies, the conceptual model was built under the theoretical framework of TPB but yet taken a different approach in exploring the relationships. This extends the widely discussed literature linking personality variables to investor behavior. Second, the direct relationships between personality traits and investors’ attitudes and investment strategy are expected and supported by the existing research, and the results add to the literature. Third, a significant contribution of this research is the moderating role of risk capacity in influencing the individual’s perception towards investment attitude. Though risk capacity and personality traits directly influence investment attitude, the multiplicative effect of both is fascinating to examine, as we did in this study. Fourth, a significant contribution of this study to the behavioral finance literature is the support for moderated moderated-mediation hypothesis, which has not been examined before, to the best of our knowledge. Particularly in a developing country, the investor’s behavior is rarely examined using the variables we considered in this study. Several studies were conducted in an Indian context, but the complex relationships unraveling the three-way interaction were not discussed very infrequently. Therefore, the study makes a unique contribution to the growing body of literature in behavioral finance. Practical contributions This study has several contributions to the practitioners and investment brokers interested in studying the investment portfolios of individual investors. First, this study highlights the importance of personality traits that may profoundly influence the investment behavior of individuals. Second, the investment brokers need to consider the risk capacity of individuals and risk-taking or risk-aversive behaviors because the risk capacity is not a psychological variable but has a significant effect on the investment attitude and investment strategy. Third, the investor’s investment priorities need to be considered while suggesting their investment portfolios. Fourth, the practitioners need to understand that the investment priorities of individuals differ from person to person. For example, some individuals express their priority to satisfy their retirement needs, whereas some may express buying a house or property; others may invest in a child plan (for education or marriage needs). Therefore, investment priorities play a significant role in individuals’ investment attitudes and investment strategy. The investment strategies of individuals also differ: some individuals act on the information obtained from television, newspapers, magazines, and peers, whereas others may rely on the information provided by the investment brokers or consultants. In the present-day digital information age, individuals have access to various information models, and how the information is received, interpreted, and acted upon depends on the personality traits. For example, individuals who are high on extraversion and openness to experience act positively, whereas emotionally unstable individuals tend to be risk-averse and pessimistic in their investment decisions. Therefore, this study guides the investors as to the essential factors that need to be considered before making decisions. Limitations and future research The results from the study should be interpreted in light of some of the limitations. First, the self-report surveys have the inherent problem of common method bias and social desirability bias. However, we have statistically checked for the common method bias by performing Harman’s single-factor analysis and found that a single variable explained less than 30 percent of the variance. Hence, common method bias was not a problem with this study. Second, we assume that social desirability bias is minimized by assuring the respondents that the survey responses would be kept confidential to answer the questions dispassionately. Third, the results from this study may have some generalizability problems because the focus of this study was on the respondents from the southern part of India. However, to the extent the investor’s behavior is identical across different states of India, we expect the results to be generalizable. Another limitation of this study is the representativeness of the sample. We have collected data using convenience sampling. However, since the sample size is significant, we assume no sampling bias. The present study offers several avenues for future research. First, this study focused on big-five personality traits in an aggregated way. Though individuals exhibit stable personality traits across this five-factor model, it may be likely that each trait may influence the investment behavior of individuals. It would be interesting to explore the investment behavior concerning each of the traits to have a broader understanding of the nature of relationships. Second, the demographic variables (such as income, gender, family size, number of children, etc.) may influence the investment behavior. We controlled for these demographic variables. Future researchers may examine if there are any gender differences in investment behavior. It would also be interesting to compare and contrast the investor’s behavior of developing countries with developed countries to see if any cultural differences exist. Further, comparisons of investors’ behavior in other developing countries to see if any differences exist, as the personality traits in different countries may impact investors’ behavior. Finally, a more significant sample may help test this model on a large scale to make the results generalizable across other countries. Conclusion This study is a modest attempt to understand better how various personality traits influence investment behavior, particularly in India’s developing country. This study provided evidence that personality traits play a vital role in financial decision-making. Most importantly, the study highlighted the importance of considering investors’ investment priorities and risk capacity in deciding about investment strategy. As the investors’ behavior constantly changes according to the market situation, researchers continue to examine the impact of personality on financial decision-making. The study provides a simple model, not a pioneering one. Still, it may be extended by adding additional variables to strengthen the understanding of investors’ behavior, particularly in a developing country perspective. We hope the model presented may drive future researchers to extend the research to benefit both investors and literature. Appendix 1 See Table Table 8 Confirmatory factor analysis Alpha Composite reliability Standardized Loadings (λyi) Reliability (λ2yi) Variance (Var(εi)) Average Variance- Extracted Estimate Σ (λ2yi)/ [(λ2yi) + (Var(εi))] Agreeableness” I see myself as someone 0.81 0.80 0.50 AG1: is helpful and unselfish with others 0.73 0.53 0.47 AG2:Has a forgiving nature 0.68 0.47 0.53 AG3: Generally trusting 0.67 0.44 0.56 AG4: Is considerate and kind to almost everyone 0.75 0.56 0.44 Conscientiousness I see myself as someone 0.82 0.81 0.55 CON1: Does a thorough job 0.71 0.50 0.50 CON2: Is a reliable worker 0.78 0.61 0.39 CON3: Perseveres until the task is finished 0.72 0.52 0.48 CON4: Does things efficiently 0.73 0.53 0.47 CON5: Makes plans and follows through with them 0.76 0.58 0.42 Openness to experience I see myself as someone 0.87 0.80 0.54 OE1: Is original, comes up with new ideas 0.71 0.51 0.49 OE2: Is curious about many different things 0.73 0.53 0.47 OE3: Is ingenious, a deep thinker 0.75 0.56 0.44 OE4: Has an active imagination 0.78 0.61 0.39 OE5: Is inventive 0.71 0.50 0.50 Extraversion I see myself as someone 0.71 0.74 0.52 EX1: Is talkative 0.74 0.55 0.45 EX2: Is full of energy 0.73 0.53 0.47 EX3: Generates a lot of enthusiasm 0.70 0.49 0.51 EX4: Has an assertive personality 0.70 0.49 0.51 Emotional stability I see myself as someone 0.81 0.79 0.52 ES1: Is relaxed, handles stress well 0.71 0.50 0.50 ES2:Is emotionally stable, not easily upset 0.77 0.59 0.41 ES3: Remains calm in tense situations 0.74 0.55 0.45 ES4: Can be tense (R) 0.71 0.50 0.50 ES5: Worries a lot (R) 0.66 0.44 0.56 Investment attitude 0.83 0.89 0.52 IA1: I trust in managing my investments effectively 0.71 0.51 0.49 IA2: I am confident in tried and tested investments practices rather than trying new ideas 0.72 0.52 0.48 IA3: I accept that financial experts cannot win preferred returns in the market for the long term, so index funds are the best investments 0.71 0.50 0.50 IA4: I accept that with the right information and effort, individuals and the board can get very rich through dynamic portfolio scoring 0.71 0.50 0.50 IA5: Once I settle for an investments choice, I don’t change it for a while 0.70 0.50 0.50 IA6: I have the confidence to contribute investments continuously throughout my life 0.72 0.52 0.48 IA7: I believe that it is essential to set clear money-related goals 0.70 0.50 0.50 IA8: I usually audit the performance of my investments with showcase benchmarks 0.74 0.55 0.45 IA9: I carefully audit the data related to the money I receive via email 0.79 0.62 0.38 Investment priority 0.89 0.88 0.53 IP1: I invest my pension amount to satisfy my retirement objectives 0.70 0.49 0.51 IP2: To ensure a comfortable retirement 0.73 0.54 0.46 IP3: I invest the money as a principle instalment of my house 0.72 0.52 0.48 IP4: To achieve high growth in investments 0.75 0.56 0.44 IP5: To protect income in case of death/disability 0.73 0.53 0.47 IP6: To ensure transfer of assets to dependents smoothly 0.76 0.58 0.42 IP7: To invest in an endowment plan (Assured returns + Risk cover) 0.70 0.49 0.51 IP8: To invest in unit linked insurance plan (Market linked returns +  Risk cover) 0.75 0.56 0.44 Risk capacity 0.88 0.91 0.54 RC1: I pull back my investment funds in money market stores for emergencies 0.75 0.56 0.44 RC2: I take a loan for promising long term investing opportunity 0.75 0.56 0.44 RC3: I take a loan for promising short term investing opportunity 0.73 0.54 0.46 RC4: I make necessary changes to improve my investment performance, using my judgment 0.73 0.54 0.46 RC5: I wait it out, anticipating future improvements over the long run 0.73 0.54 0.46 RC6: I consult with a financial advisor before taking any action? 0.72 0.52 0.48 RC7: I indulge in panic selling 0.71 0.50 0.50 RC8: I assess the tax implications of the investment 0.73 0.53 0.47 RC9: I determine my return objective for the investment 0.75 0.56 0.44 RC10: I am real gambler willing to task risk after completing adequate research? 0.74 0.55 0.45 Investment strategy 0.92 0.91 0.55 IS1: I review my overall investment goals 0.73 0.54 0.46 IS2: I consider the variety of investment options 0.78 0.61 0.39 IS3:I get investment information from financial advisor (Individual / Institutional) 0.72 0.51 0.49 IS4:I get investment information from television 0.73 0.54 0.46 IS5:I buy/sell investments over online trading? 0.74 0.54 0.46 IS6: I use investment analysis/management software? 0.77 0.59 0.41 IS7: I discuss with my family/friends who are knowledgeable in trading 0.72 0.52 0.48 IS8:I assess the convenience with which the investment can be made, looked after and disposed 0.73 0.54 0.46 IS9:I weigh all the pros and cons and analyze all the facts before taking financial decisions 0.70 0.49 0.51 IS10:Safety of investment is the most important factor I look at when choosing a investment strategy 0.75 0.56 0.44 8. Acknowledgements The authors want to thank Professor Han Woo Park, the Editor-in-Chief, and the anonymous reviewers for the constructive suggestions in the earlier versions of the manuscript. Funding The research does not have any funding. Declarations Conflict of interest The authors do not have any conflict of interest. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ==== Refs References Adam AA Shauki ER Socially responsible investment in Malaysia: behavioral framework in evaluating investors’ decision-making process J. Clean. Prod. 2014 80 224 240 Ajzen I The theory of planned behaviour Organiz Behav Human Decision Process 1991 50 179 211 Ajzen I Driver BL Application of the theory of planned behaviour to leisure choice J. Leis. Res. 1992 24 207 224 10.1080/00222216.1992.11969889 Ali I Personality traits, individual innovativeness and satisfaction with life J. Knowl. Innov. 2019 4 1 38 46 10.1016/j.jik.2017.11.0022444-569X/ Allport GW Vernon PE The field of personality Psychol. Bull. 1930 27 10 677 Ananthan S Panchanathan V Subasri S A study on risk tolerance and risk capacity of post graduate students Int. J. Appl. Bus. Econ. Res. 2017 15 13 343 352 Aydemir SD Aren S Do the effects of individual factors on financial risk-taking behaviour diversify with financial literacy? Kybernetes 2017 46 1706 1734 10.1108/k-10-2016-0281 Aydin AE Selcuk AE An investigation of financial literacy, money ethics and time preferences among college students: a structural equation model Int. J. Bank Marketing. 2019 37 880 900 10.1108/ijbm-05-2018-0120 Baddeley, M., Burke, C., Tobler, P., and Schulz, W. (2010). Impacts of personality on herding in financial decision making. In: Cambridge Working Papers in Economics (1006). Faculty of Economics, University of Cambridge. Baker HK Kumar S Goyal N Personality traits and investor sentiment Rev. Behav. Finance 2021 13 4 354 369 10.1108/RBF-08-2017-0077 Barasinska N Schäfer D Stephan A Individual risk attitudes and the composition of financial portfolios: evidence from german household portfolios Quarterly Rev. Econ. Finance 2012 52 1 1 14 Barber BM Odean T Constantinides GM Harris M Stulz RM The behaviour of individual investors Handbook of the Economics of Finance 2013 Amsterdam Elsevier 1533 1570 Belcher LJ Prior perceptions, personality characteristics and portfolio preferences among fund managers: an experimental analysis J. Behav. Financ. 2010 11 239 248 Belsky G Gilovich T Why smart people make big mistakes-and how to correct them: lessons from the new science of behavioural economics 1999 New York, NY Simon and Schuster Bhoj J Understanding Indian investors behavior biases EPRA Int. J. Res. Develop 2019 4 11 18 24 Brown S Taylor K Household finances and the “big five’ personality traits J. Econ. Psychol. 2014 45 197 212 Charles A Kasilingam R Do Investors’ emotions determine their investment personality? Parikalpana: KIIT J. Manag 2014 10 2 45 60 Charness G Gneezy U Imas A Experimental methods: Eliciting risk preferences J. Econ. Behav. Organ. 2013 2013 87 43 51 Chiang TC Li JD Tan L Empirical investigation of herding behavior in Chinese stock markets: evidence from quantile regression analysis Glob. Financ. J. 2010 21 111 124 Comrey AL Lee HB A First Course in Factor Analysis 1992 2 Hillsdale, NJ Lawrence Erlbaum Corter JE Chen Y-J Do investment risk tolerance attitudes predict portfolio risk? J. Bus. Psychol. 2005 20 3 369 381 Costa PT McCrae RR NEO PI-R professional manual, psychological assessment resources 1992 Odessa TX Dam RMML Role of an attitude and financial literacy in stock market participation Int. J. Manag. IT Eng. 2017 7 137 149 De Bortoli D da Costa JN Goulart M Campara J Personality traits and investor profile analysis: a behavioral finance study PLoS ONE 2019 14 3 e0214062 10.1371/journal.pone.0214062 30917175 Durand RB Newby R Peggs L Siekierka M Personality J. Behav. Financ. 2013 14 2 116 133 Elliott MA Ainsworth K Predicting university undergraduates’ binge-drinking behavior: a comparative test of the one- and two-component theories of planned behavior Addict. Behav. 2012 37 92 101 21945010 Fernandes D Lynch JG Jr Netemeyer RG Financial literacy, financial education, and downstream financial behaviors Manage. Sci. 2014 60 8 1861 1883 Filbeck G Hatfield P Horvath P Personality dimensions and measures of risk tolerance: variance/Skew and scenario response assessment J. Bus. Econ. Res. 2009 7 9 55 70 Friend I Blume ME The demand for risky assets Am. Econ. Rev. 1975 65 5 900 922 Fung L Durand RB Baker HK Ricciardi V Personality traits Investor behavior: the psychology of financial planning and investing 2014 Hoboken John Wiley and Sons, Inc. 99 115 Furnham A Fudge C The five-factor model of personality and sales performance J. Individ. Differ. 2008 29 1 11 16 Gambetti E Giusberti F The effect of anger and anxiety traits on investment decisions J. Econ. Psychol. 2012 33 6 1059 1069 Goulart M Da Costa JN Santos A Takase E Da Silva S Psychophysiological correlates of the disposition effect PLoS ONE 2013 8 1 e54542 10.1371/journal.pone.0054542 23355877 Goulart M da Costa Jr NC Andrade EB Santos AA Hedging against embarrassment J. Econ. Behav. Organ. 2015 116 310 318 Grable JE Roszkowski MJ The influence of mood on the willingness to take financial risks J. Risk Res. 2008 11 7 905 923 Greenberg D Shtudiner Z Can financial education extend the border of bounded rationality? Mod. Econ. 2016 7 2 103 108 Gunkel M Schlaegel C Langella IM Peluchette JV Personality and career decisiveness: an international empirical comparison of business students’ career planning Pers. Rev. 2010 39 4 503 524 Hair JF Black WC Babin B Anderson R Multivariate data analysis 2019 8 London Cengage Learning Hayes AF Introduction to mediation, moderation, and conditional process analysis: a regression-based approach 2018 2 New York, NY Guilford Press Heo W Grable JE Rabbani AG A test of the association between the initial surge in COVID-19 cases and subsequent changes in financial risk tolerance Rev. Behav. Finance 2021 13 1 3 19 10.1108/RBF-06-2020-0121 Isidore RR Christie P Review of the influence of investor personality (Big 5 model) on investor behavior Int. J. Res. Finance Marketing 2017 7 7 23 32 Jain R Jain P Jain C Behavioral biases in the decision making of individual investors IUP J. Manag. Res. 2015 14 7 27 Jamshidinavid B Chavoshani M Amiri S The impact of demographic and psychological characteristics on the investment prejudices in Tehran stock Eur. J. Business Social Sci 2012 1 5 41 53 Kansal, P., and Singh, S. (2013).Investment Behaviour of Indian Investors: Gender Biasness. In: Proceedings of Seventh National Conference on Indian Capital Market: Emerging Issues, IBS Gurgaon, India, Available at SSRN: https://ssrn.com/abstract=2358344 Kapteyn A Teppa F Subjective Measures of Risk Aversion, Fixed Costs, and Portfolio Choice J. Econ. Psychol. 2011 32 4 564 580 Kimball MS Sahm CR Shapiro MD Imputing risk tolerance from survey responses J. Am. Stat. Assoc. 2008 103 483 1028 1038 20407599 Krejcie RV Morgan DW Determining sample size for research activities Educ.psychol. Meas. 1970 30 3 607 610 Lai C-P Personality traits and stock investment of individuals Sustainability 2019 11 5474 10.3390/su11195474 Leary MM Reilly MD Brown FW A study of personality preferences and emotional intelligence Leadersh. Org. Dev. J. 2009 30 5 421 434 Lusardi A Mitchell OS Curto V Financial literacy among the young J. Consumer Affairs 2010 44 2 358 380 Lusardi, A., Olivia S. Mitchell, O.S.: Planning and Financial Literacy: How Do Women Fare? Am. Econ. Rev. 98(2): 413–417 (2008) Mak, M.K.Y., Ip, W.H.: An exploratory study of investment behaviour of investors, 9, 1–12 (2017). 10.1177/1847979017711520 Mandal B Roe BE Risk tolerance among national longitudinal survey of youth participants: the effects of age and cognitive skills Economica 2014 81 323 522 543 Manner, C.K. (2017) American Psychiatric Association. (2013). Diagnostic and Statistical manual of mental disorders (5th ed.). Washington, DC. Mayfield C Perdue G Wooten K Investment management and personality type Finan. Serv. Rev. 2008 17 3 219 237 McCrae RR Costa PT Jr Personality trait structure as a human universal Am. Psychol. 1997 52 5 509 516 9145021 Miotto AP Parente JG Antecedents and consequences of household financial management in Brazilian lower-middle-class RAE-Revista De Administração De Empresas 2015 55 1 50 64 10.1590/S0034-759020150106 Moreschi RW Incorporating investor risk tolerance into the financial planning process J. Personal Finance 2004 3 89 98 Mushinada VNC Veluri VSS Elucidating investors rationality and behavioural biases in Indian stock market Rev. Behav. Fin. 2019 11 2 201 219 10.1108/RBF-04-2018-0034 Nadeem MA Qamar MAJ Nazir MS Ahmad I Timoshin A Shehzad K How Investors attitudes shape stock market participation in the presence of financial self-efficacy Front. Psychol. 2020 11 553351 10.3389/fpsyg.2020.553351 33192804 Nandan T Saurabh K Big-five personality traits, financial risk attitude and investment intentions: study on Generation Y Int. J. Business Forecasting Market. Intell. 2016 2 2 128 150 Nga JK Yien KL The influence of personality trait and demographics on financial decision making among Generation Y Young Consumers 2013 14 3 230 243 Nigam RM Srivastava S Banwet DK Behavioral mediators of financial decision making – a state-of-art literature review Review of Behavioral Finance 2018 10 1 2 41 10.1108/RBF-07-2016-0047 Oehler A Wendt S Wedlich F Horn M Investors’ personality influences investment decisions: experimental evidence on extraversion and neuroticism J. Behav. Finance 2018 19 1 30 48 Pak O Mahmood M Impact of personality on risk tolerance and investment decisions: a study on potential investors of Kazakhstan Int. J. Commer. Manag. 2015 25 4 370 384 Pan CH Statman M Investor personality in investor questionnaires J. Invest. Consult. 2013 14 1 48 56 Parks-Leduc L Feldman G Bardi A Personality traits and personal values: a meta-analysis Pers. Soc. Psychol. Rev. 2015 19 1 3 29 24963077 Parrotta JL Johnson PJ The impact of financial attitudes and knowledge on financial management and satisfaction of recently married individuals Financial Counsel. Plann. 1998 9 2 59 75 Podsakoff PM MacKenzie SB Lee JY Podsakoff NP Common method biases in behavioral research: a critical review of the literature and recommended remedies J. Appl. Psychol. 2003 88 5 879 903 14516251 Pompian MM Longo JM A new paradigm for practical application of behavioral finance: creating investment programs based on personality type and gender to produce better investment outcomes J. Wealth Manag. 2004 7 2 9 15 Potrich ACG Vieira KM Mendes-Da-Silva W Development of a financial literacy model for university students Manag. Res. Rev. 2016 39 3 356 376 10.1108/MRR-06-2014-0143 Riitsalu L Murakas R Subjective financial knowledge, prudent behaviour and income: the predictors of financial well-being in Estonia Int. J. Bank Market. 2019 37 934 950 10.1108/ijbm-03-2018-0071 Riley WB Chow KV Asset allocation and individual risk aversion Financ. Anal. J. 1992 48 6 32 37 Rzeszutek M Szyszka A Czerwonka M Investor’s expertise, personality traits and susceptibility to behavioral biases in the decision-making process Contemporary Economics 2015 9 337 352 Sadi R Asl HG Rostami MR Gholipour A Gholipour F Behavioral Finance: the explanation of Investors’ personality and perceptual biases effects on financial decisions Int. J. Econ. Financ. 2011 3 5 234 241 Sadiq MN Khan RAA Impact of personality traits on investment intention: the mediating role of risk behaviour and the moderating role of financial literacy J. Finance Econ. Res. 2019 4 1 1 18 10.20547/jfer1904101 Saleem S Mahmood F Usman M Bashir M Shabbir R Determinants of Investment behavior in mutual funds: evidence From Pakistan Front. Psychol. 2021 12 666007 10.3389/fpsyg.2021.666007 34322059 Saurabh K Nandan T Role of financial risk attitude and financial behaviour as mediators in financial satisfaction: empirical evidence from India South Asian J. Business Stud. 2018 7 207 224 10.1108/sajbs-07-2017-0088 Shi J Yao Y Zhan C Mao Z Yin F Zhao X The relationship between big five personality traits and psychotic experience in a Large Non-clinical Youth Sample: the mediating role of emotion regulation Front. Psych. 2018 9 648 10.3389/fpsyt.2018.00648 Shtudiner Z Risk Tolerance, time preference and financial decision making: differences between self-employed people and employees Mod. Econ. 2018 9 12 2150 2163 Sindhu, K.P., Kumar, S.: Influence of risk perception of investors on investment decisions: An empirical analysis. J. finance bank manag. 2(2), 15–25 (2014) Soldz S Vaillant GE The Big Five personality traits and the life course: A 45-Year longitudinal study J. Res. Pers. 1999 33 208 232 Strömbäcka C Lind T Skagerlund K Västfjäll D Tinghög G Does self-control predict financial behavior and financial well-being? J. Behav. Exp. Financ. 2017 14 1 30 38 Sultana ST An empirical study of Indian individual investors’ behaviour Global J. Finance Manag. 2010 2 1 19 33 Tekce B Yılmaz N Are individual stock investors overconfident? Evidence from an emerging market J. Behav. Exp. Financ. 2015 5 35 45 Tsui AS Pearce JL Porter LW Hite JP Ferris GR Choice of employee-organization relationship: Influence of external and internal organizational factors Research in Personnel and Human Resource Management 1995 JAI Pres Greenwich, CT 117 151 Verma R Verma P Behavioral biases and retirement assets allocation of corporate pension plans Rev. Behav. Finance 2018 10 4 353 369 10.1108/RBF-01-2017-0009 Wood R Zaichkowsky JL Attitudes and trading behaviour of stock market investors: a segmentation approach J. Behav. Financ. 2004 5 170 179 10.1207/s15427579jpfm0503_5 Yen SH Chang YS Wu MC Behavioral intention of earnings management: the explanation of agency problem moral development and theory of planned behavior NTU Manag. Rev. 2016 26 2 107 138 Young S Gudjonsson GH Carter P Terry R Morris R Simulation of risk-taking and it relationship with personality Personality Individ. Differ. 2012 53 3 294 299 Zhang Y Zheng X A study of the investment behavior based on behavioral finance Eur. J. Business Econ 2015 10 1 5
PMC009xxxxxx/PMC9214194.txt
==== Front Qual Quant Qual Quant Quality & Quantity 0033-5177 1573-7845 Springer Netherlands Dordrecht 35756090 1440 10.1007/s11135-022-01440-7 Article Tracing knowledge evolution flows in scholarly restaurant research: a main path analysis Rejeb Abderahman abderrahmen.rejeb@gmail.com 1 Abdollahi Alireza abdollahi.alirez@gmail.com 2 Rejeb Karim karim.rejeb@fsb.ucar.tn 3 Mostafa Mohamed M. moustafa.m@gust.edu.kw 4 1 grid.6530.0 0000 0001 2300 0941 Department of Management and Law, Faculty of Economics, University of Rome Tor Vergata, Via Columbia, 2, 00133 Rome, Italy 2 grid.412265.6 0000 0004 0406 5813 Department of Business Administration, Faculty of Management, Kharazmi University, Tehran, Iran 3 grid.419508.1 0000 0001 2295 3249 Faculty of Sciences of Bizerte, University of Carthage, Tunis, Tunisia 4 grid.448933.1 0000 0004 0622 6131 Gulf University for Science and Technology, Hawally, Kuwait 22 6 2022 2023 57 3 21832209 18 5 2022 © The Author(s), under exclusive licence to Springer Nature B.V. 2022 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. Restaurant research has received significant attention globally. This article aims to examine the evolution and the knowledge structure of restaurant research over the past decades. We also investigate the restaurant research hotspots and knowledge diffusion paths based on 1489 articles extracted from the Web of Science database. Furthermore, we conduct a keyword co-occurrence network analysis and four different types of main path analyses to scrutinize the historical formation of the restaurant research. Results revealed that restaurant research mainly focused on five research themes: consumer behavior, consumer satisfaction, social media, green restaurants, and authenticity. While consumer behavior has been the mainstream topic, the focus of this line of research has recently shifted from traditional to luxury and ethnic restaurants. Furthermore, our analysis has detected several recent changes in response to the COVID-19 pandemic. By examining the knowledge structure of restaurant research, we reveal its knowledge diffusion paths and provide avenues for future research in this vast and interdisciplinary research field. Keywords Restaurant research Consumer behavior Consumer satisfaction Keyword co-occurrence Main path analysis issue-copyright-statement© Springer Nature B.V. 2023 ==== Body pmcIntroduction In recent decades, the restaurant industry has attracted significant attention from both scholars and practitioners (Chuah et al. 2021; Liu et al. 2020a, b; Rajput and Gahfoor 2020). According to DiPietro (2017), research on restaurants has increased considerably over the last three decades. To date, restaurant research represents one of the most important areas in the hospitality sector (Denizci Guillet and Mohammed 2015; Line and Runyan 2012). Indeed, as scholarly knowledge progresses in a scientific discipline, it becomes imperative for scholars to employ quantitative tools to review and uncover the knowledge domain’s intellectual structure (Mostafa 2020; Rivera and Pizam 2015). Ferreira et al. (2014) argued that as research fields mature and become increasingly complex, scholars should periodically attempt to evaluate the knowledge generated and amassed to identify new contributions, uncover new patterns and research traditions, and grasp the subjects discussed, the theories and methodologies applied, and investigate the intellectual structure and the potential research directions in a field. Thus, given the enormous interest in restaurant research, it is imperative to examine this knowledge domain in a systematic and comprehensive manner. Currently, some efforts have been undertaken to review prior restaurant-related scholarly research. For example, DiPietro (2017) conducted a review of the foodservice and restaurant literature published over the past decade in the leading hospitality and tourism outlets. Rodríguez-López et al. (2020) investigated the development of the restaurant research by employing bibliometric analysis. The authors identified the structure of relationships between previous and emerging themes, outlined research trends and offered a longitudinal perspective on the scholarly work published between 2000 and 2018. Although these reviews provide valuable information regarding scholarly restaurant research, no prior studies have so far applied the main path analysis (MPA) to examine the knowledge structure and the evolution flows of this domain. This is surprising given that this technique has been used in the literature to analyze knowledge domains in several research fields (Fu et al. 2019; Xiao et al. 2014; Xu et al. 2020). To bridge this lacuna, we apply the objective MPA technique to conduct a comprehensive analysis of the knowledge/intellectual structure of restaurant research. Thus, this review aims to employ a keyword co-occurrence network analysis and MPA to explore the scholarly restaurant domain over the last decades. Using these quantitative approaches, not only the research hotspots can be discovered, but also the critical points shaping the historical formation of the restaurant domain. In addition, four distinct main paths are analyzed to lucidly explain the knowledge dissemination flows and structure of this domain. The use of quantitative methods reduces the analysis bias that might result from subjective reasoning. The combination of keyword co-occurrence clustering and MPA can deepen scholars’ understanding of the complete history of restaurant research and help them understand the current state of this research domain and identify its future directions. By so doing, we believe that we make at least three contributions to the existing literature. First, by combining keyword co-occurrence clustering and MPA to examine the restaurant domain, we remedy a clear lacuna in previous research. Second, we provide a systematic analysis to investigate the knowledge transmission patterns from various angles, considering the local (forward and backward), global and key-route main paths, which helps reveal the “hidden structure” of the vast and multidisciplinary restaurant research. Third, by applying these fairly sophisticated quantitative methods, we vividly detect the evolutionary progress of the restaurant literature. More specifically, we aim to find answers to the following research questions (RQ):RQ 1. What are the major topics/themes discussed in scholarly restaurant research? RQ 2. What is the knowledge structure of restaurant research over the last decades? RQ 3. What are the current trends/hotspots and the potential research directions in the field? The structure of this paper is as follows. Section two deals with the data and methodology used to conduct the review. Section three presents the analysis of both the keyword co-occurrence network and the MPA approaches. Section four discusses the research findings, while Section five provides avenues for future research. Finally, Section six briefly concludes the research article. Method Data collection Data quality constitutes a precondition to meaningful and interpretable results. In this respect, the Web of Science Core Collection (WoSCC) represents one of the most trustworthy and reliable sources covering several impactful journals (Rejeb et al. 2021b; Xiao et al. 2014). Moreover, WoSCC is commonly utilized by researchers as it enables them to conduct bibliometric analyses in different scientific fields (Mostafa 2020; Rodríguez-López et al. 2020). Thus, in the current study, the WoSCC is utilized as the main platform for data collection. Figure 1 presents the detailed research procedure of the study. Following Rodríguez-López et al. (2020), the search query applied in the present work is the following: TI=(restaurant*) OR AK=(restaurant*), where TI and AK stand for the title field and author keywords field, respectively. The search in these fields is preferred in previous studies (Hernández et al. 2017; Sixto-Costoya et al. 2021; Villa et al. 2018) since it helps to avoid non-pertinent entries and achieve greater accuracy in the results (Alnajem et al. 2021; Gao and Ruan 2018). The review is based on four sub-databases within the WoSCC, namely Science Citation Index Expanded (SCI-EXPANDED), Social Science Citation Index (SSCI), Art & Humanities Citation Index (A&HCI), and Emerging Sources Citation Index (ESCI). The time interval extends from 1970 to 2021, and the publications were collected on August 8, 2021. Only journal articles and reviews in English language were selected for the final analysis. Furthermore, the subject area was limited to Hospitality, Leisure, Sport, Tourism; Management; Business; and Operations Research Management Science, thus helping to mitigate discrepancy in research results, ensure a thorough exploration of the restaurant field, and enable better generalizability and systematization (Rejeb et al. 2022). For the sake of clarity and transparency, the search query used for the retrieval of publications is presented in "Appendix 1". After manually going through all the articles’ metadata to exclude irrelevant (off-topic) publications, a total of 1489 documents were extracted and downloaded from the database. Fig. 1 Research procedure Keyword co-occurrence network To obtain an in-depth understanding of restaurant research, we constructed a keyword co-occurrence network. Similar to a co-citation network, a keyword co-occurrence network shows the respective relationships between co-occurring author-supplied keywords (Abdollahi et al. 2021; Rejeb et al. 2021a, b; Yoon and Park 2020). Lee and Su (2010) noted that a keyword co-occurrence network analysis enables the researcher to identify research topics and capture the hotspots or research frontiers in a specific knowledge domain. Two keywords have a closer connection in the network if they appear in the same publications more frequently. By analyzing the keyword co-occurrence network, we aim to study the main content from the used keywords and portray the current structure of restaurant research. Owing to its high compatibility with the BibExcel tool, the software chosen for constructing this network is the VOSviewer. In this network, the radius of the node corresponds to the number of occurrences of each keyword, while the width of the links reflects the number of times each couple of keywords co-occur in publications. By clustering keywords, it is possible to determine the critical topics addressed in restaurant research. MPA Among various methods of citation-based analysis, we conducted cluster analysis and MPA. For the first, we adopted a keyword co-occurrence analysis. This bibliometric relational technique identifies the keywords used together more frequently in publications. These keywords are set as clusters, and a keyword co-occurrence network visualizes the association between them. The network could provide significant insights into different research foci and distribution of knowledge in a specified field (Börner et al. 2003; Rejeb et al. 2020). MPA can complement cluster analysis by tracing a scientific domain’s knowledge diffusion and research paths. With the application of MPA, we endeavor to efficiently handle a huge number of papers and unearth the interrelationships and knowledge diffusion trajectories in a scientific discipline. Furthermore, we applied MPA because of its capability to identify the mainstream literature and related themes, which entail potential directions for future research (Chuang et al. 2014). MPA also allows researchers to detect the structural backbone of the formation of restaurant research and to estimate the direct and indirect influences of a paper, thereby providing a more accurate estimation of the value of the paper. The detailed information gained from the multiple main paths helps us ascertain the most important themes in the restaurant literature that surface in different periods and how these themes evolved. The restaurant-related topics stem from objective citation relationships among publications, which can more precisely reflect the current state of the restaurant field and eliminate researchers’ interpretations and judgments (Raghuram et al. 2010). By conducting MPA and keyword co-occurrence network analysis, one could identify knowledge divergence, schools of thought, or paradigms and explore current and future trends in a research strand (Rejeb et al. 2022a; Tseng et al. 2021; Xu et al. 2020). Initially introduced by Hummon and Dereian (1989), MPA represents a popular method being adopted by an increasing number of scholars to reveal the outstanding publications that have made major contributions to various domains (Liu et al. 2013). MPA-related studies could be divided into two main strands: the ones that developed the MPA and those that applied MPA in different contexts (Liu et al. 2019). For example, works applying MPA include reviews on corporate social responsibility (Lu and Liu 2014), strategic management (resource-based view) (Lu and Liu 2013), social commerce (Tang 2017), data quality (Xiao et al. 2014), the Internet of Things (IoT) (Fu et al. 2019), blockchain technology (Tseng et al. 2021; Yu and Pan 2021; Yu and Sheng 2021), supply chain bullwhip effect (Yu and Yan 2021) and sustainable technology innovation (Zhang et al. 2020). To explain how MPA works, we presented a simple citation network (see Fig. 2). Consider two publications where one cites another. The publications are called nodes (e.g., A, B, and F), and a link is shaped from cited to citing node (e.g., A-C, A-D, and G-J). Nodes cited by others and do not cite other publications are called sources (e.g., A and B). Meanwhile, nodes not cited and only cite other documents are called sinks (e.g., H, I, and J). Fig. 2  A simple citation network with SPC values Traversal weight is a key concept in MPA. It refers to different methods to assign different values to links. Among various methods such as search path link count (SPLC), search path node pair (SPNP), and node pair projection count (NPPC) (Hummon and Dereian 1989), we applied search path count (SPC) (Batagelj 2003). To determine the SPC value, one should count different paths that traversed the link, starting from a source till reaching a sink. For example, the SPC value of E-J is 2 because two paths are traversing through E-J, namely, A-E-J and B-E-J. The weighted network is extracted by calculating all the SPCs. The next step is to trace the main paths. In our study, we adopted local (forward and backward) main path analysis, global main path analysis, and key-route main path analysis to scrutinize the knowledge structure of restaurant research. These paths complement each other and could not be replaced (Yu and Sheng 2020). While the analysis of local main paths could determine the significant connections, the analysis of the global main path could reveal the path with the highest SPC. Contrary to these paths, the analysis of the key-route main path could extract knowledge divergence-convergence in a research field (Liu et al. 2013; Liu and Lu 2012). To extract the forward local main path, we start with sources and compare their links. Then, the link(s) with the highest SPC are selected, and the nodes at the end of the selected link(s) are considered new starting points. We continue this process until reaching a sink. The resulted path is the forward local main path. In our example, it is presented by solid lines in Fig. 3. Fig. 3 The forward local main path While the forward local main path starts from sources and moves forward to sinks, the backward local main path moves backward from sinks to sources. The first depicts the publications with the most followers, where the latter portrays the ones that have taken the most ideas from previous papers (Liu and Lu 2012). Figure 4 illustrates the backward local main path for our example. Fig. 4 The backward local main path Neither forward nor backward local paths are necessarily the path with the highest SPC value. For this reason, the analysis of the global main path is used to extract the path. The paths with the highest SPC value (24) in our sample are drawn with solid lines in Fig. 5. Fig. 5 The global main path None of the above-mentioned paths necessarily extract all the links with the highest SPCs. Thus, the key-route main path analysis is used starting from the links with the highest SPCs. Then, the path is determined by moving forward till reaching a sink and moving backward till reaching a source (Liu and Lu 2012; Rejeb et al. 2022a, b, c). Figure 6 presents the key-route 2 main paths for our example. 2 refers to choosing 9 and 6 as the two highest SPCs. One could reveal more details by choosing more key-routes. Fig. 6 The key-route 2 main path Results Keyword co-occurrence network results We conducted a keyword co-occurrence network analysis to reveal the various research clusters in restaurant research. This helps us to identify critical research foci that have provided significant contributions to the field. We started by extracting, reviewing, and refining authors’ keywords as the unit of analysis. For example, the full-length keywords were abbreviated and replaced (e.g., Word of Mouth by WoM). To generate the network, we imported the data into the VOSviewer software. Then, we applied density-based spatial clustering using the full counting method, which calculates the total number of occurrences of a keyword in all publications (Kriegel et al. 2011). Unlike the fractional counting method, the full counting method is widely used by researchers due to its intuitiveness and ease of interpretation (Perianes-Rodriguez et al. 2016; Waltman and van Eck 2015). We set the threshold to six keyword occurrences. As a result, a network with six clusters was obtained (see Fig. 7). In the network, each node represents a keyword. The node’s color represents the cluster to which the node has been assigned. The node’s size is proportional to the number of keyword occurrences. Finally, the distance between nodes reveals the density. In other words, the higher the density, the closer the nodes. Furthermore, Table 1 lists the top 10 most frequent keywords in each cluster. Fig. 7 Restaurant research keyword co-occurrence network Table 1 Top 10 most frequent keywords in each cluster Cluster 1 Cluster 2 Cluster 3 Restaurant Customer satisfaction Restaurant industry Consumer behaviour Service quality CSR Hospitality Behavioral intention Franchising Foodservice Satisfaction Firm performance Hotel Emotion Financial performance Tipping Loyalty Restaurant type Innovation Perceived value Internationalization COVID-19 Trust Job satisfaction Tourism Customer loyalty Moderating effect Revenue management Full-service restaurant Casual dining restaurant Cluster 4 Cluster 5 Cluster 6 Restaurant management Green restaurant Authenticity Online review Attitude Ethnic restaurant Social media Theory of planned behavior Brand equity eWoM Restaurant menu Brand loyalty Dining experience Menu labeling Servicescape Restaurant service Green practices Perceived quality Service failure Local food Brand image WoM Gender Brand trust Service recovery Menu design Perceived authenticity Restaurant experience Food choice Advertisement From the figure, we see that the most significant cluster is the red one. It is a generic cluster and indicates the vital importance of consumer behavior in foodservice operations, restaurants, hotels, tourism, and overall hospitality industry research. Consumer behavior constitutes the result of multiple intrinsic and extrinsic factors, such as the motivations of various consumers, food attributes, and the environments where food choices are made (Camillo et al. 2010). In the current cluster, the relationship between consumer behavior and innovation and how they impact one another have attracted scholars’ attention (Laužikas et al. 2015; Torabi Farsani et al. 2016). To offer a positive consumer experience, it is crucial to deploy information and communication technologies (ICT) applications and innovation in the foodservice sector. For example, in the study of Chuah et al. (2021), behavioral intentions are measured in terms of consumers’ innovativeness and willingness to pay more for robotic restaurants. Furthermore, the recent COVID-19 pandemic has significantly influenced consumer behavior and highlighted the role of innovation in ensuring responsiveness and business survival (Hemmington and Neill 2021), enhancing order accuracy, optimizing productivity, and improving customer relationships and satisfaction (Gavilan et al. 2021; Hakim et al. 2021; Linh et al. 2021; Min et al. 2021; Vig and Agarwal 2021). Finally, some researchers in this cluster have investigated the tipping behavior of consumers (Beer and Greitemeyer 2019; Kowalczuk and Gębski 2021; Lynn 2021; Maynard andMupandawana 2009; Seiter et al. 2011, 2016; Thrane and Haugom 2020). The second cluster in green revolves around customer satisfaction. Several researchers have focused on customer satisfaction in the restaurant context (Agrawal and Mittal 2019; Dwaikat et al. 2019; Mannan et al. 2019; Rajput and Gahfoor 2020; Ryu et al. 2008; Xia and Ha 2021). They have also investigated the relationship between customer satisfaction and service quality, emotion, trust, and perceived value and demonstrated how customer satisfaction could shape and impact behavioral intentions and customer loyalty in various types of restaurants, including full-service restaurants (Anggraeni et al. 2020; DiPietro and Levitt 2019; Mursid and Wu 2021; Tuncer et al. 2021). The third cluster in blue emphasizes the importance of the corporate social responsibility (CSR) concept within the restaurant industry. As is the case with other industries, scholars in this field argue that it is not sufficient for restaurants to just maximize their financial performance. Instead, they should address social and environmental concerns as this would positively impact their reputation and enhance their financial performance (Theodoulidis et al. 2017; Yoon and Chung 2018). For example, CSR could positively influence job satisfaction, employee engagement, and, consequently, firm performance (Kim and Kim 2020). Furthermore, scholars have examined the moderating effects of CSR and its relationship with internationalization, franchising, as well as restaurant type and risk (Jung et al. 2018a, b; Bora and Lee 2020). The fourth cluster in yellow is labeled as online reviews, indicating the critical role of social media in customers’ communication and the effects of WoM and eWoM on restaurants’ success or failure. Customers are increasingly sharing their views on restaurant services and experiences. In this cluster, researchers focused on how these shared views impact emotions and intentions (Huifeng and Ha 2021; Oliveira and Casais 2019; Popy and Bappy 2020). In addition, studies sought to answer how restaurants could better exploit positive and negative reviews to make effective recovery strategies after service failures, improve reputation, and enhance social capital and performance (Chang and Cheng 2021; Kim and Velthuis 2021; Micu et al. 2017). The fifth cluster in purple focuses on green restaurants and sustainability. Green restaurants have become widely prevalent due to environmental concerns and consumers’ needs for locally-grown and organic foods (Liu et al. 2020a, b). Unlike traditional restaurants, green restaurants commit efforts to reduce waste, increase water efficiency, and use sustainable furnishings and building materials (Ham and Lee 2011). In general, researchers explored the theme of green restaurants from various perspectives, including customer intentions, restaurant performance, and adoption drivers of green practices (Tehrani et al. 2020; Teng and Wu 2019; TM et al. 2021). Theory of planned behavior seems to be very popular in explaining consumers’ attitudes, intentions and perceptions of the restaurant and the food choice differences between genders, ages, and regions (Jang et al. 2015; Kim et al. 2013; Moon 2021). Moreover, several studies have examined the impacts of green restaurant menus or organic menus on consumer intentions, highlighting menu labeling and design techniques (e.g., information about local foods) as a fundament to persuade consumers to buy green and sustainable foods (Cai et al. 2021; Cerdá Suárez et al. 2018; Shafieizadeh and Tao 2020; Shin et al. 2019). Finally, the last cluster in aqua deals with consumer-brand relationships. The vital role of brands in the restaurant industry has been portrayed by several scholars (Hwang et al. 2011; Jin et al. 2012; Kwon et al. 2020; Lu et al. 2015; Wang and Mattila 2015). The high frequency of the keywords “Authenticity” and “Ethnic Restaurant” indicates the heightened importance of providing an authentic consumer experience and promoting ethnic cuisines. Overall, studies in this cluster have focused on antecedent factors (e.g., servicescape, perceived quality, brand and restaurant experience, and advertisement) that impact consumer behavior and enhance brand-related concepts such as brand trust, brand loyalty, brand equity, brand image, and (perceived) authenticity. While most studies belong to the marketing and sustainability strands, other fields like supply chain management, strategic management, and digital transformation can enrich restaurant research and contribute to this amazing knowledge domain. MPA results We conducted local (forward and backward) main paths analysis, global main path analysis, and key-route main path analysis. These paths reveal the most important trajectories of restaurant research and complement each other. In the figures, each node represents a paper (i.e., unit of analysis) accompanied by the lead author’s name and publication year. The directed links depict the knowledge flow, and their thickness reflects their importance or a higher search path count (SPC) value. Local main paths Figures 8 and 9 present the local main paths, comprising 12 papers and 14 papers, respectively. Overall, the forward and backward local main paths do not share similar papers. Fig. 8 Restaurant research forward local main path Fig. 9 Restaurant research backward local main path It is evident that Caldwell and Hibbert (2002) represents the first article on the forward local main path that marks the initial formation of restaurant research. In this study, the authors have examined different consumer behavior variables, including perceived and actual time spent in the restaurant, money, enjoyment of the experience, and future behavioral intentions. They further explored the impact of music tempo and preference on these variables. Strongly connected to the previous paper, Jang and Namkung (2009) have used the stimulus–organism–response framework to investigate the relationship between perceived quality (product, atmospherics, and service), emotions (positive and negative), and behavioral intentions. Results revealed that restaurateurs should devote more attention to enhancing service quality and atmospherics to create positive emotions and deliver quality products to alleviate customers’ negative emotions. Subsequently, Ha and Jang (2010) explored the impact of perceived service and food quality on customer satisfaction and loyalty and the moderating effect of the perception of atmospherics in Korean restaurants. In an innovative research, Jeong and Jang (2011) scrutinized factors that cause customers to participate in positive eWOM. These factors include service and food quality, atmosphere, and price fairness. Ponnam and Balaji (2014) focused on casual dining restaurants and examined the relationship between visitation motives and restaurant attributes. At this point, authenticity or perceived authenticity has emerged in scholars’ keywords. For example, Lu et al. (2015) examined the relationship between authenticity, brand equity, and brand choice intention. The authors found that consumers’ authenticity perception constitutes a key determinant of brand equity, which considerably impacts consumers’ choice of ethnic restaurants. Youn and Kim (2017) investigated the effects of ingredients, names, and stories about food origins on perceived authenticity and purchase intentions. In the context of independent, full-service mainstream ethnic restaurants, the connections among perceived authenticity, perceived value, perceived quality, and behavioral intentions are examined by Liu et al. (2018). Results revealed that restaurant authenticity positively impacts perceived value and that respondents closely acquainted with Italian culture and food attribute more value to restaurant authenticity. Finally, Chen et al. (2020a) looked into the effects of perceived authenticity on perceived quality, perceived value, and behavioral intentions in a traditional branded restaurant. Two paths have emerged at the extremity of the forward main path analysis. One path contains two papers revolving around nostalgia. For instance, Chen et al. (2020b) examined the role of nostalgia in affecting consumers’ loyalty intentions at traditional Chinese restaurants and found that consumers with nostalgic feelings tend to perceive a higher value of their dining experience, which results in higher loyalty intentions. In a similar vein, Gu et al. (2021) examined the impact of nostalgia-evoking stimuli on customers’ consequent assessment and post-purchase behavioral intention. The authors found that associations between nostalgia stimuli and epistemic, emotional, and nostalgia-seeking benefits were confirmed partially. The other path includes one paper. Building on signaling theory, Song and Kim (2021) explored the relationship between four aspects of time-honored restaurants, which are the restaurants that maintain good social recognition based on their establishment time. In addition, the relationship between brand heritage, brand evaluation, consumer experience, and behavioral outcomes are studied. The above analysis uncovers several findings. First, consumer communication, WOM, and eWOM have a significant role in restaurant success in light of the emergence and enhancement of social media. Second, there is an emphasis on authenticity and its critical importance in brand attributes, consumer satisfaction, and purchasing intentions. Third, recent studies have focused on nostalgia as a psychological need that influences consumer behavior, revisit intention, and brand authenticity. Unlike the previous path, the backward local main path moves backward and starts from sink nodes, which are not cited by other nodes but only cite other nodes in the citation network. By utilizing this variant, we can trace the roots of the latest publications. At the beginning of the backward local main path, three branch trajectories are revealed. In the first trajectory, earlier research on benefit segmentation in the restaurant industry was conducted by Lewis (1981). This research has identified five attributes determining consumer choice, including food quality, menu variety, price, atmosphere, and convenience. Next, Law et al. (2008) explored the perceived importance of attributes related to selecting Hong Kong’s restaurants from the viewpoint of individual visit schemes and packaged travelers from Mainland China. In the second trajectory, Kim and Kim (2005) investigated the role of brand equity in luxury hotels and chain restaurants’ performance, and later, Hyun (2009) developed and tested a customer equity model for chain restaurant brand formation. The third trajectory starts with Ladhari et al. (2008), who explored customer satisfaction with services and its determinants and consequences. Finally, this path continues with Hyun (2010) and converges at Hyun et al. (2011). Focusing on the chain restaurant industry, Hyun (2010) identified food quality, service quality, price, location, and environmental factors impacting customer loyalty formation. Also, the author highlighted the role of these factors in increasing customer satisfaction. In another study, Hyun et al. (2011) examined the relationship between advertising, emotional responses induced by advertising, perceived value, and behavioral intentions. The backward local main path continues with Kim et al. (2012) and Chang (2013), who studied the relationship between brand attitude, utilitarian value, hedonic value, well-being perception, and behavioral intentions for the first, and perceived value, customer satisfaction, and corporate reputation for the latter. Similar to some papers in the forward local main path, the vital role of social media is stressed in the study of Kang et al. (2015). Their research focused on the relationship between members’ participation, monetary sales promotion, and customer-brand relationships in online communications. Following the seminal work of Kang et al. (2015), three reviews appeared: one critical review of restaurant and foodservice research (DiPietro 2017), a systematic review of authenticity in dining restaurants (Le et al. 2019), and a bibliometric analysis of restaurant research (Rodríguez-López et al. 2020). Finally, the last paper in the path has investigated the antecedents and drivers of quality performance based on dynamic capability theory (Liu et al. 2020a). The focus is also placed on micro, small, and medium hotels and restaurants, indicating the importance of small and medium enterprises in economic development. Two new insights could be extracted based on the current analysis. The first is that some researchers in the restaurant industry, in parallel with other marketing scholars, felt the need to incorporate mathematical and financial concepts in marketing and brand management. Furthermore, structured reviews that systematize and summarize the restaurant literature have attracted scholars’ attention. Global main path While the local main paths look for the largest local SPC, the global main path searches for the overall largest SPC. As depicted in Fig. 10, the global main path has four papers in common with the backward local main path and none in common with the forward local main path. Fig. 10 Restaurant research global main path The dominant presence of marketing field research can be inferred from the analysis of the global main path. The papers in the path can be divided into three stages. In the primary stage (1981–2011), initial attempts were made to investigate the restaurant industry from the perspective of consumers’ intention and restaurant selection. The endeavors in this stage continued via addressing the chain restaurant industry utilizing existing and new concepts such as relationship quality, loyalty, emotional responses, and perceived value. The focus of the next stage (2012–2019), which witnessed a plethora of publications, is luxury restaurants. New concepts like brand prestige, price premiums, and willingness to pay emerged. For instance, Hwang and Hyun (2012) underscored the important role of brand prestige in customer satisfaction and positive behavioral intentions in luxury restaurants. The authors explore the factors and consequences influencing brand prestige formation. Furthermore, the influence of environmental and non-environmental cues on emotional responses and consequently on behavioral intentions is studied by Hyun and Kang (2014). Subsequently, Yang and Mattila (2016) were among the first to bring the concept of perceived value in the luxury industry, specifically in hospitality and restaurant research. They also investigated its relationship with purchase intentions. Moving further in this direction, Chen and Peng (2018) analyze this relationship for traveling consumers incorporating the “food image” factor to previous models. In another paper, Kiatkawsin and Han (2019) explored the psychological constructs of willingness to pay in luxury restaurants. Materialism, bandwagon effects, snobbism, and hedonic and gastronomic knowledge were identified as the most critical drivers for paying price premiums. In the last stage (2020–2021), the pandemic crisis, specifically COVID-19, and the need for innovative and socially responsible solutions were highlighted. Although the focus of the first papers is on the vital role of knowledge of luxury gastronomy in enhancing destination attractiveness Batat (2021a), a shift happens in the interest of researchers. As such, a divergence happens at Batat (2021b), who investigated the response strategies of Michelin-starred chefs and the business transformation toward social bricolage entrepreneurial thinking during the COVID-19 pandemic. At the end of the global main path, authors aim to address COVID-19 challenges. For instance, Linh et al. (2021) examined the role of the pandemic in pushing customers toward online purchasing based on self-protective behavior theory. Finally, De Guzman et al. (2021) scrutinized the social responsibility-related initiatives undertaken by chefs during the pandemic. In summary, at the start of the global main path, the link is much denser than the links at the middle and ending of the path, indicating that earlier research has received increased attention while recent research attracts a limited number of citations. Nevertheless, the appearance of those articles at the tail confirms the criticality of the successors in the global main path. The position of recent research has to be evaluated over time as more publications continue to appear. Key-route main path The key-route main path can reveal more details about the historical formation of scholarly restaurant research. To uncover additional insights, this study chooses the number of key-routes with a step size 5 and eventually selects 25. Meanwhile, the local method is used to generate the path. The key-route main path is depicted in Fig. 11, which shows the knowledge structure of restaurant research. This path contains almost all the studies appearing on the local and global main paths, apart from seven new papers marked with aqua color. This section is devoted to the analysis of these papers. Fig. 11 Restaurant research key-route local main path In the first paper, Mattila and Ro (2008) examined customers’ emotional responses after a service failure in a restaurant setting. According to the authors, customers with emotions of anger and disappointment are likely to make different dissatisfaction responses such as negative word-of-mouth, direct complaining, and switching. However, worried customers do not usually do the same. In general, customer satisfaction or dissatisfaction results from the interaction process between restaurant employees and customers. For example, the friendliness and attitude of employees may be closely related to customer satisfaction with foodservice. Therefore, restaurant managers should understand customers’ perception processes regarding emotion and cognition (Kim and Moon 2009). Inspecting the knowledge structure, Mattila and Ro (2008) and Kim and Moon (2009) merge in Liu and Jang (2009), who explored the relationships among dining atmospherics, emotional responses, perceived value, and behavioral intentions in the context of Chinese restaurants. It is argued that dining atmospherics influence customer positive emotions, negative emotions, and perceived value. Furthermore, Liu and Jang (2009) investigated customers’ perceptions of Chinese restaurants in the United States using the Importance-Performance Analysis (IPA) approach. Findings revealed that environmental cleanliness and attentive service are two critical areas wherein Chinese managers can enhance their restaurants. The next two papers, Ryu and Han (2011) and Ryu et al. (2012), investigated the role of the physical environment in shaping customers’ experience in restaurants. Finally, Ha and Jang (2013) identified consumer-dining values for each restaurant segment using a means-end approach and found that convenience, success, and economic values are largely associated with fast-food restaurants. In contrast, casual dining restaurants offer emotional and belonging values. Fine dining restaurants are also found to be strongly linked to emotion and quality life values. Discussion This study aims to analyze the critical topics in the restaurant domain using a keyword co-occurrence network and an MPA citation network of a total of 1489 articles in the restaurant literature. Drawing on the largest subnetwork, several paths are generated to reveal the knowledge flows of the restaurant field from various perspectives. The historical formation of this research field has been vividly illustrated based on the study of the forward and backward local main paths. Moreover, the global main path was applied to determine the most significant path, while the key-route main path was used to reveal the complex knowledge structure of restaurant research. The analysis of the keyword co-occurrence network and the MPA leads to several findings, which can be presented along these lines: The analysis of the keyword co-occurrence network shows that restaurant research has focused on multiple foci, including consumer behavior, consumer satisfaction, social media, green restaurants, and authenticity. Research about consumer behavior occupies a high percentage. As a dynamic interaction of cognition, emotion, and physical activities, consumer behavior attracted significant attention in the past years due to the competitive nature of the restaurant industry. Related keywords to consumer behavior include tipping, behavioral intention, satisfaction, emotion, perceived value, etc. Given the importance of customer satisfaction in the restaurant industry, studies about the determinants of good consumer experience, customer loyalty, revisit intention, and positive word of mouth have captured scholars’ interest. Recently, the restaurant industry has been hit severely by the COVID-19 pandemic. This was triggered mainly by public concern, lockdowns, and social distancing requirements. The pandemic has changed the way restaurants used to conduct their day-to-day operations and led to enormous declines in sales, layoffs, and disruptions. The analysis of the four main paths confirms that consumer behavior has been the mainstream topic over the past decades. In the forward local main path, papers tend to focus on consumer behavior variables (e.g., purchase intention, consumer-brand relationship, attitudes, choice criteria). Research also concentrated on the impact of service quality, atmospherics, e-WOM, and authenticity. Papers at the end of the path researched the concept of nostalgia as an essential component in experiential consumer contexts. Unlike the forward local main path, the backward local main path reveals several papers examining the determinants of consumer choice, including food quality, menu variety, price, atmosphere, and convenience. Brand equity has also been a source of interest for scholars since it enables restaurant managers to improve customer satisfaction and retention. This study has several findings on the global main path. For instance, Lewis (1981) and Law et al. (2008), as the two articles on the beginning of the path, studied benefit segmentation and restaurant selection in the foodservice industry. Second, most of the articles on the path are devoted to examining relationship quality, loyalty, and emotional responses. In addition, researchers increasingly focused on luxury restaurants suggesting that this type of service provides customers with high-quality products that bring a high perception of the quality of life. In essence, the high quality of services and products in luxury restaurants offers consumers trust, which leads to savings in information costs. Furthermore, scholars have looked at the impact of the COVID-19 pandemic on the performance of restaurants. Understanding this topic will evoke managers’ attention to implement innovative and socially responsible solutions to improve customer satisfaction and motivate future visitation. Finally, the new papers on the key-route main path predominately focus on customers’ emotional responses to the physical environment and dining atmospherics. The research focus has shifted from traditional restaurants to luxury restaurants as customers become demanding and expect superior and exceptional restaurant services. In this regard, restaurants are regarded as places where consumers enjoy high-quality food and services that lend an increased perception of prestige, comfort, and quality of life. Recently, COVID-19 has stressed the importance of hygiene and sanitation for customers searching for risk-free food consumption and restaurant experience. Finally, the success of restaurants has been attributed to several factors. First, most studies have emphasized the role of consumer communication, WOM, and eWOM to shape consumer experiences and increase purchase intentions. Second, the mounting demand for authenticity has resulted in substantial research that has associated restaurant aspects with restaurant authenticity and further related authenticity perceptions to customer satisfaction and revisit intentions. Recent literature has also linked nostalgia to consumer behavior, return intentions, and brand authenticity. This line of research has shown that the attraction of restaurants stems mainly from their capability to evoke nostalgia or memories and use them to improve business revenues and profits. Future research directions Based on the previous discussions, this study suggests several future research directions. There is a need to integrate several theories and grasp the decision-making process customers engage in when selecting restaurants that have experienced the effects of the COVID-19 pandemic. Therefore, the current predictors of customer behavior may not be comprehensive. Future studies may build on other theories and examine factors to explain customer behavior by including other constructs such as culture, target groups, and restaurant type. Future research can focus on customers’ attitudes, perceptions, and behavior toward CSR initiatives in restaurants. For example, whether perceived CSR increases behavioral intentions of eliminating food waste remains understudied. Additionally, customer response to food waste prevention in restaurants should be evaluated, particularly for customers with higher levels of socially responsible consumption. Online reviews represent vital decision support within consumers’ purchase decision-making processes in the restaurant industry (Fernandes et al. 2021; Lee and Kim 2020; Mejia et al. 2019). For example, Dixit et al. (2019) noted that the relevance of online reviews in the restaurant industry is substantiated by the fact that more than 75% of readers of online reviews from a sample of 2000 adults in the US reported that reviews significantly influenced their purchase decisions. Zhang et al. (2010) also noted that the volume of online reviews was positively related to restaurants’ online popularity. Accordingly, increased attention is required to study the determinants of the perceived usefulness of consumer-generated online reviews and their influence on consumer purchase and revisit decisions. Furthermore, a pending research question is how online reviews can reflect the current quality of restaurant products and services. Online reviews are expected to improve customer awareness of reviewed restaurants and decrease the perceived risk of information asymmetry. As a result, studies on the ways and techniques to ensure the credibility of online reviews are necessary to help restaurant managers understand their customers and enhance their performance. Even though green restaurants are increasing in number, research on such a type of restaurants largely remains scarce (Hwang and Lee 2019). Therefore, proposed potential avenues of future research include exploring how green restaurants can compete competitively with traditional restaurants while being affordable for the guests. Little research has been conducted to study the relationship between perceptions of restaurant authenticity and customer satisfaction. Consequently, the investigation of how perceptions of restaurant authenticity can impact customer satisfaction is encouraged as customers tend to attach importance to food-related features of restaurant authenticity (de Vries and Go 2017). Therefore, future studies should examine the impact of essential and peripheral features of authenticity on customer satisfaction and restaurant performance. Recently, the COVID-19 pandemic has remarkably affected the foodservice industry. The pandemic compels restaurant managers and operators to adopt practices that reduce frontline employees’ concerns and fears during crises to allay their feelings of job insecurity and emotional exhaustion (Chen and Eyoun 2021). From the consumer perspective, the fear of infection has led to substitute restaurant experiences with at-home consumption (Kim et al. 2021). While such circumstances constitute an opportunity for restaurateurs to increase their delivery and pick-up services, there is also a potential to integrate new technologies like service robots to maintain their conventional ways of delivering restaurant services and replace frontline employees. Hence, future research should be devoted to clarifying the role of emerging technologies such as big data, blockchain, drones, and artificial intelligence in increasing restaurant resilience against disruptions and disastrous events. Of additional interest is assessing how to engage consumers in technology-driven restaurant services. Empirical studies are also imperative to better understand the factors that enable or hinder the adoption of new technologies during crises caused by pandemics. Conclusions The restaurant industry plays a critical role in the economy. Recently, restaurant research has gained significant interest from both researchers and practitioners. On the basis of 1489 articles extracted from the WoSCC, this study employs two quantitative approaches, namely a keyword co-occurrence network analysis and MPA to reveal the core topics and the influential publications that make impactful contributions to restaurant research and the knowledge transmission structure and patterns over the past five decades with the support of different main paths, including the local (forward and backward), global, and key-route main paths. The clusters of the keyword co-occurrence network show that consumer behavior is the most critical theme in the restaurant literature. The local main path comprehensively portrays the restaurant domain’s dynamic formation, indicating that the scholarly focus has been moved from traditional restaurants to luxury and ethnic restaurants over the study period. The analysis of the global main shows that the links from Lewis (1981) to Law et al. (2008) and Hyun and Kang (2014) to Yang and Mattila (2016) have the highest SCP values, which are the most critical links in the development of restaurant research. Moreover, the analysis of the key-route main path shows the knowledge transmission trajectories contributing to this domain more comprehensively. To the best of authors’ knowledge, no studies have combined keyword co-occurrence network and MPA to examine the knowledge dissemination trajectories of the whole restaurant field. The analysis of different main paths reveals a clear picture of the dynamic formation process from different perspectives, which provides profound insights for scholars to improve their comprehension of the initiation of restaurant research over the past decades. Unlike conventional review methods and bibliometric studies, this study provides novel ideas for analyzing the restaurant literature. On the one hand, MPA aids scholars in determining the most critical activities in developing the restaurant domain and unearthing its knowledge flows comprehensively and systematically. Furthermore, some future research directions are suggested to enrich existing restaurant research. Despite its contributions, this study has some limitations. First, we relied only on one academic database to extract the articles. As a result, relevant publications not indexed in this database may be omitted from the analysis. Thus, the findings of the MPA may change as more articles are indexed in other databases. In this work, the keywords were searched in the title and keywords fields. Therefore, future studies may replicate the search query considering the abstract field to capture any potentially relevant but missing publications. Similarly, the results may not entirely uncover the formation of the whole restaurant domain. While the four main paths unearth the knowledge transmission trajectories from diverse perspectives, some relevant publications may not be discussed in this work. In other words, the MPA presents some limited research works, which cannot offer enough information on the full evolution process of the restaurant domain. Therefore, how to extract suitable data and apply a proper method to explain the comprehensive progress of this academic discipline can be considered in future works. Second, this study does not consider the difference in terms of importance between the citing articles and the cited articles. Therefore, the importance of the articles included in the citation network should be considered in future studies. Finally, we limited articles to English and some specific subject areas, which implies that some important research papers in other languages and from different subject areas are not included in this analysis. Future research may combine databases and articles published in different languages to test the robustness of our results. Appendix 1 Search query: TI=(restaurant*) OR AK=(restaurant*)) AND LANGUAGE: (English) AND DOCUMENT TYPES: (Article OR Review) Refined by: WEB OF SCIENCE CATEGORIES: ( HOSPITALITY LEISURE SPORT TOURISM OR MANAGEMENT OR BUSINESS OR OPERATIONS RESEARCH MANAGEMENT SCIENCE ) Timespan: All years. Indexes: SCI-EXPANDED, SSCI, A&HCI, ESCI. Declarations Conflict of interest The authors have no conflict of interest to declare. All co-authors have seen and agree with the contents of the manuscript and there is no financial interest to report. We certify that the submission is original work and is not under review at any other publication. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ==== Refs References Abdollahi A Rejeb K Rejeb A Mostafa MM Zailani S Wireless Sensor networks in agriculture: insights from bibliometric analysis Sustainability 2021 13 21 12011 10.3390/su132112011 Agrawal SR Mittal D How Does Transparency Complement Customer Satisfaction and Loyalty in the Restaurant Business? Global Bus. Rev. 2019 20 6 1423 1444 10.1177/0972150919848935 Alnajem M Mostafa MM ElMelegy AR Mapping the first decade of circular economy research: a bibliometric network analysis J. Industrial Prod. Eng. 2021 38 1 29 50 10.1080/21681015.2020.1838632 Anggraeni A Sulistyo LIH Affandy N The antecedents of satisfaction and revisit intention for full-service restaurants: an empirical study of the food and beverage industry in Jakarta Int. J. Asian Bus. Inform. Manage. (IJABIM) 2020 11 3 101 118 Batagelj, V.: Efficient algorithms for citation network analysis. arXiv preprint cs/0309023 (2003) Batat W The role of luxury gastronomy in culinary tourism: an ethnographic study of Michelin-starred restaurants in France Int. J. Tourism Res. 2021 23 2 150 163 Beer A Greitemeyer T The effects of background music on tipping behavior in a restaurant: A field study Psychol. Music 2019 47 3 444 450 10.1177/0305735618755887 Börner K Chen C Boyack KW Visualizing knowledge domains Ann. Rev. Inf. Sci. Technol. 2003 37 1 179 255 Cai, C.H., Ding, A., Legendre, T.S.: Exploring persuasive sales techniques to improve customer acceptance of sustainable but unfamiliar menu in restaurants. Int. J. Contemp. Hosp. Manage. (2021) Caldwell C Hibbert SA The influence of music tempo and musical preference on restaurant patrons’ behavior Psychol. Mark. 2002 19 11 895 917 Camillo A Kim WG Moreo PJ Ryan B A model of historical development and future trends of Italian cuisine in America Int. J. Hospitality Manage. 2010 29 4 549 558 10.1016/j.ijhm.2009.09.002 Cerdá Suárez, L.M., Ramírez, R., Palos Sánchez, P.R.: The influence of health and environment-focused values on restaurateur satisfaction in organic restaurants: a descriptive analysis in Spain. (2018) Chang, K.-C.: How reputation creates loyalty in the restaurant sector. Int. J. Contemp. Hosp. Manage. (2013) Chang K-C Cheng Y-S How online service recovery reviews influence behavioral intentions in the hospitality context: Regulatory focus and loss aversion perspectives J. Hospitality Tourism Manage. 2021 46 440 455 Chen A Peng N Examining consumers’ intentions to dine at luxury restaurants while traveling Int. J. Hospitality Manage. 2018 71 59 67 Chen H Eyoun K Do mindfulness and perceived organizational support work? Fear of COVID-19 on restaurant frontline employees’ job insecurity and emotional exhaustion Int. J. Hospitality Manage. 2021 94 102850 10.1016/j.ijhm.2020.102850 Chen Q Huang R Hou B Perceived authenticity of traditional branded restaurants (China): impacts on perceived quality, perceived value, and behavioural intentions Curr. Issues Tourism 2020 23 23 2950 2971 Chen Q Huang R Zhang A A bite of nostalgia: The influence of nostalgia in consumers’ loyalty intentions at traditional restaurants J. Hospitality Tourism Manage. 2020 45 604 614 Chuah SH-W Aw EC-X Cheng C-F A silver lining in the COVID-19 cloud: examining customers’ value perceptions, willingness to use and pay more for robotic restaurants J. Hospitality Mark. Manage. 2021 0 0 1 28 10.1080/19368623.2021.1926038 Chuang TC Liu JS Lu LYY Lee Y The main paths of medical tourism: From transplantation to beautification Tour. Manag. 2014 45 49 58 10.1016/j.tourman.2014.03.016 De Guzman, A.B., Mesana, J.C.B., Roman, J.A.M.: Examining Chefs’ Social Responsibility (CSR) during the COVID-19 pandemic. Anatolia,1–11. (2021) de Vries HJ Go FM Developing a common standard for authentic restaurants Serv. Ind. J. 2017 37 15–16 1008 1028 10.1080/02642069.2017.1373763 Denizci Guillet B Mohammed I Revenue management research in hospitality and tourism: A critical review of current literature and suggestions for future research Int. J. Contemp. Hospitality Manage. 2015 27 4 526 560 10.1108/IJCHM-06-2014-0295 DiPietro, R.: Restaurant and foodservice research: A critical reflection behind and an optimistic look ahead. Int. J. Contemp. Hosp. Manage. (2017) DiPietro RB Levitt J Restaurant authenticity: factors that influence perception, satisfaction and return intentions at regional American-style restaurants Int. J. Hosp. Tour. Adm. 2019 20 1 101 127 Dixit S Jyoti Badgaiyan A Khare A An integrated model for predicting consumer’s intention to write online reviews J. Retailing Consumer Serv. 2019 46 112 120 10.1016/j.jretconser.2017.10.001 Dwaikat NY Khalili SA Hassis SM Mahmoud HS Customer Satisfaction Impact on Behavioral Intentions: The Case of Pizza Restaurants in Nablus City J. Qual. Assur. Hospitality Tourism 2019 20 6 709 728 10.1080/1528008X.2019.1616040 Fernandes E Moro S Cortez P Batista F Ribeiro R A data-driven approach to measure restaurant performance by combining online reviews with historical sales data Int. J. Hospitality Manage. 2021 94 102830 10.1016/j.ijhm.2020.102830 Ferreira M Pinto CF Serra FR The transaction costs theory in international business research: a bibliometric study over three decades Scientometrics 2014 98 3 1899 1922 Fu H Wang M Li P Jiang S Hu W Guo X Cao M Tracing knowledge development trajectories of the internet of things domain: A main path analysis IEEE Trans. Industr. Inf. 2019 15 12 6531 6540 Gao C Ruan T Bibliometric analysis of global research progress on coastal flooding 1995–2016 Chin. Geogra. Sci. 2018 28 6 998 1008 10.1007/s11769-018-0996-9 Gavilan D Balderas-Cejudo A Fernández-Lores S Martinez-Navarro G Innovation in online food delivery: Learnings from COVID-19 Int. J. Gastronomy Food Sci. 2021 24 100330 10.1016/j.ijgfs.2021.100330 Gu Q Li M Kim SS The role of nostalgia-evoking stimuli at nostalgia-themed restaurants in explaining benefits, consumption value and post-purchase behavioral intention Int. J. Hospitality Manage. 2021 96 102955 Ha J Jang SS Effects of service quality and food quality: The moderating role of atmospherics in an ethnic restaurant segment Int. J. Hospitality Manage. 2010 29 3 520 529 Ha J Jang S Shawn Attributes, consequences, and consumer values: A means-end chain approach across restaurant segments Int. J. Contemp. Hospitality Manage. 2013 25 3 383 409 10.1108/09596111311311035 Hakim MP Zanetta LD da Cunha DT Should I stay, or should I go? Consumers’ perceived risk and intention to visit restaurants during the COVID-19 pandemic in Brazil Food Res. Int. 2021 141 110152 33642018 Ham S Lee S US Restaurant Companies’ Green Marketing via Company Websites: Impact on Financial Performance Tour. Econ. 2011 17 5 1055 1069 10.5367/te.2011.0066 Hemmington, N., Neill, L.: Hospitality business longevity under COVID-19: The impact of COVID-19 on New Zealand’s hospitality industry. Tour. Hosp. Res. 1467358421993875 (2021). 10.1177/1467358421993875 Hernández JB Chalela S Arias JV Arias AV Research trends in the study of ICT based learning communities: a bibliometric analysis Eurasia J. Math. Sci. Technol. Educ. 2017 13 5 1539 1562 10.12973/eurasia.2017.00684a Huifeng, P., Ha, H.-Y.: Temporal effects of online customer reviews on restaurant visit intention: the role of perceived risk.Journal of Hospitality Marketing & Management,1–20. (2021) Hummon NP Dereian P Connectivity in a citation network: The development of DNA theory Social networks 1989 11 1 39 63 Hwang J Hyun SS The antecedents and consequences of brand prestige in luxury restaurants Asia Pac. J. Tourism Res. 2012 17 6 656 683 Hwang J Yoon Y-S Park N-H Structural effects of cognitive and affective reponses to web advertisements, website and brand attitudes, and purchase intentions: The case of casual-dining restaurants Int. J. Hospitality Manage. 2011 30 4 897 907 Hwang K Lee B Pride, mindfulness, public self-awareness, affective satisfaction, and customer citizenship behaviour among green restaurant customers Int. J. Hospitality Manage. 2019 83 169 179 10.1016/j.ijhm.2019.05.009 Hyun SS Creating a model of customer equity for chain restaurant brand formation Int. J. Hospitality Manage. 2009 28 4 529 539 Hyun SS Predictors of relationship quality and loyalty in the chain restaurant industry Cornell Hospitality Quarterly 2010 51 2 251 267 Hyun SS Kang J A better investment in luxury restaurants: environmental or non-environmental cues? Int. J. Hospitality Manage. 2014 39 57 70 Hyun SS Kim W Lee MJ The impact of advertising on patrons’ emotional responses, perceived value, and behavioral intentions in the chain restaurant industry: The moderating role of advertising-induced arousal Int. J. Hospitality Manage. 2011 30 3 689 700 Jang SS Namkung Y Perceived quality, emotions, and behavioral intentions: Application of an extended Mehrabian–Russell model to restaurants J. Bus. Res. 2009 62 4 451 460 Jang SY Chung JY Kim YG Effects of environmentally friendly perceptions on customers’ intentions to visit environmentally friendly restaurants: An extended theory of planned behavior Asia Pac. J. Tourism Res. 2015 20 6 599 618 Jeong E Jang SS Restaurant experiences triggering positive electronic word-of-mouth (eWOM) motivations Int. J. Hospitality Manage. 2011 30 2 356 366 Jin N Lee S Huffman L Impact of restaurant experience on brand image and customer loyalty: Moderating role of dining motivation J. Travel Tourism Mark. 2012 29 6 532 551 Jung, S.Y., Dalbor, M., Lee, S.: Internationalization as a determinant of systematic risk: the role of restaurant type. Int. J. Contemp. Hosp. Manag. (2018a) Jung S Kim JH Kang KH Kim B Internationalization and corporate social responsibility in the restaurant industry: Risk perspective J. Sustainable Tourism 2018 26 7 1105 1123 Kang, J., Tang, L.R., Fiore, A.M.: Restaurant brand pages on Facebook: do active member participation and monetary sales promotions matter? Inte. J. Contemp. Hosp. Manage. (2015) Kiatkawsin K Han H What drives customers’ willingness to pay price premiums for luxury gastronomic experiences at michelin-starred restaurants? Int. J. Hospitality Manage. 2019 82 209 219 Kim, B., Velthuis, O.: From reactivity to reputation management: online consumer review systems in the restaurant industry. J. Cult. Econ. 1–19. (2021) Kim B Lee S The impact of material and immaterial sustainability on firm performance: The moderating role of franchising strategy Tour. Manag. 2020 77 103999 Kim H Kim WG The relationship between brand equity and firms’ performance in luxury hotels and chain restaurants Tour. Manag. 2005 26 4 549 560 Kim, I., Jeon, S.M., Hyun, S.S.: Chain restaurant patrons’ well-being perception and dining intentions: the moderating role of involvement. Int. J. Contemp. Hosp. Manage. (2012) Kim J Kim J Wang Y Uncertainty risks and strategic reaction of restaurant firms amid COVID-19: Evidence from China Int. J. Hospitality Manage. 2021 92 102752 10.1016/j.ijhm.2020.102752 Kim, M., Kim, J.: Corporate social responsibility, employee engagement, well-being and the task performance of frontline employees. Manage. Decis. (2020) Kim WG Moon YJ Customers’ cognitive, emotional, and actionable response to the servicescape: A test of the moderating effect of the restaurant type Int. J. Hospitality Manage. 2009 28 1 144 156 10.1016/j.ijhm.2008.06.010 Kim YJ Njite D Hancer M Anticipated emotion in consumers’ intentions to select eco-friendly restaurants: Augmenting the theory of planned behavior Int. J. Hospitality Manage. 2013 34 255 262 Kowalczuk, I., Gębski, J.: Factors influencing restaurant tipping behaviour–the case of Poland. Int. J. Cult. Tour. Hosp. Res. (2021) Kriegel H-P Kröger P Sander J Zimek A Density-based clustering Wiley Interdisciplinary Reviews: Data Mining and Knowledge Discovery 2011 1 3 231 240 Kwon, J.-H., Jung, S.-H., Choi, H.-J., Kim, J.: Antecedent factors that affect restaurant brand trust and brand loyalty: focusing on US and Korean consumers. J. Product Brand Manage. (2020) Ladhari R Brun I Morales M Determinants of dining satisfaction and post-dining behavioral intentions Int. J. Hospitality Manage. 2008 27 4 563 573 Laužikas M Tindale H Tranavičius L Kičiatovas E Effects of consumer behaviour on innovations in fast food industry Entrepreneurship and Sustainability Issues 2015 3 1 85 Law R To T Goh C How do Mainland Chinese travelers choose restaurants in Hong Kong?: An exploratory study of individual visit scheme travelers and packaged travelers Int. J. Hospitality Manage. 2008 27 3 346 354 Le TH Arcodia C Novais MA Kralj A What we know and do not know about authenticity in dining experiences: A systematic literature review Tour. Manag. 2019 74 258 275 Lee J Kim Y-K Online Reviews of Restaurants: Expectation-Confirmation Theory J. Qual. Assur. Hospitality Tourism 2020 21 5 582 599 10.1080/1528008X.2020.1712308 Lee P-C Su H-N Investigating the structure of regional innovation system research through keyword co-occurrence and social network analysis Innovation 2010 12 1 26 40 10.5172/impp.12.1.26 Lewis RC Restaurant advertising-appeals and consumers intentions J. advertising Res. 1981 21 5 69 74 Line ND Runyan RC Hospitality marketing research: Recent trends and future directions Int. J. Hospitality Manage. 2012 31 2 477 488 10.1016/j.ijhm.2011.07.006 Linh DH Dung ND Son HN Kingsbury A The Responses of Consumers to the Online Ordering and Delivery of Meals by Restaurants During COVID-19: A Case Study of Thai Nguyen City, Vietnam J. Electron. Commer. Organ. (JECO) 2021 19 3 65 84 Liu, H., Li, H., DiPietro, R.B., Levitt, J.A.: The role of authenticity in mainstream ethnic restaurants: evidence from an independent full-service Italian restaurant. Int. J. Contemp. Hosp. Manag. (2018) Liu JS Lu LY An integrated approach for main path analysis: Development of the Hirsch index as an example J. Am. Soc. Inform. Sci. Technol. 2012 63 3 528 542 Liu JS Lu LY Ho MH-C A few notes on main path analysis Scientometrics 2019 119 1 379 391 Liu JS Lu LY Lu W-M Lin BJ Data envelopment analysis 1978–2010: A citation-based literature survey Omega 2013 41 1 3 15 Liu, J.-M., Borazon, E.Q., Santamaria, J.G.O.: Antecedents of quality performance in the Philippine micro, small, and medium hospitality sector. Asia Pac. Bus. Rev. 1–24 (2020a) Liu K-N Hu C Lin M-C Tsai T-I Xiao Q Brand knowledge and non-financial brand performance in the green restaurants: Mediating effect of brand attitude Int. J. Hospitality Manage. 2020 89 102566 10.1016/j.ijhm.2020.102566 Liu, Y., Jang, S.: (Shawn). The effects of dining atmospherics: an extended Mehrabian–Russell model. Int. J. Hosp. Manage. 28(4), 494–503. (2009a). 10.1016/j.ijhm.2009.01.002 Liu, Y., Jang, S., Shawn, the U.S.:). Perceptions of Chinese restaurants in : What affects customer satisfaction and behavioral intentions?. Int. J. Hosp. Manage. 28(3, 338–348. (2009b). 10.1016/j.ijhm.2008.10.008 Lu ACC Gursoy D Lu CY Authenticity perceptions, brand equity and brand choice intention: The case of ethnic restaurants Int. J. Hospitality Manage. 2015 50 36 45 Lu LY Liu JS An innovative approach to identify the knowledge diffusion path: the case of resource-based theory Scientometrics 2013 94 1 225 246 Lu LY Liu JS The knowledge diffusion paths of corporate social responsibility–from 1970 to 2011 Corp. Soc. Responsib. Environ. Manag. 2014 21 2 113 128 Lynn M Effects of the Big Five personality traits on tipping attitudes, motives, and behaviors Int. J. Hospitality Manage. 2021 92 102722 Mannan M Chowdhury N Sarker P Amir R Modeling customer satisfaction and revisit intention in Bangladeshi dining restaurants J. Modelling Manage. 2019 14 4 922 947 10.1108/JM2-12-2017-0135 Mattila AS Ro H Discrete Negative Emotions and Customer Dissatisfaction Responses in a Casual Restaurant Setting J. Hospitality Tourism Res. 2008 32 1 89 107 10.1177/1096348007309570 Maynard LJ Mupandawana M Tipping behavior in Canadian restaurants Int. J. Hospitality Manage. 2009 28 4 597 603 10.1016/j.ijhm.2009.03.011 Mejia J Mankad S Gopal A A for Effort? Using the Crowd to Identify Moral Hazard in New York City Restaurant Hygiene Inspections Inform. Syst. Res. 2019 30 4 1363 1386 10.1287/isre.2019.0866 Micu A Micu AE Geru M Lixandroiu RC Analyzing user sentiment in social media: Implications for online marketing strategy Psychol. Mark. 2017 34 12 1094 1100 Min, J., Yang, K., Kim, J.: The role of perceived vulnerability in restaurant customers’ co-creation behavior and repatronage intention during the COVID-19 pandemic. J. Vacat. Market.,13567667211014932. (2021) Moon S-J Investigating beliefs, attitudes, and intentions regarding green restaurant patronage: An application of the extended theory of planned behavior with moderating effects of gender and age Int. J. Hospitality Manage. 2021 92 102727 Mostafa MM A knowledge domain visualization review of thirty years of halal food research: Themes, trends and knowledge structure Trends Food Sci. Technol. 2020 99 660 677 10.1016/j.tifs.2020.03.022 Mursid, A., Wu, C.H.-J.: Halal company identity and halal restaurant loyalty: the role of customer satisfaction, customer trust and customer-company identification. J. Islam. Market. (2021) Oliveira, B., Casais, B.: The importance of user-generated photos in restaurant selection. J. Hosp. Tour. Technol. (2019) Perianes-Rodriguez A Waltman L van Eck NJ Constructing bibliometric networks: A comparison between full and fractional counting J. Informetrics 2016 10 4 1178 1195 10.1016/j.joi.2016.10.006 Ponnam A Balaji MS Matching visitation-motives and restaurant attributes in casual dining restaurants Int. J. Hospitality Manage. 2014 37 47 57 Popy, N.N., Bappy, T.A.: Attitude toward social media reviews and restaurant visit intention: a Bangladeshi perspective.South Asian J. Bus. Stud. (2020) Raghuram S Tuertscher P Garud R Research Note—Mapping the Field of Virtual Work: A Cocitation Analysis Inform. Syst. Res. 2010 21 4 983 999 10.1287/isre.1080.0227 Rajput A Gahfoor RZ Satisfaction and revisit intentions at fast food restaurants Future Bus. J. 2020 6 1 13 10.1186/s43093-020-00021-0 Rejeb A Rejeb K Abdollahi A Zailani S Iranmanesh M Ghobakhloo M Digitalization in Food Supply Chains: A Bibliometric Review and Key-Route Main Path Analysis Sustainability 2022 14 1 83 10.3390/su14010083 Rejeb A Rejeb K Zailani S Are Halal Food Supply Chains Sustainable: A Review And Bibliometric Analysis J. Foodserv. Bus. Res. 2021 24 5 554 595 10.1080/15378020.2021.1883214 Rejeb, A., Rejeb, K., Zailani, S., Kayikci, Y.: Knowledge diffusion of halal food research: a main path analysis. J. Islamic Market. (2022b). 10.1108/JIMA-07-2021-0229 Rejeb A Suhaiza Z Rejeb K Seuring S Treiblmaier H The Internet of Things and the circular economy: a systematic literature review and research agenda J. Clean. Prod. 2022 350 131439 10.1016/j.jclepro.2022.131439 Rejeb A Treiblmaier H Rejeb K Zailani S Blockchain research in healthcare: a bibliometric review and current research trends J. Data Inform. Manage. 2021 3 2 109 124 10.1007/s42488-021-00046-2 Rejeb, M.A., Simske, S., Rejeb, K., Treiblmaier, H., Zailani, S.: Internet of Things research in supply chain management and logistics: a bibliometric analysis Internet of Things,100318. (2020) Rivera MA Pizam A Advances in hospitality research: “from Rodney Dangerfield to Aretha Franklin Int. J. Contemp. Hospitality Manage. 2015 27 3 362 378 10.1108/IJCHM-03-2014-0146 Rodríguez-López ME Alcántara-Pilar JM Barrio-García D Muñoz-Leiva F A review of restaurant research in the last two decades: A bibliometric analysis Int. J. Hospitality Manage. 2020 87 102387 Ryu K Han H New or repeat customers: How does physical environment influence their restaurant experience? Int. J. Hospitality Manage. 2011 30 3 599 611 10.1016/j.ijhm.2010.11.004 Ryu K Han H Kim T-H The relationships among overall quick-casual restaurant image, perceived value, customer satisfaction, and behavioral intentions Int. J. Hospitality Manage. 2008 27 3 459 469 10.1016/j.ijhm.2007.11.001 Ryu K Lee H Gon Kim W The influence of the quality of the physical environment, food, and service on restaurant image, customer perceived value, customer satisfaction, and behavioral intentions Int. J. Contemp. Hospitality Manage. 2012 24 2 200 223 10.1108/09596111211206141 Seiter JS Brownlee GM Sanders M Persuasion by Way of Example: Does Including Gratuity Guidelines on Customers’ Checks Affect Restaurant Tipping Behavior? J. Appl. Soc. Psychol. 2011 41 1 150 159 10.1111/j.1559-1816.2010.00706.x Seiter JS Givens KD Weger H The Effect of Mutual Introductions and Addressing Customers by Name on Tipping Behavior in Restaurants J. Hospitality Mark. Manage. 2016 25 5 640 651 10.1080/19368623.2015.1040140 Shafieizadeh K Tao C-WW How does a menu’s information about local food affect restaurant selection? The roles of corporate social responsibility, transparency, and trust J. Hospitality Tourism Manage. 2020 43 232 240 Shin YH Im J Jung SE Severt K Motivations behind consumers’ organic menu choices: the role of environmental concern, social value, and health consciousness J. Qual. Assur. Hospitality Tourism 2019 20 1 107 122 Sixto-Costoya A Castelló-Cogollos L Aleixandre-Benavent R Valderrama-Zurián JC Global scientific production regarding behavioral addictions: An analysis of the literature from 1995 to 2019 Addict. Behav. Rep. 2021 14 100371 10.1016/j.abrep.2021.100371 34938832 Song, H., Kim, J.-H.: Developing a brand heritage model for time-honoured brands: extending signalling theory.Curr. Issues in Tourism 1–18 (2021) Tang, K.-Y.: The development of social commerce research: a main path analysis of the literature (pp.&nbsp;1–5). Presented at the 2017 Portland International Conference on Management of Engineering and Technology (PICMET), IEEE. (2017) Tehrani M Fulton L Schmutz B Green cities and waste management: The restaurant industry Sustainability 2020 12 15 5964 Teng, Y.-M., Wu, K.-S.: Sustainability development in hospitality: the effect of perceived value on customers’ green restaurant behavioral intention. Sustainability, 11(7), 1987. (2019) Theodoulidis B Diaz D Crotto F Rancati E Exploring corporate social responsibility and financial performance through stakeholder theory in the tourism industries Tour. Manag. 2017 62 173 188 Thrane C Haugom E Peer effects on restaurant tipping in Norway: An experimental approach J. Econ. Behav. Organ. 2020 176 244 252 10.1016/j.jebo.2020.04.010 TM A Kaur P Ferraris A Dhir A What motivates the adoption of green restaurant products and services? A systematic review and future research agenda Bus. Strategy Environ. 2021 30 4 2224 2240 Torabi Farsani N Sadeghi R Shafiei Z Shahzamani Sichani A Measurement of satisfaction with ICT services implementation and innovation in restaurants (Case study: Isfahan, Iran) J. Travel Tourism Mark. 2016 33 2 250 262 Tseng F-M Gil EINP Lu LY Developmental trajectories of blockchain research and its major subfields Technol. Soc. 2021 66 101606 Tuncer Ä Unusan C Cobanoglu C Service quality, perceived value and customer satisfaction on behavioral intention in restaurants: An integrated structural model J. Qual. Assur. Hospitality Tourism 2021 22 4 447 475 Vig S Agarwal RN Repercussions of COVID-19 on small restaurant entrepreneurs: The Indian context Strategic Change 2021 30 2 145 152 10.1002/jsc.2398 Villa E Ruiz L Valencia A Picón E Electronic Commerce: Factors Involved in its Adoption from a Bibliometric Analysis J. Theoretical Appl. Electron. Commer. Res. 2018 13 1 39 70 10.4067/S0718-18762018000100104 Waltman L van Eck NJ Field-normalized citation impact indicators and the choice of an appropriate counting method J. Informetrics 2015 9 4 872 894 10.1016/j.joi.2015.08.001 Wang C-Y Mattila AS The impact of servicescape cues on consumer prepurchase authenticity assessment and patronage intentions to ethnic restaurants J. Hospitality Tourism Res. 2015 39 3 346 372 Xia Y Ha H-Y Does Customer Orientation Matter? Direct and Indirect Effects in a Service Quality-Sustainable Restaurant Satisfaction Framework in China Sustainability 2021 13 3 1051 10.3390/su13031051 Xiao Y Lu LY Liu JS Zhou Z Knowledge diffusion path analysis of data quality literature: A main path analysis J. Informetrics 2014 8 3 594 605 Xu S Hao L An X Pang H Li T Review on emerging research topics with key-route main path analysis Scientometrics 2020 122 1 607 624 Yang, W., Mattila, A.S.: Why do we buy luxury experiences? Measuring value perceptions of luxury hospitality services. Int. J. Contemp. Hosp. Manage. (2016) Yoon B Chung Y The effects of corporate social responsibility on firm performance: a stakeholder approach J. Hospitality Tourism Manage. 2018 37 89 96 Yoon J Park HW Pattern and trend of scientific knowledge production in North Korea by a semantic network analysis of papers in journal titled technological innovation Scientometrics 2020 124 2 1421 1438 10.1007/s11192-020-03497-3 Youn H Kim J-H Effects of ingredients, names and stories about food origins on perceived authenticity and purchase intentions Int. J. Hospitality Manage. 2017 63 11 21 Yu D Pan T Tracing the main path of interdisciplinary research considering citation preference: A case from blockchain domain J. Informetrics 2021 15 2 101136 10.1016/j.joi.2021.101136 Yu D Sheng L Knowledge diffusion paths of blockchain domain: the main path analysis Scientometrics 2020 125 1 471 497 Yu D Sheng L Influence difference main path analysis: Evidence from DNA and blockchain domain citation networks J. Informetrics 2021 15 4 101186 10.1016/j.joi.2021.101186 Yu D Yan Z Knowledge diffusion of supply chain bullwhip effect: main path analysis and science mapping analysis Scientometrics 2021 126 10 8491 8515 10.1007/s11192-021-04105-8 Zhang B Ma L Liu Z Literature Trend Identification of Sustainable Technology Innovation: A Bibliometric Study Based on Co-Citation and Main Path Analysis Sustainability 2020 12 20 8664 Zhang Z Ye Q Law R Li Y The impact of e-word-of-mouth on the online popularity of restaurants: A comparison of consumer reviews and editor reviews Int. J. Hospitality Manage. 2010 29 4 694 700 10.1016/j.ijhm.2010.02.002
PMC009xxxxxx/PMC9238018.txt
==== Front J Dev Econ J Dev Econ Journal of Development Economics 0304-3878 0304-3878 Elsevier B.V. S0304-3878(22)00084-0 10.1016/j.jdeveco.2022.102929 102929 Regular Article Cash transfers as a response to COVID-19: Experimental evidence from Kenya Brooks Wyatt a Donovan Kevin b⁎ Johnson Terence R. c Oluoch-Aridi Jackline de a Arizona State University, United States of America b Yale School of Management, United States of America c University of Virginia, United States of America d Strathmore University, Kenya e University of Notre Dame, United States of America ⁎ Corresponding author. 28 6 2022 9 2022 28 6 2022 158 102929102929 13 3 2022 13 6 2022 24 6 2022 © 2022 Elsevier B.V. All rights reserved. 2022 Elsevier B.V. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. We deliver one month’s average profit to a randomly selected group of female microenterprise owners in Dandora, Kenya, arriving just in advance of an exponential growth in COVID-19 cases. Relative to a control group, firms recoup about one third of their initial decline in profit, and food expenditures increase. Control profit responds to economic conditions and government announcements during our study period, and treatment effects are largest when control profit is at its lowest. PPE spending and precautionary management practices increase to mitigate the health risks of more intensive firm operation, but only among those who perceive COVID-19 as a major risk. Keywords COVID-19 Cash transfers Microenterprises Women ==== Body pmc1 Introduction One of the defining features of poverty is the difficulty of coping with economic downturns. While developed countries deploy numerous policy tools to deal with negative shocks, high levels of informality and other related complications in the developing world make it difficult to provide a similar social safety net. Few modern events have highlighted this problem like the coronavirus pandemic. Faced with the necessity of responding quickly to a large, unprecedented negative shock, various programs sprang up to respond. In this paper, we study one policy that has received substantial attention both within the COVID-19 crisis and more broadly as part of designing the social safety net in developing countries: a short-term unconditional cash transfer (UCT). By June 2020, 191 countries had initiated some form of cash transfers to combat the COVID-19 crisis (Gentilini et al., 2020). We implement a randomized controlled trial in which we deliver a one-time UCT to a particularly vulnerable group: female microenterprise owners in Dandora, Kenya, an informal settlement in Nairobi county. We deliver this transfer immediately preceding the initial exponential growth in COVID-19 cases in Kenya, and study the impact of a one-time cash injection throughout the beginning of the COVID-19 crisis on business and consumption outcomes among the poor. This population is one that is particularly affected by this crisis. In addition to making up the majority of employment in many developing countries (Gollin, 2008), these firms tend to operate in “non-essential” sectors and rely heavily on face-to-face interactions, leaving them vulnerable due to the particular features of the COVID-19 shock (Alfaro et al., 2020).1 In the first 4 months of 2020, average profit among our sample fell from 2 to 1 USD per day. We randomly divide our sample of business owners into a treatment group that receives 5000 KES (≈ 50 USD, equal to approximately 1 month of average profit in January 2020 among our sample) and a control group that receives 500 KES (≈ 5 USD) to cover mobile costs and time for participation. The ubiquity of mobile money – already a key aspect of informal social insurance networks (Jack and Suri, 2014) – allowed us to quickly deliver the treatment without any in-person meetings and before the rise of infections. While there were 700 cumulative cases in Kenya when we completed delivery of the transfers on May 12, 2020 there were 1,286 two weeks later (World Health Organization, 2020). We gathered data from April to August 2020 (discussed in Section 3) to trace the impulse response to the shock, observing the average participant every 2.5 weeks. Our results show that a one-time transfer significantly improves outcomes among the poor. We find that weekly business profits double relative to control (from a naturally low base given the depressed economy), restoring approximately one-third of the initial decline observed between January and May 2020. Household food expenditures also rise by 8 percent relative to control. While the initial COVID-19 shock was substantial, firm profitability fluctuates substantially over our study period as well. A particularly pronounced downturn started in June 2020 when cases started increasing rapidly and the government tightened restrictions on non-essential businesses. Indeed, we see profit and food expenditures in the control group drop by 36 and 13 percent, respectively, compared to the weeks before. We use this to study variation in the treatment over time. We find that the treatment effect is most pronounced in precisely this period, with the treatment effect on profit increasing by 68 percent. The impact on food spending is twice as high during this period. Thus, the one-time cash transfer both recoups lost profit and allows entrepreneurs to more effectively smooth consumption. We note, of course, that there is an existing literature studying cash transfers in “normal” times, though the goals of this literature differ from our study.2 Even setting that difference aside, whether or not the impact of an intervention conducted under normal conditions provides a reliable estimate of the impact in exceptional circumstances is itself an empirical question. Rosenzweig and Udry (2020), in particular, urge caution in interpreting any intervention divorced from the aggregate state of the economy from which it is derived. This fact differentiates our work in two ways. First, it need not be the case that the gains observed in other studies hold in the current crisis given the constraints on both customer demand and firm operation. Second, and particularly relevant to COVID-19, endogenous responses to treatment may affect public health and the progression of the epidemic itself.3 Along these lines, we find that treated firms are 5 percentage points more likely to be in operation and remain open for an additional half hour per day. Thus, at least at the level of transfer we deliver, we find little evidence that the treatment generates the “shut down as a luxury” effect hypothesized in both policy and the popular press (e.g. Glassman et al., 2020). Instead, there is a potential tradeoff between economic and public health that must be considered when designing policy in this context.4 Although firms that remain or re-open in response to the intervention might become additional vectors of disease, the cash provided by the treatment might also allow them to invest in personal protective equipment (PPE, such as hand sanitizers and masks) or adopt other behaviors that mitigate the public health risk. We find evidence that entrepreneurs in the treatment group increase spending on personal protective equipment by 17 percent and increase an index of mitigation practices such as hand washing and mask wearing by 0.23 standard deviations. Moreover, we find that these effects depend critically on the beliefs. Among those who believed the coronavirus to be no more deadly than the seasonal flu at baseline, we observe no change in PPE spending or practices. This implies a potentially important and policy-relevant complementarity between cash transfers and information campaigns, such as Banerjee et al. (2020a), to minimize health risk without stifling the social insurance benefits of cash transfers. 1.1 Related literature This paper speaks to two closely related literatures. The first is the explosion of work around the impact and potential policy responses to COVID-19. This has taken many forms, including studies on optimal shutdown policies (Alon et al., 2020b), the development of targeting tools to prevent leakage (Blumenstock, 2020), mask wearing (Abaluck et al., 2021), and the role played by pensions (Bottan et al., 2021, Banerjee et al., 2021). More closely related is work focused on the delivery of unconditional cash to households. Most of this work focuses on transfers to households, such as Londoño-Vèlez and Querubín (2022), finding small but positive effects on measures of household well-being. We advance this growing body of work in two ways. First, we focus on outcomes for the main income-generating activity of the poor, microenterprise operation. Given the interaction between household and firm accounts common among the poor, we view this as an important margin regardless of whether the transfer is officially delivered to the household or firm. A number of our results highlight the interaction of these two. Moreover, by conducting our own surveys and operating our own RCT, we can add granularity that help highlight relevant mechanisms. For example, we study the interaction of decisions with beliefs about COVID-19 severity. These informal microenterprises do not show up in government firm censuses and rarely are details like beliefs available. More closely related is work by Banerjee et al. (2020b). Like us, they study firms, though in rural Kenya where there are likely substantial differences in density, the impact of the COVID-19 demand shock, and other economic features are likely different than the urban setting we focus on here.5 Moreover, they study an ongoing universal basic income program, meaning that firms were already treated when COVID-19 began. We focus on a new, unexpected transfer program. Thus, we view our results as filling an important policy-relevant gap in this growing literature. Work that focuses more broadly on cash transfers to firms focuses almost exclusively on long-run development concerns like poverty traps or other sources of misallocation (de Mel et al., 2008, Blattman et al., 2014). Yet low fiscal capacity in many developing countries leaves open an important role for short-term, well-timed cash transfers (Jensen, 2019). We contribute to this literature by addressing this issue, as the impact of a cash transfer in the middle of a substantial economic depression need not have any relation to those delivered during normal times, especially if demand is constrained (e.g. Rosenzweig and Udry, 2020). De Mel et al. (2012) study the role of cash transfers in response to a major tsunami in Sri Lanka, but the literal destruction of capital has little relation to the COVID-19 crisis. As such, we add new evidence to a broad literature on social safety nets in developing countries. See Hanna and Olken (2018) for a recent review. 2 Economic environment during the study Dandora is a dense, urban settlement in Nairobi with 150,000 residents. It is the site of a sprawling 30 acre trash dump that services all of Nairobi despite being declared full in 2001, and its pollution plays a major role in poor health and respiratory issues among its residents (Kimani, 2007). This, along with the density of Dandora and surrounding settlements, lead to substantial anxiety that COVID-19 would spread quickly among its residents. As approximately 59 percent of all cases in the “first wave” were in Nairobi county (Kenya Ministry of Health, 2020), these concerns seem well-founded. In response to the first confirmed case in Kenya on March 13, 2020, the government instituted a series of measures designed to limit personal interactions. On March 15, a curfew and travel ban were simultaneously announced. All bars and restaurants were ordered not to provide seating to customers and only offer food to go on March 22. On April 6, movement into and out of Nairobi was suspended for 21 days. We return to these policy changes in the next section to study how they affect the impact of the intervention. Our sample focuses on female entrepreneurs living in Dandora. In addition to making up the majority of small businesses in the area, qualitative survey evidence shows women bearing the brunt of the economic impact in Dandora and other slums surrounding Nairobi (Population Council, 2020). Combined with the fact that these female-run microenterprises are substantially less profitable than those run by men (Brooks et al., 2018), this suggests a particular vulnerability to such an economic downturn among Dandora women. 2.1 Economic contraction and policy response The COVID-19 shock and associated government response were felt across Kenya, including Dandora. We find that average profit declines by 47 percent between January and late April 2020. These findings are consistent with the expectations and qualitative responses observed at baseline. Eighteen percent of our sample had closed their businesses between January and May 2020 at least temporarily, while 47 percent expected the COVID-19 crisis to shut down their business, at least temporarily. Like most governments, the Kenyan government was aware that the aforementioned restrictions were likely to cause economic hardship. In response, they simultaneously implemented a number of policies designed to partially stabilize incomes. These policies included tax relief to the poorest earners and a reduction of income tax in mid-March. As of April 1, 2020, the government suspended the listing of negative credit information with the Credit Reference Bureau of any person or micro or small business with an overdue loan, along with a decrease in the VAT rate from 16 to 14 percent and an elimination of mobile transfer fees. These policies, however, provided little relief to many of the most vulnerable microenterprises and households with who are less connected to the formal economy, which is a common issue in designing a social safety net in developing countries. In our baseline survey conducted in April–May 2020, only 17 percent of business owners had received any government relief. Few, for example, utilize the formal loan market or pay taxes, implying little direct benefit from the implemented policies. Similarly, there is little NGO reach into Dandora. Ninety-five percent of our sample received no help from any NGO (no one mentions cash transfers, in particular). These numbers remain roughly constant among the control group throughout the study period ending August 2020. Thus, our study takes place among a population that is among the most vulnerable to such an economic downturn and faces a substantial contraction in profit. Yet, at the same time, there is little relief from either the government or NGOs. A final question is the margins that COVID-19 affected. We asked respondents about the business harms caused by COVID-19 (data collection is detailed in the next section). Thirty-seven percent of control firms mentioned an increase in costs from their suppliers. On the other hand, 80 percent highlighted a lack of customers and 43 percent noted that the instituted curfews in Nairobi decreased demand from customers at night.6 Thus, the COVID-19 shock has elements of both a supply and demand shock, with perhaps a greater salience of the demand-side given that nearly all respondents mention some demand issue. We use Section 4.3 to expand on this discussion in terms of treatment effects after detailing the main results. 3 Data collection and experimental design From October 2019 to January 2020, we were conducting an in-person cross-sectional survey of 4,500 female-run microenterprises in Dandora for a separate research project. As COVID-19 began to spread around the world, we drew a sample from this group to study the impact of a quick and one-time unconditional cash transfer as a response to the economic downturn. We selected 800 women to be part of the study. Of those, 753 were successfully enrolled. Those 753 were then randomized into treatment (367) and control (386). We then began a continuous data collection process on April 23, 2020. Starting on that date, we contacted each participant by phone to collect another pre-treatment data point. At the end of that survey round, we informed the participant if she was in the treatment group. Immediately following the completion of this survey wave, we re-randomized the call list and began contacting individuals again. Our enumeration team moved through the list, with each participant either completing the survey or recording 4 unsuccessful contact attempts (on 4 consecutive days). Once this was complete, the list was re-randomized and begun again. We refer to the completion of this procedure as a “wave” of the survey. Each wave took approximately two weeks, and on average, we have 6 observations per participant after completing data collection in August 2020. The goal of this high frequency data collection was to capture the fast-moving response both of the coronavirus and to better trace the impulse response to the initial shock. As such, all flow variables are recorded with one week recall. Cash transfers were delivered in the first two weeks of May 2020 by mobile money (M-PESA). The treatment group received 5000 KES and the control group received 500 KES (as compensation for surveys and air time required to answer). The scale of the treatment transfers was designed to be approximately equal to one month of average profit among our sample as observed in January 2020. Fig. 1 summarizes this data collection timeline, indicates the time at which the cash was delivered, and plots the daily cumulative of COVID-19 cases in Kenya from the World Health Organization COVID-19 Dashboard (World Health Organization, 2020). Our treatment is delivered immediately preceding the high growth rate period of cases, and our data collection period covers most of the initial COVID-19 wave in Kenya. In the Online Appendix we provide balance checks and find no difference between control and treatment groups along a number of dimensions. The joint F-test p-value is 0.984 across 15 relevant baseline variables. In addition, in the Online Appendix we estimate the relationship between the number of surveys completed and observable characteristics of participants. Treatment status is uncorrelated with number of responses or attrition. The only statistically significant predictor of the number of responses is age, and the magnitude is small. Moving from the fifth percentile (age 25) to ninety-fifth percentile (age 58) of the age distribution predicts 0.53 additional surveys.Fig. 1 Cumulative COVID-19 Cases in Kenya and RCT Timeline. Figure notes: This figure plots cumulative COVID-19 cases in Kenya at a daily frequency from [35] beginning on January 3, 2020. It further includes our data collection periods (shaded area) and cash delivery date (dashed line). 4 Empirical results Our main specification takes the form (4.1) yit=βTit+θi+γt+ɛit, where yit is some outcome for individual i at wave t, Tit=1 if i is treated at wave t, and θi and γt are individual and wave fixed effects. Standard errors are clustered at the individual level. We focus on the continual data collection from April–August 2020, though the results are robust to the inclusion of the earlier baseline data from January 2020. For non-indicator variables we trim outcomes at 1 percent to eliminate misreporting and outliers. We report relevant variables (e.g., profit, revenue, etc.) as inverse hyperbolic sine (IHS) transformations, allowing coefficients to be interpreted as approximate growth rates without dropping zeros that would generate misleading results during this period.7 With the IHS caveat noted, we will refer to these treatment effects as percentage changes. All monetary values are reported in KES (with a nominal exchange rate of 106 KES = 1 USD during the study period). Additional robustness on both the regression specification and the adjustments to outcome variables are provided in the Online Appendix, and our results do not rely on the choices made here. 4.1 Economic and business impact of the UCT Table 1 reports the average treatment effects of the intervention on business and household outcomes. We observe a substantial increase in profit, revenues, and inventory spending within treated businesses. Profit doubles relative to control, with a point estimate of 0.99 (p=0.000). A different way to interpret this change is that it recoups about one-third of the decline in profit we observe between January and May. Some of these additional resources are re-invested into the business in terms of higher inventory spending, which increases by 152 percent (p=0.000), while some is used for consumption, with food expenditures increasing by 8 percent (p=0.072).Table 1 Economic and business outcomes. OUTCOMES (1) (2) (3) (4) (5) (6) Profit Revenue Inventory Food Open Daily Expenditures Expenditures Hours Treat 0.990*** 0.762*** 1.515*** 0.080** 0.056** 0.176** (0.255) (0.243) (0.309) (0.041) (0.027) (0.080) Observations 4,046 3,996 3,997 4,019 4,112 4,052 R-squared 0.011 0.007 0.011 0.014 0.007 0.011 Ind FE Y Y Y Y Y Y Control Average 4.967 6.481 4.405 8.176 0.829 2.262 All measured in as inverse hyperbolic sines except Open. Standard errors clustered at the individual level in parentheses. Control averages taken over entire time period of study. *** p < 0.01, ** p < 0.05, * p < 0.1. Yet, the results show that the treatment also induces businesses to operate more intensively on average. Firms are 6 percentage points more likely to be open (p=0.046) and are open 18 percent longer per day (p=0.050). This occurred at the same time that the government was taking action to reduce interpersonal interaction. Hence, this effect may work against the government’s public health objectives. We return to the COVID-specific tradeoffs embedded in this result in Section 4.2. 4.1.1 Variation over time Our previous results show that the UCT helps stabilize income in the immediate aftermath of the shock. However, after the treatment delivery, the Kenyan government was instituting and removing various restrictions in response to rapidly-changing public health conditions. A particularly important period of this response was during June and early July, when it was clear that the virus was likely to become a lasting and global pandemic.8 Those restrictions were eventually lifted on July 7, 2020, along with loosening of restrictions on air travel and religious worship. To study the dynamics of business outcomes, we divide our sample period into the waves of the survey.9Fig. 2(a) shows the evolution of IHS food expenditures and profit among the control group by survey wave. The vertical axis shows changes in those outcomes for the control group relative to wave 2 (which covers surveys conducted May 27–June 9). This shows that this period of heightened restrictions was particularly damaging to business profit in the control group.Fig. 2 Evolution of Food Expenditures and Profit. Figure notes: Figure (a) plots the evolution of average profit and food expenditures among control firms. Figures (b) and (c) plot the evolution of the treatment effect over time along with the 95 percent confidence interval, derived as β^t from the regression yit=θi+∑t=17βt(Tit×1[wave=t])+γt+ɛit with standard errors clustered at the individual level. The gray shading indicates the period of severe lockdown procedures in Nairobi. Motivated by this observation, we ask if the treatment has a differential effect during this period when interaction is more limited. Fig. 2, Fig. 2 begin with the evolution of the treatment effect over time, derived from the regression estimates βˆt in the regression yit=∑t=17βt(Tit×1[wave=t])+θi+γt+ɛit. Both peak during this restricted period.10 We test this systematically by defining a variable called “Restricted” that is equal to 1 during the period of heightened restrictions and interact it with the treatment indicator. We present evidence in Table 2 that the treatment effect is larger along a number of dimensions during this period, consistent with the transfer increasing household wealth and allowing for more consumption smoothing. We find that the treatment effect is larger in terms of profit, revenue, food expenditures, and hours open. In addition, we find an additional 4 percentage point increase in being open during this period (p=0.115), but the effect slightly above standard cutoffs for statistical significance. We find no differential impact on inventory expenditures (p=0.547 on the interaction), consistent with the more forward-looking nature of that choice. The results in this section show two key results. First, the one time transfer helps recoup some of the lost income during the initial economic shock. In our context of COVID-19, the cash transfer causes business to regain approximately one-third of the average decline in profit between January and May 2020. Moreover, that same one-time transfer helps most during the period in which restrictions on interaction were most intense.Table 2 Timing variation in economic outcomes. VARIABLES (1) (2) (3) (4) (5) (6) Profit Revenue Inventory Food Open Daily Expenditures Expenditures Hours Treat 0.884*** 0.650*** 1.558*** 0.065 0.050* 0.153* (0.260) (0.246) (0.315) (0.042) (0.027) (0.081) Treat ×Restricted 0.604*** 0.637*** −0.193 0.084* 0.040 0.135* (0.233) (0.237) (0.320) (0.048) (0.025) (0.075) Observations 4,046 3,996 3,997 4,019 4,112 4,052 R-squared 0.014 0.010 0.013 0.016 0.011 0.014 Ind FE Y Y Y Y Y Y Flow variables measured as inverse hyperbolic sines in KES. Standard errors clustered at the individual level in parentheses. Control averages taken over entire time period of study. *** p < 0.01, ** p < 0.05, * p < 0.1. 4.2 COVID-19 preventative measures As formalized in a number of recent papers extending standard SIR models, individual decisions concerning economic well-being and physical health are endogenous. Therefore, adjustments to one potentially effect the other, a key feature of the pandemic. An implication of this is that economic policy cannot be considered separately from public health policy. In our context, we find that the UCT induces owners to open their businesses and operate them more intensively relatively to the control group at precisely the time when this is likely to increase public health risk. The risks, however, can be mitigated by the entrepreneurs’ actions and investments in sanitation, particularly when they have additional cash on hand to purchase PPE, sanitizer, and soap. To study this policy-relevant trade-off in more detail, we document the extent to which the treatment induces changes in mitigation practices, and also highlight the potential complementarity with other interventions that have been proposed and utilized in the fight against COVID-19. We consider two measures of health risk mitigation: spending on personal protective equipment (PPE) in the past week and an index of public health-related management practices. The latter is constructed from 9 practices related to safe business operation, measured as the z-score.11 Columns (1) and (3) in Table 3 show the average effect on both mitigation measures. We find that despite causing businesses to remain open and operate more intensively, the treatment also causes them to increase protective measures against the spread of COVID-19 while operating. PPE spending increases by 17 percent (p=0.014), while our management practices index increases by 0.22 standard deviations above baseline mean (p=0.006).Table 3 COVID-19 health practices. VARIABLES (1) (2) (3) (4) PPE PPE Protective Protective expenditures expenditures measures measures (z-score) (z-score) Treat 0.170** 0.223*** 0.225*** 0.286*** (0.069) (0.075) (0.082) (0.090) Treat ×Low Belief of Risk −0.245** −0.292** (0.102) (0.115) Observations 3,243 3,210 4,112 4,066 R-squared 0.064 0.066 0.045 0.047 Ind FE Y Y Y Y Control Average 5.858 5.858 0.182 0.182 Columns (1) and (2) are measured as IHS. Columns (3) and (4) are standardized z-score of 9 management practices designed to limit COVID-19 spread. Standard errors clustered at the individual level in parentheses. *** p < 0.01, ** p < 0.05, * p < 0.1. The results show that individuals use the transfer to remain open more safely than they had previously been operating. Using the average baseline PPE spending is 214 KES, our point estimate implies a 17 percent increase of 36 KES of spending per week. In concrete terms of particular investments, this corresponds to one 50 KES cloth mask per 1.4 weeks or a 250 KES bottle of hand sanitizer once every 6.9 weeks. The extent to which this mitigates the spread of COVID-19 requires estimates of the elasticity of viral transmission to spending, about which it was not possible to gather data. We next turn to studying the type of individual who makes these changes, and link our results relate to other key COVID-19 policies. 4.2.1 The importance of beliefs in mitigation changes A broad literature highlights the importance of beliefs in the take-up of health products, both during COVID-19 (Arce et al., 2021, Banerjee et al., 2020a) and under normal circumstances (Dupas, 2014). Motivated by this work, we study the importance of baseline beliefs of COVID-19 severity on the willingness to change mitigation practices. Throughout the study, we ask participants to state their belief about the mortality risk of COVID-19.12 We find substantial variation, with over 20 percent believing COVID-19 to be no more deadly than the seasonal flu and over 50 percent believing it more deadly than typhoid.13 We study the importance of these beliefs for willingness to change behavior by interacting our treatment with a “low belief of risk” indicator, which is equal to 1 for those with a baseline belief that COVID-19 mortality is no greater than the seasonal flu. This is measured at baseline, pre-treatment.14 We interact this indicator with the treatment indicator with the results in columns (2) and (4) of Table 3. Among those with low perceived risk, the interaction term has the opposite sign and similar magnitude to the treatment variable. The net effect is that those with low perceived risk of COVID-19 severity do not change preventative practices, while those with a higher assessment increase PPE spending and mitigation practices.15 The results provide new evidence on the relationship between beliefs and cash transfers in managing the relationship between economic and public health during short-run stabilization policy, and suggests important complementarity with information interventions (e.g. Banerjee et al., 2020a). Together, such a suite of policy adjustments may be able to induce safer re-opening without eliminating the economic gains generated by the UCT.16 4.3 Discussion of mechanisms We discussed in Section 2.1 that the COVID-19 downturn had elements of both supply and demand shocks, at least in terms of problems highlighted by control firm owners. Here, we attempt to better unpack some potential mechanisms. The results are provided in Appendix. We first focus on supply-side issues. Treated firms are no more likely (or less likely) to switch suppliers. Second, treatment and control firms are equally likely to miss a sale due to lack of inputs or materials. Both of these seem consistent with the relatively larger importance of the demand channel in qualitative responses highlighted in Section 2.1. Another possibility is that the increased spending on PPE caused the increase in profit. For examples, customers may have increased their demand for sanitary stores at which to purchase goods. We test this and find that firm owners who underestimate the risk of COVID-19 actually see a larger treatment effect on their profit. However, they see no change in food expenditures relative to the control. Increases in food expenditures is concentrated among those who do not underestimate COVID-19’s risk. Thus, one possibility is that, informed by their own beliefs, these firm owners place different marginal returns on different expenditure categories and react accordingly. 4.4 Other forms of heterogeneity Our results show that there substantial impacts from an unconditional cash transfer during a particularly severe economic downturn. As it relates to COVID-19, there is little existing evidence on how such a transfer impacts microenterprise owners and many hypotheses on how it should. We explore various margins of heterogeneity in Appendix. Our main finding from these results are that married women see a smaller impact on their profit, with a treatment effect half that of an unmarried women (p=0.036). Moreover, treated married women are no more likely to be open than control owners and have similar daily hours. Food expenditures are similarly lower, but noisily estimated. One possibility is that this is a function of intra-household bargaining or the particular costs of the pandemic borne by married women.17 The alternative is that they use the transfer for higher marginal value activities other than their business. Indeed, over 40 percent of treated firm owners claim that at least part of the transfer is spent directly on household items (food, rent, etc.).18 We lack the data to probe these questions more deeply, and therefore caution the interpretation of these effects as a measure of household welfare. We note that better understanding this heterogeneous impact in the context of emergency transfers is an important avenue for future work. 5 Conclusion This paper provides new experimental evidence on the impact of a one-time cash transfer during a severe global downturn. We utilize mobile money to deliver transfers to female micro-entrepreneurs in Dandora, Kenya, a group that was both particularly vulnerable to the economic consequences of the COVID-19 pandemic and received little assistance from the government and NGOs. This paper helps to inform the recent debate about policy responses to COVID-19. Our results show that UCTs are effective at helping microenterprise owners maintain their livelihoods and engage in consumption smoothing when needed public health measures are taken. Profit increases by 40 percent, making up approximately one-third of the decline observed during the initial shutdown implemented by the Kenyan government, while simultaneously increasing inventory and food consumption. We further find that mitigation practices increase, but only among those with sufficiently high beliefs about COVID-19’s severity. Thus, our results bring new evidence on the potentially important complementarity between information and economic interventions. These results demonstrate that UCTs may play an important role in mitigating the economic costs of a public health crisis for entrepreneurs who make up a large part of the urban workforce in developing countries. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Appendix A Supplementary data The following is the Supplementary material related to this article. MMC S1 Supplementary material contains additional results. Data availability Replication files available at https://doi.org/10.17632/zs5p47vx8k Acknowledgments Thanks to conference and seminar participants at the Central Bank of Chile, the PEGNet-DIE Workshop on Social Protection During Pandemics, and Yale University for a number of useful comments. We are grateful to the Ford Family Program at the University of Notre Dame and J-PAL’s Jobs and Opportunity Initiative (Grant #JOI-1375) for funding and to Brian Ambutsi for his excellent work managing the project in the field. This project was approved by the IRBs of Strathmore University and Yale University, along with the National Commission for Science, Technology and Innovation (NACOSTI) in Kenya . AEA RCT Registry ID: AEARCTR-0005704. 1 In addition, both cross-country and Kenyan evidence points to the particular burden borne by women during this crisis (Alon et al., 2020a, Population Council, 2020). Recent studies of such gendered distortions in “normal” times include Hardy and Kagy (2018) and Field et al. (2021), while Jayachandran (2020) provides a review. 2 For example, de Mel et al. (2008) uses cash transfers to measure the average return to capital, Blattman et al. (2014) studies whether cash allows individuals to start a business and thus escape a poverty trap, and Egger et al. (2020) studies the general equilibrium effects of large transfers at the village level. Our focus is on the short-run stabilization effect of cash transfers. 3 This point has been formalized in “behavioral” or “economic” susceptible–infected–recovered (SIR) models (see, for example, Eksin et al., 2019, Atkeson et al., 2021 and references therein). 4 We do not attempt to quantify the optimal tradeoff of these forces within the context of our RCT, as we were unable to collect relevant health and interaction data. These moments are necessary to credibly estimate the properly-modified SIR model that would be required to study the overall welfare change induced by this tradeoff. See Alvarez et al. (2021) and Acemoglu et al. (2020) among many others for theoretical and quantitative evaluations of such tradeoffs. Alon et al. (2020b) quantitatively evaluate such in a model for developing countries. 5 The Kenyan government explicitly forbade movements out of Nairobi to rural areas with the goal of minimizing the virus spread. Thus, the government similarly acknowledged these spatial differences. 6 Customers were free to offer as many answers as they wanted, hence the percentages need not sum to one. 7 The derivative of natural log is 1/x and the derivative of inverse hyperbolic sine is 1/1+x2, so that if x is large and positive, 1/1+x2≈1/|x|=1/x. 8 Low case counts in April and May created some hope that the initial restrictions would be short-lived, a fact reflected in much of the media reporting around this time. While Kenya had amassed 535 cumulative cases by May 6, there were 1,984 new cases reported between May 6 and June 6 alone (World Health Organization, 2020). 9 As noted in Section 3, a wave began when the list of all participants was randomized, and was completed when each participant had either been surveyed or four attempts to contact them were completed. When a wave was completed, the next wave began again immediately. 10 The remaining outcomes are provided in Appendix. 11 We construct an index of these practices by counting the number implemented and normalizing by baseline levels. Specifically, we construct the z-score for individual i at time t as (∑j=191ijt−μ0)/σ0, where 1ijt=1 if individual i implemented practice j at week t and the mean and standard deviation are from baseline responses. The Online Appendix provides the 9 practices considered and adoption of these practices at baseline. 12 The specific question asked if 5,000 people contracted COVID-19, how many do they believe would die? Participants were given options that had both a number and a disease with that mortality risk. The lowest risk option was a common cold (< 1 death in 5,000 cases) and the highest was ebola (4,000 deaths per 5,000 cases). 13 The histogram of responses is provided in the online appendix. 14 In the Appendix we test whether these beliefs respond to treatment. We do not find any changes along this dimension. 15 As with any type of research around externality-producing activities, social desirability bias may be present in these responses. That said, it would have to take a particular form to explain our results. It would have to be the case that the bias is largest in treated owners that have relatively high perception of COVID-19 severity, then approximately equal among the average control owners and treated owners who have relatively low perceived risk of COVID-19. 16 Relatedly, in a large-scale RCT on free mask delivery in Bangladesh, Abaluck et al. (2021) that information nudges at the household level do not increasing proper mask wearing (conditional on a free mask), but promotion and reminders at the market-level do seem to matter. 17 Field et al. (2021), for example, shows how the structure of the household may impact outcomes in normal times. Moreover, the large cost of the pandemic on women has been pointed out in many developed countries (Alon et al., 2020a) and corroborated locally with qualitative survey evidence in Kenya (Population Council, 2020). 18 Almost no one claims it was given directly to a spouse (1 individual) or a friend (3 individuals). Sixty-three percent claim it was used on business activities. Though these categories are not exclusive, there is a correlation coefficient of −0.40 between reporting spending on household items versus business items. Appendix A Supplementary material related to this article can be found online at https://doi.org/10.1016/j.jdeveco.2022.102929. ==== Refs References Abaluck Jason Kwong Laura H. Styczynski Ashley Haque Md. Ashraful Kabir Alamgir Bates-Jeffries Ellen Crawford Emily Benjamin-Chung Jade Benhachmi Salim Raihan Shabib Rahman Shadman Zaman Neeti Winch Peter J. Hossain Md. Maqsud Reza Hasan Mahmud Luby Stephen P. Mobarak Ahmed Mushfiq Normalizing community mask-wearing: A cluster randomized trial in Bangladesh Science 375 6577 2021 eabi9069 Acemoglu, Daron, Chernozhukov, Victor, Werning, Iván, Whinston, Michael D., 2020. Optimal Targeted Lockdowns in a Multi-Group SIR Model. NBER Working Paper 27102. Alfaro, Laura, Becerra, Oscar, Esalava, Marcela, 2020. EMEs and COVID-19: Shutting Down in a World of Informal and Tiny Firms. NBER Working Paper 27360. Alon, Titan M., Doepe, Matthias, Olmstead-Rumsey, Jane, Tertilt, Michèle, 2020a. The Impact of Covid-19 on Gender Equality. NBER Working Paper 26947. Alon, Titan M., Kim, Minki, Lagakos, David, VanVuren, Mitchell, 2020b. How Should Policy Responses to the Covid-19 Pandemic Differ in the Developing World?. NBER Working Paper 27273. Alvarez Fernando Argente David Lippi Francesco A simple planning problem for COVID-19 lockdown, testing and tracing Am. Econ. Rev. Insights 3 3 2021 367 382 Arce Julio S. Solís Warren Shana S. COVID-19 vaccine acceptance and hesitancy in low and middle income countries, and implications for messaging Nature Medicine 27 2021 1385 1394 Atkeson Andrew G. Kopecky Karen Zha Tao Behavior and the transmission of COVID-19 American Economic Review Papers and Proceedings 111 2021 356 360 Banerjee, Abhijit, Alsan, Marcella, Breza, Emily, Chandrasekhar, Arun G., Chowdhury, Abhijit, Duflo, Esther, Goldsmith-Pinkham, Paul, Olken, Benjamin A., 2020a. Messages on COVID-19 Prevention in India Increases Symptoms Reporting and Adherence to Preventative Behaviors Among 25 Million Recipients with Similar Effects on Non-recipient Members of their Communities. NBER Working Paper 27496. Banerjee Abhijit Dfulo Esther Grela Erin Schilbach Frank McKelway Madeline Sharma Garima Vaidyanathan Girija Did pensions protect the eldery during the COVID-19 pandemic? Working paper 2021 Banerjee Abhijit Faye Michael Krueger Alan Niehaus Paul Suri Tavneet Effects of a universal basic income during the pandemic Working Paper 2020 Blattman Christopher Fiala Nathan Martinez Sebastian Generating skilled self-employment in developing countries: Experimental evidence from Uganda Q. J. Econ. 129 2 2014 697 752 Blumenstock Joshua Machine learning can help get COVID-19 aid to those who need it most Nat. World View 2020 https://www.nature.com/articles/d41586-020-01393-7 Bottan Nicolas Hoffman Bridget Vera-Cossio Diego A. Stepping up during a crisis: The unintended effects of a noncontributory pension program during the Covid-19 pandemic J. Dev. Econ. 150 2021 Brooks Wyatt Donovan Kevin Johnson Terence R. Mentors or teachers? Microenterprise training in Kenya Am. Econ. J.: Appl. Econ. 10 4 2018 196 221 de Mel Suresh McKenzie David Woodruff Christopher Returns to capital in microenterprises: Evidence from a field experiment Q. J. Econ. 123 4 2008 1329 1372 De Mel Suresh McKenzie David Woodruff Christopher Enterprise recovery following natural disasters Econom. J. 122 559 2012 64 91 Dupas Pascaline Short-run subsidies and long-run adoption of new health products: Evidence from a field experiment Econometrica 82 1 2014 197 228 25308977 Egger Dennis Haushofer Johannes Miguel Edward Niehaus Paul Walker Michael General equilibrium effects of cash transfers: experimental evidence from Kenya Working Paper 2020 Eksin Ceyhun Paarporn Keith Weitz Joshua S. Systematic biases in disease forecasting – the role of behavior change Epidemics 27 2019 96 105 30922858 Field Erica Pande Rohini Rigol Natalia Schaner Simone Troyer Moore Charity On her own account: How strengthening women’s financial control impacts labor supply and gender norms Amer. Econ. Rev. 111 7 2021 2342 2375 37201159 Gentilini Ugo Almenfi Mohamed Dale Pamela Blomquist John Palacios Robert Desai Vyjayanti Moreira Vanessa Social protection and jobs responses to COVID-19: A real-time review of country measures World Bank Working Paper 2020 Glassman Amanda Chalkidou Kalipso Sullivan Richard Does One Size Fit All? Realistic Alternatives for COVID-19 Response in Low-Income Countries 2020 Center for Global Development https://www.cgdev.org/blog/does-one-size-fit-all-realistic-alternatives-covid-19-response-low-income-countries Gollin Doug Nobody’s business but my own: Self employment and small enterprise in economic development J. Monetary Econ. 55 2 2008 219 233 Hanna Rema Olken Benjamin A. Universal basic incomes versus targeted transfers: Anti-poverty programs in developing countries J. Econ. Perspect. 32 4 2018 201 226 Hardy Morgan Kagy Gisella Mind the (profit) gap: Why are female enterprise owners earning less than men? Am. Econ. Rev. Pap. Proc. 108 5 2018 252 255 Jack William Suri Tavneet Risk sharing and transaction costs: Evidence from Kenya’s mobile money revolution Amer. Econ. Rev. 104 1 2014 183 223 Jayachandran, Seema, 2020. Microentrepreneurship in Developing Countries. NBER Working Paper 26661. Jensen, Anders, 2019. Employment Structure and the Rise of the Modern Tax System. NBER Working Paper 25502. Kenya Ministry of Health COVID-19 outbreak in Kenya: Daily situation report 132 2020 https://www.health.go.ke/wp-content/uploads/2020/07/Kenya-COVID-19-SITREP-132-27-Jul-2020.pdf Kimani Njoroge G. Environmental Pollution and Impacts on Public Health: Implications of the Dandora Municipal Dumping Site in Nairobi, Kenya 2007 United Nations Environment Programme (UNEP) Londoño-Vèlez Juliana Querubín Pablo The impact of emergency cash assistance in a pandemic: Experimental evidence from Colombia Rev. Econ. Stat. 104 1 2022 157 165 Population Council Kenya: COVID-19 perceptions, prevention practices, and impact 2020 Rosenzweig Mark R. Udry Christopher R. External validity in a stochastic world: Evidence from low-income countries Rev. Econom. Stud. 87 1 2020 343 381 World Health Organization WHO coronavirus disease (COVID-19) dashboard 2020 Accessed: September 23, 2020, https://covid19.who.int/region/afro/country/ke
PMC009xxxxxx/PMC9258470.txt
==== Front Qual Quant Qual Quant Quality & Quantity 0033-5177 1573-7845 Springer Netherlands Dordrecht 35818392 1470 10.1007/s11135-022-01470-1 Article Students’ perspective on online learning during pandemic in higher education http://orcid.org/0000-0002-9438-6893 Abdullah Farooq farooq.abdullah@must.edu.pk 1 Kauser Sumera sumera.dbms@must.edu.pk 2 1 grid.449138.3 0000 0004 9220 7884 Department of Sociology, Mirpur University of Science and Technology (MUST), Mirpur, AJ&K Pakistan 2 grid.449138.3 0000 0004 9220 7884 MUST Business School, Mirpur University of Science and Technology (MUST), Mirpur, AJ&K Pakistan 6 7 2022 2023 57 3 24932505 11 6 2022 © The Author(s), under exclusive licence to Springer Nature B.V. 2022 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. This research provides an insight into the students’ perspective on online learning during the pandemic. We conducted this research in one of the universities of Azad Jammu and Kashmir (AJK). A quantitative research design was employed, and cross-sectional research method was used. An online survey form was administered by using Google survey forms on Likert scale (N = 405). The online survey and use of social media tools were adopted owing to the pandemic. The Google survey form was disseminated among the students by means of teachers through social media tools using convenient sampling technique. Chi-square results showed highly significant association among the variables. Regression analysis found that lack of technology, learning skills, and disconnectedness of internet, marking and grading issues, and mental growth are the predictors of the bad educational performance of the students. It is, thus, concluded that the students’ educational performance is badly affected due to the online learning amidst the COVID-19 pandemic in AJK. It is suggested to the higher educational institutions to take the radical measures of preparedness during any such crisis to ensure the smooth online educational and learning environment to the students. Keywords COVID-19 Online learning Pandemic Grades Mental issues Performance issue-copyright-statement© Springer Nature B.V. 2023 ==== Body pmcIntroduction The Coronavirus SARs CoV-2 greatly influenced the students’ learning in higher education institutions (HEIs) across the globe (Agormedah et al. 2020; Rizun and Strzelecki 2020; Sá and Serpa 2020). As a result of COVID-19 urgency, the HEIs primarily suspended the educational activities on campus to avoid the spread of novel virus (Armoed 2021; Lukong et al. 2020). It is pertinent to mention here that it was not possible for HEIs to keep the educational activities suspended for long (Budur et al. 2021; Leal Filho et al. 2021). The internet-based learning [online] was adopted an alternative solution to continue the educational activities (Kohli et al. 2021; Zai and Akhunzada 2020). Thus, governments took measures to contain pandemic by introducing online educational activities the world over (de Boer 2021; Rasheed et al. 2021). Consequently, Agormedah et al. (2020) in line with other researchers argued that educational activities shifted to online mode at massive level (Cecilio-Fernandes et al. 2020). This paradigm shift although brought smoothness in educational activities among developed nations (Aumjaud 2020). As developed countries have common usage of advance technology in universities (Muthuprasad et al. 2021). However, Adnan and Anwar (2020) asserted that majority of developing countries deficient in technology experienced it differently. A substantial body of research work highlighted the problems of students during pandemic in developing countries (Almaiah et al. 2020). Traditional methods of teaching are generally used in the universities of developing countries (Irfan et al. 2020). Thus, students were less likely familiar with the e-learning mode before pandemic (Wargadinata et al. 2020). At the onset of pandemic’ effects, the decision to initiate teaching activities online was dealt at different levels (Dwivedi et al. 2020; Murphy 2020). As governments in general and universities in particular took time to devise mechanism to shift teaching activities online (Ali 2020; Mishra et al. 2020). Jena (2020) analysed that online teaching affected learning of the students. Similar assertions are given by Onyema et al. (2020). They asserted that pandemic badly affected the performance of the students in higher education. They, like other researchers, further identified different factors that affect the student’ performance. These factors include grades/CGPA issues (Fatonia et al. 2020), mental growth (Khattar et al. 2020), marks criteria (Mukhtar et al. 2020), and internet issues (Tanveer et al. 2020). By the same token, Fatonia et al. (2020) revealed that online learning affected scores/grades of the students. In the similar way, Zai and Akhunzada (2020) unveiled that students questioned the marking criteria while receiving the same answer sheet (Bączek et al. 2021). Baticulon et al. (2021) noted that students are unable to learn the skills. They also found that performance of the students is affected. As a result, students suffered from anxiety, stress, tension, and fear of infection (Agormedah et al. 2020; Farooq et al. 2020; Jena 2020). Chung et al. (2020) revealed students’ issues of internet connectivity while Camara (2020) identified inefficient technology resulted into the distorted communication during the classes (Sheerman et al. 2020). Study context Like other developing countries, Pakistan is also deficient in technology (Farooq et al. 2020). Most of the educational activities are carried out traditionally on campus. It is worth mentioning that online educational activities were previously, before pandemic, limited to distance learning educational institutions in Pakistan. Although teachers and students were aware of online educational activities. However, they were neither trained nor provided equipment and environment to use online mode. Similar situation is found in HEIs of AJK. Therefore, this research is attempted in HEIs of Azad Jammu and Kashmir to know the students’ perspective regarding online learning during pandemic. Organization of the study In this article, introduction section is followed by a detailed empirical literature discussed in the context of developed, developing and Pakistan. At the end of literature, a comprehensive conceptual framework is provided for the readers with hypotheses. Third section of article is methodology. A concise methodology is provided that covers the research design, research method, population, sampling, data collection tool, sources of data collection, measurement, use of SPSS, strategies of interpretation and presentation of data. Fourth section is results derived from analysis. It contained description of demographic variables and findings of hypotheses. Last section of article comprised discussions. A precise discussion has been made for the readers. At the end conclusion is drawn based on the analysis of data. Literature review The higher education system is in the continued process of structural change (Altbach 2005; Ansell 2008; Crosier et al. 2007). The universities have to keep pace with the needs, desires, requirements, and changing landscapes of the educational activities and institutions (Gibbons 1998; Hunt 2011; Marginson and Rhoades 2002). So, information technologies and the e-learning systems are found necessary factors in carrying out the educational activities in universities (Liaw et al. 2007). Thus, the HEIs are investing more on the technologies i.e., devices and online system to keep updating the e-learning process (Salloum et al. 2019). However, in the changing landscapes of the technology, major challenge for HEIs is to integrate the proactive e-learning system to reinforce the effective learning to the students (Samsudeen and Mohamed 2019). The online learning initiative was taken owing to the pandemic situation across the globe. In the developed countries, use of technology in academia is normally carried out for the educational activities (Pearce et al. 2010; Volchik and Maslyukova 2017). The digital transformation is not a new phenomenon in higher educational institutions (Abad-Segura et al. 2020). These countries are efficient in technology and keep updating the educational e-learning systems with the passage of time (Castro Benavides et al. 2020). The online systems are utilized along with on campus educational activities according to the requirements (Xiao 2019). Normally, the e-learning has always been the part and parcel of the traditional educational system (Kuzu 2020). For the first time in history, the traditional educational system was replaced through online learning system due to the pandemic (Adnan and Anwar 2020). Initially, to curb the prevalence, the HEIs were closed, and educational activities were suspended (Chung et al. 2020). While looking at severity and dire consequences of the pandemic, educational activities were shifted to online systems as it was not possible to keep institutions closed (Fatonia et al. 2020). Although the online learning has been beneficial to the great extent however the issues have been reported by the students (Muthuprasad et al. 2021). As the research studies revealed that performance of students is affected due to online learning. Onyema et al. (2020) and Rasheed et al. (2021) revealed that students are not satisfied with complete shift of educational activities. Research also revealed that students complained about the grading and marking criteria as well (Rizun and Strzelecki 2020; Sheerman et al. 2020). In developing countries, the situation is quite different to that of the developed countries. As most of the developing countries are deficient in technology (Kituyi and Tusubira 2013; Quimno et al. 2013). Similarly, there scant use of technology in HEIs (Sife et al. 2007). The use of technology is considered only for the meetings, conferences, and special events (Crosier et al. 2007). It is asserted that means of technology is restrained for the academic activities on campus (Salloum et al. 2019; Samsudeen and Mohamed 2019; Santos et al. 2019). Adnan and Anwar (2020) argued that it was very difficult for the HEIs to initiate the online learning due to the limited use of technology. However, it was to curb the prevalence of pandemic HEIs had to shift the academic activities online (Ali 2020). It is important to mention here that developing countries undersupplied in digital technologies suffered during the pandemic (Farooq et al. 2020). The effects of such a transformation were directly experienced by the students who were neither trained nor familiar with the excessive use of technology for the sake of academic pursuits (Mukhtar et al. 2020; Mumtaz et al. 2021). As the performance of the students was affected badly, they were unable to learn the skills (Rasheed et al. 2021). Moreover, students suffered from the tension, anxiety, stress, and fears of infection (Shoaib and Abdullah 2021; Wang and Zhao 2020). Similarly, students also faced the issues of grading and marking (Wargadinata et al. 2020; Zai and Akhunzada 2020). Almaiah et al. (2020) and (Anwar et al. 2020) found that students had the issues in technology use. Sheerman et al. (2020) added that majority of undergrad students had not access to technology either laptop or smart phones. It was further complicated when they faced the poor internet connectivity. As Zai and Akhunzada (2020) and TI (2020) elaborated that the poor internet is the issues of most of the students in developing countries. In the same fashion, Wargadinata et al. (2020) also asserted that students in developing countries are unable to learn and enhance the skills. Further, it affects the performance of the students (Alkamel et al. 2021; Almaiah et al. 2020). Conceptual framework While developing the conceptual framework, we have developed the following hypotheses. Hypothesis 1 There is association between educational performance and lack of technology, grading and marking issues, low learning skills, internet, and mental issues. Hypothesis 2 The bad educational performance is due to the lack of technology, grading system and marking issues, low learning skills, internet, and mental issues. Dependent variable Educational performance. Independent variables Lack of Technology, Grades, Marking, Learning Skills, Internet, and Mental issues. Methodology Survey tool and sampling In this study, we selected quantitative research design and employed cross-sectional research method. We conducted this research in one of the universities of AJK. The Google survey was carried out from 20th October to 20th December 2020. The data was collected from the students studying in Bachelor and Master programmes. Keeping in view the lockdown situation, owing to the pandemic, it was not possible to organize a campus-based sampling survey, thus, online survey form was designed by using Google survey form (https://docs.google.com/forms/). It was also not possible to visit the students physically to get the questionnaire filled. Thus, the questionnaire was designed in English language and converted into Google survey form. Primarily, it has been helpful in the present situation of COVID-19 where social distancing and social isolation is strictly enforced to curtail the spread of virus. Secondly, students are not available on campus rather online learning/ teaching activities were started since the pandemic. To determine sample size, we disseminated Google survey form among 1228 students. Out of 1228 students, 405 responded and filled the questionnaire. Thus, sample size of study was n = 405. We did not use probability sampling technique as we were not sure whether the students will respond or not despite having data. To avoid the inconvenience, we used nonprobability convenience sampling technique. Among the four faculties, 46 teacher were identified, contacted and shared the Google survey form i.e., 15 from Arts, 12 from Sciences, 11 from Engineering and 8 from Health Sciences. The purpose of selecting the teacher was to access students because they were directly in contact with the students via online learning. By means of teachers, students were contacted and Google survey form was shared with them. The Google survey form was shared through a link containing brief introduction, objective, information about anonymity and confidentiality, procedure, and statement about the voluntary nature of survey was also printed on the front page of survey form. The survey from was circulated among teachers via university WhatsApp group and teachers further circulated among the students through WhatsApp and Microsoft Teams. As Microsoft teams is recommended by university for the online learning. Thus, it is believed that every student would have the Teams account. The Google survey form was distributed among the 1228 students while 405 students responded over a period of two months. Thus, the response rate has been 33%. Measures The survey form comprised two portions. First portion was demographic information, and second portion was on the problems faced by the students due to online learning during the pandemic. In personal information portion, we asked question of age, educational level, faculty, and residence. In second portion, ten questions were asked about the issues they face in learning due to the pandemic. The second portion was purely designed on the Likert scale. After the formulation, the questionnaire was pretested, and omissions were removed. Thus, the Cronbach’s Alpha ranged from 0.72 to 0.83 and to overall 0.88. Statistical Analysis was done and frequency (N) distribution of the demographic information was determined by means of SPSS. Two hypotheses were formulated and tested by employing Chi-square and Regression Model respectively. First hypothesis was to check the association of educational performance with lack of technology, grading and marking issues, learning skills, internet, and mental issues In the second hypothesis, predictors of bad educational performance of the students were: use of technology, grading and marking issues, learning skills, internet, and mental issues. The data was documented while all the statistical analyses were performed using SPSS Statistics, version 20, and Microsoft Excel 2018. Results Socio-demographic characteristics Table 1 showed that the demographic information of the students. As the age of students is distributed as, 69.4 percent students fall in age bracket 20–25, 25.9 percent were of age 26–31 years and 4.7 [percent were found above than 32 years of age. The students belonged to four faculties of university. As 29.6 percent belonged to faculty of arts, 25.6 percent fitted into the faculty of arts, 25 percent in faculty of engineering and 19.7 percent from faculty of health sciences. The distribution of students according to the residence is found interesting as 62 percent belonged to the rural areas as compared to 38 percent belonged to urban areas. The educational level of students ranged from BS to PhD. A major proportion of students’ 67.4 percent fall in the BS category, 19.8 percent having MSc/MA educational level, and 9.4 percent have MS and only 3.5 percent were earning the PhD degrees.Table 1 The demographic characteristics of the students Sr. no. Variables Referents Count Percentage 1 Age 20–25 281 69.4 26–31 105 25.9 32 and Above 19 4.7 Total 405 100.0 2 Faculty Arts 120 29.6 Science 104 25.6 Engineering 101 25 Health Sciences 80 19.7 Total 405 100.0 3 Residence Rural 251 62.0 Urban 154 38.0 Total 405 100.0 4 Educational Level BS 273 67.4 MSc/MA 80 19.8 MS 38 9.4 PhD 14 3.5 Total 405 100.0 Hypotheses testing Hypothesis 1 There is association between educational performance and lack of technology, grading and marking issues, low learning skills, internet, and mental issues. Table 2 shows the association of educational performance with different variables. As the lack of technology is highly significant with the results of p < 0.000. It is noted that results of all the variables included in hypothesis were most significant. The results suggest that the lack of technology impacts the performance of the students to the great extent during pandemic crisis. Similar arguments are given by Coman et al. (2020). They stated that technology has affected the educational performance of the students. The low grades are also highly significant with the low education performance indicating that performance is affected (Adnan and Anwar 2020). It is further revealed by Barrot et al. (2021). They asserted that low. grades affect the performance of students. The effects on mental growth are also highly significant to the educational performance of the students (Faisal et al. 2021). As Abdullah and Shoaib (2021) found psychosocial impacts on the lives of people. Similarly, the performance is significantly associated with the educational performance of the students resulting that the marking issues negatively affected performance of the students (Fatonia et al. 2020). The rests suggested that further supported by Ahmad et al. (2022). They found that performance is impacted by the low marking grades. The association between performance and learning skills is also significant that construes students’ performance is affected, and they are unable to learn the skills due to online learning (Wang et al. 2020). Similar assertions are given by Dutta and Smita (2020) who described nexus of learning and performance are important for the good performance. In the same fashion, internet issue have association with the performance that shows that the performance is affected by the internet disconnectedness (Wargadinata et al. 2020). Similar results are given by many studies (Adnan and Anwar 2020). Based on the above findings, it is argued that educational performance has strong association with the lack of technology, low grades, effects in mental growth, marking issues, low learning skills and internet issues (Agormedah et al. 2020; Onyema et al. 2020; Tanveer et al. 2020). Thus, it is argued, the due to the online learning performance of the students in AJK in badly impacted due to internet disconnectedness. It is noted that students have less access to technology either laptop or smart phones (Rahiem 2021). Similarly, it is noteworthy that the students are unable to learn the skills at home (Hashemi 2021). Owing to these issues, students experience mental issues of stress, anxiety, tension, and fears (Abdullah and Shoaib 2021). Moreover, students also experienced the issues of score, marking and internet.Table 2 Chi-Square statistical test (dependent variable = educational performance) No. Variable/s Pearson value df P-value i Lack of Technology 222.661a 6 .000 ii Low Grades 217.023a 8 .000 iii Effect on Mental Growth 325.455a 8 .000 iv Marking Issues 260.286a 8 .000 v Low Learning Skills 58.790a 6 .000 vi Internet Issues 309.314a 8 .000 Total number of observations (n) = 405 Hypothesis 2 The bad educational performance is due to the lack of technology, grading system and marking issues, low learning skills, internet, and mental issues. Table 3 revealed determinants of bad educational performance. It showed the most significant values of p values in each category of the analysis i.e., P < 0.000. These results how that lack of technology, grading and marking issue, low learning skills, internet and mental issues are predictor of the negative educational performance of the students. These significant values highlight the impact on the educational performance of the students. As the performance is affected using technology as the students were not aware about the use of technology and suffered in educational achievements (Abad-Segura et al. 2020; Castro Benavides et al. 2020). Similar findings are given by (Mahyoob 2020). He argued that use of technology has key role in educational performance. The performance of students is also affected by the grades of the students (Farooq et al. 2020). It is further supported by the argument of Tadesse and Muluye (2020) who noted that performance is linked with grades of the students. Findings revealed marks criteria discriminatory (Zai and Akhunzada 2020). It is also argued by (Tadesse and Muluye 2020). They stated that students were unable to learn the skills due to online learning (Tanveer et al. 2020). It is pertinent to mention that students suffered from the internet connectivity issues (Simamora 2020). All these issues added on the mental issues of stress, anxiety, tension and fears in students (Faisal et al. 2021; Tang et al. 2020). It is thus found that the educational performance is affected by the different predictors (Hashemi 2021; Tadesse and Muluye 2020). By looking at the ß values, we found that learning skills and internet issues are the major indicators of the bad educational performance of the students (Fig. 1).Table 3 An OLS multiple regression predicting educational performance of students (standard errors and parameter estimates) Sr. no. Unstandardized coefficients Standardized coefficients Variables B Std. error Beta t Sig. i Technology .170 .013 .312 11.016 .000 ii Grades .140 .011 .240 8.613 .000 iii Mental Growth .154 .012 .277 9.983 .000 iv Marks Criteria .113 .016 .167 6.043 .000 v Learning Skills − .270 .023 − .314 − 10.766 .000 vi Internet Issues − .142 .014 − .303 − 11.374 .000 (Constant) 1.191 .046 20.821 .000 F = 106.473, Sig. = .000  R Square = 0.429, Adjusted R Square = 0.425. df = 6  Total number of Observation (n) = 405 Discussions The online educational activities were commenced amidst the pandemic due to the urgency of the disease (Aboagye et al. 2020; Adnan and Anwar 2020; Shoaib and Abdullah 2020). It has been revealed that the online educational activities were quite new in most of the developing countries like Pakistan (Cecilio-Fernandes et al. 2020; Chung et al. 2020). As these countries were either incapacitated or none even through to shift the whole system of education on e-learning (de Boer 2021; Dwivedi et al. 2020). However, same happened in Pakistan and the learning was shifted to the online (Adnan and Anwar 2020; Ali 2020). This shift of educational activities has created a vivid gap in educational performance of the students the world over (Fatonia et al. 2020). Similar issues have been reported in Pakistan (TI 2020) and we also found that educational performance is affected badly due to online learning system during the pandemic. The research across the globe indicated the different factors of the bad educational performance of the students (Agormedah et al. 2020; Baticulon et al. 2021; Tanveer et al. 2020). These included, the lack of technology, grading and score issues, marks criteria, learning skills, internet issues and mental issues experienced by the students during the online learning (Khattar et al. 2020; Lukong et al. 2020). Crosier et al. (2007) found that the students in developing countries suffered due to the poor technology as the HEIs and management was not even prepared to initiate the learning online. Thus, due to lack or deficient technology, students were not able to properly take the online classes (Rasheed et al. 2021). Similar issues we found in the study that due to deficient technology students suffered in pandemic while learning online. The learning skills of the students were not enhanced, and they also experienced the issues of low grading and marking issues (Leal Filho et al. 2021). It further affected the performance of the students (Rasheed et al. 2021). In this study, we also found same issues of grading and marking impacting the students’ performance (Azlan et al. 2020). Owing to the week network, they were not able to attend the classes regularly (Lembani et al. 2020). The results of our study also endorsed the bad connectivity of students that further affected the performance. Research revealed that, due to all these factors, students experienced the mental health issues of stress, anxiety, tension, and fears (Faisal et al. 2021; Khan et al. 2020; Tang et al. 2020; Wang et al. 2020). In this case, we also reached at the vantage point that the students suffered from the mental issues due to the lack of technology and disconnected internet. It is thus revealed that the educational performance of the students was badly impacted due to the online learning amidst the pandemic crisis. Conclusion We reached at the conclusion that the educational performance of the students is mainly impacted by the lack of technology including internet. Similarly, students were unable to learn the skills and improve the scores. As the grading and marking criteria also impacted the scores of the students. Owing to these issues, they suffered from the mental issues of anxiety, tension, stress, and fears of losing scores and maintain the consistency. It is, thus, concluded that the students’ educational performance is badly affected due to the online learning midst the COVID-19 pandemic in AJK. It is suggested to the higher educational institutions to take the radical measures of preparedness during any such crisis to ensure the smooth online educational and learning environment to the students.Fig. 1 An OLS multiple regression predicting educational performance of students Authors' contributions This review article is written by the first and corresponding author while second author revisited the article and made major changes. Funding The funding for this study was not available. Availability of data and material All the material and data used in this study is available as many data bases were focused. Code availability The data is simply processed through EndNote 9 and no other software is used. Declarations Conflict of interest Authors declare no potential conflict of interest. Consent to publish All the authors contributed to the article and consented to publish the article. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ==== Refs References Abad-Segura E González-Zamar M-D Infante-Moro JC RuipérezGarcía G Sustainable management of digital transformation in higher education: global research trends Sustainability 2020 12 5 2107 Abdullah F Shoaib M Psychosocial impacts of COVID-19 pandemic: a cross-sectional study of Mirpur Pakistan Int. Rev. Sociol. 2021 31 470 Aboagye, E., Yawson, J. A., & Appiah, K. N.: COVID-19 and E-learning: the challenges of students in tertiary institutions. Soc. Educ. Res. 2(1), 1–8 (2020). 10.37256/ser.212021422. Adnan M Anwar K Online learning amid the COVID-19 pandemic: students' perspectives Online Submiss. 2020 2 1 45 51 Agormedah EK Henaku EA Ayite DMK Ansah EA Online learning in higher education during COVID-19 pandemic: a case of Ghana J. Educ. Technol. Online Learn. 2020 3 3 183 210 Ahmad, A., Shoaib, M., & Abdullah, F.: COVID-19 black swan and personal protective equipment (PPE) in Pakistan. Health Educ. 122(4), 365–373 (2022). 10.1108/HE-06-2021-0093. Ali W Online and remote learning in higher education institutes: a necessity in light of COVID-19 pandemic High. Educ. Stud. 2020 10 3 16 25 Aliyyah RR Rachmadtullah R Samsudin A Syaodih E Nurtanto M Tambunan ARS The perceptions of primary school teachers of online learning during the COVID-19 pandemic period: a case study in Indonesia J. Ethn. Cult. Stud. 2020 7 2 90 109 Alkamel MAA Chouthaiwale SS Yassin AA AlAjmi Q Albaadany HY Arpaci I Al-Emran M Al-Sharafi MA Marques G Online testing in higher education institutions during the outbreak of COVID-19: challenges and opportunities Emerging Technologies During the Era of COVID-19 Pandemic 2021 Cham Springer Almaiah MA Al-Khasawneh A Althunibat A Exploring the critical challenges and factors influencing the E-learning system usage during COVID-19 pandemic Educ. Inf. Technol. 2020 25 5261 5280 Altbach PG Patterns in higher education development Am. High. Educ. Twenty-First Cent. Soc. Polit. Econ. Challeng. 2005 2 15 37 Ansell BW University challenges: explaining institutional change in higher education World Polit. 2008 60 2 189 230 Anwar M Khan A Sultan K The barriers and challenges faced by students in online education during Covid-19 pandemic in Pakistan Gomal Univ. J. Res. 2020 36 1 52 62 Armoed, Z. (2021). The COVID-19 pandemic: Online teaching and learning at higher education institutes. Paper presented at the IOP Conference Series: Earth and Environmental Science. Aumjaud, B. E. (2020). Critical reflection on teaching and assessment practices in a higher education setting in Mauritius during the COVID-19 pandemic national lockdown. Editors: Dr UG Singh (University of KwaZulu-Natal, South Africa) Prof CS Nair (Victorian Institute of Technology, Australia) e-ISBN: 978-1-990901-49-2, 160. Azlan CA Wong JHD Tan LK Nizam MS Huri AD Ung NM Pallath V Tan CPL Yeong CH Ng KH Teaching and learning of postgraduate medical physics using Internet-based e-learning during the COVID-19 pandemic–A case study from Malaysia Phys. Med. 2020 80 10 16 33070007 Bączek M Zagańczyk-Bączek M Szpringer M Jaroszyński A Wożakowska-Kapłon B Students’ perception of online learning during the COVID-19 pandemic: a survey study of Polish medical students Medicine 2021 100 7 e24821 33607848 Barrot JS Llenares II Del Rosario LS Students’ online learning challenges during the pandemic and how they cope with them: the case of the Philippines Educ. Inf. Technol. 2021 26 6 7321 7338 Baticulon RE Sy JJ Nicole RI Alberto MB Baron C Robert EC Mabulay LG Rizada T Christl JS Tiu CA Clarion JC Reyes B Barriers to online learning in the time of COVID-19: a national survey of medical students in the Philippines Med. Sci. Educ. 2021 31 615 33649712 Besser, A., Flett, G. L., & Zeigler-Hill, V.: Adaptability to a sudden transition to online learning during the COVID-19 pandemic: understanding the challenges for students. Scholarship Teach. Learn. Psychol. 8(2), 85–105 (2022). 10.1037/stl0000198 Budur T Demir A Cura F University readiness to online education during Covid-19 pandemic Int. J. Soc. Sci. Educ. Stud. 2021 8 1 180 200 Camara W Never let a crisis go to waste: large-Scale assessment and the response to COVID-19 Educ. Meas. Issues Pract. 2020 39 3 10 18 Castro Benavides LM Tamayo Arias JA Arango Serna MD Branch Bedoya JW Burgos D Digital transformation in higher education institutions: a systematic literature review Sensors 2020 20 11 3291 32526998 Cecilio-Fernandes D Parisi MCR Santos TM Sandars J The COVID-19 pandemic and the challenge of using technology for medical education in low and middle income countries MedEdPublish 2020 9 74 Chung E Subramaniam G Dass LC Online Learning readiness among university students in Malaysia amidst COVID-19 Asian J. Univ. Educ. 2020 16 2 46 58 Coman C Țîru LG Meseșan-Schmitz L Stanciu C Bularca MC Online teaching and learning in higher education during the coronavirus pandemic: students’ perspective Sustainability 2020 12 24 10367 Crosier, D., Purser, L., & Smidt, H.: Trends 5: Universities Shaping the European Higher Education Area: EAU (2007). https://eua.eu/downloads/publications/trends%20v%20universities%20shaping%20the%20european%20higher%20education%20area.pdf. de Boer H COVID-19 in Dutch higher education Stud. High. Educ. 2021 46 1 96 106 Dutta S Smita MK The impact of COVID-19 pandemic on tertiary education in Bangladesh: students’ perspectives Open J. Soc. Sci. 2020 8 09 53 Dwivedi YK Hughes DL Coombs C Constantiou I Duan Y Edwards JS Gupta B Lal B Misra S Prashant P Raman R Impact of COVID-19 pandemic on information management research and practice: transforming education, work and life Int. J. Inform. Manag. 2020 55 102211 Faisal RA Jobe MC Ahmed O Sharker T Mental health status, anxiety, and depression levels of Bangladeshi university students during the COVID-19 pandemic Int. J. Mental Health Add. 2022 20 3 1500 1515 Farooq F Rathore FA Mansoor SN Challenges of online medical education in Pakistan during COVID-19 pandemic J. Coll. Phys. Surg. Pak 2020 30 6 67 69 Fatonia NA Nurkhayatic E Nurdiawatid E Fidziahe GP Adhag S Irawanh AP Julyantoj O Azizik E University students online learning system during Covid-19 pandemic: advantages, constraints and solutions Syst. Rev. Pharm. 2020 11 7 570 576 Gibbons, M.: Report on Higher Education Relevance in the 21st Century. World Bank, Washington DC (1998). Hashemi A Effects of COVID-19 on the academic performance of Afghan students’ and their level of satisfaction with online teaching Cogent Arts Human. 2021 8 1 1933684 Hunt, C.: National strategy for higher education to 2030: Department of Education and Skills. Report of strategy group. Ireland (2011). Irfan M Kusumaningrum B Yulia Y Widodo SA Challenges during the pandemic: use of e-learning in mathematics learning in higher education Infinity J. 2020 9 2 147 158 Jena, P. K.: Impact of Covid-19 on higher education in India. Int. J. Adv. Educ. Res. (IJAER) 5(3), 77–81 (2020) Khan AH Sultana MS Hossain S Hasan MT Ahmed HU Sikder MT The impact of COVID-19 pandemic on mental health & wellbeing among home-quarantined Bangladeshi students: a cross-sectional pilot study J. Affect. Disord. 2020 277 121 128 32818775 Khattar, A., Jain, P. R., & Quadri, S. (2020). Effects of the disastrous pandemic COVID 19 on learning styles, activities and mental health of young Indian students-a machine learning approach. Paper presented at the 2020 4th International Conference on Intelligent Computing and Control Systems (ICICCS). Kituyi, G., & Tusubira, I.: A framework for the integration of e-learning in higher education institutions in developing countries. Int. J. Educ. Dev. ICT, 9(2), 19–36 (2013). Kohli H Wampole D Kohli A Impact of online education on student learning during the pandemic Stud. Learn. Teach. 2021 2 2 1 11 Kuzu ÖH Digital transformation in higher education: a case study on strategic plans Bыcшee Oбpaзoвaниe в Poccии 2020 29 3 9 23 Leal Filho W Price E Wall T Shiel C Azeiteiro UM Mifsud M Brandli L Farinha CS Caeiro S Salvia AL Vasconcelos CR COVID-19: the impact of a global crisis on sustainable development teaching Environ. Dev. Sustain. 2021 23 8 11257 11278 33424430 Lembani R Gunter A Breines M Dalu MTB The same course, different access: the digital divide between urban and rural distance education students in South Africa J. Geogr. High. Educ. 2020 44 1 70 84 Liaw S-S Huang H-M Chen G-D An activity-theoretical approach to investigate learners’ factors toward e-learning systems Comput. Hum. Behav. 2007 23 4 1906 1920 Lukong T Tombari C Mbome B Ankinibom C Fru P Atong H Mbi TC Juliet ME Psychological implications of COVID-19 on students learning outcome at the University of Buea, Cameroon Am. Res. J. Human. Soc. Sci. 2020 3 8 1 14 Mahyoob M Challenges of e-learning during the COVID-19 pandemic experienced by EFL learners Arab World English J. (AWEJ) 2020 11 4 351 Marginson S Rhoades G Beyond national states, markets, and systems of higher education: a glonacal agency heuristic High. Educ. 2002 43 3 281 309 Mishra L Gupta T Shree A Online teaching-learning in higher education during lockdown period of COVID-19 pandemic Int. J. Educ. Res. Open 2020 1 100012 35059663 Mukhtar K Javed K Arooj M Sethi A Advantages, Limitations and Recommendations for online learning during COVID-19 pandemic era Pakistan J. Med. Sci. 2020 36 S27 Mumtaz N Saqulain G Mumtaz N Online academics in Pakistan: COVID-19 and beyond Pakistan J. Med. Sci. 2021 37 1 283 Murphy MP COVID-19 and emergency eLearning: Consequences of the securitization of higher education for post-pandemic pedagogy Contemp. Sec. Policy 2020 41 3 492 505 Muthuprasad T Aiswarya S Aditya K Jha GK Students’ perception and preference for online education in India during COVID-19 pandemic Soc. Sci. Human. Open 2021 3 1 100101 Onyema EM Eucheria NC Obafemi FA Sen S Atonye FG Sharma A Alsayed AO Impact of Coronavirus pandemic on education J. Educ. Pract. 2020 11 13 108 121 Pearce, N., Weller, M., Scanlon, E., & Kinsley, S.: Digital scholarship considered: How new technologies could transform academic work. Education 16(1)Spring 2010, 33–44 (2010). Quimno, V., Imran, A., & Turner, T.: Introducing a sociomaterial perspective to investigate e-learning for higher educational institutions in developing countries. ACIS 2013: Information Systems: Transforming the Future: Proceedings of the 24th Australasian Conference on Information Systems, 1– 12 (2013). https://researchrepository.rmit.edu.au/discovery/fulldisplay/alma9921861133701341/61RMIT_INST:ResearchRepository. Rahiem MD Remaining motivated despite the limitations: University students’ learning propensity during the COVID-19 pandemic Child Youth Serv. Rev. 2021 120 105802 33318719 Rasheed R Rizwan A Javed H Sharif F Zaidi A Socio-economic and environmental impacts of COVID-19 pandemic in Pakistan—an integrated analysis Environ. Sci. Pollut. Res. 2021 28 19926 Rizun M Strzelecki A Students’ acceptance of the Covid-19 impact on shifting higher education to distance learning in Poland Int. J. Environ. Res. Public Health 2020 17 18 6468 32899478 Sá MJ Serpa S The global crisis brought about by SARS-CoV-2 and its impacts on education: an overview of the Portuguese panorama Sci Insigt Edu Front 2020 5 2 525 530 Salloum SA Al-Emran M Shaalan K Tarhini A Factors affecting the e-learning acceptance: a case study from UAE Educ. Inf. Technol. 2019 24 1 509 530 Samsudeen SN Mohamed R University students’ intention to use e-learning systems Inter. Technol. Smart Educ. 2019 16 219 Santos H Batista J Marques RP Digital transformation in higher education: the use of communication technologies by students Proced. Comput. Sci. 2019 164 123 130 Sheerman L Marston HR Musselwhite C Morgan D COVID-19 and the secret virtual assistants: the social weapons for a state of emergency Emerald Open Res. 2020 2 19 19 Shoaib M Abdullah F Risk reduction of COVID-19 pandemic in Pakistan Soc. Work Public Health 2020 35 7 557 568 32811345 Shoaib, M., & Abdullah, F.: COVID-19 backlash: psycho-social impacts of outbreak in Pakistan. Health Educ. 121(3), 265–274 (2021).10.1108/HE-07-2020-0047. Sife A Lwoga E Sanga C New technologies for teaching and learning: challenges for higher learning institutions in developing countries Int. J. Educ. Develop. ICT 2007 3 2 57 67 Simamora RM The challenges of online learning during the COVID-19 pandemic: an essay analysis of performing arts education students Stud. Learn. Teach. 2020 1 2 86 103 Tadesse S Muluye W The impact of COVID-19 pandemic on education system in developing countries: a review Open J. Soc. Sci. 2020 8 10 159 170 Tang W Hu T Yang L Xu J The role of alexithymia in the mental health problems of home-quarantined university students during the COVID-19 pandemic in China Person. Individ. Differ. 2020 165 110131 Tanveer M Bhaumik A Hassan S UlHaq I Covid-19 pandemic, outbreak educational sector and students online learning in Saudi Arabia J. Entrep. Educ. 2020 23 3 1 14 TI, S. K.: Response analysis, challenges & strategic vision for pakistan amidst the COVID-19 crisis. On August, 21 (2020). Volchik V Maslyukova E Performance and sustainability of higher education: key indicators versus academic values J. Sec. Sustain. Issues 2017 6 3 501 512 Wang C Zhao H The impact of COVID-19 on anxiety in Chinese university students Front. Psychol. 2020 11 1168 32574244 Wang X Hegde S Son C Keller B Smith A Sasangohar F Investigating mental health of US college students during the COVID-19 pandemic: cross-sectional survey study J. Med. Internet Res. 2020 22 9 e22817 32897868 Wargadinata W Maimunah I Eva D Rofiq Z Student’s responses on learning in the early COVID-19 pandemic Tadris J. Educ. Teacher Train. 2020 5 1 141 153 Xiao J Digital transformation in higher education: critiquing the 5-year development plans (2016–2020) of 75 Chinese universities Distance Educ. 2019 40 4 515 533 Zai SAY Akhunzada AS Challenges and responses of higher education institutions to align higher education with COVID-19 realities: a thematic analysis Int. J. Dist. Edu. E-Learn. 2020 6 1 109 129
PMC009xxxxxx/PMC9362354.txt
==== Front Int Rev Public Nonprofit Mark International Review on Public and Nonprofit Marketing 1865-1984 1865-1992 Springer Berlin Heidelberg Berlin/Heidelberg 343 10.1007/s12208-022-00343-5 Original Article Barriers to volunteering in the field of intellectual disability: a cluster analysis Cruz Soraia soraiacruz89@hotmail.com 1 http://orcid.org/0000-0003-4194-9127 Ferreira Marisa Roriz mferreira@estgf.ipp.pt 2 http://orcid.org/0000-0002-3644-3992 Borges Ana aib@estg.ipp.pt 2 http://orcid.org/0000-0002-7626-0509 Casais Beatriz bcasais@eeg.uminho.pt 34 1 ESTG - P.PORTO, Felgueiras, Portugal 2 CIICESI, ESTG - P.PORTO, Felgueiras, Portugal 3 grid.10328.38 0000 0001 2159 175X School of Economics & Management, University of Minho, Braga, Portugal 4 CICS.NOVA.UMinho, Braga, Portugal 5 8 2022 2023 20 2 341366 16 2 2022 3 7 2022 © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022, corrected publication 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. This paper aims to characterise the profiles of individuals likely to feel discouraged to volunteer in the field of intellectual disability. The socio-emotional contours of intellectual disability hinder the involvement of volunteers in this field. There is evidence of the particular barriers to volunteering in activities involving intellectually disabled people, but there is a dearth of research on the characteristics of individuals that mention such barriers. A survey applied to 197 individuals allowed, through latent classes, to identify three clusters of individuals—assuming volunteering as having a negative impact; unawareness of the reality of intellectual disability; and no barriers to volunteering; and three groups of barriers to volunteering in the field of intellectual disability—characteristics of intellectually disabled people; awareness; introversion. Based on the characteristics of the clusters identified, the study addresses possible strategies to overcome the constraints, aiming at involving volunteers in activities targeting individuals with intellectual impairments and to better target the recruitment of volunteering actions in this field. The continuous understanding of barriers to donate time can allow institutions to minimise constraints and overcome hurdles by emphasising the value of experiences that meet the motivations of volunteers. Keywords Volunteering Non-profit organizations Barriers Intellectual disability issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2023 ==== Body pmcIntroduction The United Nations (UN) plays a critical role in addressing a host of global problems via the implementation of the Seventeen Goals of Sustainable Development (SDGs). Goal ten, “reduce inequality”, assumes that no one is left behind, although the current context of the COVID-19 pandemic has deepened existing inequalities, particularly in the most vulnerable communities. The general goals and objectives include a call for action to help mitigate inequalities. In this sense, the continuous role of non-profit organizations (NPOs) is critically important in addressing these social challenges (Chaves-Avila & Gallego-Bono, 2020) by encouraging individuals to volunteer to causes that support the UN’s SDGs (Badruesham et al., 2021; Fergusson & McFarlane, 2022). In Europe, volunteering rates vary according to the country under analysis (Southby et al., 2019). In countries like Switzerland, Germany or Spain, the number of volunteers has been decreasing (Studer, 2015). Outside of Europe, there are several countries that are receptive to volunteering. For instance, England has a rate of 27% of adults doing formal volunteering on a regular basis; but, on the other hand, 42% of this population only volunteers on an occasional basis (Southby et al., 2019). The relationship established between the volunteer and the hosting organisation is key to volunteer retention (Brudney & Meijs, 2014; Ferreira et al., 2012; Tiltay & Islek, 2020; Vinton, 2012). It is critically important that the volunteers positively identify themselves with the organisation and embody its mission, culture and values (Anastasiadis & Barkoukis, 2020), as this attitude will increase the likelihood that they will connect to the organisation (Hager & Brudney, 2004; Karl et al., 2008). Based on the expectations and needs of volunteers, managers can more easily adapt the offer and harmonise the needs of the organisation with those of the volunteers (Bjerneld et al., 2006; Vanderstichelen et al., 2020). Many NPOs rely on volunteers as core resources for the development of their activities (Willems & Dury, 2017), although volunteer work is directly related to a "supply" that constitutes an important productive resource (Gaymard & Chauvet, 2016). This is particularly true in the current pandemic scenario, since the COVID-19 crisis has exposed various vulnerabilities (Kumar et al., 2020), while having simultaneously triggered a massive wave of real concern and empathy for others (Trautwein et al., 2020). Many researchers argue that volunteers are heterogeneous (Bussell & Forbes, 2002). However, several studies associate certain characteristics with the behaviour of a volunteer, which allows grouping volunteers according to their personal characteristics and/or behaviours (Dolnicar & Randle, 2007; Ramirez-Valles, 2006; Sherer, 2004). On the other hand, the social and family environment significantly contributes to the degree of involvement in volunteer work (Hu et al., 2016). Thus, it is of key importance that NPOs define appropriate strategies to attract volunteers and in parallel manage resources to motivate them, because volunteers are a valuable resource for these organisations (Ivonchyk, 2019; Wit et al., 2017). Besides the motivation to donate time to the social economy, there are several barriers to volunteering (McKenzie et al., 2021; Southby et al., 2019; Sundeen et al., 2007). Although several studies mention that volunteering can bring benefits to the various stakeholders — volunteers, the organisation and its public, as well as the community itself (Ganesh & Mcallum, 2012; Handy & Srinivasan, 2004; Wit et al., 2022) —, not all individuals are equally predisposed to volunteering (Macduff et al., 2009; Netting et al., 2005). Efficient management of non-profit organisations and volunteer recruitment critically implies understanding both the motivations to engage in social economy activities and the barriers that hinder such involvement. NPOs should enhance the value proposition of volunteering activities to address such motivations and reduce potential barriers. There are currently several studies on volunteering in the most diverse areas. However, the literature mentions that volunteering in the specific area of disability is scarce (Fort et al., 2017; Gaymard & Chauvet, 2016; McConkey et al., 2021; Smith et al., 2018), and NPOs acting in this field face difficulties in recruiting resources due to the negative public opinion associated with people with mental illnesses (Gaymard & Chauvet, 2016). Most contacts with intellectually disabled people are informal and happen through neighbours, friends or family members (Han et al., 2020). Despite the key importance of cultivating practices of inclusiveness in the community and the changing perceptions towards stigma and discrimination regarding intellectual disability, this topic requires more dynamism in recruiting volunteers, given that volunteering plays a key role for NPOs by bringing perceived benefits, but also for the community and the volunteers themselves. Volunteering in the field of intellectual disability to promote social inclusion in the community is of paramount importance and, although the benefits of volunteering and motivations are well documented in the literature, as previously presented, the novelty of our paper is related to (i) the understanding of the volunteer barriers to volunteering in the specific area of disability and (ii) the identification of profiles of potential volunteers that allow us to comprehend the barriers to volunteering in the area of disability. The general goal of this paper is to characterise the profiles of individuals likely to feel discouraged to volunteer in the field of intellectual disability. Accordingly, we specifically intend to (i) understand the reasons why individuals generally tend to avoid volunteer work, (ii) understand the reasons given by individuals for not doing volunteer work in the specific area of intellectual disability, and (iii) identify the profiles of people who feel hindered by the different barriers identified in this particular area. Theoretical framework Volunteering in the area of intellectual disability Social exclusion is a major problem in the lives of intellectually disabled people (Nicholson & Cooper, 2013). Negative attitudes by others influence society's responses and intellectual disability tends to be associated with prejudiced attitudes (Walker & Scior, 2013). Intellectually disabled people are one of the groups most marginalised by society (Louw et al., 2020), as they are often excluded from participating in social activities and have limited opportunities when it comes to developing friendships (Louw et al., 2020; McKenzie et al., 2021; Walker & Scior, 2013). Thus, finding effective ways to combat negative attitudes and discriminatory behaviours is a key priority for researchers in the field of intellectual disability (Walker & Scior, 2013). Several studies acknowledge the importance of friendships for an individual's social inclusion process (Botero-Rodríguez et al., 2021; McConkey et al., 2021; Wilson et al., 2017). Such studies prove that people with intellectual disabilities, especially those with a higher degree of disability, have fewer friends and social relationships than people with a lower degree of disability (Robinson et al., 2020); thus, finding a network of friends to provide them with assistance is central and urgent. Typically, to be part of the community, intellectually disabled people require explicit stimuli to encourage their interaction (Louw et al., 2020), because they desire to interact socially, but lack the ability to relate (Wilson et al., 2017). In this sense, social communication and education play a key role in promoting the inclusion of these people by promoting the acquisition of skills that they would otherwise lack (Louw et al., 2020). In terms of volunteering, contact with disabled people is central for healthy coexistence and social inclusion of these people (Rimmerman et al., 2000). Therefore, the contact with these people positively affects the subsequent contact between both parties (Rimmerman et al., 2000). Contacts prior to volunteering — i.e., in everyday life, between intellectually disabled people and people without any disabilities — have positively impact the acceptance of people with intellectual disabilities; on the other hand, indirect contacts — e.g., through movies — also produces positive effects and can potentially reach wider audiences (Walker & Scior, 2013). Thus, continuous contact with people with disabilities is an opportunity to draw positive perceptions from these interactions (Rimmerman et al., 2000). Motivations for volunteering in the field of intellectual disability The analysis of a group of volunteers working in the area of disability has found that after coming into contact with this reality volunteers were able to achieve a better understanding and deal differently with this public, even outside the organizations (Silva, 2014). Silva argues that interacting with disabled people emotionally enriches volunteers, i.e., they feel more tolerant, empathetic, humble and supportive, and downplay the opinion of others more, and on a social level they are able to establish a better relationship with the people around them. The relationship between a so-called normal individual and an intellectually disabled person provides benefits to both parties (Wilson et al., 2017). Socialisation improves personal health and well-being, and expanding the personal circle of friends can enhance social development (Botero-Rodríguez et al., 2021; Wilson et al., 2017; Zboja et al., 2020), and potentially foster greater social contact and improvements in the psychosocial domain (Wilson et al., 2017). On the other hand, volunteers develop a greater sense of self-care (Botero-Rodríguez et al., 2021; Morris et al., 2017). For example, caregivers in the area of dementia people face great challenges and they need support on many levels, as these people face a higher risk of developing physical and mental health problems, as well as a lower quality of life (Halvorsrud et al., 2020). In this way, volunteers play a major role in supporting caregivers by providing them with social and emotional support, as well as the expertise to help them cope better with their work context (Halvorsrud et al., 2020). Some studies show that befriending programmes carried out with volunteers bring numerous benefits, as they can reduce depression and loneliness by improving the quality of life of intellectually disabled people (Botero-Rodríguez et al., 2021; Wilson et al., 2017), at the same time, volunteers feel motivated to participate in this type of programme, as they see this as an opportunity to serve the community, help others, grow as a person and increase their awareness of mental health (Botero-Rodríguez et al., 2021; Silva, 2014; Wilson et al., 2017). Appendix Table 1 summarizes the motivations for volunteering in the area of intellectual disability. Barriers to volunteering – globally and specifically in the field of intellectual disability Several studies show that individuals are subject to various barriers to volunteering (McKenzie et al., 2021; Southby et al., 2019; Sundeen et al., 2007), and we can identify internal and external barriers (Brandão & Bruno-Faria, 2017; M’Sallem, 2022; Southby et al., 2019; Sundeen et al., 2007), as we can see in Table 2. Internal barriers can be shaped by the internal environment, and personal characteristics can influence the predisposition to volunteer (Friedman et al., 2015; Oliveira & Pinheiro, 2021; Shinbrot et al., 2021; Southby et al., 2019); in turn, external barriers can be related to the market, government and other external networks (Breeze, 2014; Hansen & Slagsvold, 2020; Oliveira & Pinheiro, 2021; Schwingel et al., 2017; Whittaker et al., 2015) (Appendix Table 2). Society's "negative view" of people with mental illness reproduces an unfavourable context for their inclusion in society, and having little knowledge about disability or mental illness can generate fear and apprehension, which in turn can lead volunteers to decline carrying out work with this specific audience (Gaymard & Chauvet, 2016). Some studies mention that volunteers feel confused, afraid and even disgusted by these people, as they fail to understand that people with disabilities behave differently, and look different from what is socially accepted; on the other hand, such social differences between the various individuals can prompt volunteers to feel that they should protect intellectually disabled people, since social norms dictate so (Fort et al., 2017; Khoo & Engelhorn, 2011). The sharing of experiences between them can produce behaviour changes and greater acceptance of these people (Fort et al., 2017), although some volunteers report that contacting with intellectually disabled people is not always enjoyable, and in some cases the experiences can be difficult, as the volunteer feels unable to cope with the problems associated with mental illness and feels that it is necessary to have a professional in the field of psychology to make this contact (Southby et al., 2019). People with intellectual disabilities are perceived by others on the basis of their disability, and the relationship they may have with other individuals is viewed on the basis of their dependence on the other person (Robinson et al., 2020). On the other hand, intellectually disabled people are often perceived by volunteers as more prone to become violent, which negatively impacts the number of people willing to undertake volunteer work with them (Gaymard & Chauvet, 2016), therefore, these people are often isolated from society and are subject to labels and discrimination (McConkey et al., 2021). Intellectually disabled people are also perceived as exhibiting maladaptive behaviour and appearance, prompting others to feel shame or embarrassment (Botero-Rodríguez et al., 2021; Woodgate et al., 2020); at the same time, some volunteers feel fear or disgust of people with intellectual disabilities, and the same happens when the volunteer experiences the reality of these people and compares it to their own (Southby et al., 2019). Studies in the area of childhood show that the type of disability influences how individuals behave; thus, people with disabilities related to active participation, problem solving and emotional self-regulation are less accepted by society (McKenzie et al., 2021; Woodgate et al., 2020). On the other hand, these same authors find that the continuous presence of a support person limits the interaction with the disabled person, which is further compounded by their personal limitations in communication. However, the greater the informal contact with disabled people, the greater their acceptance (Han et al., 2020). Individuals with previous experiences with people with disabilities are more comfortable carrying out activities with this target audience and demonstrate more favourable attitudes towards their social inclusion (Han et al., 2020); thus, for certain volunteers, intellectually disabled people are perceived as someone who is different and should be accepted and understood (Botero-Rodríguez et al., 2021). Appendix Table 3 summarizes the barriers to volunteering in the area of intellectual disabilities. The general goal of this paper is to characterise the profiles of individuals likely to feel discouraged to volunteer in the field of intellectual disability. Thus, we have broken down the general objective into smaller parts that address the various aspects of the problem. Specifically, we intend to (i) understand the reasons why individuals generally tend to avoid volunteer work, (ii) understand the reasons given by individuals for not doing volunteer work in the specific area of intellectual disability, and (iii) identify the profiles of people who feel hindered by the different barriers identified in this particular area. Methodology The data were collected based on an online questionnaire structured with closed-ended questions. The questionnaire was distributed online, by e-mail, to the Portuguese population for a period of approximately 4 weeks between mid-August and early September 2021, targeting participants aged 18 years or older with internet access. The questionnaire was divided into three groups. Group I consisted of the sociodemographic characterization of the sample under study, composed by items such as age, gender, level of education and professional situation, as well as information regarding whether or not the respondent had performed volunteering activities, the frequency and area of such volunteering, and whether such volunteering was specifically performed in the area of intellectual disabilities Group II was made up of 21 questions (see Appendix Table 4) aimed at understanding the barriers to volunteering in general and to find whether there are any reasons that more strongly influence the decision to volunteer. Group III was composed of 16 questions aimed at understanding the barriers to volunteering in the area of intellectual disabilities (see Appendix Table 5). The data were processed and analysed using the software FACTOR (Ferrando & Lorenzo-Seva, 2017) for the factor analysis, and the R software for the latent class analysis. For the factor analysis, given the nominal nature of the responses (“Yes”, “No” and “Don’t Know”), we considered the Robust Diagonally Weighted Least Squares (RDWLS) extraction method (Asparouhov & Muthén, 2010). Additionally, the parallel analysis method with random permutation of the observed data (Timmerman & Lorenzo-Seva, 2011) was used to decide on the number of factors to be retained, and the rotation used was the Robust Promin (Lorenzo-Seva & Ferrando, 2019). The adequacy of the correlation matrix of the items was analysed using the Bartlett and Kaiser–Meyer–Olkin (KMO) sphericity test. The adequacy of the model was assessed using the Root Mean Square Error of Approximation (RMSEA), Comparative Fit Index (CFI) and Tucker-Lewis Index (TLI) fit indices. Latent class analysis (LCA) was used to group the respondents of the study population according to their perceptions on volunteering to identify response patterns based on observed characteristics and relate them to a set of latent classes (the clusters) — in our case, this was done through the answers to the 16 questions that make up the questionnaire. To carry out this analysis, we used R software, in particular the poLCA package (Linzer & Lewis, 2011). To determine the optimal number of clusters, we adjusted several models by considering different numbers of clusters and compared the values obtained for the Bayesian Information Criterion (BIC) (Schwarz, 1978), since it is the most suitable criterion to apply in this methodology (Forster, 2000). Our sample has 197 fully completed questionnaires, with respondents aged 18 years or older and who had not previously volunteered in the area of intellectual disabilities in Portugal. Results presentation and discussion First, we did a factor analysis to the 21 questions of Group 2 of our questionnaire, and the analysis returned an adequate grouping into 3 factors (Appendix Table 6), with Bartlett's tests of sphericity (statistic = 750; g.l. = 201, proof value < 0.001) and KMO (0.75822) suggesting that the correlation matrix of the items is adequate. One item (item 7) showed a very low factor loading (< 0.3), so it was removed from the analysis (Field, 2013; Hair et al., 1998). The items showed adequate factor loadings, with high factor loadings in their respective factors. The composite reliability of the factors, measured by the ORION estimate (Overall Reliability of fully-Informative prior Oblique N-EAP scores), was adequate (above 0.70) for all factors. The values of the replicability measure of the factor structure (H-index) suggest that the factors may not be replicable in future studies, since they are lower than 0.80. However, in general, the factor structure presented adequate adjustment indexes (RMSEA = 0.027; CFI = 0.983; TLI = 0.976).Factor 1: Inertia and negative perceptions – this factor focuses on internal barriers related to the willingness to volunteer. Most individuals do not spontaneously seek opportunities to volunteer; sometimes they are only predisposed to do so when invited by others; furthermore, many people do not feel the need to perform volunteer work because they do not recognize its added value or claim not having time to dedicate to this activity (Willems & Dury, 2017). Factor 2: Scepticism – this factor essentially focuses on external barriers to undertaking volunteering. Trust in organisational leadership is key for the volunteer to feel that they are performing necessary and meritorious work (Souder, 2016); on the other hand, the type of volunteer work is key, as volunteers have to feel in possession of all the necessary skills to perform that work in order to be recognised for merit and gain visibility both within the organization and abroad (Hager & Brudney, 2011). Factor 3: Mental strength – this factor focuses on the responsibility to be a volunteer. By participating in a voluntary activity, the individual is accepting responsibility and must understand what this entails and whether they meet the necessary conditions to perform this work (Willems & Dury, 2017). Barriers related to physical conditions show a correlation level around 0.500. Meeting physical conditions in certain areas of volunteer work is essential to develop this type of work (Khoo & Engelhorn, 2011; Southby et al., 2019). Group 3 of our questionnaire comprises 16 questions and the analysis returned an adequate grouping into 3 factors, with Bartlett's tests of sphericity (statistic = 924.9; g.l. = 120, proof value < 0.001) and KMO (0.86059) suggesting that the correlation matrix of the items is adequate. The items showed adequate factor loadings, and the composite reliability of the factors is also adequate (above 0.70) for all factors. However, the values of the replicability measure of the factor structure (H-index) suggest that only factor 2 may not be replicable in future studies, since it is below 0.80, although the value is close to 0.80. Overall, the factor structure presented adequate adjustment indexes (RMSEA = 0.036; CFI = 0.992; TLI = 0.987).Factor 1: Characteristics of intellectually disabled people with – this factor groups together issues related to knowledge about the reality of people with intellectual disabilities and the potential risks that interacting with these people may entail. Only by being aware of the potential risk that they may run when coming into contact with intellectually disabled people can volunteers feel safe to embrace volunteering in this specific social area (Fort et al., 2017). In our research, about 1/3 of the sample is composed of individuals who show fear or cannot yet define their opinion regarding coexistence with people with disabilities and their behaviours (Gaymard & Chauvet, 2016). Factor 2: Awareness – this factor groups together issues related to perceptions and awareness. Society's negative view regarding intellectually disabled people can shape behaviours and attitudes towards these people (Gaymard & Chauvet, 2016). These people are strongly dependent on others as they need constant support in their activities and the fact that they do not have many possibilities to meet people can make them more dependent on the volunteer (Woodgate et al., 2020). Factor 3: Introversion – this factor groups contains the most varied information. It is important for volunteers to be fully aware that their reality is different from the reality of these people, since in most cases intellectually disabled people face limitations in their social life, go out less and do fewer activities (Southby et al., 2019); if volunteers fail to be fully aware of this reality, they could feel that they are not prepared to deal with this situation (Woodgate et al., 2020). Second, regarding patterns of responses, the latent class analysis of the answers on the 16 items of Group 3 of the questionnaire resulted in 3 different clusters (see Table 7). This grouping is the most adequate because it presented the lowest BIC when compared to the analyses performed considering two clusters (BIC = 5231.205) and four clusters (BIC = 5056.664) (Appendix Table 7). In Appendix Table 8, the clusters are characterized according to the demographic data, presenting frequencies (n) and percentages for the variables "Gender", "Educational level", "Professional situation" and "Did you Volunteer in the last year (2020)?"; and mean and standard deviation (SD) for the variable "Age", together with the number of participants with complete data for each variable of interest. Statistically significant differences were found between the medians of the ages in at least one of the clusters, at 1% significance level. Analysing the mean and median values of this variable, one notices that the ages are higher in cluster 1. On the other hand, the ages in clusters 2 and 3 are more similar, but lower in cluster 3. Additionally, the cluster grouping is independent regarding the variables Gender, Professional situation and Voluntary work done the previous year, since there is no significant difference in the distribution of individuals based on these variables. By analysing the variable Level of Education, we perceive that the clustering is not independent of the respondents' level of education. Thus, we found that respondents with the 1st cycle of education are grouped in cluster 3; respondents with the 2nd and 3rd cycles of education are mostly grouped in cluster 1. Regarding secondary education, we found that they are mostly distributed by clusters 2 and 3. Finally, clusters 2 and 3 group the individuals who did not specify their level of education. Below is a description of each cluster obtained.Cluster 1: assuming volunteering as having a negative impact – this cluster (estimated at 23.30% of the population) includes individuals who are, on average, 41 years old and mostly female (63.64%). With regard to the level of education, there are individuals having from the 2nd cycle to higher education, with the latter comprising most of the respondents (42.42%). Regarding the professional situation, the vast majority are employed (93.94%). Figure 1 (Appendix 2) shows cluster 1 (where each Vi represents question Qi of the Group 3 of the questionnaire). This cluster brings together the individuals who mostly answered "yes". This group of individuals assumes that the barriers indicated regarding volunteering in the field of intellectual disabilities are real for their specific situation and may prevent them from engaging in volunteering. Cluster 2: unawareness of the reality of intellectual disability – this cluster (estimated at 31.10% of the population) comprises individuals who are, on average, 34 years old and mostly female (63.38%). Regarding the level of education, Secondary Education (26.76%) and Higher Education (64.79%) prevail. Regarding the professional situation, most individuals in this cluster are employed (71.83%), followed by a smaller number of students (22.54%). Figure 2 (Appendix 2) shows cluster 2. This cluster groups the individuals who mostly answered "No" or "Don't know". This group assumes two situations: on the one hand, they do not have enough knowledge about the reality of intellectual disability to be able to take an informed position on the issues raised; on the other hand, when they have doubts, they assume that this lack of knowledge would not be an obstacle to volunteering. Cluster 3: no barriers to volunteering – this cluster (estimated at 45.50% of the population) groups mostly female respondents (73.12%); regarding the level of education, most individuals have completed Higher Education (70.97%). Regarding their professional situation, the majority of respondents are employed (67.74%) followed by students (26.88%). Figure 3 (Appendix 2) shows cluster 3. This cluster groups the individuals whose highest frequency of answers is "No". This group of individuals implicitly assumes that they could do volunteering with people with intellectual disabilities, as they do not consider that the issues raised could be barriers to this activity. Discussion, implications and managerial recommendations No single sector, organization or individual can be isolated in tackling the social, economic and environmental challenges emphasized in the UN’s Sustainable Development Goals (Chaves-Avila & Gallego-Bono, 2020). In this sense, coherent efforts by governments, private, public and social sectors are critical to deal with these major difficulties. It is vitally important for NPOs to identify barriers to volunteering and find ways to tackle them, particularly in the area of intellectual disabilities, which combines barriers to volunteering itself and the stigma inherent in this area of action, aiming at reducing inequalities. Three major groups of barriers to volunteering in the specific area of intellectual disabilities were identified in our results:Characteristics of intellectually disabled people Awareness Introversion The first major barrier regards the characteristics of intellectually disabled people, where issues related to "volunteering with people with intellectual disabilities can be dangerous for me" or "people with intellectual disabilities can become violent" are grouped together. In other words, many individuals do not volunteer because they are afraid of interacting with intellectually disabled people, which demonstrates that they are unaware of the specific characteristics of these people (Willems & Dury, 2017; Woodgate et al., 2020). Regarding awareness, we found that it focuses on points related to both the intellectually disabled person and the volunteer. Many volunteers find it difficult to interact publicly with people who are considered different and who may display behaviours that are considered maladaptive by society. Many individuals are not aware of the needs and specific differences of intellectually disabled people. We also find individuals that do not know how to cope when they become aware that "people with intellectual disabilities are less likely to make friends" or to "lead an active social life" (Gaymard & Chauvet, 2016; Willems & Dury, 2017). Finally, introversion brings together the barriers related to the volunteer’s psychological makeup and feelings, as well as the socialization limitations of people with intellectual disabilities (Willems & Dury, 2017). The respondents recognized that the lack of knowledge about people with intellectual disabilities may result in the volunteers not knowing how to handle the situation when faced with the limitations that they perceive in intellectually disabled people. Each individual has their own way of reacting to the other and sometimes it is difficult to understand the limitations to which people with intellectual disabilities are subjected. The clusters that were found suggest an analysis that can help organisations operating in the field of intellectual disabilities to create different strategies to attract, recruit and retain volunteers. The clusters present a division into three distinct groups. The first cluster groups the individuals who consider that all the questions are barriers to volunteering, as mentioned in some studies of the literature review. In the second cluster, most of the individuals are unaware of the reality of people with intellectual disabilities; contrary to the literature review, this group is not able to clearly define their perceptions. Finally, the third cluster includes individuals who do not perceive any barriers to volunteering, but for some reason do not engage in such activities. Our results provide empirical support of the importance of understanding the barriers to volunteering in a particular area. These findings suggest that NPO practitioners should consider all the available possibilities to expand volunteering opportunities. The call to action can be streamlined through different methods, such as persons (CEOs, endorsers, older volunteers, among others), symbols, or other options that might include more traditional media, social networks, or more recent formats, such as podcasts. In this vein, the general justifications for the strategies presented below consider that significant predictors of the willingness to volunteer include age, reliance on information sources and past volunteering activities (Brewis & Holdsworth, 2011; Rosychuk et al., 2008); therefore, it seems appropriate to use activities such as organising sessions in schools and other public places (e.g., parishes) where volunteer activities might have taken place in the past, as well as in companies, since corporate volunteering is a growing trend with win–win impact (Licandro et al., 2022). At the same time, confronting the disability stigma among the general public might produce important positive benefits (Walker & Scior, 2013). Regarding cluster 1, since this is a group of individuals who perceive volunteering as something negative and worthless, it is important to reverse this perception and promote volunteering as a valuable activity that has a positive impact on various aspects. Organizations may have little weight individually, but they may develop partnerships either through social networks, the media (television and radio, among others), or even with municipalities in order to promote activities aimed at raising awareness, such as:Dissemination of a promotional video on social networks about disability and the importance of volunteering; Provision of information about volunteering and intellectually disabled people in places of common access, such as health centres, tax offices, social security offices, schools, employment centres and vocational training centres; Information sessions in schools, large companies and other groups (e.g., parishes). Individuals in cluster 2 are unaware of the reality of intellectual disability. Therefore, it is critically important to inform them about this specific reality. Once well informed about intellectual disability, this group may be able and willing to do volunteer work with intellectually disabled people. In order to promote such predisposition and greater awareness, it would be important to reach potential volunteers from an early age, for which it is crucial to create partnerships with different schools and promote activities such as:Dissemination of a promotional video on social networks to showcase the daily life of these people; Distribution of appealing flyers containing concise and specific information about intellectual disabilities; Promoting clarification and information sessions, focusing on what intellectual disability is, how to act towards these people, and what to expect. Finally, in cluster 3 there is a group of individuals who mention no barriers to volunteering but fail to engage in such activities. It will be important to work on a set of activities to provide knowledge about volunteering and ensure simple ways to start engaging in this activity or even to understand its importance. Thus, to motivate this group of individuals it would be important to establish partnerships between organisations and student associations and/or companies to dynamize activities such as:A podcast including interviews with caregivers, NPOs and psychologists, among others, to highlight the importance of volunteering; A campaign for recruiting volunteers by sponsoring people with intellectual disabilities; Open day at the NPO with activities and socialisation with intellectually disabled people. Conclusions Volunteering motivations, intentions and behaviours have been extensively researched, with significant positive implications for volunteer recruitment in non-profit organisations. However, understanding barriers to volunteer is a less explored area. Our research deeply explored the barriers to volunteering in the field of intellectual disabilities and identifies three clusters of profiles that are faced with three distinct groups of barriers. These results pinpoint the importance of giving people opportunities to start volunteering so it is essential to deconstruct the perceptions related to intellectual disability, create awareness, and fight the lack of knowledge. Organising the clusters of barriers related to the profiles of individuals facilitates the perception of the barriers encountered and suggests a set of possible strategies to attract volunteers. In terms of theoretical implications, based on the theoretical knowledge of motivations and barriers to volunteering, this paper discusses the area of intellectual disabilities, which is one of the priority research areas to address inclusiveness and reduce inequalities. As so, we have identified and discussed the major groups of barriers to volunteering in the specific area of intellectual disabilities. The analysis of clustering provides additional comprehension on the importance of individual giving behaviour and advances in the field of non-profit marketing. In fact, the practical implications of our work were shown by presenting, for each identified cluster, a set of activities that aimed at reducing barriers regarding volunteering in the specific area of intellectual disabilities, which potentially will help organisations to attract, recruit and retain volunteers. The main limitation of the study is the sample size, which hinders the generalizability of the conclusions. Another limitation is that we assume volunteers’ intention to volunteer as the actual behaviour, although it might not be true, and finally we should mention that there are other variables not considered here that might be part of volunteers’ barriers. Volunteering can be one of the means to reduce inequalities, particularly in vulnerable communities, therefore there is a need to work together in order to make NPOs stronger in the way they attract and work with volunteers, further research may explore this topic with a broader population in other geographies. Other opportunities for future research may include specific volunteers from other areas (e.g., sports) inquiring if they consider volunteering in the area of intellectual disabilities and try to understand potential barriers. A final challenge for future research lies in defining which resolutions are suitable to manage the ongoing changes and the vicissitudes of the non-profit sector and volunteerism. Appendix 1 Table 1 Motivations for volunteering in the field of intellectual disability Motivations Authors personal enrichment (Silva, 2014) improved interpersonal relationships (Silva, 2014; Wilson et al., 2017) improved health and well-being (Botero-Rodríguez et al., 2021; Wilson et al., 2017) improved psychosocial control (Wilson et al., 2017) opportunity to serve the community (Halvorsrud et al., 2020; Morris et al., 2017) Table 2 Barriers to volunteering in general Barriers Authors Internal Barriers reconciliation of responsibilities (Colibaba et al., 2019; Shinbrot et al., 2021; Southby et al., 2019; Willems & Dury, 2017) personal skills (Colibaba et al., 2019; Southby et al., 2019; Willems & Dury, 2017) economic situation (Southby et al., 2019; Sundeen et al., 2007) self-will (Willems & Dury, 2017) other hobbies (Oliveira & Pinheiro, 2021) family disapproval (Oliveira & Pinheiro, 2021) health barriers (Hansen & Slagsvold, 2020) External Barriers commuting and time (Joag et al., 2020; Oliveira & Pinheiro, 2021; Shinbrot et al., 2021) organisational leadership (Kappelides et al., 2018; Souder, 2016) recognition of work (Hager & Brudney, 2011; Kappelides et al., 2018) unfamiliarity with volunteering (Sundeen et al., 2007; Willems & Dury, 2017) lack of training (Oliveira & Pinheiro, 2021; Shinbrot et al., 2021) lack of interesting activities (Oliveira & Pinheiro, 2021) lack of information (Hansen & Slagsvold, 2020) Table 3 Barriers to volunteering in the field of intellectual disability Barriers Authors Volunteers’ characteristics perception of intellectual disability (Gaymard & Chauvet, 2016) lack of knowledge about intellectual disability (Gaymard & Chauvet, 2016; Southby et al., 2019) fear and apprehension (Gaymard & Chauvet, 2016; Robinson et al., 2020) Intellectually disabled person’s characteristics maladaptive behaviour and appearance (Botero-Rodríguez et al., 2021; McConkey et al., 2021) dependency (Robinson et al., 2020; Woodgate et al., 2020) limitations in communication (Woodgate et al., 2020) Table 4 Barriers to volunteer (group II – questionnaire) Barriers Item Authors Internal Responsibility Q1 Volunteering carries a lot of responsibility (Willems & Dury, 2017) Q2 By volunteering I can be given responsibilities that I don't want (Willems & Dury, 2017) Physical boundaries Q3 Volunteering is physically hard for me (Willems & Dury, 2017) Q4 I need more energy to volunteer (Willems & Dury, 2017) Q5 I don't have the right skills to volunteer (Willems & Dury, 2017) Q6 Volunteering does not bring me any benefits (Willems & Dury, 2017) Economic situation Q8 Volunteering brings expenses that I cannot afford (Sundeen et al., 2007) Q9 I have more important things to do than volunteering (Willems & Dury, 2017) Stress from volunteering Q10 I associate volunteering with depressing work (Willems & Dury, 2017) Q11 Volunteering makes me unhappy (Willems & Dury, 2017) Q12 I have no interest in volunteering (Sundeen et al., 2007) External Lack of time Q13 I don't have the time to volunteer (Sundeen et al., 2007; Willems & Dury, 2017) Q14 I don't have transportation to commute to do volunteering (Sundeen et al., 2007) Q15 I consider volunteering to be a waste of time (Willems & Dury, 2017) Organization Q16 The organisations where I can volunteer serve the wrong purposes (Willems & Dury, 2017) Lack of benefits Q17 I feel that volunteering is not recognised (Sundeen et al., 2007) Q18 Volunteering does not give the recognition (visibility) that I want (Willems & Dury, 2017) Lack of knowledge Q19 I have not had opportunities to volunteer (Willems & Dury, 2017) Q20 I don't know organisations where I could volunteer (Willems & Dury, 2017) Q21 I have never been invited to do volunteering (Willems & Dury, 2017) Table 5 Barriers to volunteer in the area of intellectual disability (group III – questionnaire) Barriers Item Authors Volunteer characteristics Intellectual disability perception Q1 Volunteering with people with intellectual disabilities would make me unhappy (Willems & Dury, 2017) Q2 When I compare my reality with that of people with intellectual disabilities, I realise that they have less chances to fulfil activities/dreams (Gaymard & Chauvet, 2016; Willems & Dury, 2017) Q3 I feel that I don't know how to deal with the specificities of people with intellectual disabilities (Gaymard & Chauvet, 2016; Willems & Dury, 2017) Q4 I feel that when I started volunteering with people with intellectual disabilities, I might be disappointed (Willems & Dury, 2017) Q5 Realising that people with intellectual disabilities have a less active social life and few friends would make me more aware of their situation (Willems & Dury, 2017; Woodgate et al., 2020) Lack of knowledge about intellectual disability Q6 I feel that volunteering with people with intellectual disabilities could be dangerous for me (Willems & Dury, 2017) Q7 I am afraid of the reaction of people with intellectual disabilities (Woodgate et al., 2020) Q8 I feel that people with intellectual disabilities are prone to become violent (Willems & Dury, 2017; Woodgate et al., 2020) Risks Q9 I feel that volunteering with people with intellectual disabilities carries a lot of risks for me (Willems & Dury, 2017) Characteristics of persons with intellectual disability Appearance and behaviour Q10 I would feel uncomfortable volunteering with people with intellectual disabilities (Willems & Dury, 2017) Q11 I feel that people with intellectual disabilities have maladaptive behaviours (Botero-Rodríguez et al., 2021; McConkey et al., 2021) Q12 I feel that living with people with intellectual disabilities in public would be difficult for me because of their appearance (Botero-Rodríguez et al., 2021; McConkey et al., 2021) Dependency Q13 I feel that the tasks involved in volunteering with people with intellectual disabilities would make me anxious/stressed (Willems & Dury, 2017) Q14 I fear that people with intellectual disabilities would become too dependent on the volunteer (Willems & Dury, 2017; Woodgate et al., 2020) Q15 I feel that the dependence of people with intellectual disabilities on their carer will be a barrier to my relationship as a volunteer (Woodgate et al., 2020) Communication skills Q16 I feel that realising the limitations that people with intellectual disabilities have in reality would make me feel disappointed (Willems & Dury, 2017) Table 6 Factorial structure of group 2 Item Factor 1 Factor 2 Factor 3 Q1 Volunteering carries a lot of responsibility 0.379 Q2 By volunteering I can be given responsibilities that I don't want 0.574 Q3 Volunteering is physically hard for me 0.546 Q4 I need more energy to volunteer 0.5 Q5 I don't have the right skills to volunteer 0.442 Q6 Volunteering does not bring me any benefits 0.416 Q8 Volunteering brings expenses that I cannot afford Q9 I have more important things to do than volunteering 0.407 Q10 I associate volunteering with depressing work 0.335 Q11 Volunteering makes me unhappy 0.446 Q12 I have no interest in volunteering 0.399 Q13 I don't have the time to volunteer 0.432 Q14 I don't have transportation to commute to do volunteering 0.336 Q15 I consider volunteering to be a waste of time 0.367 Q16 The organisations where I can volunteer serve the wrong purposes 0.562 Q17 I feel that volunteering is not recognised 0.795 Q18 Volunteering does not give the recognition (visibility) that I want 0.583 Q19 I have not had opportunities to volunteer 0.435 Q20 I don't know organisations where I could volunteer 0.558 Q21 I have never been invited to do volunteering 0.485 Reliability (ORION) 0.763 0.771 0.711 H-Index 0.756 0.77 0.723 Table 7 Factorial structure of group 3 Item Fator 1 Fator 2 Fator 3 Q1 Volunteering with people with intellectual disabilities would make me unhappy 0.826 Q2 When I compare my reality with that of people with intellectual disabilities, I realise that they have less chances to fulfil activities/dreams 0.352 Q3 I feel that I don't know how to deal with the specificities of people with intellectual disabilities 0.793 Q4 I feel that when I started volunteering with people with intellectual disabilities, I might be disappointed 0.686 Q5 Realising that people with intellectual disabilities have a less active social life and few friends would make me more aware of their situation 0.473 Q6 I feel that volunteering with people with intellectual disabilities could be dangerous for me 0.593 Q7 I am afraid of the reaction of people with intellectual disabilities 0.709 Q8 I feel that people with intellectual disabilities are prone to become violent 0.608 Q9 I feel that volunteering with people with intellectual disabilities carries a lot of risks for me 0.799 Q10 I would feel uncomfortable volunteering with people with intellectual disabilities 0.593 Q11 I feel that people with intellectual disabilities have maladaptive behaviours 0.377 Q12 I feel that living with people with intellectual disabilities in public would be difficult for me because of their appearance 0.472 Q13 I feel that the tasks involved in volunteering with people with intellectual disabilities would make me anxious/stressed 0.593 Q14 I fear that people with intellectual disabilities would become too dependent on the volunteer 0.592 Q15 I feel that the dependence of people with intellectual disabilities on their carer will be a barrier to my relationship as a volunteer 0.682 Q16 I feel that realising the limitations that people with intellectual disabilities have in reality would make me feel disappointed 0.522 Reliability (ORION) 0.84 0.747 0.862 H-Index 0.834 0.742 0.857 Table 8 Distribution of the cluster according to demographic data Cluster 1 (n = 33) Cluster 2 (n = 71) Cluster 3 (n = 93) p-value Age   Mean (sd) 41.39 (12.51) 34.62 (12.14) 32.71 (11.02) 0,004*   Median 39.00 33.00 32.00 Gender n % n % n %   Male n(%) 12 36,36% 26 36,62% 25 26,88%   Female n(%) 21 63,64% 45 63,38% 68 73,12% Education level   1st cycle of basic education n(%) 0 0% 0 0% 3 3,23%  < 0,001**   2nd cycle of basic education n(%) 6 18,18% 1 1,41% 0 0%   3rd cycle of basic education n(%) 7 21,21% 3 4,23% 2 2,15%   Secondary education n(%) 6 18,18% 19 26,76% 19 20,43%   Higher education n(%) 14 42,42% 46 64,79% 66 70,97%   Other n(%) 0 0% 2 2,82% 3 3,23% Profissional situation   Unemployed n(%) 1 3,03% 1 1,41% 3 3,23% 0,1848**   Employed n(%) 31 93,94% 51 71,83% 63 67,74%   Student n(%) 1 3,03% 16 22,54% 25 26,88%   Other n(%) 0 0% 2 2,82% 1 1,08%   Retired n(%) 0 0% 1 1,41% 1 1,08% Did you Volunteer in the last year (2020)?   No n(%) 29 87,88% 61 85,92% 78 83,87% 0,8405**   Yes n(%) 4 12,12% 10 14,08% 15 16,13% Appendix 2 Fig. 1 Cluster 1 Figure 2Fig. 2 Cluster 2 Figure 3Fig. 3 Cluster 3 Acknowledgements Beatriz Casais acknowledges this work is financed by national funds through FCT - Foundation for Science and Technology, I.P., within the scope of the project «UIDB/04647/2020» of CICS.NOVA – Interdisciplinary Centre of Social Sciences of Universidade Nova de Lisboa. Marisa R. Ferreira and Ana Borges gratefully acknowledges financial support from FCT- Fundação para a Ciência e Tecnologia (Portugal), national funding through project UIDB/04728/2020. Declarations Conflicts of interests/Competing interests The author(s) declare(s) that there is no conflict of interest. The original version of this article was revised. Acknowledgment is updated. Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Change history 5/25/2023 A Correction to this paper has been published: 10.1007/s12208-023-00378-2 ==== Refs References Anastasiadis T Barkoukis V Beliefs of Greek sport volunteers about their competencies in volunteering Discobolul – Physical Education, Sport and Kinetotherapy Journal 2020 59 3 312 321 10.35189/dpeskj.2020.59.3.9 Asparouhov, T., & Muthén, B. (2010). Simple Second Order Chi-Square Correction. Mplus Technical Appendix, 1–8. Badruesham N Hasan H Husna M Zaki M Supporting the united nation’s sustainable development goals: A qualitative study on chow kit road marginalized group mini library makeover GADING: Journal for Social Sciences 2021 24 December 109 114 Bjerneld M Lindmark G McSpadden LA Garrett MJ Motivations, concerns, and expectations of scandinavian health professionals volunteering for humanitarian assignments Disaster Management & Response 2006 4 2 49 58 10.1016/j.dmr.2006.01.002 16580984 Botero-Rodríguez F Hernandez MC Uribe-Restrepo JM Cabariqe C Fung C Priebe S Gómez-Restrepo C Experiences and outcomes of group volunteer befriending with patients with severe mental illness: An exploratory mixed-methods study in Colombia BMC Psychiatry 2021 21 1 1 10 10.1186/s12888-021-03232-z 33388029 Brandão, S. M., & Bruno-Faria, M. F. (2017). Barreiras à Inovação em Gestão em Organizações Públicas do Governo Federal Brasileiro: análise da percepção de dirigentes. In P. Cavalcante, M. Camões, B. Cunha, & W. Severo (Eds.), Inovação no setor público: teoria, tendências e casos no Brasil (pp. 145–164). ENAP. Breeze, B. (2014). Philanthropic Journeys : new insights into the triggers and barriers for and volunteering. Brewis G Holdsworth C university support for student volunteering in england: historical development and contemporary value Journal of Academic Ethics 2011 9 165 176 10.1007/s10805-011-9129-0 Brudney JL Meijs LCPM Models of volunteer management: Professional volunteer program management in social work Human Service Organizations: Management, Leadership & Governance 2014 38 3 297 309 10.1080/23303131.2014.899281 Bussell H Forbes D Understanding the volunteer market: The what, where, who and why of volunteering International Journal of Nonprofit Volunteer Sector Marketing 2002 7 3 244 257 10.1002/nvsm.183 Chaves-Avila, R., & Gallego-Bono, J. R. (2020). Transformative policies for the social and solidarity economy: The new generation of public policies fostering the social economy in order to achieve sustainable development goals. The European and Spanish cases. Sustainability (Switzerland), 12(10). 10.3390/SU12104059 Colibaba A Skinner MW Furgal C The challenges and opportunities of sustaining volunteer-based rural libraries Public Library Quarterly 2019 38 4 410 427 10.1080/01616846.2019.1576117 de Wit A Qu EH Bekkers RH The health advantage of volunteers in Europe is larger for the elderly and the less healthy European Journal of Ageing 2022 10.1007/s10433-022-00691-5 Dolnicar S Randle M What motivates which volunteers? Psychographic heterogeneity among volunteers in Australia Voluntas - International Journal of Voluntary and Nonprofit Organizations 2007 18 2 135 155 10.1007/s11266-007-9037-5 Fergusson SJ McFarlane GA Global health engagement in the Scottish health service: A journey towards global citizenship Surgeon 2022 20 1 48 56 10.1016/j.surge.2021.11.004 34969604 Ferrando PJ Lorenzo-Seva U 10 años del programa FACTOR: Una revisión crítica de sus orígenes, desarrollo y líneas futuras Psicothema 2017 29 2 236 240 10.7334/psicothema2016.304 28438248 Ferreira Proença T Proença J Organisational influence on volunteer satisfaction and attitudes towards HRM practices: The case of hospital volunteers International Review on Public and Nonprofit Marketing 2012 9 1 27 42 10.1007/s12208-011-0071-z Field A Discovering Statistics using SPSS 2013 4 Sage Forster MR Key concepts in model selection: Performance and generalizability Journal of Mathematical Psychology 2000 44 1 205 231 10.1006/jmps.1999.1284 10733865 Fort M Lundberg N Zabriskie R Eggett D Prater MA Barney K Adolescent summer camp volunteers’ attitudes toward peers with disabilities Leisure Sciences 2017 39 3 277 294 10.1080/01490400.2016.1171740 Friedman DB Foster C Bergeron CD Tanner A Kim S A qualitative study of recruitment barriers, motivators, and community-based strategies for increasing clinical trials participation among rural and urban populations American Journal o f Health Promotion 2015 29 5 332 339 10.4278/ajhp.130514-QUAL-247 Ganesh S Mcallum K Volunteering and Professionalization: Trends in Tension? Management Communication Quarterly 2012 26 1 152 158 10.1177/0893318911423762 Gaymard S Chauvet A Volunteer work and disability: Impact on social representations and health International Journal of Psychological Studies 2016 8 3 72 10.5539/ijps.v8n3p72 Hager, M. A., & Brudney, J. L. (2004). Volunteer Management Practices and Retention of Volunteers. In Volunteer Management Capacity Study Series. The Urban Institute. Hager MA Brudney JL Problems recruiting volunteers Nonprofit Management & Leadership 2011 22 2 137 156 10.1002/nml Hair, Anderson, R., Tatham, R., & Black, W. (1998). Multivariate Data Analysis (5th ed.). Prentice Hall International. Halvorsrud L Bye A Brekke LA Bergland A Being a trained volunteer peer supporter for carers of people living with dementia in Norway: Reciprocal benefits and challenges Health and Social Care in the Community 2020 28 6 2150 2159 10.1111/hsc.13026 32490553 Han H Ariza-Montes A Tirado-Valencia P Lee S Volunteering attitude, mental well-being, and loyalty for the non-profit religious organization of volunteer tourism Sustainability (Switzerland) 2020 12 11 1 16 10.3390/su12114618 Handy F Srinivasan N Valuing volunteers: An economic evaluation of the net benefits of hospital volunteers Nonprofit and Voluntary Sector Quarterly 2004 33 1 28 54 10.1177/0899764003260961 Hansen T Slagsvold B An “army of volunteers”? Engagement, motivation, and barriers to volunteering among the baby boomers Journal of Gerontological Social Work 2020 63 4 335 353 10.1080/01634372.2020.1758269 32364438 Hu, J., Jiang, K., Mo, S., Chen, H., & Shi, J. (2016). The motivational antecedents and performance consequences of corporate volunteering: When do employees volunteer and when does volunteering help versus harm work performance? Organizational Behavior and Human Decision Processes, 137. 10.1016/j.obhdp.2016.08.005 Ivonchyk M The costs and benefits of volunteering programs in the public sector: A longitudinal study of municipal governments American Review of Public Administration 2019 49 6 689 703 10.1177/0275074019849125 Joag K Shields-Zeeman L Kapadia-Kundu N Kawade R Balaji M Pathare S Feasibility and acceptability of a novel community-based mental health intervention delivered by community volunteers in Maharashtra, India: The Atmiyata programme BMC Psychiatry 2020 20 1 20 48 10.1186/s12888-020-2466-z 31937274 Kappelides, P., Cuskelly, G., & Hoye, R. (2018). The Influence of Volunteer Recruitment Practices and Expectations on the Development of Volunteers ’ Psychological Contracts. VOLUNTAS: International Journal of Voluntary and Nonprofit Organizations. 10.1007/s11266-018-9986-x Karl KA Peluchette JV Hall LM Give them something to smile about: A marketing strategy for recruiting and retaining volunteers Journal of Nonprofit & Public Sector Marketing 2008 20 1 71 96 10.1080/10495140802165360 Khoo S Engelhorn R Volunteer motivations at a national special olympics event Physical Activity Quarterly 2011 28 1 27 39 10.1123/apaq.28.1.27 Kumar A Padhee AK Kumar S How Indian agriculture should change after COVID-19 Food Security 2020 12 4 837 840 10.1007/s12571-020-01063-6 32837635 Licandro O Yapor S Correa P Analysis of the personal factors of the volunteers as mediators between the satisfaction and the permanence in employee volunteering International Review on Public and Nonprofit Marketing 2022 19 1 127 151 10.1007/s12208-021-00299-y Linzer DA Lewis JB poLCA: An R package for polytomous variable latent class analysis Journal of Statistical Software 2011 42 10 1 29 10.18637/jss.v042.i10 Lorenzo-Seva U Ferrando PJ Robust promin: A method for diagonally weighted factor rotation Liberabit: Revista Peruana de Psicología 2019 251 99 106 10.24265/liberabit.2019.v25n1.08 Louw JS Kirkpatrick B Leader G Enhancing social inclusion of young adults with intellectual disabilities: A systematic review of original empirical studies Journal of Applied Research in Intellectual Disabilities 2020 33 5 793 807 10.1111/jar.12678 31652027 M’Sallem W Role of motivation in the return of blood donors: Mediating roles of the socio-cognitive variables of the theory of planned behavior International Review on Public and Nonprofit Marketing 2022 19 1 153 166 10.1007/s12208-021-00295-2 Macduff N Netting FE O’Connor MK Multiple ways of coordinating volunteers with differing styles of service Journal of Community Practice 2009 17 4 400 423 10.1080/10705420903300488 McConkey R Slater P Dubois L Shellard A Smith A An international study of public contact with people who have an intellectual disability Journal of Intellectual Disability Research 2021 65 3 272 282 10.1111/jir.12809 33404100 McKenzie JA Kahonde C Mostert K Aldersey HM Community participation of families of children with profound intellectual and multiple disabilities in South Africa Journal of Applied Research in Intellectual Disabilities 2021 34 2 525 536 10.1111/jar.12818 33040428 Morris SM Payne S Ockenden N Hill M Hospice volunteers: Bridging the gap to the community? Health and Social Care in the Community 2017 25 6 1704 1713 10.1111/hsc.12232 25810042 Netting FE O’ Connor MK Thomas ML Yancey G Mixing and phasing of roles among volunteers, staff, and participants in faith-based programs Nonprofit and Voluntary Sector Quarterly 2005 34 2 179 205 10.1177/0899764005275204 Nicholson L Cooper A Social exclusion and people with intellectual disabilities:A rural–urban comparison Journal of Intellectual Disability Research 2013 57 4 333 346 10.1111/j.1365-2788.2012.01540.x 22458266 Oliveira MJSP Pinheiro P Factors and barriers to tacit knowledge sharing in non-profit organizations – a case study of volunteer firefighters in Portugal Journal of the Knowledge Economy 2021 12 3 1294 1313 10.1007/s13132-020-00665-x Ramirez-Valles J Volunteering in public health: An analysis of volunteers’ characteristics and activities The International Journal of Volunteer Administration 2006 24 2 15 24 Rimmerman A Hozmi B Duvdevany I Contact and attitudes toward individuals with disabilities among students tutoring children with developmental disabilities Journal of Intellectual & Developmental Disability 2000 25 1 13 18 10.1080/132697800112758 Robinson S Hill M Fisher KR Graham A Belonging and exclusion in the lives of young people with intellectual disability in small town communities Journal of Intellectual Disabilities 2020 24 1 50 68 10.1177/1744629518765830 29587569 Rosychuk RJ Bailey T Haines C Lake R Herman B Yonge O Marrie TH Willingness to volunteer during an influenza pandemic:Perspectives from students and staff at a largeCanadian university Influenza and Other Respiratory Viruses 2008 2 2 71 79 10.1111/j.1750-2659.2008.00042.x 19453473 Schwarz, G. (1978). Estimating the Dimension of a Model. The Annals of Statistics, 6(2), 461–464. Retrieved from http://www.jstor.org/stable/2958889. Accessed December 2021 Schwingel A Wiley A Teran-Garcia M McCaffrey J Gálvez P Hawn R More than help? Volunteerism in US Latino culture Voluntas - International Journal of Voluntary and Nonprofit Organizations 2017 28 1 162 183 10.1007/s11266-016-9731-2 Sherer M National service in Israel: Motivations, volunteer characteristics, and levels of content Nonprofit and Voluntary Sector Quarterly 2004 33 1 94 108 10.1177/0899764003260659 Shinbrot, X. A., Jones, K. W., Newman, G., & Ramos-Escobedo, M. (2021). Why citizen scientists volunteer: The influence of motivations, barriers, and perceived project relevancy on volunteer participation and retention from a novel experiment. Journal of Environmental Planning and Management, 1–21. 10.1080/09640568.2021.1979944 Silva, S. (2014). Para ser “Grande”, Sê Voluntário! O impacto do voluntariado numa Instituição de Reabilitação de pessoas com deficiência. Universidade de Coimbra. Smith R Drennan V Mackenzie A Greenwood N Volunteer peer support and befriending for carers of people living with dementia: An exploration of volunteers’ experiences Health and Social Care in the Community 2018 26 2 158 166 10.1111/hsc.12477 28736867 Souder L A review of research on nonprofit communications from mission statements to annual reports VOLUNTAS: International Journal of Voluntary and Nonprofit Organizations 2016 27 6 2709 2733 10.1007/s11266-016-9699-y Southby K South J Bagnall AM A rapid review of barriers to volunteering for potentially disadvantaged groups and implications for health inequalities VOLUNTAS: International Journal of Voluntary and Nonprofit Organizations 2019 30 5 907 920 10.1007/s11266-019-00119-2 Studer, S. (2015). Volunteer management: Responding to the uniqueness of volunteers. Nonprofit and Voluntary Sector Quarterly, 0899764015597786-. 10.1177/0899764015597786 Sundeen RA Raskoff SA Garcia MC Differences in perceived barriers to volunteering to formal organizations Nonprofit Management and Leadership 2007 17 3 279 300 10.1002/nml Tiltay MA Islek MS Volunteer management of local and national nonprofit organisations: An exploratory study from Turkey International Review on Public and Nonprofit Marketing 2020 17 2 183 201 10.1007/s12208-019-00234-2 Timmerman ME Lorenzo-Seva U Dimensionality assessment of ordered polytomous items with parallel analysis Psychological Methods 2011 16 2 209 220 10.1037/a0023353 21500916 Trautwein S Liberatore F Lindenmeier J von Schnurbein G Satisfaction with informal volunteering during the COVID-19 crisis: An empirical study considering a swiss online volunteering platform Nonprofit and Voluntary Sector Quarterly 2020 49 6 1142 1151 10.1177/0899764020964595 Vanderstichelen S Cohen J Van Wesemael Y Deliens L Chambaere K The involvement of volunteers in palliative care and their collaboration with healthcare professionals: A cross-sectional volunteer survey across the Flemish healthcare system (Belgium) Health and Social Care in the Community 2020 28 3 747 761 10.1111/hsc.12905 31803986 Vinton L Professional administration of volunteer programs now more than ever: A case example Administration in Social Work 2012 36 2 133 148 10.1080/03643107.2011.564721 Walker J Scior K Tackling stigma associated with intellectual disability among the general public: A study of two indirect contact interventions Research in Developmental Disabilities 2013 34 7 2200 2210 10.1016/j.ridd.2013.03.024 23644953 Whittaker J McLennan B Handmer J A review of informal volunteerism in emergencies and disasters: Definition, opportunities and challenges International Journal of Disaster Risk Reduction 2015 13 358 368 10.1016/j.ijdrr.2015.07.010 Willems J Dury S Reasons for not volunteering: Overcoming boundaries to attract volunteers The Service Industries Journal 2017 2069 April 1 20 10.1080/02642069.2017.1318381 Wilson NJ Jaques H Johnson A Brotherton ML From social exclusion to supported inclusion: Adults with intellectual disability discuss their lived experiences of a structured social group Journal of Applied Research in Intellectual Disabilities 2017 30 5 847 858 10.1111/jar.12275 27554436 Wit, A., Mensink, W., Einarsson, T., & Bekkers, R. (2017). Beyond Service Production: Volunteering for Social Innovation. Nonprofit and Voluntary Sector Quarterly, 1–20. 10.1177/0899764017734651 Woodgate RL Gonzalez M Demczuk L Snow WM Barriage S Kirk S How do peers promote social inclusion of children with disabilities?A mixed-methods systematic review Disability and Rehabilitation 2020 42 18 2553 2579 10.1080/09638288.2018.1561955 30907279 Zboja JJ Jackson RW Grimes-Rose M An expectancy theory perspective of volunteerism: The roles of powerlessness, attitude toward charitable organizations, and attitude toward helping others International Review on Public and Nonprofit Marketing 2020 17 4 493 507 10.1007/s12208-020-00260-5
PMC009xxxxxx/PMC9385419.txt
==== Front Int Rev Public Nonprofit Mark International Review on Public and Nonprofit Marketing 1865-1984 1865-1992 Springer Berlin Heidelberg Berlin/Heidelberg 344 10.1007/s12208-022-00344-4 Original Article Celebrity appeal effectiveness in donating to the cause: Popular Culture vs. Religious Celebrities http://orcid.org/0000-0003-1700-8642 Al-Wugayan Adel A. Adel.Alwugayan@ku.edu.kw Wugayan@yahoo.com grid.411196.a 0000 0001 1240 3921 Management and Marketing Department, College of Business Administration, Kuwait University, Sabah-Al-Salem Campus, Kuwait city, State of Kuwait 18 8 2022 2023 20 2 369391 14 12 2021 5 4 2022 2 7 2022 © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022. Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. In times of crises and subsiding government support, choosing the most effective advertising message appeal in motivating donation behavior is fundamental to charity success. This study investigates the relative effectiveness of popular culture celebrities (PCC) and religious celebrities (RC) as two message appeals in motivating donation intentions intended for a ‘child suffering’ donation campaign among Kuwaiti donors. The two message appeals were presented in alternated order to a sample of 385 potential donors and the data was used to test the conceptual model using MANOVA, CFA and Structural Equation Modeling. The results showed that the type of emotions evoked (negative and positive), and emotional intensity (strong/weak) differed between the two ad appeals. Intensely evoked emotion was positively associated with ad favorability, and the latter was also found to be an antecedent of donation intentions. Conclusions and practical implications are presented and discussed. Keywords Charity message framing Nonprofit Organizations Celebrity endorsement Philanthropic behavior Donation intention Emotional response issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2023 ==== Body pmcIntroduction An integral activity of nonprofit organizations is to create effective marketing communication to garner financial support for their causes. At the heart of all communication activities lies the critical role of message appeal in attracting and motivating donations (Siemens et al., 2020; Tao et al., 2021). However, the economic challenges facing private sector entities as a result of the COVID-19 pandemic have resulted in charities struggling to compensate for the loss in their donation pool by appealing to individual donors who may be less affected by the economic slowdown. Even as charities devote significant fundraising activities to increasing their donation pool, potential donors are becoming less responsive to solicitation activities through real and virtual mediums (Salido-Andres et al., 2021), and the level of intentional message-skipping is both high and alarming (Jeon et al., 2019; Tuchman et al., 2018). The use of celebrities in advertising dates back to the end of the 18th century but has gained wide acceptance in the past three decades (Fleck et al., 2012). In philanthropic communication, celebrities often play dual roles: as high-profile donors contributing directly to the donation pool and as cause-endorsers, where they continue to garner strong message attention and influence recipients’ emotions to obtain strong giving responses (Ilicic & Baxter, 2014; Panic et al., 2016). This is important as these human brands can cut through the advertising clutter and offer to the public a high-profile positive behavior that can be mimicked and adopted by fans and followers in donating to the cause (Choi et al., 2020). Numerous studies have been dedicated to understanding how celebrities can be employed for a cause (for a review, see Halder et al., 2021). While the term celebrity indicates positive fame for a person that commands idolization, respect, and fondness, there can be different types of celebrities when marketers have to make a choice. For the purpose of this research, the use of celebrities in advertising in the Arab world in general, and the Arabian Peninsula in particular, can be classified into two main categories: Popular Culture Celebrities (PCC), which include actors, athletes, singers, writers and general media celebrities (Jerzyk & Wyczynski, 2016; Joseph & Wearing, 2014); and Religious Celebrities (RC), as described by Claessens & Van den Bulck (2015) which, in this study, include Muslim scholars, prayer leaders, and influential orators. The scant research addressing the use and efficacy of celebrities in the Arab world (Kooli et al., 2018) in general, and in Kuwait as a part of Middle Eastern cultures, involves only a tiny fraction focused on the GCC context, which is characterized by the strong interplay between Islamic faith and distinctive traditions of the Arab-Islamic culture. This is in contrast to the substantial research and numerous books dedicated to studying the use of RCs in fundraising in the US, which is widespread, with televangelists occupying both paid programs on Networks or having dedicated TV channels and radio stations working for a cause. Hence, this study is focused on examining the relative efficacy of the use of PCC and RC as two main fundraising message appeals to encourage monetary donations for a child suffering in crisis. This study contributes to the philanthropic marketing communication literature by answering the following questions: Do PCC and RC evoke similar positive and negative emotions after ad exposure? Are there any differences between evoked emotions and post-ad evaluation for each appeal? To what extent is ad evaluation associated with donation intentions? Which message appeal leads to stronger donation intentions? Literature review and hypotheses Philanthropic behavior The propensity to donate is an acquired behavior. It is shaped by beliefs and socially learned values and attitudes formed early in life (Weerts & Cabrera, 2018). These values and attitudes differ widely between world cultures. Even though the same donation behavior can be observed in two different societies, the motivation and intrinsic and extrinsic rewards may differ. This is important since the Islamic faith propounds a significant amount of teaching that calls for true Muslims to share part of their wealth with the poor through compulsory alms (zakat), handouts (sadaqat), or offering other forms of giving. Both nomadic and coastal Arab cultures are known for generous hospitality and sharing with others at times of prosperity and crisis. Against this backdrop, Halder et al., (2021) surveyed extant philanthropic marketing literature and found that consumer culture is an important moderator of source credibility in advertising while pointing out the general paucity of research on such a culture. In such a cultural setting, it is still unknown whether the interplay of religious beliefs, social values, and traditions on one side and the continued infusion of global entertainment culture on the other side is creating different preferences and motivational forces to engage in giving behavior. With increased reliance on celebrities in marketing communications in general, and philanthropic communication in particular, evoked emotional response triggered by the use of different types of celebrities in philanthropic advertising is still under-investigated. Celebrity in marketing The use of celebrities in marketing communications has been the subject of considerable marketing research in commercial and nonprofit contexts. In philanthropic communication, the use of celebrities in encouraging others to give is well-documented in the literature, where many studies have found celebrity endorsement to be instrumental in driving donation behavior (e.g., Chan & Zhang 2007, Hwang et al., 2017; Wymer & Drollinger, 2015). Through mass media and social media engagement, marketers use celebrities as “human brands” to create advertising attention, enhance evaluation, and produce favorable donation intentions (Chang & Lee, 2009; McCormick, 2016) surveyed the donation literature to identify external motivators for donating money and tangible assets and found celebrity endorsements to be among the most important external influences to motivate giving. Peterson et al., (2018) found that by evoking positive emotions, celebrity endorsements produce stronger donation intentions. To celebrities, the endorsement of donations to the cause is instrumental in improving their popularity, social profile, and income. The “celebrity-follower” connect is often described as a one-sided parasocial relationship, where fans and followers actively seek various aspects of a celebrity’s life while the latter has neither the knowledge nor the interest to reciprocate such interest (Giles, 2002). In their study, Escalas & Bettman (2017) argue that celebrities play an important role in their followers’ identity construction and found followers’ have the need to belong tendencies, which explain both the attachment to and acceptance of advertised celebrity endorsements. For celebrities to be effective, they should be perceived as: (1) a credible source in the ad (source credibility theory, Hovland & Weiss 1952); (2) possessing enough social attractiveness (source attractiveness paradigm, McGuire 1985); (3) having a public image that can be aligned with the cause (match-up hypothesis, Kamins 1990), and (4) providing culturally-embedded meanings that can be transferred from celebrity to the cause and finally to the message recipient (meaning transfer model, McCracken 1989). Celebrities should not be confused with social media influencers who are considered “micro-celebrities” and who become famous through self-branding on social media platforms as experts (Khamis et al., 2017; Schouten et al., 2020). In this study, we conceptualize celebrities as human figures who are known for their talents or distinguished achievements and can command public attention through sustained media appearances while generating continued interest among followers. These attributes are necessary, but not sufficient, to produce the desired effects of celebrities in commercials. This is in line with a recent review of the relevant literature that identified several theoretical foundations to explain the success of celebrity as a source of credibility in marketing communication, including source credibility theory, attractiveness theory, elaboration likelihood model, match-up hypothesis, and meaning transfer model (Halder et al., 2021). Celebrity endorsements influence recipients through the various stages of message reception and reaction. According to the AIDA model (hierarchy of effects model in advertising), recipients of ad messages pass through the four stages of attention, interest, desire, and action (e.g., Arulmani & Abdulla 2007) that represent the logical passing of consumers from a cognitive to an affective and, finally, to a conative state. Gaining attention is important because in a world with constant involuntary exposure to commercials, advertisers can overcome “ad blindness” by projecting celebrities to curtail ad-skipping and increase ad attention. In their empirical experimental study, Wu et al., (2012) found that using celebrities significantly improved ad attention, ad recall, and attitude toward the brand. Advertisers are also keen to leverage the strong image and identification of celebrities to generate interest in causes as followers determine the relevance between the celebrity, the advertised cause, and their values, interests, and self-images. Recipients often evaluate the truthfulness and legitimacy of the information provided before engaging in further information processing, a critical step where attachment to the featured celebrity can initiate the building of trust in the message content. Therefore, celebrities act as a credible source of information necessary to build consumer trust during message transfer that allows further processing of received information during the communication process (Escalas & Bettman, 2017). An established interest is followed by evoking the desire to donate in which this planned behavior is often contemplated in the light of expected psychological rewards (e.g., guilt reduction and warm-glow effects), social benefits (e.g., social benevolence and recognition), and even utilitarian benefits (e.g., tax deducts) and expected sacrifices (money, time, and effort). These past stages culminate in action whereby celebrity fans and followers execute the intended behavior and donate to the cause. Celebrity endorsement in philanthropic ads Are all celebrities eligible to become effective endorsers of giving to a social cause? The answer is most probably: ‘No’. Marketers must select the best celebrity to appeal to the public. As mentioned earlier, this is a function of a celebrity’s level of popularity, perceived congruency between public personality and social cause, and perceived credibility. Although there is much research on celebrity endorsements in marketing communications, little focus has been devoted to distinguishing between different types of celebrities who can evoke different motivations for giving. For example, Samman et al., (2009) studied the recallability of celebrities that participated in international development and the respondents identified 29 celebrities, including singers, actors, and politicians. However, this study did not distinguish between PPCs and RCs. Next, we outline both of these types of celebrities in the context of philanthropic advertising. PCC appeal PCCs are the most frequently used endorsers in marketing communications. Admired for their distinguished performance, recognized for their distinguished talents, and desired for their physical attractiveness, PCC can be instrumental in driving altruistic behavior. They do not just attract attention to the ads featuring the cause, they also provide credibility to the information to create interest, trust, and a stronger inclination to act. However, PCC can encourage giving only when recipients trust the genuine altruistic motivation of the featured celebrity based on consistency, distinctiveness, and the celebrity’s past altruistic behavior. More specifically, for performance celebrities to succeed in soliciting charitable giving, they first need to be legitimately associated with the cause, either by earlier engagement in previous altruistic behaviors or by affiliation with well-trusted international entities or reputable nonprofit institutions. How PCC celebrity endorsement in advertising can influence how prospective contributors perceive and donate to the cause in the traditional sense has been studied by a growing body of empirical research, both in off-line contexts (e.g., Ranganathan & Henley 2008; Peterson et al., 2018) and online (Panic et al., 2016). After ad exposure, potential donors form emotional reactions to the ad that can be either positive, negative, or mixed and that can produce message compliance to regulate emotional outcomes. For example, humanitarian assistance ads with images of poverty-ridden backgrounds where young children show severe malnutrition often evoke negative emotions (e.g., sympathy, sadness, and guilt) so compliance with the ad request to give donations should regulate the unpleasant effects of such negative emotions. In other ads, the use of celebrity images along with happy children saved from disaster is often associated with positive emotions that can also trigger ad message compliance. Therefore, one of the controversial issues in advertising appeals is how ad evaluation and behavioral intentions vary between ads that arouse overwhelmingly positive emotions, negative emotions, and mixed emotions. A study by Chang & Lee (2009) showed that advertising effectiveness increases when negative emotions are evoked by a negative message frame and that they appeal in the short run, but positive emotions are associated with ad effectiveness in the long run. In another study, Wu et al., (2012) found that the positive emotions associated with celebrity endorsement generated better donations intention. This is confirmed by Peterson et al.’s (2018) celebrity endorsement study that found a strong positive association between post-ad positive emotions and donations. Based on these findings, and as shown in Fig. 1, we propose that:H1: Popular culture celebrity endorsement appeal is expected to evoke higher positive emotions than negative emotions. H2: Popular culture celebrity endorsement appeal with higher positive emotion should lead to a more favorable ad evaluation. RC appeal In the present study, we are concerned with investigating the specific influence of RCs on message acceptance and compliance with donation requests. Because religious figures are iconic symbols of the prevailing faith or religion, they represent the dual function of being religious authority symbols and motivators for compliance. The effects of religiosity on ad like and donations have been confirmed in published research (e.g., Hopkins et al., 2014), and the presence of religious figures in an ad often triggers the recipient’s religiosity with a strong message of compliance. This is in line with the conclusions from Wymer & Drollinger’s 2015 study that found a celebrity’s expertise and admirability to be the most significant predictors of willingness to donate for a cause. According to Stever (2009), RCs are influential public figures that are identified with religious symbols, role modeling, and admired values, including care, wisdom, and generosity. Stephens (2017) emphasized the interrelationships between RCs and charitable fundraising organizations buy-in various American activities. The results obtained from the few studies in the MENA region (the Middle East and North Africa) support the role of religious figures as having effective charitable appeal. For example, RCs were found to motivate giving behavior to satisfy religious obligations in Arab cultures (Farah & El Samad, 2014). Echchaibi (2009) found support for the positive influence of religious persona in motivating giving, while Condra et al., (2019) found embedding well-recognized religious figures in fundraising messages improves campaign credibility by underscoring the role of donation in implementing religious duties. The duality of emotions in ads suggests a stronger impact on donations. While RC ads have been shown to induce dual emotions (negative and positive), the inclusion of human agony images triggers relatively stronger negative emotions, while subsequent exposure to religious figures evokes positive emotions. According to the hedonic contingency model (Bae, 2021), the sequential process of moving from negative to positive emotions (e.g., happiness) should lead to more message processing since recipients with positive emotions are more attentive to the message. The work of Anik et al., (2009) proposed that religious giving is associated with happiness more than secular giving (Konow & Earley, 2008). In light of the above, we predict that: -.H3: Religious celebrity appeal is expected to evoke more negative emotions than positive emotions. H4: Higher negative emotions associated with religious celebrity message appeal are expected to create a strong favorable ad evaluation. Ad evaluation and donation intentions Ad evaluation reflects the cognitive and emotional reaction to the ad experience. Similar to the concept of customer satisfaction with products and services, message recipients form an evaluative judgment of whether the ad was good, likable, enjoyable, helpful, positive, and informative. (Gorn et al., 2001). Considerable research suggests that ad evaluation is a key antecedent of behavioral intentions (e.g., Chen et al., 2005). This is consistent with results obtained by Silvera & Austad (2004), who found that higher advertising effectiveness is linked to high levels of ad evaluation and attitude toward the advertised product. Based on the above discussion, we expect that:H5: Higher ad evaluation is expected to be positively related to donation intentions. The strength of emotion produced by ad appeals has been studied to understand their relationships with giving as helping behavior. Choi et al., (2020) have suggested that individuals in a neutral emotional state are less inclined to participate in helping behavior and that stronger positive or negative ad appeals lead to stronger benevolence that ultimately enhances giving. More recent research has shown that appeals producing either strong positive emotion or strong negative emotion can increase helping behavior, and the ability of the ad to induce both emotions may lead to a stronger impact of ad evaluation on donation intentions. In a recent study, Bae (2021) found that not only positive emotions led to more favorable ad evaluation and donation intentions but also that a negative-positive sequence of evoked emotions further enhanced both ad evaluation and donation intentions. Based on these recent results, we expect that:H6: Irrespective of the celebrity type used, an ad evoking stronger positive and negative emotions is expected to lead to a stronger impact on donation intentions. A summary of these hypotheses and their relationships are portrayed in Fig. 1. Fig. 1 Conceptual Model Methodology Participant, design, and procedures A total of 387 Kuwaitis were recruited to participate in this study voluntarily by completing an online survey. Data were collected during the third quarter of 2021 using the stratified snowball sampling method for better population representation. With a two-week interval, thirteen participants completed the first exposure but not the second and were subsequently dropped. As shown in Table (1), our sample demographics had a mean of 43.5 years and a range of 18–69 years. The gender composition of the sample was 49% males and 51% females. Regarding education, 40.3% of the sample held undergraduate qualifications or higher, followed by 33.3% with two years of college and 26.4% with high school education or lower. The majority of the participants (63%) received income from being gainfully employed, while 21.2% were retired and 15.8% reported no work but receiving income from investments and/or family/government sources. Table 1 Sample Description Demographics Categories Frequency Percentage Gander Male 190 49.1% Female 197 50.9% Age 18–24 43 11.1% 25–34 89 23.0% 35–44 100 25.8% 45–54 93 24.0% 55–64 46 11.9% 65+ 16 4.1% Marital Status Married 269 69.5% Never married 87 22.5% Divorced/separated/widowed 31 8.0% Employment Working 244 63.0% Not Working 61 15.8% Retired 82 21.2% Education High school or less 102 26.4% 2-year post high school 129 33.3% 4-year or higher 156 40.3% Following the one-group post-test only research design (Cook et al., 2002; Ranganathan & Henley, 2008), this empirical study tested the expected effectiveness of PCC and RC message appeals on post-ad emotion, evaluation, and intention to donate. To manipulate advertising appeal as the main independent variable, the participants were presented with two advertising stimuli, with the first featuring pop culture artists and the second presenting well-known religious personas created specifically for this research. The selection of PCCs included male singers and a female TV star with credentials including a previous history in soliciting donations for children in poverty as part of the Good-Intention Ambassadors program. In contrast, well-known religious figures with a previous proven track record in helping those in need were included as RCs. As a standard protocol, a pretest was conducted to assess the validity and reliability of the measurements, the efficacy of the ad copies in producing the expected appeal effects, and to examine whether each ad appeal led to its expected impact on emotions. This was carried out using online surveys. Manipulation checks showed that both ad copies were perceived as intended. Familiarity and trust in the featured charities (international and local charities) were deemed high as results showed that the participants were familiar (98.8%) and that they trusted (97.2%) both charities in the ads. Source credibility was also assessed as respondents were familiar with featured celebrities in both ads and liked them. The mean scores for familiarity and liking were 5.86 and 5.32 on a 7-point scale for both singers, while the corresponding mean scores for RCs were 5.58 and 5.79, respectively. The collection of data started with the participants being presented with one of the two advertisement copies at different times (at least two weeks apart) in alternate order and were asked to respond to questions following each ad. To rule out the empirical presence of ad order effect, a post-experiment comparison between the alternate presentation order showed insignificant mean differences between the two groups. Measurements In this study, scales adopted from existing marketing and psychology literature were adapted to correspond to the measurement of each construct in the model. These constructs included post-ad emotion, ad evaluation, and donation intention are discussed next. Ad-induced emotion As shown in Table 2, emotional intensities were assessed by measuring (1) four negative feelings, including sadness, sorrow, shame, and distress, and (2) four positive emotions, comprising interest, hope, altruism, and determination, using a semantic differential scale. For instance, to indicate their level of sad emotions, the participants were presented with a five-point semantic differential scale ranging from (1) very pleased to (5) very sad. For positive emotions, participants were asked to indicate their post-ad positive emotions by indicating, for example, the extent they felt interested ranging from (1) not at all interested to very interested (5). Results obtained and presented in Table 3 supported scale internal consistencies of all positive and negative emotions across the two celebrity appeal conditions, with Cronbach alpha levels ranging from 0.81 to 0.97 well above the minimum level of 0.7 (Hair et al., 2009). The dimensionality of positive and negative emotions for each appeal was assessed using factor analysis procedures. Results in Table 3 also supported the unidimensionality of the positive emotions scale and negative emotions scale with a single factor extracted from each scale explaining 64% or higher of the total scale variance. Calculated mean scores for negative and positive emotions were used for subsequent analysis. Table 2 Scale characteristics Ad-induced emotion a PCC Ad RC Ad Mean b SD Mean b SD Sadness 2.64 1.09 3.67 1.12 Sorrow 2.94 1.01 3.56 1.03 Shame 2.57 1.16 3.59 1.07 Distress 2.63 1.07 3.66 1.10 Average Negative Emotion 2.70 0.99 3.62 0.98 Interest 3.59 1.02 2.9 1.11 Hope 3.40 0.98 2.82 1.05 Altruism 3.65 1.01 2.66 1.02 Determination 3.70 1.03 3.34 0.93 Average Positive Emotion 3.57 0.89 2.93 0.99 Ad favorability 3.02 1.13 3.24 1.04 Comparative ad rank 3.19 1.03 3.18 1.02 Average Ad Evaluation 3.10 0.92 3.21 0.99 Willing to donate 2.75 0.95 3.20 0.99 Likelihood of donation 2.85 1.01 3.14 1.04 Average donation intentions 2.79 0.76 3.17 0.98 a Negative emotion is the average score of sadness, sorrow, shame, and distress while Positive emotions include 4 items: Interest, Hope, Altruism, and Determination. b For negative emotion, a higher value indicates higher negative emotion and for positive emotion, a higher mean value indicates higher positive emotion. Table 3 Results of SEM measurement model for two ad appeals Constructs # of items (loading) CR AVE MSV PCC a Positive Emotion 4 (0.81, 0.83, 0.88, 0.81) 0.90 0.70 0.61 Negative Emotion 4 (0.87, 0.9, 0.9, 0.89) 0.94 0.79 0.34 Ad Evaluation 2 (0.82, 0.83) 0.81 0.68 0.61 Donation Intention 2 (0.93, 0.92) 0.92 0.91 0.40 RC b Positive Emotion 4 (0.81, 0.83, 0.69, 0.71) 0.82 0.53 0.06 Negative Emotion 4 (0.86, 0.85, 0.85, 0.87) 0.91 0.73 0.29 Ad Evaluation 2 (0.84, 0.90) 0.86 0.76 0.29 Donation Intention 2 (0.94, 0.95) 0.97 0.95 0.22 a b Fit indices for the Popular Culture Celebrities (PCC) measurement model: (χ2 = 304.19, df = 48, p = .000); CFI = 0.94, TLI = 0.92), SRMR = 0.0037). For Religious Celebrities (RC) model: (χ2 = 216.07, df = 48, p = .000); CFI = 0.95, TLI = 0.93), SRMR = 0.071) Ad evaluation Two items were used to measure how participants evaluated the ad: Ad liking (Walker & Dubitsky, 1994) and Ad ranking (Yoo, 2014). A 5-point scale of the overall measure of ad likability was used ranging from (1) didn’t like at all to (5) total liking of the ad. In ad ranking, participants in the second exposure were re-presented with the earlier ad and then asked to assess the relative favorability of the focal ad over the previous ad at the end of the survey using the following scale: (5) high favorability of focal ad, (4) moderate favorability of focal ad, (3) almost similar, (2) moderate favorability of previous ad, (1) high favorability of previous. Results have shown that the correlation between both items was high for both ads (RPPC = 0.82 and RRC = 83, p < .0001) therefore, the average of the two items was used for further analysis. Donation intentions After ad presentation, donation intention was measured using a combination of direct and indirect items. A direct question using a 5-point scale (1 = low intentions, 5 = certain donation intention) and the likelihood of donating for the cause in the next month ranging from (1) unlikely to (5) highly likely. Calculated correlations between the two items were strong and positive for both ads (RPPC= 0.84 and RRC= 0.90, p < .0001). As such, the average of the two items was used for subsequent analysis. Control variables and manipulation checks To confirm whether the ad frames were perceived as intended, several procedures were undertaken to control for possible extraneous variables. First, after ad exposure, we asked the respondents to recall what key features they had seen in the ad (names of pop culture artists and RCs, names of advertising charities) and the obtained results confirmed that proper comprehension of the key elements of the ads had been obtained. Second, to minimize the effects of extraneous variables, three control variables were included to assess pre-existing differences among participants in their baseline attitudes toward perceived need gravity, favorability of the philanthropic organization, and the type of featured celebrities. The results showed no differences in attitude toward need severity or featured charities, yet males tended to have a slightly more favorable opinion of the female singer (Mmale = 4.8 vs. Mfemale= 4.3, p = .043) while both genders showed similar favorable opinions about the male singer. Finally, to control the presentation order effects, a second ad was shown to the sample after two weeks. ANOVA procedures for mean comparison on emotion, evaluation, and intentions yielded insignificant differences between the two orders of ad presentation for all variables (for all calculated ANOVAs, calculated F(5,494) were below 1.92 with p > .11). These results support the lack of order effect bias in ad presentation and carry-over effects from one ad to the other. Measurement validation Before testing the proposed relationships in the conceptual model, factor analysis procedures were applied to assess the dimensionality of post-ad positive emotion, negative emotion, ad evaluation, and intention to donate. As shown in Table 3, the results showed that a single factor emerged for negative and positive emotions, with explained variance exceeding 64%, indicating scale unidimensionality. To confirm these results and before testing the structural model, a reflective CB-SEM measurement model was developed and tested for each message appeal ad in accordance with standard data analysis procedures (Hair et al., 2014). The results in Table 3 indicated a robust overall model fit with Comparative Fit Indices ≥ 0.95, Tucker-Lewis index ≥ 0.93, Root Mean Square Error of Approximation ≤ 0.059, and Standardized Root Mean Square Residual ≤ 0.07). These results indicated the plausibility of the measurement model of both ad appeals and allowed us to proceed into further analysis. The convergent validity of the model constructs was assessed both at the indicator and at the construct level. For each construct, the indicator-factor loading exceeded the 0.70 suggested as a reasonable minimum level (Hair et al., 2014) indicating strong indicator reliability. At the construct level, the CFA results showed all Average Extracted Variances (AVEs) exceeded the minimum level of 0.5 (Fornell & Larcker, 1981). The divergent (discriminant) validity was also supported as all Average Shared Variance ASVs were greater than the squared root of the AVEs, the Maximum Shared Variance (MSVs), and the Squared MSVs. Based on these supporting results, the average scores were used for structural model analysis for both models, as shown in Fig. 2. Fig. 2 PCC and RC Path analyses results Mediation To assess the extent of mediation in our theoretical model, the direct and indirect paths, along with their significance levels, were calculated (see Table 4). The main purpose was to determine whether emotion exerted direct, partially mediated, or fully mediated effects on donation intention via ad favorability. The results indicated that the effects of post-ad positive emotion are fully mediated through ad favorability for both PCC and RC appeals. Similar findings were also observed in negative emotions in both ads. These findings generally support full mediation relationships with the effects of emotions being completely mediated through ad favorability. Table 4 Mediation Analysis for direct and indirect effects of emotions Relationship Direct Effecta Indirect Effectsb Results PCC Ad Positive Emotions →Ad Favorability →Donation Intentions β = 0.05 (p > .05) β = 0.56** ; (p < .001) β = 0.58**; (p < .001) Full Mediation Negative Emotions→Ad Favorability→ Donation Intentions β = 0.025 (p > .05) β = 0.56** ; (p < .001) β = 0.07 ; (p > .05) No Effects RC Ad Positive Emotions→ Ad Favorability→ Donation Intentions β = 0.055 (p > .05) β = 0.30**; (p < .001) β = 0.83**; (p < .001) Full Mediation Negative Emotions→ Ad Favorability →Donation Intentions β = − 0.07 ** (p < .05) β = 0.30**; (p < .001) β = 0.57**; (p < .001) Full Mediation a Direct effect is Positive Emotions→ Donation Intentions. b Indirect effects are examined using the following paths: (1) Positive Emotions→ Ad Favorability and (2) Ad Favorability→ Donation Intentions. c Direct effects are weak as opposed to indirect β values. Hypotheses testing results Post-ad emotion and ad evaluation To test H1, positive emotions across the two conditions were analyzed using several multivariate statistical methods, including MANOVA, ANOVA, and Structural Equation Modeling (SEM). As shown in Table 2 and Fig. 2, the RC ad evoked higher mean values of the four negative emotions than the PCC ad. The statistical significance of these observed differences was tested using repeated-measure MANOVA, followed by between-conditions ANOVA comparisons. Mauchly’s test showed sphericity assumption was violated, χ2(5) = 51.32, p < .0001; therefore, Greenhouse-Geisser Epsilon (∑ = 0.96) was used to correct the degrees of freedom. The results confirmed the observed differences in Fig. 2 that PCCs produced stronger positive emotions than RCs: F(1,772) = 118.72, p < .000. Fig. 3 Positive and negative emotions As shown in Table  5, the sample response to the PCC ad had an average score for interest of (MPCC = 3.59, SD = 1.02) compared to (MRC = 2.9, SD = 1.11), and those differences were found to be statistically significant with F(1,772) = 168.9, p < .0001. Similarly, a one-way ANOVA showed the PCC ad produced higher hope emotion scores than the RC ad (MPPC = 3.4, SD = 0.98; MRC = 2.82, SD = 1.05; F(1,772) = 62.2; p < .0001). Similar results were found for altruism (MPPC = 3.65, SD = 1.01; MRC = 2.66, SD = 1.02; F(1,772) = 186.1: p < .0001) and determination (MPPC = 3.7, SD = 1.03; MRC = 3.34, SD = 0.93; F(1,772) = 31.8: p < .0001). The culmination of these results lends strong support to H1. Table 5 Descriptive and repeated-measures ANOVA for post-ad emotions across ad appeals AD APPEAL NEGATIVE EMOTIONS POSITIVE EMOTIONS Sadness Sorrow Shame Distress Interest Hope Altruism Determination PCC Ad 2.64 2.94 2.57 2.63 3.59 3.4 3.65 3.7 1.091 1.007 1.161 1.066 1.021 0.982 1.011 1.034 RC Ad 3.67 3.56 3.59 3.66 2.9 2.82 2.66 3.34 1.117 1.031 1.074 1.097 1.106 1.051 1.022 0.932 Test of Sphericity Mauchly’s W = 0.982, P < .015; G-G* = 0.989 Mauchly’s W = 0.936, P < .001; G-G* = 0.955 Between-Subjects Effects F(1,772) = 170.67, p < .000  F(1,772) = 118.72, p < .000 Multivariate Tests Pillai’s Trace F(3, 770) = 12.64, p < .000  F(3, 770) = 73.89, p < .000 One-way ANOVA F value DF =(1,772) P-value F = 81.6, p < .0001  F = 65.8, p < 0.0001  F = 161.1, p < .0001  F = 187.5, p < 0.0001  F = 169.9, p < .0001  F = 62.5, p < 0.0001  F = 186.1, p < .0001 F = 31.8, p < .0001 Within-Subjects * Main Effects F(2.966, 2289.5) = 12.71, p < .000  F(2.865,2211.9) = 66.72, p < .000 * Greenhouse-Geisser parameter used as Mauchly’s Test of Sphericity was significant p < .001; Negative Emotions Partial Eta2 = 0.08, Positive Emotions Partial Eta2 = 0.224 To examine the directional relationships between post-ad emotion, ad evaluation, and donation intentions for each type of ad appeal, the path model was specified and tested using SEM procedures. As shown in Fig. 3, all the fit indices were supportive of the proposed model in both ad appeals. Table 6 Hypotheses testing results Hypothesis Statistics Hypothesized Effects Hypothesis testing results H1 PCC Appeal Positive Emotion > Negative Emotion Average PE: 3.57 (0.89) Average NE: 2.79 (0.99) PE High NE Low Supported H2 PCC Appeal Positive Emotion → Ad Evaluation PE: β = 0.56**, (11.71) NE: β = − 0.07, (-1.44) + Supported H3 RC Appeal Negative Emotion > Positive Emotion Average PE: 2.93 (0.99) Average NE: 3.62 (0.98) PE Low NE High Supported H4 RC Appeal Negative Emotion →Ad Evaluation PE: β = β = 0.30, (7.47) NE: β = β = 0.57, (13.90) + Supported H5 PCC & RC Appeals Advertising evaluation→ Donation intentions PCC: β = 0.58 (13.77) RC: β = 0.83 (28.92) + Supported H6 PCC & RC Appeals Donation intentions: Dual Emotional Intensity (DEI) > Single Emotional Intensity (SEI) PCC: R2 = 0.36 RC: R2 = 0.68 DEI > SEI Supported According to H2, higher positive emotion was expected to produce a more favorable ad evaluation in the PCCs’ ad appeal as opposed to negative emotion. The results from path analysis using SEM supports this prediction (Fig. 3). The directional path between post-ad positive emotion and ad evaluation was positive and statistically significant (β = 0.56, CR = 11.71, p < .0001), while the effects of negative emotion on ad evaluation were negligible (β = − 0.07, CR=-1.44, p < .151). These results largely support H2. H3 predicted that the RC ad would evoke stronger negative emotions than the PCC ad. Results from repeated-measure MANOVA (Table 6; Fig. 3b) were significant, F(1,772) = 170.67, p < .000 indicating overall differences between the four emotions between the two ads. To examine each emotion separately, results from the follow-up ANOVA between-subjects mean scores comparisons supported predicted differences for sadness (MRC=3.67; MPCC= 2.64, F(1,772) = 81.6; p < .0001), sorrow (MRC=3.56; MPCC= 2.94, F(1,772) = 65.81; p < .0001), shame (MRC=3.59; MPCC= 2.57, F(1,772) = 161.11; p < .0001), and distress (MRC=3.66; MPCC = 2.63, F(1,772) = 178.5; p < .0001). Based on these results, H3 is supported. H4 suggested that for RC appeal, negative emotion would positively enhance advertisement evaluation more than positive emotion. The results show this prediction to be holding (Fig. 2). The negative emotion →Ad Evaluation directional path was strong and significant (β = 0.57, CR = 13.90, p < .0001), while the effect of positive emotion on ad evaluation was significant but weak (β = 0.30, CR = 7.47 p < .0001). These results support H4. Consistent with the predictions of H5, the results of this study support the positive directional relationship between advertising evaluation and donation intentions for both ad appeals. More specifically, the ad evaluation → donation intentions for the PCC appeal were strong and positive (β = 0.58, CR = 13.77, p < .0001), and similar results were observed in the RC ad appeal (β = 0.83, CR = 28.92, p < .0001). H6 postulated that ad appeals evoking significant negative and positive emotion (dual emotional intensity) are more likely to produce stronger donation intentions than appeals evoking either positive or negative emotion alone. The results in Fig. 3 show that the PCC ad produced strong positive emotions only (M = 3.57), with a significant positive impact on donation intentions (mediated through ad favorability) that explained 33% of the variance. In contrast, the RC ad appeal generated significant positive emotion (M = 2.93) and negative emotion (M = 3.62), with a significant positive impact on donation intentions that explained 68% of the variance. Discussion In the context of celebrity endorsement ads in nonprofit philanthropic marketing communications, this study sought to assess the impact of evoked emotion on post-ad evaluation and, consequently, on donation intentions. This study focused on PCC and RC ad appeals to motivate potential donors to respond to human suffering donation using vivid imagery (Burt & Strongman, 2005). Both positive and negative emotions showed distinct and reliable unidimensionality, lending strong support to their content and convergent validity. The obtained results from testing the hypotheses provided important findings that help in the construction of the ads to increase compliance with the cause by understanding the efficacy of both ads in driving the expected emotional and behavioral intention responses to these major philanthropic advertising appeals. This study holds the level of emotional intensity and the type of emotions generated by the ads to be important determinants of message compliance. The results from testing H1 show that PCC appeal generated more positive emotional responses than negative emotions, indicating that, even with the pictorial depiction of human suffering, the presence of celebrities was more influential in determining the type of emotion evoked. Using a famous singer and actor with a well-recognized status in the performing arts and entertainment, as well as in international humanitarian relief circles, created a favorable attitude toward the ad via positive emotions only. The feelings of interest, hope, altruism, and determination were more pronounced compared to negative feelings reflecting sadness, sorrow, shame, and distress. It seems more plausible that source likability (Chebat et al., 1992) coupled with overt positive affect (smiling, well-dressed celebrities) enhanced the elicitation of positive emotions in the context of a child suffering donation campaign. Furthermore, based on the analysis performed to test H2, these results showed that a strong positive emotional intensity can affect ad evaluation. More specifically, the relatively weak level of negative emotion failed to have any effect on the recipients’ judgments of ad favorability, while the strong level of positive emotion intensity positively influenced these ad favorability judgments. The results of testing religious celebrity’s ad appeal underscore the potentially effective dual influence of intense negative and positive emotions on ad evaluation and donation intentions. The combined presence of featuring child suffering and religious icons have activated strong negative emotional responses that have been recognized by previous literature to create stronger inclinations to donate (De Luca et al., 2016; Huber et al., 2011) but this seems to be inconsistent with other research, where positive emotion is more likely to lead to donation (Peterson et al., 2018). Interestingly, the combinations of these imageries and the call for help also produced positive emotions that may have been less emotionally intense but exerted noticeable effects on ad evaluation. Although both emotions are incompatible, they seem to be jointly influencing ad evaluation and subsequently leading to higher donation intentions, with twice as much as explained variance reported by the PCC ad appeal with single emotional intensity. The ability to explain donation intention was substantially stronger when the ad appeal managed to elicit both emotions than when the ad triggered a single emotion. The combined effects of dual emotions are consistent with recent findings from the literature (Bae, 2021). As such, it appears that the duality of triggered emotions seems to be more conducive to producing ad message compliance. Another major finding of this study is that it confirms the direct link between the perceived quality of the ad and the propensity to donate across the two ad appeals. The influence of emotion is completely mediated through ad evaluation since emotions failed to exert any significant direct influence of ad evaluation on donation intention. The level of emotions failed to produce significant and substantive direct effects on donation intentions. Therefore, even with intensely evoked emotions, failure to generate strong ad favorability may not lead to stronger message compliance. Conclusions and implications Conclusions Even though the use of celebrities as human brands continues to be an expensive tool in philanthropic marketing communication, the value of their endorsements in generating donations has shown varying degrees of success (Peterson et al., 2018), even as potential donors are aware of celebrity profile and poverty-reduction (Samman et al., 2009). This renewed skepticism toward the usefulness of celebrity endorsement may not be confined to Western markets and could extend to other parts of the world, where the third sector is essential to respond to urgent humanitarian needs and social problems. In this study, we shift the research focus toward exploring the role of celebrities in generating message compliance in Kuwait as a part of the Middle Eastern culture where the interplay of religion, customs, traditions, and social values may be different than Western or Eastern cultures. This research is the first to be undertaken to explore the usefulness of celebrity endorsements in motivating donations to the cause and based on the results and discussion, it is possible to make the following conclusions. It is possible to conclude from this study that while the use of celebrities is important in soliciting charitable contributions, employing RCs is more effective in drawing donations than using PCCs in this part of the world. This is supported by our findings that indicated a higher intention to donate in the RC ad than in the PCC ad (refer to Table 2). RC congruity with soliciting for the cause seems to be stronger and more accepted by potential donors than PCC. Therefore, it might be recommended that philanthropic marketers examine both source credibility and the celebrity’s congruity with the cause before recruiting PCCs. Theoretical implications Regarding ad-induced emotions, our findings showed that not only the co-occurrence of positive and negative emotional responses is possible, but it has also shown that ads evoking such dual emotional intensity can be more successful in creating stronger donation intentions. It seems that, while negative emotions are a direct response to the observed human calamity, which is often inner-directed and uncomfortable, positive emotions can help regulate such distress. This is relevant as our measures of positive emotions represent relevant positive responses to alleviate human suffering. In conclusion, ads showing pain and suffering while providing positive outcomes that are dependent on expected donations may have a better chance of increasing donation message compliance. Practical implications The results obtained in this research show that charities can use RC to obtain significantly better donation intentions than using PCC. Particularly, RC can project donations as an important activity that aligns the fulfillment of religious values and the need to respond to relieve human suffering that ultimately improving how individuals view themselves and relieving induced negative emotions. Charity promoters need to select RCs that enjoy both trust and a positive image to produce post-ad message compliance. Limitations and directions for future research. Despite the theoretical and practical contributions of this study on exploring emotional responses to two types of celebrity endorsement appeals and their impact on ad evaluation, as well as the participants’ willingness to donate, there are potential limitations that may need to be considered. The message appeals in this study were focused on portraying child human suffering. The tragic nature of human suffering in this study has severely limited the use of other more pronounced positive emotional appeals (e.g., humor, adventure, challenge). Therefore, to achieve this, research may be extended to other socially worthy causes, such as supporting the arts, education, and sciences. This study is focused on examining the effects of copy advertisement used in digital media or print. Since copy ads are inherently static and lack the support of other, stronger, elements of audio-visual ads, the added effects of music, voice tones, and a succession of images were not examined in this study. While our choice of copy ads coincides with its wide use by organizations due to relative ease and its low cost, research into other forms of advertising may be fruitful. Another limitation of this study is its inability to study donation intentions in a competitive context, where other concurrent calls for donations for worthy causes may alter the emotional reactions and behavioral intentions following ad exposure. As this study is primarily focused on the initial exposure to the two advertisement appeals and the triggering of specific responses, the results may be different if the recipients were exposed to recent past exposures to donation advertisements and the carry-over effects related to prior experiences. The relatively adequate sample has helped in reducing the effects of baseline differences, including prior exposure experiences, mood, and ad-skipping tendencies; however, future studies may need to assess the impact of these potential individual differences. Appendix 1: Message Appeals A. Popular Culture Celebrities (PCC) ad appeal B. Religious Celebrities (RC) ad appeal Declaration Conflict of interest The author of this research has no conflict of interest. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ==== Refs References Anik, L., Aknin, L. B., Norton, M. I., & Dunn, E. W. (2009). Feeling good about giving: The benefits (and costs) of self-interested charitable behavior. Harvard Business School Marketing Unit Working Paper, 10–012 Arulmani G Abdulla A Capturing the ripples: Addressing the sustainability of the impact of social marketing Social Marketing Quarterly 2007 13 4 84 107 10.1080/15245000701678438 Bae M The Effect of Sequential Structure in Charity Advertising on Message Elaboration and Donation Intention: The Mediating Role of Empathy Journal of Promotion Management 2021 27 1 177 209 10.1080/10496491.2020.1809597 Burt CD Strongman K Use of images in charity advertising: Improving donations and compliance rates International Journal of Organisational Behaviour 2005 8 8 571 580 Chan, K., & Zhang, C. (2007). Living in a celebrity-mediated social world: The Chinese experience. Young Consumers Chang CT Lee YK Framing charity advertising: Influences of message framing, image valence, and temporal framing on a charitable appeal 1 Journal of Applied Social Psychology 2009 39 12 2910 2935 10.1111/j.1559-1816.2009.00555.x Chebat, J. C., Laroche, M., Baddoura, D., & Filiatrault, P. (1992). Effects of source likability on attitude change through message repetition. ACR North American Advances Chen MJ Grube JW Bersamin M Waiters E Keefe DB Alcohol advertising: What makes it attractive to youth? Journal of Health Communication 2005 10 6 553 565 10.1080/10810730500228904 16203633 Choi J Li YJ Rangan P Yin B Singh SN Opposites attract: Impact of background color on effectiveness of emotional charity appeals International Journal of Research in Marketing 2020 37 3 644 660 10.1016/j.ijresmar.2020.02.001 Claessens N Van den Bulck H Parasocial relationships with audiences’ favorite celebrities: The role of audience and celebrity characteristics in a representative Flemish sample Communications 2015 40 1 43 65 10.1515/commun20140027 Condra LN Isaqzadeh M Linardi S Clerics and scriptures: Experimentally disentangling the influence of religious authority in Afghanistan British Journal of Political Science 2019 49 2 401 419 10.1017/S0007123416000569 Cook TD Campbell DT Shadish W Experimental and quasi-experimental designs for generalized causal inference 2002 MA Houghton Mifflin Boston De Luca R Ferreira M Botelho D When guilt induces charity: The emotional side of philanthropy European Journal of Business and Social Sciences 2016 5 02 44 58 Echchaibi N Hyper-Islamism? Mediating Islam from the halal website to the Islamic talk show Journal of Arab & Muslim Media Research 2009 1 3 199 214 10.1386/jammr.1.3.199_1 Escalas JE Bettman JR Connecting with celebrities: How consumers appropriate celebrity meanings for a sense of belonging Journal of Advertising 2017 46 2 297 308 10.1080/00913367.2016.1274925 Farah MF El Samad L The effects of religion and religiosity on advertisement assessment among Lebanese consumers Journal of International Consumer Marketing 2014 26 4 344 369 10.1080/08961530.2014.919126 Fleck N Korchia M Le Roy I Celebrities in advertising: Looking for congruence or likability? Psychology & Marketing 2012 29 9 651 662 10.1002/mar.20551 Fornell C Larcker DF Structural equation models with unobservable variables and measurement error: Algebra and statistics 1981 Los Angeles, CA Sage Publications Sage CA Giles DC Parasocial interaction: A review of the literature and a model for future research Media Psychology 2002 4 3 279 305 10.1207/S1532785XMEP0403_04 Gorn G Tuan Pham M Yatming Sin L When arousal influences ad evaluation and valence does not (and vice versa) Journal of Consumer Psychology 2001 11 1 43 55 10.1207/S15327663JCP1101_4 Hair, J., Black, W., Babin, B., & Anderson, R. (2009). Multivariate Data Analysis 7th Edition Pearson Prentice Hall: JOUR Hair, J. F., Black, W. C., Babin, B. J., Anderson, R. E., & Tatham, R. L. (2014). Pearson new international edition. Multivariate data analysis, Seventh Edition. Pearson Education Limited Harlow, Essex Halder D Pradhan D Roy Chaudhuri H Forty-five years of celebrity credibility and endorsement literature: Review and learnings Journal of Business Research 2021 125 397 415 10.1016/j.jbusres.2020.12.031 Hopkins CD Shanahan KJ Raymond MA The moderating role of religiosity on nonprofit advertising Journal of Business Research 2014 67 2 23 31 10.1016/j.jbusres.2013.03.008 Hovland CI Weiss W Source credibility and effective communication Public Opinion Quarterly 1952 16 1 635 650 Huber, M., Van Boven, L., & McGraw, A. P. (2011). External and Internal Influences on Emotion Based Donation Decisions. The Science of Giving: Experimental Approaches to the Study of Charity Hwang S Bae J Kim HJ The effects of prior reputation and type and duration of charitable donation on celebrities’ personal public relations: An investigation based on attribution theory Asian Journal of Communication 2017 27 3 304 321 10.1080/01292986.2017.1284875 Ilicic J Baxter S Fit in celebrity–charity alliances: When perceived celanthropy benefits nonprofit organisations International Journal of Nonprofit and Voluntary Sector Marketing 2014 19 3 200 208 10.1002/nvsm.1497 Jeon YA Son H Chung AD Drumwright ME Temporal certainty and skippable in-stream commercials: Effects of ad length, timer, and skip-ad button on irritation and skipping behavior Journal of Interactive Marketing 2019 47 144 158 10.1016/j.intmar.2019.02.005 Jerzyk, E., & Wyczynski, K. (2016). The nationality and the type of celebrities endorsing products versus ethnocentric attitudes of polish consumers. Entrepreneurship, Business and Economics-Vol. 1 (pp. 501–514). Springer Joseph J Wearing SL Does Bear do it for you? Gen-Y gappers and alternative tourism Annals of Leisure Research 2014 17 3 314 339 10.1080/11745398.2014.953554 Kamins MA An investigation into the “match-up” hypothesis in celebrity advertising: When beauty may be only skin deep Journal of Advertising 1990 19 1 4 13 10.1080/00913367.1990.10673175 Khamis S Ang L Welling R Self-branding,‘micro-celebrity’ and the rise of Social Media Influencers Celebrity Studies 2017 8 2 191 208 10.1080/19392397.2016.1218292 Konow J Earley J The hedonistic paradox: Is homo economicus happier? Journal of Public Economics 2008 92 1–2 1 33 10.1016/j.jpubeco.2007.04.006 Kooli C Habsi A Abadli R Celebrity Endorsement and Its Effect: Arabic World Perspectives International Journal of Advanced Research 2018 6 2 182 188 10.21474/IJAR01/6426 Mainardes, E. W., Laurett, R., Degasperi, N. C. P., & Lasso, S. V. (2017). External motivators for donation of money and/or goods.International Journal of Nonprofit and Voluntary Sector Marketing, 22(2), e1568 McCormick K Celebrity endorsements: Influence of a product-endorser match on Millennials attitudes and purchase intentions Journal of Retailing and Consumer Services 2016 32 39 45 10.1016/j.jretconser.2016.05.012 McCracken G Who is the celebrity endorser? Cultural foundations of the endorsement process Journal of Consumer Research 1989 16 3 310 321 10.1086/209217 McGuire, W. J. (1985). Attitudes and attitude change.The Handbook of Social Psychology,233–346 Panic K Hudders L Cauberghe V Fundraising in an interactive online environment Nonprofit and Voluntary Sector Quarterly 2016 45 2 333 350 10.1177/0899764015587715 Peterson N Tripoli E Langenbach K Devasagayam R Celebrity endorsements and donations: Empirical investigation of impact on philanthropic giving Business Perspectives and Research 2018 6 2 79 89 10.1177/2278533718765533 Ranganathan SK Henley WH Determinants of charitable donation intentions: A structural equation model International Journal of Nonprofit and Voluntary Sector Marketing 2008 13 1 1 11 10.1002/nvsm.297 Salido-Andres N Rey-Garcia M Alvarez-Gonzalez LI Vazquez-Casielles R Mapping the field of donation-based crowdfunding for charitable causes: Systematic review and conceptual framework VOLUNTAS: International Journal of Voluntary and Nonprofit Organizations 2021 32 2 288 302 10.1007/s11266-020-00213-w Samman E Auliffe EM MacLachlan M The role of celebrity in endorsing poverty reduction through international aid International Journal of Nonprofit and Voluntary Sector Marketing 2009 14 2 137 148 10.1002/nvsm.339 Schouten AP Janssen L Verspaget M Celebrity vs. Influencer endorsements in advertising: The role of identification, credibility, and Product-Endorser fit International Journal of Advertising 2020 39 2 258 281 10.1080/02650487.2019.1634898 Siemens JC Raymond MA Choi Y Choi J The influence of message appeal, social norms and donation social context on charitable giving: Investigating the role of cultural tightness-looseness Journal of Marketing Theory and Practice 2020 28 2 187 195 10.1080/10696679.2020.1717968 Silvera, D. H., & Austad, B. (2004). Factors predicting the effectiveness of celebrity endorsement advertisements.European Journal of Marketing Stephens, R. J. (2017). Culture, Entertainment, and Religion in America. In Oxford Research Encyclopedia of Religion Stever GS Parasocial and social interaction with celebrities: Classification of media fans Journal of Media Psychology 2009 14 3 1 39 Tao W Li ZC Chen ZF Ji YG Public responses to nonprofit social media messages: The roles of message features and cause involvement Public Relations Review 2021 47 2 102038 10.1016/j.pubrev.2021.102038 Tuchman AE Nair HS Gardete PM Television ad-skipping, consumption complementarities and the consumer demand for advertising Quantitative Marketing and Economics 2018 16 2 111 174 10.1007/s11129-017-9192-y Walker D Dubitsky TM Why liking matters Journal of Advertising Research 1994 34 3 9 19 Weerts DJ Cabrera AF Alumni giving as civic expression Philanthropy & Education 2018 2 1 1 24 10.2979/phileduc.2.1.01 Wu WY Linn CT Fu CS Sukoco BM The role of endorsers, framing, and rewards on the effectiveness of dietary supplement advertisements Journal of Health Communication 2012 17 1 54 75 10.1080/10810730.2011.585689 Wymer W Drollinger T Charity appeals using celebrity endorsers: Celebrity attributes most predictive of audience donation intentions Voluntas: international journal of voluntary and nonprofit organizations 2015 26 6 2694 2717 10.1007/s11266-014-9546-y Yoo CY Branding potentials of keyword search ads: The effects of ad rankings on brand recognition and evaluations Journal of Advertising 2014 43 1 85 99 10.1080/00913367.2013.845541
PMC009xxxxxx/PMC9444819.txt
==== Front Fam J Alex Va Fam J Alex Va TFJ sptfj Family Journal (Alexandria, Va.) 1066-4807 1552-3950 SAGE Publications Sage CA: Los Angeles, CA 10.1177/10664807221123562 10.1177_10664807221123562 COVID-19 Pandemic Associations Between Children's Emotion Regulation, Mindful Parenting, Parent Stress, and Parent Coping During the COVID-19 Pandemic https://orcid.org/0000-0003-1460-3876 Moran Megan J. 1 Murray Samantha A. 1 LaPorte Emily 2 Lucas-Thompson Rachel G. 1 1 Department of Human Development & Family Studies, College of Health & Human Sciences, 3447 Colorado State University , Fort Collins, CO, USA 2 Department of Psychology, 6111 University of Notre Dame , South Bend, IN, USA Megan J. Moran, Department of Human Development & Family Studies, College of Health & Human Sciences, Colorado State University, 1570 Campus Delivery, Fort Collins, CO 80523, USA. Email: megan.joy.moran@colostate.edu 4 9 2022 7 2023 4 9 2022 31 3 426431 © The Author(s) 2022 2022 SAGE Publications This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections. Stress among parents has increased during the COVID-19 pandemic. Research prior to the pandemic indicates that parents of children who struggle with emotion regulation (ER) and who themselves are less mindful report more stress and diminished coping abilities. We know little, however, about these associations in the context of COVID-19. To prevent COVID-related deteriorations in parent well-being and child outcomes and to support parents during this potentially challenging time, it is important to understand the factors that are associated with increased stress as well as adaptive coping. This paper discusses the association between children's ER, mindful parenting (MP), parent stress, and parents’ coping with parenting during the pandemic in a sample of 217 caregivers of school-aged children (91.0% mothers). Results indicated that children's ER was associated with parents’ self-reported coping with parenting in the pandemic but was not associated with increased stress. Further, MP moderated the association between children's ER and coping, such that parents who were the most mindful and had children with better ER skills reported significantly greater ability to cope with pandemic parenting. Coping was lower for other combinations of ER and mindful parenting. These findings contradict those from before COVID, suggesting the relationship between children's ER and parent outcomes may differ in the COVID-19 context, and offering insights into which parents may be most likely to struggle with coping with pandemic parenting. COVID-19 parenting stress mindful parenting coping emotion regulation typesetterts19 ==== Body pmcThe COVID-19 pandemic has caused dramatic changes in daily life for families across the United States, including school closures and shifts to online/hybrid learning, restricted access to out-of-school activities and recreational spaces, and limited opportunities for peer interaction. Research conducted prior to the pandemic suggests that high levels of parenting stress predict negative outcomes for parents, children, and the family unit as a whole (Deater-Deckard & Panneton, 2017). There is growing evidence that stress among parents has increased since the beginning of COVID-19 (Calvano et al., 2022). Moreover, experiencing cumulative COVID-related stressors is associated with not only just stress but also mental health problems in parents (Brown et al., 2020). To identify which groups of parents are most in need of support, it is critical to test whether known correlates of parent stress before COVID-19 continue to place parents at greater risk for increased stress during the ongoing pandemic. It is also important to identify those factors that predict better coping with the challenges of pandemic parenting. Based on research conducted prior to the pandemic, children's difficulties with emotion regulation (ER) are a particularly robust predictor of parent stress, both cross-sectionally (McBride et al., 2002) and longitudinally (Williford et al., 2007). For example, poor ER in children can lead to difficult temperament and behavior, and subsequent increases in parenting stress (Solem et al., 2011). Pre-pandemic evidence that children's ER is related to levels of parent stress is consistent, however, we do not know whether this association shows different patterns during COVID-19. Because parents were spending more time in daily caregiving of their children during the period of pandemic-related restrictive measures (Lee et al., 2021), they may have had fewer opportunities (i.e., time, physical space) to engage in coping and recovery from parent stress. Increased time together and limited outlets for both parents and children may mean that stressors like children's ER would be even more likely to predict parent stress than prior to the pandemic. Thus, investigating the relationship between ER and coping within this unique context is imperative for identifying parents and children most at risk for adverse outcomes, particularly given uncertainty regarding how long COVID-19 will continue to impact families. Pre-pandemic research also suggests that individual differences in parents’ appraisals of stress moderate the effect of that stress on parent and family well-being (Trute et al., 2010). An important factor that shapes our experience of stress is intrapersonal mindfulness, the tendency to pay attention to and accept present-moment experience, which is argued to buffer against negative effects of stressful experiences by changing stress appraisals and reducing stress reactivity (Creswell & Lindsay, 2014). Intrapersonal mindfulness has been shown to buffer the effects of stress on mental and psychological health (Bränström et al., 2011; Lu et al., 2019). In addition, mindful parenting (MP) is the application of mindfulness to parenting, specifically, bringing a nonjudgmental and present-moment-focused attention to one's child and one's parenting. According to Duncan et al. (2009), MP facilitates a more positive experience of parenting and improved parental well-being, supports adoption of more adaptive parenting practices, and increases parent-child affection, which lead to improvements in child outcomes. Intrapersonal mindfulness is commonly incorporated into psychotherapy and counseling (Baer, 2003). Mindful parenting is a newer concept, with a smaller body of research evidence; thus, clinicians may be less familiar with and/or less likely to incorporate mindful parenting into work with clients. Considering together the theoretical model of MP (Duncan et al., 2009) and the mindfulness stress-buffering hypothesis (Creswell & Lindsay, 2014), we expect that MP would be helpful in times of particularly high parenting-related stress. Although intrapersonal mindfulness buffers against the negative mental and physical health effects of general stressors (Bränstrom et al., 2011), the extent to which MP serves to buffer the effects of robust parenting stress (ER) has not been investigated. Intervention studies show MP may lead to improvements in parent internalizing and externalizing symptoms (Bögels et al., 2014), reduced stress (van der Oord et al., 2012), and increased satisfaction with parenting (Singh et al., 2007). MP also is thought to support parents’ beliefs in their competence and efficaciousness due to its emphasis on self-compassion (Duncan et al., 2009). Parents’ perceived competence in their ability to parent has been associated with more effective parenting practices, which are important for child outcomes (Jones & Prinz, 2005). Particularly in the current context of widely reported distress among parents, understanding the role of parents’ beliefs in their ability to cope with pandemic-related challenges to parenting is an important gap. In this study, we sought to test whether 1) children's ER difficulties were associated with parent stress during the pandemic, consistent with pre-pandemic evidence; 2) children's ER difficulties were associated with worse coping among parents; and 3) MP moderates the relationship between ER and either of these outcomes, such that more mindful parents report less stress and better adjustment if their children have low ER abilities, relative to less mindful parents. Method Participants Participants were 217 caregivers in the United States. Demographic information is reported in Table 1. Participants were eligible to complete the survey if they had at least one child between 4 and 12 years old. Parents of children in this age were recruited because they are the most likely to a) be most affected by school closures, and b) still be involved in a significant level of childcare (compared to older children). Only one parent per household could complete the survey. Table 1. Sociodemographic Characteristics of the Sample (n = 217). n % Mothers 98 91.0 Fathers 8 7.4 Other caregivers 2 1.9 Age of child reported on (Mean/SD) 8.63 2.48 Race  Hispanic 12 6.0  Asian 10  Black/African American 7  White 163 82.5  2 or more races 7 2.5  Other 3 1.5 Region  Midwest 146 75.3  Southeast 2 1.0  Southwest 1 0.5  West 58 23.2 Yearly household income  <$51,000 39 21.5  $51–70,999 14 6.4  $71–90,999 19 8.8  $91–110,999 20 8.7  $111–130,999 24 11.0  $131–150,999 15 6.9  >$151,000 50 23.1 Co-parenting relationship 166 76.5 Number of school-aged children in the household (Mean/SD) 3.06 1.12 Procedure Participants were recruited through school listserv emails and social media posts to complete an online survey. Parents provided their informed consent, and then answered questions about their stress, their child's emotion regulation, and how well they believed they were able to cope with parenting during the pandemic. Parents were instructed to report the age of their oldest child under 12 years old and respond to all questions with that child in mind. Responses were checked for validity using a series of steps similar to Bauermeister et al. (2012), and cases of duplicate IP addresses/email addresses, or those with nonsensical qualitative responses and/or survey completion times that were unrealistically faster than the estimated completion time were removed. Cases which did not complete at least 25% of the survey were also removed. Participants were compensated $5 for completing the survey. Data were collected between February and May 2021. All procedures were approved by the Institutional Review Board. Measures Child emotion regulation Participants completed the 8-item ER subscale of the Emotion Regulation Checklist (ERC; Shields & Cicchetti, 1997, reporting on their child's emotional expression, empathy, and emotional self-awareness (e.g., “Can say when s/he is feeling sad, angry or mad, fearful or afraid”) on a four-point scale (1 = never to 4 = almost always; α = 0.72). Interpersonal mindfulness in parenting scale Parents completed the 10-item Interpersonal Mindfulness in Parenting Scale (IEM-P; Duncan, 2007), indicating on a scale of 1 (never true) to 5 (always true) how often certain statements applied to them (e.g., “When I’m upset with my child, I notice how I am feeling before I take action”; α = 0.71). Perceived stress scale Participants completed a four-item version of the Perceived Stress Scale (PSS-4, Cohen et al., 2014), a widely used measure of stress appraisals. Participants responded, on a scale of 0 (never) to 4 (very often) to questions related to how often in the last month they had experienced general stress (e.g., “In the last month, how often have you felt difficulties were piling up so high that you could not overcome them?”). In this sample, the PSS demonstrated acceptable internal consistency (α = 0.78). Coping with pandemic parenting Participants responded to an author-developed question, “How well have you been able to adjust to parenting in the pandemic,” on a five-point scale from “extremely well” to “not well at all.” Results Analyses were conducted using the Statistical Package for the Social Sciences (SPSS, version 22.0; IBM SPSS). Descriptive statistics were computed for all sociodemographic and study variables (Table 1). Preliminary analyses included tests of normality to ensure there were no outliers and that parametric tests were appropriate. Bivariate correlations were examined between all study variables (Table 2). Table 2. Summary of Intercorrelations, Means, and Standard Deviations of Study Variables. 1. 2. 3. 1. Emotion Regulation 2. Mindful Parenting .39** 3. Parent Stress −.28** −.36** 4. Parent Coping .33** .34** −.52** M 29.72 36.4 5.35 3.47 SD 3.63 3.93 2.72 .92 In all of the rest of the analyses, we included child age and sex as covariates because parents may respond differently to child behavior based on these characteristics (Podolski & Nigg, 2001). We also included parent race and income as covariates, as these may be associated with different effects of COVID-19 on well-being (Wanberg et al., 2020). First, we performed two multiple regressions to examine whether children's ER predicted parent stress and coping (Table 3). In the first model, we examined parent stress as the outcome; the model was not significant, R2 = .10, F(5, 89) = 1.97, p = .09. Child ER did not account for significant variation in parent stress (rsp = −.13, p = .21). In the second model, child ER significantly predicted coping, R2 = .13, F(5,89) = 2.54, p = .03. The unique variance accounted for by child ER was rsp = .24, p = .02. Table 3. Associations Between Child ER and Parent Outcomes. Parent Stress B SE β p Constant 11.35 2.49 .00 Child age −.16 .09 −.17 n.s. Female −.29 .53 −.06 n.s. Race: Non-white −.15 .78 −.02 n.s. Household income >$101K/year −1.03 .52 0.21 n.s. Emotion Regulation −.10 .08 −.13 n.s. R2 = .10 Parent Coping B SE β p Constant .84 .84 n.s. Child age .01 .03 .04 n.s. Female .21 .18 .12 n.s. Race: Non-white .36 .26 .14 n.s. Household income > $101K/year .17 .18 .10 n.s. Emotion Regulation .06 .03 .25 <.05 R2 = .13 We then conducted two multiple regressions using PROCESS for SPSS (Hayes, 2017) to examine the moderating effect of MP on the associations between child ER and parent stress and parent coping (Table 4). Although the overall model predicting stress was significant, R2 = .20, F(7,85) = 3.10, p = .01, the interaction of MP and child ER was not significant. The model predicting parent adjustment was significant: R2 = .22, F(7,85) = 3.40, p < .01 According to the effect size standards of Cohen (1988), the moderating effect of MP was significant but small-to-moderate in size: ΔR2 = .04, F(1, 85) = 4.39, p = .04. Using Johnson–Neyman significance region testing, we found that MP increased the positive association between child ER and parent adjustment, but only at high levels of MP ( + 1SD above the mean) and high levels of children's ER ( + 1 SD above the mean) (Figure 1). Otherwise, MP did not change the association between child ER and parent adjustment. Figure 1. Mindful parenting moderation of effect of child emotion regulation on parent coping. Note. Trajectory of parents’ coping with pandemic parenting as children's emotion regulation increases, when Mindful Parenting (MP) scores were at one standard deviation above the mean, at the mean, and one standard deviation below the mean. Table 4. MP Moderating Association Between Child ER and Parent Outcomes. Parent Stress B SE p Constant 6.44 24.46 n.s. Child age −.12 .09 n.s. Female −.51 .51 n.s. Race: Non-white .04 .74 n.s. Household income > $101K/year −1.31 .51 .011 Emotion Regulation (ER) .35 .79 n.s. Mindful Parenting (MP) .07 .69 n.s. ERxMP −.01 .02 n.s. R2 = .20 Parent Coping B SE p Constant 16.81 8.43 .049 Child age .00 .03 n.s. Female .21 .18 n.s. Race: Non-white .31 .26 n.s. Household income > $101K/year .27 .17 n.s. Emotion Regulation (ER) −.52 .27 n.s. Mindful Parenting (MP) −.43 .24 n.s. ERxMP .02 .01 .039 R2 = .22 Discussion In this study, we investigated whether children's ER was associated with parent stress and ability to cope with pandemic parenting and whether MP moderated these associations. Contrary to research from prior to the pandemic (McBride et al., 2002; Williford et al., 2007), children's ER was not associated with parent stress. It was, however, associated with better coping with pandemic parenting. Furthermore, this association was moderated by MP such that only parents who were the most mindful and had children with the strongest ER abilities reported significantly better coping. These findings provide important information about the ways that COVID-19 may be influencing family dynamics and suggest that there may be important qualifications to theory and prior evidence that suggests MP is associated with reduced stress and more adaptive coping. Interestingly, coping but not stress was significantly associated with ER. This finding was counter to our hypothesis that children's ER would be associated with increased parent stress, particularly during COVID-19 when many parents were spending more time with their children. It is possible that, during COVID-19, new stressors overshadowed ER as a significant source of parent stress. Furthermore, whereas our measure of stress was global, our coping measure was COVID- and parenting-specific and may relate more directly to child behavior. This distinction might partially explain why coping, but not stress, was related to children's ER in our sample. In addition, the moderation finding suggests MP plays a role in the association between child ER and coping, particularly for those parents of children with high ER. MP may optimize the association between children's adaptive ER and parents’ own sense of positive adjustment to parenting during COVID-19. This finding is in line with what we would expect given that MP emphasizes awareness of one's child (Duncan et al., 2009). It is possible that mindful parents may be better able to appreciate their children's strong ER skills and translate those into positive parenting outcomes. Among parents of children with low ER, mindful parents were no more likely to report successful coping than nonmindful parents, however. This finding contradicts research suggesting that more mindful individuals are better able to cope with high levels of stress (Bergin & Pakenham, 2016; Bränström et al., 2011) and perhaps highlights the importance of attending to the distinction between mindfulness and MP. Although intrapersonal mindfulness may be particularly helpful in times of stress (Creswell & Lindsay, 2014), mindful parenting is a relational process and thus may be more influenced by the shift in parent-–child relationship dynamics (e.g., amount of time spent together, parent taking on more teaching roles) we observed during the pandemic (Lee et al., 2021; Weaver & Swank, 2021). The impact of the pandemic on children may offer other explanations for the limited benefits of MP in this study. First, one study found that child ER difficulties increased during the pandemic (Giannotti et al., 2021). It is possible that some children in our sample were experiencing pronounced ER difficulties for the first time during the pandemic. The onset of ER difficulties combined with challenges of pandemic parenting may have rendered previously helpful MP practices less effective for some parents. Additionally, children with low ER may have been experiencing more difficulty adjusting to the pandemic. One study of school-aged children found that high ER was associated with greater routine maintenance, a behavioral indicator of positive adjustment (Dominguez et al., 2020). In light of research that mindfulness is associated with greater empathy (Jones et al., 2019; Trent et al., 2016), and theory suggesting MP involves greater awareness of one's child, more mindful parents of children with low ER may have been more keenly aware of their child's increased distress during the pandemic, which could have adversely affected their coping. Future studies should examine the roles of increased awareness of one's child and/or empathy in mindful parenting, and how we might better support mindful parents of children with regulatory difficulties. The contributions of this study should be considered with certain limitations in mind. The sample was predominantly mothers who were White and upper-middle class. Particularly given that COVID-19 has had disparate impacts across demographic groups (e.g., Rogers et al., 2020), future studies on this topic should include more representative samples. Further, data relied on self-report only, and social desirability effects likely played a role in parent responses. Additionally, the coping outcome was assessed using a single author-developed item, which helped facilitate a brief, minimally burdensome survey; however, a more robust measure of this outcome is preferable. Despite these limitations, these results suggest that ER may be operating differently during COVID-19 in terms of its association with parent stress, and that the benefits of MP for parent coping may be limited to only those parents whose children exhibit strong ER skills. These preliminary findings highlight a potentially important avenue for intervention with parents and families. To allow us to more confidently translate these findings into implications for clinical practice, future research should investigate the direction of these effects longitudinally. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article ORCID iD: Megan J. Moran https://orcid.org/0000-0003-1460-3876 ==== Refs References Baer R. A . (2003). Mindfulness training as a clinical intervention: A conceptual and empirical review. Clinical Psychology: Science and Practice, 10 (2 ), 125. 10.1093/clipsy.bpg015 Bauermeister J. A. Pingel E. Zimmerman M. Couper M. Carballo-Diéguez A. Strecher V. J. (2012). Data quality in HIV/AIDS web-based surveys. Field Methods, 24 (3 ), 272–291. 10.1177/1525822x12443097 23180978 Bergin A. J. Pakenham K. I . (2016). The stress-buffering role of mindfulness in the relationship between perceived stress and psychological adjustment. Mindfulness, 7 (4), 928–939. 10.1007/s12671-016-0532-x Bögels S. M. Hellemans J. van Deursen S. Römer M. van der Meulen R . (2014). Mindful parenting in mental health care: Effects on parental and child psychopathology, parental stress, parenting, coparenting, and marital functioning. Mindfulness, 5 (5 ), 536–551. 10.1007/s12671-013-0209-7 Bränström R. Duncan L. G. Moskowitz J. T . (2011). The association between dispositional mindfulness, psychological well-being, and perceived health in a Swedish population-based sample. British Journal of Health Psychology, 16 (2), 300–316. 10.1348/135910710X501683 21489058 Brown S. M. Doom J. R. Lechuga-Peña S. Watamura S. E. Koppels T . (2020). Stress and parenting during the global COVID-19 pandemic. Child Abuse & Neglect, 110 (Pt 2 ), 104699. 10.1016/j.chiabu.2020.104699 32859394 Calvano, C., Engelke, L., Di Bella, J., Kindermann, J., Renneberg, B., & Winter, S. M. (2022). Families in the COVID-19 pandemic: parental stress, parent mental health and the occurrence of adverse childhood experiences—results of a representative survey in Germany. European child & adolescent psychiatry, 31(7), 1–13. 10.1007/s00787-021-01739-0 Cohen, J. (1988). Statistical Power Analysis for the Behavioral Sciences (2nd ed.). Erlbaum. Cohen S. Kamarck T. Mermelstein R. (2014). Perceived Stress Scale. In PsycTESTS Dataset. 10.1037/t02889-000 Creswell J. D. Lindsay E. K . (2014). How does mindfulness training affect health? A mindfulness stress buffering account. Current Directions in Psychological Science, 23 (6 ), 401–407. 10.1177/0963721414547415 Deater-Deckard K. Panneton R. (Eds.). (2017). Parental stress and early child development: Adaptive and maladaptive outcomes. Springer. 10.1007/978-3-319-55376-4 Domínguez B. Romero L. L. Fraguela J. A. G. Triñanes E. R . (2020). Emotion regulation skills in children during the COVID-19 pandemic: Influences on specific parenting and child adjustment. Revista de Psicología Clínica con Niños y Adolescentes, 7 (3 ), 81–87. doi:10.21134/rpcna.2020.mon.2042 Duncan L. G. (2007). Assessment of mindful parenting among parents of early adolescents: Development and validation of the Interpersonal Mindfulness in Parenting scale. The Pennsylvania State University. Duncan L. G. Coatsworth J. D. Greenberg M. T . (2009). A model of mindful parenting: Implications for parent-child relationships and prevention research. Clinical Child and Family Psychology Review, 12 (3 ), 255–270. 10.1007/s10567-009-0046-3 19412664 Giannotti, M., Mazzoni, N., Bentenuto, A., Venuti, P., & de Falco, S. (2022). Family adjustment to COVID-19 lockdown in Italy: Parental stress, coparenting, and child externalizing behavior. Family Process, 61(2), 745–763. 10.1111/famp.12686 Hayes A. F. (2017). Introduction to mediation, moderation, and conditional process analysis: A regression-based approach. Guilford Publications. Jones S. M. Bodie G. D. Hughes S. D . (2019). The impact of mindfulness on empathy, active listening, and perceived provisions of emotional support. Communication Research, 46 (6 ), 838–865. 10.1177/0093650215626983 Jones T. L. Prinz R. J . (2005). Potential roles of parental self-efficacy in parent and child adjustment: A review. Clinical Psychology Review, 25 (3 ), 341–363. 10.1016/j.cpr.2004.12.004 15792853 Lee S. J. Ward K. P. Chang O. D. Downing K. M . (2021). Parenting activities and the transition to home-based education during the COVID-19 pandemic. Children and Youth Services Review, 122 , 105585. 10.1016/j.childyouth.2020.105585 33071407 Lu F. Xu Y. Yu Y. Peng L. Wu T. Wang T. , … & Li M. (2019). Moderating effect of mindfulness on the relationships between perceived stress and mental health outcomes among Chinese intensive care nurses. Frontiers in Psychiatry, 10 , 260. 10.3389/fpsyt.2019.00260 31057445 McBride B. A. Schoppe S. J. Rane T. R . (2002). Child characteristics, parenting stress, and parental involvement: Fathers versus mothers. Journal of Marriage and Family, 64 (4 ), 998–1011. 10.1111/j.1741-3737.2002.00998.x Podolski C. L. Nigg J. T . (2001). Parent stress and coping in relation to child ADHD severity and associated child disruptive behavior problems. Journal of Clinical Child Psychology, 30 (4 ), 503–513. 10.1207/S15374424JCCP3004_07 11708238 Rogers T. N. Rogers C. R. VanSant-Webb E. Gu L. Y. Yan B. Qeadan F. (2020). Racial disparities in COVID-19 mortality among essential workers in the United States. World Medical & Health Policy, 12 (3 ), 311–327. 10.1002/wmh3.358 32837779 Shields A. Cicchetti D . (1997). Emotion regulation among school-age children: The development and validation of a new criterion Q-sort scale. Developmental Psychology, 33 (6 ), 906–916. 10.1037//0012-1649.33.6.906 9383613 Singh N. N. Lancioni G. E. Winton A. S. Singh J. Curtis W. J. Wahler R. G. McAleavey K. M . (2007). Mindful parenting decreases aggression and increases social behavior in children with developmental disabilities. Behavior Modification, 31 (6 ), 749–771. 10.1177/0145445507300924 17932234 Solem M. B. Christophersen K. A. Martinussen M . (2011). Predicting parenting stress: Children’s behavioural problems and parents’ coping. Infant and Child Development, 20 (2 ), 162–180. 10.1002/icd.681 Trent N. L. Park C. Bercovitz K. Chapman I. M . (2016). Trait socio-cognitive mindfulness is related to affective and cognitive empathy. Journal of Adult Development, 23 (1 ), 62–67. 10.1007/s10804-015-9225-2 Trute, B., Benzies, K. M., Worthington, C., Reddon, J. R., & Moore, M. (2010). Accentuate the positive to mitigate the negative: Mother psychological coping resources and family adjustment in childhood disability. Journal of Intellectual and Developmental Disability, 35(1), 36–43. 10.3109/13668250903496328 van der Oord S. Bögels S. M. Peijnenburg D . (2012). The effectiveness of mindfulness training for children with ADHD and mindful parenting for their parents. Journal of Child and Family Studies, 21 (1 ), 139–147. 10.1007/s10826-011-9457-0 22347788 Wanberg C. R. Csillag B. Douglass R. P. Zhou L. Pollard M. S . (2020). Socioeconomic status and well-being during COVID-19: A resource-based examination. Journal of Applied Psychology, 105 (12 ), 1382–1396. 10.1037/apl0000831 33090858 Weaver J. L. Swank J. M . (2021). Parents’ lived experiences with the COVID-19 pandemic. The Family Journal, 29 (2 ), 136–142. 10.1177/1066480720969194 Williford A. P. Calkins S. D. Keane S. P . (2007). Predicting change in parenting stress across early childhood: Child and maternal factors. Journal of Abnormal Child Psychology, 35 (2 ), 251–263. 10.1007/s10802-006-9082-3 17186365