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PMC009xxxxxx/PMC9243801.txt	==== Front J Food Sci Technol J Food Sci Technol Journal of Food Science and Technology 0022-1155 0975-8402 Springer India New Delhi 35789583 5528 10.1007/s13197-022-05528-8 Review Article Bioactive metabolites in functional and fermented foods and their role as immunity booster and anti-viral innate mechanisms Varsha Kontham Kulangara 1 Narisetty Vivek 2 Brar Kamalpreet Kaur 34 Madhavan Aravind 5 Alphy Maria Paul 67 Sindhu Raveendran 8 Awasthi Mukesh Kumar 9 Varjani Sunita 10 http://orcid.org/0000-0003-4191-8048 Binod Parameswaran binodkannur@niist.res.in 67 1 grid.254567.7 0000 0000 9075 106X School of Medicine, University of South Carolina, Columbia, SC 29209 USA 2 Moolec Science, Innovation Centre, Gallows Hill, CV34 6UW, Warwick, UK 3 grid.21100.32 0000 0004 1936 9430 Department of Civil Engineering, Lassonde School of Engineering, York University, North York, Toronto, Ontario M3J 1P3 Canada 4 grid.468122.b 0000 0004 5906 3081 Centre Technologique des Résidus Industriels en Abitibi Témiscamingue, 433 Boulevard du collège, J9X0E1, Rouyn-Noranda, Canada 5 grid.418917.2 0000 0001 0177 8509 Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, 695 014 India 6 grid.419023.d 0000 0004 1808 3107 Microbial Processes and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology, Trivandrum, Kerala 695 019 India 7 grid.469887.c 0000 0004 7744 2771 Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002 India 8 Department of Food Technology, T K M Institute of Technology, Kollam, Kerala 691505 India 9 grid.144022.1 0000 0004 1760 4150 College of Natural Resources and Environment, Northwest A & F University, Yangling, 712 100 Shaanxi China 10 Gujarat Pollution Control Board, Paryavaran Bhavan, CHH Road, Sector 10 A, Gujarat Gandhinagar, 382010 India 24 6 2022 9 2023 60 9 23092318 19 4 2022 18 5 2022 © Association of Food Scientists & Technologists (India) 2022 Live microorganisms in the fermented foods termed probiotics and their secondary metabolites with bioactive potential were considered as potential anti-viral capabilities through various mechanisms. Given the importance of functional and fermented foods in disease prevention, there is a need to discuss the contextualization and deep understanding of the mechanism of action of these foods, particularly considering the appearance of coronavirus (COVID-19) pandemic, which is causing health concerns and increased social services globally. The mechanism of probiotic strains or their bioactive metabolites is due to stimulation of immune response through boosting T-lymphocytes, cytokines, and cell toxicity of natural killer cells. Proper consumption of these functional and fermented foods may provide additional antiviral approaches for public benefit by modulating the immune functions in the hosts. Supplementary Information The online version contains supplementary material available at 10.1007/s13197-022-05528-8. Keywords Anti-viral metabolites Immunity Fermented foods COVID-19 Functional foods issue-copyright-statement© Association of Food Scientists & Technologists (India) 2023 ==== Body pmcIntroduction The process of fermentation has long been used to increase the shelf life, flavour and functional properties of food. In addition to help food last longer, fermentation increases the nutritional value, and the probiotic bacteria present in fermented food confer health benefits that comprise reducing the risk of type 2 diabetes and cardiovascular diseases by decreasing total and LDL cholesterol (Marco et al. 2017). Multiple clinical trials investigated the advantages of fermented food and exposed the ability of kimchi and yogurt to downsize the risk of type 2 diabetes (Chen et al. 2014), Chungkookjang to decrease obesity (Byun et al. 2016), and the capacity of fermented milk and rye bread to control infection and irritable bowel syndrome (Laatikainen et al. 2016). Among this health promoting and infectivity demoting effects include the antiviral activity of certain fermented foods owing to the presence of live bacteria in it, and the examples are Chr. Hansen (http://www.chr-hansen.com/); Kingdom Supercultures (https://kingdomsupercultures.com/); Probitat (http://www.probitat.eu/); 3FBIO Ltd (ENOUGH) (https://www.enough-food.com/); Fermbiotics (https://www.fermbiotics.com/). Functional foods (FFs) are distinguished by their nutraceuticals. Nutraceuticals are either whole foods or food ingredients that provide health benefits, such as disease prevention and/or treatment. This is generally associated with their microvascular, anti-inflammatory, and anti-oxidation properties in highly affected individuals. Active FFs are rich in polyphenols, terpenoids, flavonoids, and unsaturated fatty acids ingredients are among the widely active functional foods to be consumed (Alkhatib et al. 2018). Recently, Acquah et al. (2020) reported that some bioactive peptides presented many similar hormonal and neurological activities of human system (Acquah et al. 2020). On the other side, fermented food products contain probiotics (García-Burgos et al. 2020). Probiotics are “live microorganisms which when administered in adequate amounts confer a health benefit on the host”. Covid-19 was observed to be a severe acute respiratory syndrome (SARS) which is named as SARS corona virus 2 or SARS-CoV-2 (Lai et al. 2020). Broadly, coronaviruses are large and enveloped mainly found in humans and mammals and known to cause respiratory, gastrointestinal, and neurological disease. Through genetic recombination and mutation, corona viruses can be more infectious. Stringent measures were taken by various countries based on their resource limitations, geography, population, and political factors. Although these severe interventions, since Feb. 2020 and as of March 17, 2022, the outbreak has infected almost 464 million people and killed over 6.06 million. Previous studies have shown that 65% of airborne MERS-CoV virus remains viable in the air and infectious after 60 min (Pyankov et al. 2018). The presence of SARS-CoV-2 in hospitals and entrance to department stores in Wuhan, China (Liu et al. 2020), air outlet fans in a COVID-19 outbreak center in Singapore (Ong et al. 2020) and hospital isolation rooms in Nebraska (Santarpia et al. 2020) were observed. Recently, some preliminarily results have shown that the virus can survive up to 3 h as aerosol and infect cells throughout this period (van Doremalen et al. 2020). A ferret model of SARS-CoV-2 infection that reiterates aspects of human disease has also confirmed the potential of virus airborne transmission (Kim et al. 2020). A recent study reported that SARS-CoV-2 can be viable for 4 h on copper, 24 h on cardboard, 2–3 days on plastic and stainless steel (Guo et al. 2020). Generally, SARS-CoV-2 is transmitted via respiratory pathways, but they may spread via multiple dominant routes. An acceptor individual must receive an infectious dose of the virus from a donor, either directly through the air or indirectly through deposits of the virus on various surfaces. Molecular based detection techniques, like plaque assay, Enzyme-Linked Immunosorbent Assay (ELISA), Lateral-Flow (immuno) Assay (LFA), Polymerase Chain Reaction (PCR) and Surface Plasmon Resonance (SPR) assay are identified quality and quantitative techniques for virus detection. Approximately 120 candidates are hardly working to formulate vaccines based on either nucleic acids, inactivated or live attenuated virus, and recombinant proteins (Le et al. 2020). Other approaches based on monoclonal antibodies, hyperimmune globulin will be another option. The antiviral role of FFs and fermented foods for the defence of COVID-19 is lacking and has not yet been established. However, recent reports showed that diabetes is considered a risk factor for the development and diagnosis of COVID-19 (Guo et al. 2020). Fermented foods generally contain single or multiple genera of live probiotic microorganisms that has positive impact on the host beneficially preserving the intestinal microbiota that in return has modulatory role in immune responses and human health (Fig. 1). Herein, we present antiviral role of fermented foods containing of probiotic and bioactive compounds; mechanism to stimulate immunity; case studies of viral infections and their prevention or treatment and different types of fermented foods available worldwide. This review leads to inculcating the knowledge of benefits of probiotics and fermented foods in reducing the risk of COVID-19 or other viral infections.Fig. 1 Schematic representation of applications of probiotics and bioactive metabolites Antiviral activity of fermented foods containing probiotics and bioactive compounds The plethora of fermented foods is derived from plants and animal resources. Plant-based fermented foods are tempeh, kimchi, tempoyak, and tapai. While animal-based fermented foods include kefir, cheese, yogurt, sauces, other dairy and meat products (Tamang et al., 2016; Raji et al. 2017; Khalil et al. 2018; Lee et al. 2020). Alcoholic beverages like fermented porridge made of sorghum and maize in South American countries (Tamang et al. 2020). Fermented foods are enriched with anti-microbial end products such as various organic acids, ethanol and peptides or bacteriocins and several studies report the antiviral potential of fermented foods in-vitro and in-vivo. The probiotic bacteria and bioactive compounds in fermented foods possess antiviral activities against gut and respiratory and viruses. These active foods stimulate immune system function by increasing the synthesis of pro-inflammatory cytokines and T lymphocytes (CD3+, CD16+, CD56+) (Muhialdin et al. 2021). Lactobacillus plantarum LBP-K10 isolated from kimchi synthesised cyclic di-peptides that inhibited the growth of the influenza A (H3N2) virus (Kwak et al. 2013), while another study reported declined survival of feline calicivirus and murine norovirus proliferation during Dongchimi fermentation along with an increase in lactic acid bacteria (LAB) (Lee et al. 2012). Likewise, soy extracts fermented with Aspergillus fumigatus F-993 or A. awamori FB-133 showed therapeutic potential by decreasing hepatitis A virus titers in-vitro (Ghanem et al. 2020). The cell free supernatant of yogurt has antiviral activity for RNA viruses such as enterovirus 71 and influenza, porcine epidemic diarrhoea virus and Coxsackie A and B viruses (Choi et al. 2010). Polyphenols, bioactive peptides, exopolysaccharides, linoleic acid, and vitamins are among the bioactive compounds found in fermented foods (Hayes and García-Vaquero 2016). Spanish sausage release angiotensin-converting enzyme inhibitor (ACE-I) when L. pentosus and S. carnosus used as a inoculum for the fermentation (Mora et al. 2015). The fermentation of Ruditapes philippinarum clams with Bacillus natto stimulate hyper-production of ACE-I peptide synthesis exerts anti-cancer property (Chen et al. 2018). However, further studies assessing the full potential of the probiotics to combat COVID-19 should be carried out (Olaimat et al. 2020) (Table 1). Clinical impact of probiotics and bioactive compounds against viral infections in humans High mutation rates of RNA viruses lead to their rapid evolution and better environmental adaptability (Carrasco-Hernandez et al. 2017). Various case studies report the ability of fermented and probiotic food to reduce respiratory tract infections. In one case study, some COVID-19 patients exhibited Bifidobacterium and Lactobacillus dysbiosis. The aged patients who suffered severely from COVID-19 had poor gut microbiota diversity (Dhar et al., 2020). Probiotics L. acidophilus, Bifidobacterium, and Saccharomyces boulardii, as well as minerals and vitamins, were found to reduce the complications of massive antibiotic-associated diarrhoea and Clostridium difficile infections. (Horowitz et al. 2020). The simultaneous intake of probiotics with azithromycin decreases the severity of Candida albicans infection. In another study, COVID-19-like symptoms in a young boy disappeared after 2 days of probiotic administration. (Ji et al. 2020). The administration of probiotics as an adjunct protected 97% patients against SARS-CoV2 infection. According to the recent trail, patients with severe disease recovered more easily by probiotics therapy (87.5% vs. 40.4%, p = 0.037) compared to non-severe ones. A human clinical trial describes oral intake of the probiotic L. fermentum CECT5716 increased NK cells proliferation after vaccination when compared to the group without probiotic consumption (Olivares et al. 2007). A study conducted on elderly people found to be having a significant increase in NK cell activity (Makino et al. 2010). At the same time, a randomized control clinical trial among women consumed 1073R-1-yogurt yogurt (n = 479) demonstrated IFN-γ production with no increase in NK cell activity (Kinoshita et al. 2019). A control trial revealed that the probiotic strain Lactobacillus GG holds an adjuvant potential (Davidson et al. 2011). In children, for acute rotavirus diarrhoea, probiotic administration can relieve symptoms (Grandy et al. 2010). Multiple clinical trials are underway where the adeptness of probiotic and other dietary supplements is being investigated to alleviate the symptoms of COVID-19 infection (Table 2). In the last two years of CoviD-19 pandemic, priority was to prevent the spreading, reduce the infections, save the lives, inculcate the knowledge of vaccination and healthy diet. Frontline health teams would benefit from the development of cutting-edge technology and the collection of available evidence. Sufficient nutrition improves health and boosts immunity, which aids in the prevention and treatment of infections. In this review we have discussed the role of probiotics in combating COVID-19 based on recent evidences, as well as their role as immune-modulators and antiviral agents. Further investigations on impact of probiotic strains and their bioactive compounds on COVID-19 affected individuals are awaiting (Kurian et al. 2021). However, more research needs to be done to study the production titres of interleukins, interferons, antibodies, and viral count due to probiotic administration during viral infection especially SARS-CoV-2. Immune modulatory mechanisms by probiotics and fermented food The health benefits conferred by fermented food are mainly attributed to the presence of live probiotic bacteria present which colonize the intestine and impart favourable effects. Lymphocytes, NK cells, macrophages and neutrophils are capable of mediating antibody dependent cell mediated cytotoxicity (ADCC) against virus infected cells and various probiotic and fermented food are reported to induce these immune cells. Multiple clinical trials have shown the ability of fermented food products with probiotics to improve NK cell activity and L. casei strain Shirota is a principal probiotic strain with this ability (Takeda and Okumura 2007). Additionally, consumption of dairy yogurt containing probiotics increased NK cell, IL-12, IFNγ and IgG1 levels in a randomized, open-label, placebo-controlled study conducted in 200 healthy volunteers (Lee et al. 2017). Probiotics play critical role in resistance against viral infections particularly in elderly people with age-related decline in lymphoid cell activity, by modulating the immune responses of hosts. Randomized control trials show that probiotic consumption significantly increased NK cell activity and CD56-positive lymphocytes in peripheral circulation in healthy elderly individuals (Gui et al. 2020). Probiotic intakes enhance cellular immunity in elderly who had poor pretreatment immune responses. Dietary supplementation of probiotic B. lactis HN019 increased helper (CD4 (+)) and activated (CD25 (+)) T lymphocytes, polymorphonuclear cells and natural killer cells in healthy elderly volunteers (Gill et al. 2001). Probiotic consumption found to increase natural and acquired immunity in mice and significantly improved serum antibody responses to antigens administered orally and systemically (Gill et al. 2000). Oral administration of heat killed probiotics from Mongolian dairy products augmented IFN -α, IL-12, and IFN -γ productions and increased NK cell activity leading to alleviated influenza symptoms in mice (Takeda and Okumura 2007). Similarly, oral administration of L. rhamnoses CRL1505 improved resistance to RSV infection in infant mice via IFN-γ and IL-10 secretion, which resulted in the activation of CD103+ and CD11bhigh dendritic cells and the generation of CD3+CD4+IFN-γ+ Th1 cells, with subsequent attenuation of strong Th2 reactions associated with RSV challenge (Chiba et al. 2013). An in vitro model study demonstrated the ability of probiotic bacteria to decrease vesicular stomatitis viral infection by production of nitric oxide and inflammatory cytokines such as IL-6 and IFN-γ (Ivec et al. 2007). When L. casei DK128 was administered into a mice intranasally, reduction in the weight and viral loads was observed, which might elicit the protection against different subtypes of influenza viruses, and mice are observed to be immune to primary infection and subsequently developed heterosubtypic secondary virus infection. The protective effect was linked to an increase in alveolar macrophage cells in the lungs and airways, the early induction of virus-specific antibodies, and lower levels of pro-inflammatory cytokines and innate immune cells (Fig. 2) (Jung et al. 2017).Fig. 2 Possible mechanism of anti-viral activity by probiotics Exopolysaccharides (EPS) secreted by probiotic microrganisms in fermented food contribute towards their immunomodulatory ability and antiviral potential in-vivo. Consumption of yogurt consisting of the starter culture L. delbrueckii ssp. bulgaricus OLL1073R-1 and secreted EPS reduced influenza virus titer in mice. The prognosis observed significant increase of anti-influenza virus antibodies such as IgA and IgG1 along with augmented NK cell activity. In knockout mice, the presence of myeloid differentiation factor 88, EPS produced by this probiotic strain activated NK cells through IL-12- and IL-18-mediated IFN-γ production. The same probiotic strain demonstrated resistance flu virus by inducing NK cell activity in human subjects (Makino et al. 2016). EPS produced by L. delbrueckii TUA4408L improved the resistance to rotaviral infection by preventing the viral replication, activation of Toll-like receptor 3 rendering antiviral innate immune response in porcine intestinal epithelial cells. The study also reports L. delbrueckii TUA4408L and its EPS activated interferon regulatory factor (IRF)-3 and nuclear factor κB (NF-κB) signalling pathways leading to improved expression of the antiviral factors IFN-β, Myxovirus resistance gene A (MxA) and RNaseL (Kanmani et al. 2018). In addition to EPS, short chain fatty acids (SCFAs) produced by these microorganisms are observed to regulate immune responses (Parada Venegas et al. 2019). Indirectly D-phenyl lactate produced by various lactic acid bacteria regulates the immune reactions stimulated by G-protein coupled receptors by activating regulatory hydroxycarboxylic acids (Peters et al. 2019). Lactate and pyruvate also contribute to enhanced immune responses in mice models by inducing GPR31-mediated dendrite protrusion of intestinal CX3CR1+ cells (Morita et al. 2019). The modulation of gut microbiota seems to be a one of the approaches to combat viral infections including COVID-19, but it needs to be further confirmed through animal models (Akour 2020). Overall, research indicates that fermented foods and probiotics contain high or low molecular weight bioactive metabolites that elicit modulations in the immune system rendering health benefits. Future outlook Fermentation by microbes applies various unconventional and uncharacterised enzymes to produce hydrolysates of protein with varying compositions of peptides. By utilizing highly efficient bacteria and by optimizing conditions of fermentation, a wide array of proteases could be produced to hydrolyse peptides and proteins with varying amino acid composition and different chain length could be synthesised in accordance to different enzyme specificity, possibly producing unique sequences of peptide with novel anti-viral bioactive properties. It is predictable that the greatest perplexing part for researchers dealing with functional food bioactive peptides is to warrant the full bioavailability of the bioactive component after their consumption. The bioavailability of bioactive peptide is based on the capability of the peptides to resist proteolytic activity in the intestine and serum, and their potential to enter into the blood stream and consequently, exercising their biological activity. Hence, it is critical to improve the processing settings in order to retain their biological activities. Encapsulation is one of the well-characterised technologies to improve the bioavailability of functionally active peptides. This technique has been extensively applied in the nutraceutical, and food industries to encapsulate biologically active components. Encapsulation of bioactive is economically viable as this technique could avoid the interaction of the peptides with environment and/or other components in the food matrix, decrease the consequence from processing, intensify peptide stability, protect peptides against digestive enzymes and improve bioavailability. Since functionally active foods are graded as a normal or enriched with bioactive, it has certain side effects, although the research work in this perspective is not adequate to support this statement. Even though much cell line based, and animal model studies have been widely explored to examine the bioactivity of food derived bioactive, inadequate data on human experiments is available. More research data on human clinical trials are required to validate the efficiency of food derived bioactivities. Along with this other safety parameters, like cytotoxicity, allergic response of the functional food should be evaluated before commercialization. Viral diseases are considered as an immune compromised state resulting from poor consumption of micronutrients, vitamins and other trace elements. Several research previously indicated enhanced function of the immune system by taking those many fermented and functional foods including essential fatty and amino acids, and the above-mentioned minerals and vitamins (Calder and Kew 2002). Satisfactory diet-based consumption, and supplementation of such functional foods, contribute to sustaining optimal levels in the humans, which improves several characteristics of the immune function, and provides an important antiviral prevention of COVID-19. On the other hand, less strong immune activation has been proved to be the primary threat factor for COVID-19, which makes it appropriate to define the defensive role of functional food particles benefits in the perspective of preventing COVID-19 and other viral diseases (Grant et al. 2020). Examination of outcome of viral disease management in high-risk populations and aged people is very central. Large number of viral and COVID 19 infection rate is reported in older adults and persons with other co-morbidities. The prevalence of COVID-19 in people with diabetes is high and now considered a hazard factor for the progression COVID-19 (McGurnaghan et al. 2021). Therefore, best “immune-modulating” functional foods could provide the finest prevention and progression of the viral diseases. The use of functional foods to combat viral diseases would especially benefit the elderly, which has become a growing sector of the world population. Conclusion Fermentation by microbe’s functions as a potent technique to supplement foods with biologically active peptides from various animal or plant sources. These bioactive compounds produced in the fermented foods tends to boost the immune response either directly or indirectly against the viral infections by modulating the lymphocytes, NK cells, macrophages and neutrophils that are capable of mediating antibody dependent cell mediated cytotoxicity. Several works have been documented to unveil novel bioactive components from fermented foods and other edible plant by products. It is possible that the varieties of biopeptides from various fermented food will continue to develop in the coming years. Further awareness of these health beneficial fermented foods and their compositions could help in improving the health and wellness of the society. Table 1 Antiviral bioactives from functional and fermented food Probiotic microbes or Fermented foods Salient Feature Mode of action References Bifidobacterium animalis Prevent upper respiratory tract infection Inhibit viral replication (Smith et al. 2013) L. plantarum Prevent gastroenteritis COVID virus Reduces granulocyte, diminishes virus recovery (Yang et al. 2017) L. lactis Prevent respiratory tract infection Activates plasmacytoid dendrtitic cell (Kokubo et al. 2019) L. plantarum Gastroenteritis coronaviruses (TGEV) Reduces inflammation and tissue injury (Yang et al. 2017) Lactobacillus casei DN-114 001; Dan Active/Actimel Reduced incidence and duration of RTIs − (Guillemard et al. 2010) Kefir Zika, hepatitis C, influenza, rotaviruses Enhanced macrophage synthesis, increases phagocytosis, enhanced synthesis of (CD4+), CD8 + cells, immunoglobulins, neutrophilss, and various cytokines (IL-2, IL-12, INF-γ). (Hamida et al. 2021) Yoghurt Inhibit Enterovirus − (Choi et al. 2010) Fermented ginseng extracts Inhibit influenza virus H1N1, H3N2, H5N1, and H7N9 strains Viral inoculation with extract of ginseng formed better immune responses against the 20 infection with homologous and heterosubtypic virus. (Wang et al. 2018) Black ginseng Inhibit influenza virus Black ginseng improved the levels of GM-CSF and IL-10 at the time of infection (Kim et al. 2019) Dietary xylitol Inhibit influenza virus A − (Yin et al. 2014) Chongkukjang (Traditional Korean feremented food) Influenza virus A − (Wei et al. 2015b) Resveratrol (From red grapes) Inhibit Epstein-Barr virus Downregulation of antiapoptotic proteins (De Leo et al. 2012) Zingiberofficinale (Ginger) Anti-chikungunya activity − (Kaushik et al. 2020) Curcumin Inhibit Zika and chikungunya viruses Curcumin interferes with virus-cell binding. (Mounce et al. 2017) Table 2 Ongoing clinical trials where probiotics and dietary supplements are used against COVID-19 No. Clinical trial identifier Intervention Aim 1 NCT04621071 Probiotics Evaluation of the efficacy of probiotics to dcrease the duration and symptoms of COVID-19 2 NCT04458519 Probiorinse Reduction of severity of COVID-19 symptoms 3 NCT04390477 Probiotic Effect of probiotic on COVID-19 infection 4 NCT04366180 L. coryniformis K8 Effect of probiotic in the incidence and prevention of COVID-19 infection in health workers 5 NCT04734886 L. reuteri DSM 17,938 Impact of probiotic supplementation on SARS-CoV-2 specific antibody response following COVID-19 infection 6 NCT04666116 Dietary supplements including probiotics To check the changes in viral load in COVID-19 infection 7 NCT04847349 Probiotics Efficacy of probiotic intervention to boost the immunity in unvaccinated people infected previously with SARS-CoV-2 8 NCT04420676 Synbiotic (Omnibiotic AAD) To check the ability to reduce gastrointestinal problems in COVID-19 patients 9 NCT04813718 Omni-Biotic Pro Vi 5 Analysis of post-Covid syndrome 10 NCT04399252 L. rhamnosus GG In order to study the consequence of microbiome in COVID-19 exposed household contacts Supplementary Information Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 556 kb) Author's contribution KKV, VN, AM, KKB, and MPA: Collecting articles and Writing original draft. RS: Conceptualization, Methodology, Writing - original draft. MKA, SV: Writing, Reviewing and Editing, Formal analysis. PB: Project Administration, Conceptualization and Visualization. Funding (Information that explains whether and by whom the research was supported): No funding to mention and no funding received for the particular work mentioned in the manuscript. Declarations The authors declare that the work described has not been published before (except in the form of an abstract, a published lecture or academic thesis), it is not under consideration for publication elsewhere, its submission to JFST publication has been approved by all authors as well as the responsible authorities – tacitly or explicitly – at the institute where the work has been carried out, if accepted, it will not be published elsewhere in the same form, in English or in any other language, including electronically without the written consent of the copyright holder, and JFST will not be held legally responsible should there be any claims for compensation or dispute on authorship. Conflict of 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. Kontham Kulangara Varsha and Vivek Narisetty these authors contributed equally and Co-first authors. 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PMC010xxxxxx/PMC10155280.txt	==== Front Mol Ther Mol Ther Molecular Therapy 1525-0016 1525-0024 American Society of Gene & Cell Therapy S1525-0016(23)00193-4 10.1016/j.ymthe.2023.03.033 Commentary Extracellular vesicles: A promising therapy against SARS-CoV-2 infection Leyfman Yan 15 Gohring Greta 25 Joshi Muskan 36 Menon Gayathri Pramil 36 Van de Kieft Alexandra 46 Rivero Tania del 26 Bellio Michael A. 26 Mitrani Maria Ines mari@organicell.com 26∗ 1 Icahn School of Medicine at Mount Sinai South Nassau, Oceanside, NY, USA 2 Organicell Regenerative Medicine, Davie, FL, USA 3 Tbilisi State Medical University, Tbilisi, Georgia 4 Cornell University, Ithaca, NY, USA ∗ Corresponding author: Mari Mitrani, MD, PhD, Organicell Regenerative Medicine, Davie, FL 33314, USA. mari@organicell.com 5 These authors contributed equally 6 These authors contributed equally 03 5 2023 03 5 2023 31 5 11961200 © 2023 The American Society of Gene and Cell Therapy. 2023 The American Society of Gene and Cell Therapy ==== Body pmcSevere acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) has infected over 650 million people and claimed the lives of nearly 7 million since the start of the pandemic. While SARS-CoV-2 is becoming endemic with several preventative therapies, an effective treatment against severe disease remains unavailable. Immunocompromised patients remain vulnerable given the limited efficacy of vaccinations and are at risk of respiratory failure, organ failure, and septic shock if infected.1 The development of therapeutics to combat the progression and severity of SARS-CoV-2 infection presents an opportunity to explore innovative approaches to treating viral diseases. Novel therapeutic strategies aim to target the host response to hyper-inflammation and prevent the cytokine storm that is often associated with severe COVID-19 cases.2 In recent years, researchers have focused on intracellular secreted factors, such as extracellular vesicles (EVs), to improve and build upon the knowledge gained from cell-based research and spearhead the use as potential therapeutic agents for various diseases, including SARS-CoV-2. EVs are small membranous structures secreted by the cell membrane or the cell’s internal recycling pathways and have emerged as a promising therapeutic strategy due to their involvement in a range of biological processes, including cell signaling, immune response, and disease progression. The objective of this analysis is to examine the potential efficacy of EV-based therapies in the treatment of SARS-CoV-2 severity, with a particular emphasis on their common mechanisms and suitability for future therapeutic use in human patients. Severe SARS-CoV-2 acts via direct and indirect pathways to cause local and systemic injury. In the direct pathway, severe SARS-CoV-2 utilizes its spike protein to bind to angiotensin-converting enzyme 2 (ACE-2), allowing entry into cells. Cells in the nasopharyngeal tract and lungs are most prone to damage by SARS-CoV-2 due to higher cell surface expression of the ACE-2 receptor.3,4 After direct cellular entry, SARS-CoV-2 replicates using host machinery, and viral-mediated damage results in the secretion of pro-inflammatory cytokine interleukin-6 (IL-6).5 Clinically, this presents with anosmia and ageusia with rapid progression to dyspnea and respiratory failure, ultimately resulting in multi-organ damage.6 The virus also acts via an indirect pathway to induce systemic injury. SARS-CoV-2-infected cells can undergo pyroptosis, which leads to the release of damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs).7 This mobilizes antigen-presenting cells (APCs)—including dendritic cells and pulmonary macrophages—that recognize PAMPs and DAMPs and release pro-inflammatory cytokines and chemokines, including interferon (IFN)-γ, IL-6, IP-10, and IL-1β. IL-1β further drives the activation of pro-inflammatory pathways, resulting in the recruitment of neutrophils and cytotoxic T cells and the upregulation of cytokines—mainly IL-6. Hypoxia induced by SARS-CoV-2 triggers further IL-6 secretion.8 IL-6 also modulates its own expression by upregulating the production of IL-10 (anti-inflammatory). However, in the presence of SARS-CoV-2, there is significantly greater IL-6 production, resulting in a net pro-inflammatory state. Dysregulation of the innate immune response leads to increased inflammation and end-organ damage.9,10 One promising treatment modality for severe SARS-CoV-2 infection is EVs. EVs can secrete proteins and anti-inflammatory molecules that can modulate the host immune response. Additionally, EVs may act as a negative regulatory element in the transmission of viral infection.11 Given these properties, EVs act at multiple points within the direct and indirect pathways to inhibit the inflammatory cascade (Figure 1). EVs can inhibit viral replication and thereby decrease direct viral injury.12 Their ability to block IL-6, IL-6 precursors (IL-1β), and inflammatory cytokines (tumor necrosis factor α [TNF-α], IL-8, and MIP-2) at multiple points within the pathway13,14 while upregulating IL-10 results in downregulation of cytokine production and reduction in systemic injury.Figure 1 Mechanistic efficacy of extracellular vesicles against severe SARS-CoV-2 infection SARS-CoV-2 acts through the direct and indirect pathway to induce systemic inflammatory injury. Extracellular vesicles secrete proteins and anti-inflammatory molecules to effectively block inflammatory mediators and pathways at multiple points along the pathways, resulting in downregulation of inflammation, cytokine release, and systemic damage. Given their ability to act on multiple pathways, EVs can provide a more comprehensive and effective approach to treating complex diseases.15 To highlight the therapeutic properties of EVs, we conducted a review of 9 studies reporting the effects of EV therapy on lung injury models (Table 1). The reported outcomes of the reviewed EV therapies in experimental models (Table 1) indicate lung injury recovery, improved respiratory function, and overall survival. This was achieved by (1) reducing pro-inflammatory cytokines, (2) enhancing anti-inflammatory cytokines, (3) decreasing neutrophil infiltration, and (4) increasing macrophage polarization to the anti-inflammatory M2 phenotype. EV administration also resulted in downregulation of IL-1β, TNF-α, IL-6,16,17,18 MIP-1,18,19 MIP-2, and CXCL2,18,20 in addition to upregulation of IL-10.16,21,22 Moreover, EVs reportedly preserved alveolar structure,19 reduced alveolar wall thickness,18,21,23 and inhibited virus-induced apoptosis in lung epithelial cells.22 Finally, the ability of mesenchymal stem cell (MSC)-EVs to transfer cargo, such as miR-27a-3p, increased M2 macrophage polarization, effectively reducing TNF-α17 and inhibiting lung fibrosis.24Table 1 Articles reporting the effects of EV therapy on lung injury models Source of EVs Model Sample EV effects on cytokines and inflammatory molecules Pathological outcomes Source Adipose MSCs sepsis-induced ALI: in vivo mouse lung tissueblood ↓IL-6, ↓TNF-⍺, ↓IL-1β, ↑EBI3-protein, ↑P28-protein↓IL-27 reduction in pulmonary inflammation and lung tissue injury (↓macrophage infiltration), increased survival rate Wang et al.16 Amniotic fluid BPD: in vivo rat lung tissue ↓IL-1⍺, ↓IL-1β, ↓MCP-1, ↓MIP-1⍺ significant decrease of pulmonary hypertension, preservation of alveolar structure, reduction in vascular remodeling, suppression of lung inflammation, reduction of macrophage infiltration Bellio et al.19 Adipose MSCs ALI: in vivo mouseALI: in vitro mouse lung tissueBALBMDMs ↓TNF-⍺, ↓IL-1β, ↓IL-6, ↑IL-10, ↓iNOS, ↓NF-κB↓TNF-⍺, ↓IL-1β, ↓iNOS, ↑ YM-1, ↑MRC-1, ↑mi-27-a-3p reduction of pulmonary endothelial barrier, inflammation (↓ pro-inflammatory cytokines, ↑ anti-inflammatory cytokines, ↓ neutrophils), and alveolar septal thickening Wang et al.17 Adipose MSCs ALI: in vivo mouseALI: in vitro mouse lung tissueBALBMDMs ↓IL-1β, ↑IL-10↓IL-6, ↑↓IL-1β, ↓TNF-⍺, ↓iNOS, ↑TGF-β1, ↑YM-1 reduction in inflammation (↓ neutrophils, ↓macrophage recruitment) and alveolar wall thickness Huang et al.21 Bone marrow MSCs ALI: in vivo mouseALI: in vitro mouse BALRAW267.4 ↓MIP-2, ↓TNF-⍺, ↑LTB4↓MRP1-protein, ↑miR-145 antimicrobial effect (↑ monocyte phagocytosis, ↓bacterial levels), reduction of inflammation (↓leukocytes, ↓neutrophils) Hao et al.20 Umbilical cord jelly MSCs influenza-induced ALI: in vitro human AEC no particular mechanism studied restoration of alveolar fluid clearance, reduction alveolar protein permeability 29 Umbilical cord EPC (rich in miR-126) ALI: in vivo mouseALI: in vitro human lung tissueBALAEC ↓TNF-⍺, ↓IL-1β, ↓IL-6, ↓IFN-γ, ↓MIP-1↓MIP-2, ↓MIG, ↓IP-10, ↓MPO↑Claudin1, ↑Claudin4, ↑Occludin reduction of inflammation (↓ pro-inflammatory cytokines, ↑ anti-inflammatory cytokines, ↓ neutrophils), alveolar wall thickness, and hyaline membrane formation Zhou et al.18 Whole blood fibrosis: in vivo mouse lung tissue ↓hydroxyproline reduction of immune cell recruitment, alveolar wall thickness, and collagen deposition Sun et al.23 Bone marrow MSCs influenza-induced ALI: in vivo piginfluenza-induced ALI: in vitro pigs lung tissueLECs ↓TNF-⍺, ↓CXCL10, ↑IL-10↓apoptosis inhibition of viral replication, reduction of inflammation, decrease in virus-induced lung lesions, inhibited virus-induced apoptosis in lung epithelial cells Khatri et al.22 AECs, alveolar epithelial cells; ALI, acute lung injury; BAL, bronchioalveolar lavage; BMDMs, bone marrow-derived macrophages; BPD, bronchopulmonary dysplasia; CXCL, chemokine (C-X-C motif) ligand; EPC, endothelial progenitor cell; EVs, extracellular vesicles; IFN, interferon; IL, interleukin; LECs, lymphatic endothelial cells; LTB4, leukotriene B4; MCP, monocyte chemotactic protein; MIG, monokine induced by gamma interferon; MIP, macrophage induced protein; MIR, microRNA; MPO, myeloperoxidase; MRC-1, mannose receptor C-type 1; MRP1, multidrug resistance associated protein 1; MSC, mesenchymal stem/stromal cell; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NOS, nitric oxide synthase (iNOS, inducible; eNOS, endothelial); RAW267.4, monocyte/macrophage lineage; TGF, transforming growth factor; TNF, tumor necrosis factor; YM-1, Chitinase 3-like 3, a macrophage protein. The translation of EV-based therapies from acute lung injury models to human clinical studies have significant potential for the treatment of SARS-CoV-2-induced acute respiratory distress syndrome (ARDs). Preclinical models of lung injury have shown upregulated inflammatory responses and migration of neutrophils and macrophages to pulmonary tissues (Table 1). This was verified pathologically and shown to be due to an upregulation of IL-6. In preclinical models, EVs have demonstrated an ability to dampen inflammation and reduce T cell proliferation caused by SARS-CoV-2, establishing the rationale for present clinical trials.25 Several EV-based therapies have entered clinical trials with the aim of assessing safety, efficacy, administration route, and optimal dosing in various respiratory conditions. A complete list of ongoing clinical trials on the use of EV-based therapeutics in COVID-19 treatment is shown in Table 2. Due to the rapid spread of COVID-19 and lack of effective therapies, several studies were approved on an emergency basis by ethical committees. In a study where amniotic fluid-derived EVs were administered to high-risk patients with mild-to-moderate COVID-19, results showed a significant decrease in CRP, IL-6, and TNF-α, as well as stabilized absolute lymphocyte count (ALC).26 Additional clinical testing performed on three severely ill patients with COVID-19 revealed a decrease in inflammatory biomarkers and improvements in patient clinical status and respiratory function.27 Both studies were completed without any adverse events or safety concerns.Table 2 List of clinical trials on the use of EV-based therapeutics in COVID-19 management Referencea Official title Status NCT04493242 Extracellular Vesicle Infusion Treatment for COVID-19 Associated ARDS (EXIT-COVID19) completed NCT05787288 A Clinical Study on Safety and Effectiveness of Mesenchymal Stem Cell Exosomes for the Treatment of COVID-19 recruiting NCT04657458 Expanded Access for Use of bmMSC-Derived Extracellular Vesicles in Patients With COVID-19 Associated ARDS available NCT05116761 ExoFlo™ Infusion for Post-Acute COVID-19 and Chronic Post-COVID-19 Syndrome not yet recruiting NCT05354141 Bone Marrow Mesenchymal Stem Cell Derived EVs for COVID-19 Moderate-to-Severe Acute Respiratory Distress Syndrome (ARDS): A Phase III Clinical Trial recruiting NCT05228899 Zofin to Treat COVID-19 Long Haulers recruiting NCT04902183 Safety and Efficacy of Exosomes Overexpressing CD24 in Two Doses for Patients With Moderate or Severe COVID-19 recruiting NCT05216562 Efficacy and Safety of EXOSOME-MSC Therapy to Reduce Hyper-inflammation In Moderate COVID-19 Patients (EXOMSC-COV19) recruiting NCT04798716 The Use of Exosomes for the Treatment of Acute Respiratory Distress Syndrome or Novel Coronavirus Pneumonia Caused by COVID-19 (ARDOXSO) not yet recruiting NCT05387278 Safety and Effectiveness of Placental Derived Exosomes and Umbilical Cord Mesenchymal Stem Cells in Moderate to Severe Acute Respiratory Distress Syndrome (ARDS) Associated With the Novel Corona Virus Infection (COVID-19) recruiting NCT04491240 Evaluation of Safety and Efficiency of Method of Exosome Inhalation in SARS-CoV-2 Associated Pneumonia. (COVID-19EXO) completed NCT04384445 Zofin (Organicell Flow) for Patients With COVID-19 active, not recruiting NCT04657406 Expanded Access to Zofin for Patients With COVID-19 available a Obtained from clinicaltrials.gov using “extracellular vesicles” or “exosomes” as search strings, with results restricted to COVID-19. The ongoing COVID-19 pandemic caused by SARS-CoV-2 highlights the critical need for effective therapies to mitigate disease progression and reduce severity. EV-based therapeutics have shown the capacity to attenuate the hyper-inflammatory response caused by SARS-CoV-2 and promote repair of damaged lung tissue in preclinical models, with similar results when translated into SARS-CoV-2 patients. In addition, EVs may harbor therapeutic applications to tackle the prolonged symptoms of infection (long COVID) that are associated with prolonged overactivation and exhaustion of immune cells.28 The overview presented in this work highlights the innovative use of EVs as a promising approach to address severe SARS-CoV-2 infections. Recent progress in clinical trials has also laid the groundwork for the development of effective EV-based therapies for a broad range of viral infections. Acknowledgments Y.L. would like to acknowledge the mentors who have played a profound role in their career development and to the patients who inspire them to strive for greatness daily. Y.L. also wants to acknowledge MSSN for its support of scholarly endeavors. Funding: Funding information is not applicable. Author contributions Y.L., idea conception; primary author for design, framework, and refinement of severe SARS-CoV-2 model, EVs as a therapeutic agent against severe SARS-CoV-2; review of literature; summarizing and organizing of data; main manuscript writing contribution; participation in post-peer review manuscript revisions. G.G., primary author for introduction, extracellular vesicle therapy, and future direction and conclusion. M.J., main manuscript writing; literature review; addition of substantial, clinically oriented written content. G.P.M., main manuscript writing; literature review; addition of substantial, clinically oriented written content. A.V.d.K., main manuscript writing; literature review; addition of substantial, clinically oriented written content. M.I.M., editing and revision of manuscript. M.A.B., editing and revision of manuscript. T.d.R., editing and revision of manuscript. All authors read, reviewed, and approved the final manuscript. Declaration of interests G.G., M.I.M., T.d.R., and M.A.B. are employees of Organicell Regenerative Medicine. M.I.M. is the Chief Science Officer, serves on the Organicell Regenerative Medicine Board of Directors, and holds equity in the company. ==== Refs References 1 Stawicki S.P. Jeanmonod R. Miller A.C. Paladino L. Gaieski D.F. Yaffee A.Q. De Wulf A. Grover J. Papadimos T.J. Bloem C. The 2019–2020 novel coronavirus (severe acute respiratory syndrome coronavirus 2) pandemic: a joint american college of academic international medicine-world academic council of emergency medicine multidisciplinary COVID-19 working group consensus paper J. Glob. Infect. Dis. 12 2020 47 93 10.4103/jgid.jgid_86_20 32773996 2 Dorward D.A. Russell C.D. Um I.H. Elshani M. Armstrong S.D. Penrice-Randal R. Millar T. Lerpiniere C.E.B. Tagliavini G. Hartley C.S. Tissue-specific immunopathology in fatal COVID-19 Am. J. Respir. Crit. Care Med. 203 2021 192 201 10.1164/rccm.202008-3265OC 33217246 3 Yan R. Zhang Y. 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PMC010xxxxxx/PMC10183479.txt	==== Front 0100714 6400 Pediatr Res Pediatr Res Pediatric research 0031-3998 1530-0447 36380070 10.1038/s41390-022-02386-0 nihpa1847232 Article Placental microRNAs relate to early childhood growth trajectories Kennedy Elizabeth M. 1 Hermetz Karen 1 Burt Amber 1 Pei Dong 2 Koestler Devin C 2 Hao Ke 3 Chen Jia 4 Gilbert-Diamond Diane 5 Ramakrishnan Usha 6 Karagas Margaret R 57 Marsit Carmen J 1* 1 Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, Georgia 2 Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, Kansas 3 Department of Genetics and Genome Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 4 Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York 5 Department of Epidemiology, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire 6 Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, Georgia 7 Children’s Environmental Health and Disease Prevention Research Center at Dartmouth, Dartmouth College, Lebanon, New Hampshire AUTHOR CONTRIBUTIONS: EMK, DCK, KH, JC, DG-D, MRK and CJM conceptualized and designed the study. KH, AB and DP acquired data. EMK analyzed and interpreted the data. EMK Drafted the article. KH, AB, DP, DCK, KH, JC, DG-D, UR, MRK and CJM critically reviewed and carefully revised the article. All authors approved of the version to be published. * Corresponding Author: carmen.j.marsit@emory.edu, Permanent Address: 1518 Clifton Road, Claudia Nance Rollins Room 2021, Atlanta, GA 30322, Phone: +1-404-712-8912 5 11 2022 15 11 2022 15 5 2024 10.1038/s41390-022-02386-0http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms Background Poor placental function is a common cause of intrauterine growth restriction, which in turn is associated with increased risks of adverse health outcomes. Our prior work suggests that birthweight and childhood obesity-associated genetic variants functionally impact placental function and that placental microRNA are associated with birthweight. To address the influence of the placenta beyond birth, we assessed the relationship between placental microRNAs and early childhood growth. Methods Using the SITAR package, we generated two parameters that describe individual weight trajectories of children (0–5 years) in the New Hampshire Birth Cohort Study (NHBCS, n = 238). Using negative binomial generalized linear models, we identified placental microRNAs that relate to growth parameters (FDR<0.1), while accounting for sex, gestational age at birth, and maternal parity. Results Genes targeted by the six growth trajectory-associated microRNAs are enriched (FDR<0.05) in growth factor signaling (TGF/beta: miR-876; EGF/R: miR-155, Let-7c; FGF/R: miR-155; IGF/R: Let-7c, miR-155), calmodulin signaling (miR-216a), and NOTCH signaling (miR-629). Conclusions Growth-trajectory microRNAs target pathways affecting placental proliferation, differentiation and function. Our results suggest a role for microRNAs in regulating placental cellular dynamics and supports the Developmental Origins of Health and Disease hypothesis that fetal environment can have impacts beyond birth. CATEGORY OF STUDY: Population Study ==== Body pmcINTRODUCTION The Developmental Origins of Health and Disease (DOHaD) posits that in utero exposures can induce permanent maladaptive changes that “program” the fetus to have increased risk of later-life diseases1. The placenta is the master regulator of the intrauterine environment and an ideal tissue in which to test the DOHaD paradigm. This ephemeral organ facilitates the exchange of gases, nutrients and waste for the developing embryo2,3, in addition to aiding nutrient metabolism, and acting as an endocrine organ critical for early development. Thus, its functions are responsible for proper development and programming of the offspring. MicroRNAs are 21–25 base pair non-coding RNAs that regulate gene expression post-transcriptionally via sequence complementarity to the 3’ untranslated region of mRNA transcripts. microRNA-mediated gene regulation is achieved through target mRNA translational inhibition or degradation4. MicroRNAs are proposed to regulate more than 50% of human genes4–7, emphasizing their dynamic utility as post-transcriptional regulators of gene expression. Placental microRNAs shape placental development and function by targeting genes that regulate trophoblast proliferation and differentiation, apoptosis, invasion, cellular metabolism, as well as vasculo- and angio-genesis7. In a study of placental microRNA sequencing data from more than 500 mother-infant pairs, in two independent cohorts, we have previously identified a group of placental microRNAs that are associated with birthweight. The most robust birthweight differentially expressed microRNA, miR-532, was associated with the differential expression of placental adipokines, leptin and adiponectin receptor8. The placental transcriptome may have lasting metabolic impact beyond birth. Using parallel genomic and transcriptomic data from the Rhode Island Child Health Study (RICHS), Peng et al. reports that DNA variants that predict placental gene expression level expression quantitative trait loci; eQTLs for a given gene are over-represented among loci that associate with childhood obesity and BMI9. Compared to eQTLs for seven adult tissues, placental eQTLs were most strongly enriched among results from genome-wide association studies that link genomic loci to birthweight, childhood obesity, and childhood BMI. These results provide evidence for the ability of the placental transcriptional landscape to have a lasting impact on early childhood growth and metabolism9. In this study, we pose the question: Do microRNAs that regulate the placental mRNAs have a lasting impact on childhood growth? To address this question, we model childhood weight from birth to five years of age in the New Hampshire Birth Cohort Study (NHBCS). Using parameters derived from individual growth curves, we relate placental microRNA expression, from small-RNA sequencing, with early childhood growth. We use in silico methods to predict mRNA targets of interesting microRNAs and pathway analysis to add biological context to our findings. MATERIALS AND METHODS Cohort The New Hampshire Birth Cohort Study. NHBCS was initiated in 2009 and is an ongoing study comprised of a cohort of mother-infant pairs (N=1,971 as of 2021). Pregnant women between 18 and 45 years of age were recruited from the study’s participating prenatal care clinics in New Hampshire. Women were included in the cohort if their primary source of drinking water was from an unregulated residential well, they had resided in the same household since their last menstrual period and had no plans to move before delivery. All participants provided written informed consent in accordance with the requirements of the Committee for the Protection of Human Subjects, the Institutional Review Board (IRB) of Dartmouth College. In this study, NHBCS participants were singleton pregnancies recruited between February 2012 and September 2013. Data collection Anthropomorphic measures. NHBCS (N=1,971 as of 2021) has parallel demographic and anthropomorphic measures for mothers and newborns, as well as placental microRNA transcript abundance (n=322). Up to 14 weight measurements between birth and five years of age were abstracted from pediatric medical records (Ages: birth, 2 weeks, 1 month, 2 months, 4 months, 6 months, 9 months, 12 months, 15 months, 18 months, 2 years, 3 year, 4 years and 5 years; Fig. 1, n=317). Study participants were excluded from the analysis if they had less than three separate weight observations, but were not excluded for intermediate missing observations, leaving 238 participants for growth trajectory analysis (Fig. 1). Additional study covariates. Gestational age and fetal sex were abstracted from newborn medical records. z-Scores were calculated for gestational age. Self-reported maternal parity was collected by questionnaire. Tissue collection. Fetal placental samples were collected at delivery; sections were obtained two centimeters (cm) from the umbilical cord and free of maternal decidua. Collected tissue was immediately placed in RNA later solution (Life Technologies, Grand Island, NY) and stored at 4 °C for at least 72 hours and stored at −80 °C. microRNA isolation and sequencing. Total RNA was extracted from placenta using the Qiagen miRNeasy Mini Kit and a TissueLyser LT (Qiagen, Frederick, MD) following manufacturer’s protocol. Briefly, 25–35 mg of placental tissue was placed in a 2 ml round bottom tube with 700 ul of Qiazol Lysing Reagent and one 5 mm stainless steel bead. The tissue was homogenized on the TissueLyser LT for 2 minutes at 40 Hz. The resulting homogenate was processed with the Qiagen miRNeasy Mini Kit and eluted in 30 μl RNase-free water. The RNA was quantitated on a NanoDrop 2000 (Thermo Fisher, Waltham, MA) and quality checked on Agilent Bioanalyzer using the Agilent RNA 6000 Nano kit (Agilent, Santa Clara, CA). Single end, 1 × 75 bp next generation sequencing of placental microRNA was performed by Qiagen Genomic Services (Frederick, Maryland). smallRNA-Seq Processing and Quality Control. Raw FASTQ reads obtained from a total of 322 NHBCS samples were subject to adaptor trimming with cutadapt v1.1610. The 3’ adaptor sequence (AACTGTAGGCACCATCAAT) was trimmed based on vendor’s recommendation (Qiagen). After adaptor trimming, fastQC v0.11.5 was used to process the trimmed reads and QC results were aggregated using MultiQC v1.5 for visualization11. One sample failed QC and was removed. Then we used trimmed reads and miRDeep2 to quantify microRNA12. In short, miRDeep2 was used to first perform alignment using bowtie1 with human genome hg3813. The ‘Quantifier’ module in miRDeep2 was used to obtain raw counts of microRNAs with miRBase version 2214. Sample filtering and transcript filtering. Raw counts were imported into DESeq2 for normalization and differential expression analysis. microRNAs with less than one count per million in more than 10 percent of samples were removed. Samples from participants with less than three weight observations were removed from analysis, leaving 238 samples. Of the 2,656 microRNA transcripts that mapped, 777 remained after filtering. Normalization. Filtered microRNA raw counts were imported to DESeq2 for normalization and differential expression analysis. For all data sets, parametric estimates of dispersion were calculated, and the median ratio method was used to estimate size factors for normalization for modeling with DESeq215. Normalized counts were exported from DESeq2 for surrogate variable analysis. RICHS RNAseq count data are available via dataverse (https://doi.org/10.15139/S3/FUC5EW) and the methods for collection and processing are available elsewhere8. Library size normalized microRNA count observations among the most extreme 0.01% for each microRNA were flagged as count outliers. We replaced flagged outlier microRNA observations with the mean normalized count for that microRNA across samples. Our treatment of outliers is similar to the method DESeq2 utilizes to replace outliers16. Among 184,926 individual observations, 185 were replaced. Statistical analyses Modeling childhood growth trajectory. The R package SITAR was used to model growth trajectory for all study participants with at least three weight observations (n = 238)17. Individual children’s growth curves were visually assessed for outlier measures. Three observations were removed (Fig. S1). The children’s weights were natural log transformed to meet the normality assumption of the SITAR method. Briefly, SITAR is a shape invariant model, with individual random effects for each child, that estimates an average growth curve across samples. A set of three parameters are generated for each individual that, through translation (vertical/horizontal shift) and rotation (counter/clockwise), transform the average growth curve to match each individual’s growth. The parameters, random effects, have mean zero and standard deviations estimated from the data. These parameters - size, intensity and tempo, are interpreted as percentiles relative to the average because the weights were natural log transformed. The size parameter represents average size for any child relative to the average child and is graphically represented as a vertical shift of the weight curve (Fig. 2). Tempo, the age at peak weight intensity, was not estimated for this analysis, since no measures were estimated around the peak of infant growth (6 weeks); intensity is expressed as a percentage deviation from mean intensity with higher values representing faster growth than average. Graphically, intensity represents a rotation of the weight curve (Fig. 2). We modeled the transformed weights using 10 degrees of freedom, and adjusted for child sex in the models that generated the size and intensity parameters. Surrogate variable analysis. To adjust for batch effects, cell-type heterogeneity and other unknown sources of technical variation, we estimated a surrogate variable from the normalized transcript reads via the svaseq function in the sva package that incorporates the Combat algorithm18,19. In the svaseq function, the iteratively re-weighted least squares algorithm was used to estimate a surrogate variable based on empirically-derived control transcripts. The full model (mod argument) used for svaseq differed by application. The null model (mod0 argument) used all covariates except the outcomes variables - intensity and size. Differential expression analyses. microRNA transcript counts were modeled using a negative binomial generalized linear model with significance testing for differentially expressed transcripts via Wald tests in DESeq216. The microRNA transcripts were regressed on either the size or intensity parameters from SITAR. The intensity analysis included covariates for parity and gestational age (z-score). Three samples were missing information for parity and were removed from the intensity analysis (n = 235). The size analysis included covariates for primigravida and maternal education (beyond high school). Five samples were missing information for the maternal education variable and were removed from the size analysis (n = 230). One surrogate variable was also included as a covariate in both regression models (discussed in previous section). We considered microRNAs with a false discovery rate between less than 10% to be of interest and any with a false discovery rate less than 5% to be differentially expressed (DEmiR) with either size or growth intensity. Plots of normalized DEmiR counts vs either intensity or size were examined for outlier observations. Sensitivity analysis. To assess potential confounding of DEmiR effects by pre-eclampsia, maternal pre-pregnancy BMI, gestational weight gain or birthweight, potential confounders were individually added to the DEA model in DESeq2. Effect estimates and standard errors were collected for intensity and size DEmiRs for comparison with original model statistics. Target mRNA prediction. Potential mRNA targets of significant microRNAs were identified from mirDIP 4.1.11.2, an online database of human microRNA-target predictions20. mirDIP integrates microRNA target prediction across 30 different resources, providing nearly 152 million human microRNA-target predictions. Using the individual source ranking and confidence measures, mirDIP assigns a unified rank and confidence score using the quadratic function. For this analysis, the predictions with the top 1% confidence scores (very high confidence) were returned for each microRNA20. The resulting microRNA-target mRNA pairs were carried forward in the analysis. Putative target filtering. Predicted microRNA-target mRNA pairs were excluded if the mRNAs were not expressed in placenta in the RICHS whole transcriptome data. Pathway analysis. Pathway over-representation analysis was conducted in consensuspathDB21, which aggregates data from 12 separate pathway analysis databases. For each pathway gene set, consensus path DB calculates a p-value according to the hypergeometric test for the genes in both the putative target genes and the pathway gene set. All mRNAs not filtered for low reads in the RICHS whole transcriptome dataset were included as the background, or null distribution, for the test. RESULTS This study analyzed data from children enrolled in the New Hampshire Birth Cohort Study (NHBCS). Parallel placental microRNA transcript abundance was available for this cohort, as well as up to 14 weight measures between birth and 5 years, collected from well-child-checks. Study participants were excluded from the analysis if they had less than three separate weight observations, but were not excluded for intermediate missing observations (Fig. 1). Observations as a fraction of participants in the study at each measurement remained high throughout the study, despite attenuated participation with time, especially after one year (Fig. 1). 48% of participants had at least 12 of the 14 potential observations and only 2% had less than 5 observations (median observations across participants is 11, ranged 3–14). Growth trajectory modeling was performed for 238 NHBCS participants. Growth Trajectory modeling. We modeled childhood weight growth trajectory using SuperImposition by Translation And Rotation (SITAR)17. SITAR provided two parameters to describe each child’s growth. Both parameters are random effects with mean zero and standard deviation of one. The size parameter is given as a percent, relative to the fitted weight curve for all participants, for the average size of each individual child. Higher size is graphically represented as an upward vertical shift in a child’s weight growth curve. The size parameter in this analysis ranged between −37% and 31% (Fig. 2, red and blue lines). The intensity parameter is expressed as a percentage deviation from the mean intensity for all participants, with higher values representing faster growth than average. Higher growth intensity is graphically represented as a counterclockwise rotation in a child’s weight growth curve. The intensity parameter for this analysis ranged between −9% and 12% (Fig. 1, purple and cyan lines). Characteristics of the participants for this study are shown in Table 1. Due to missingness in variables included in the models for the intensity and size differential gene expression analysis, three children were excluded in the intensity analysis (n = 235) and eight children were excluded in the size analysis (n = 230). The exclusion of children for the downstream analysis did not change the demographic distributions for each analysis (data not shown). Differential microRNA expression analysis. To analyze the associations between growth trajectory parameters and placental microRNA expression, we performed differential expression analysis. For each growth trajectory parameter and microRNA transcript individually, transcript abundances were regressed on corresponding growth trajectory parameter using DESeq216. Covariates were included in the model if they were associated with the variable of interest (intensity or size) in univariate regression analyses (Table 2). For the intensity analysis, models also included maternal parity, gestational age (z-scores) and one surrogate variable (to account for batch effects, cell type heterogeneity, and other sources of unknown variability). For the size analysis, primigravida, maternal educational attainment and one surrogate variable were included in the models. Of the 777 microRNA transcripts that passed quality control filtering for the analyses, three and one had FDR < 0.05 and 0.1 for the intensity analysis (p-value < 3.8×10−4, Figs 3, S2), respectively. Two microRNAs in the intensity analysis had p-values less than the Bonferroni family-wise error rate threshold (p-value < 6.4×10−5, Figs 3, S2). In the Size analysis, no microRNAs had FDR < 0.05, but two microRNAs had FDR<0.1 (FDR=0.054, p-value < 1.4×10−4). MicroRNAs that associate with intensity are hsa-miR-155–5p (estimate = 0.12; standard error: 0.02; FDR = 1.1×10−4), hsa-let-7c-5p (estimate = −0.03; standard error: 8×10−3; FDR = 0.01), and hsa-miR-629–3p (estimate = 0.05; standard error: 0.01; FDR = 0.04; Fig. 3). The intensity DEmiRs have modest effects. hsa-miR-876–5p (estimate = −0.06; standard error: 0.02; FDR = 0.07) does not pass the FDR threshold for significance, but is suggestive of an association with growth intensity. Although no microRNAs in the size analysis passed the FDR threshold for significance, hsa-miR-216a-5p (estimate = 0.61; standard error: 0.16; FDR = 0.054; Fig. 3) and hsa-let-7d-3p (estimate = −0.22; standard error: 0.06; FDR = 0.054; Fig. 3) are suggestive of an association between microRNA abundance and average size. The estimates represent the log2 fold-change in microRNA abundance for one percent change in intensity or size. Birthweight percentile was not included in the model because of its potential involvement in the causal path of growth trajectory. Of the microRNAs that were associated with growth trajectory with an FDR < 0.1, three (miR-155, miR-629, and let-7c) were also associated with birthweight (FDR<0.1) in NHBCS8. Because only four participating mothers had pre-eclampsia, it was not included in the primary analysis. However, the potential for pre-eclampsia and other potential confounders (pre-eclampsia, maternal pre-pregnancy BMI, gestational weight gain and birthweight) to attenuate significant associations (Fig. 3) between placental microRNAs and growth trajectory parameters was assessed in sensitivity analyses (Fig. S3). As expected for a variable along the causal path, the inclusion of birthweight as a covariate in the model strongly attenuated the estimated log2 fold change for intensity among microRNAs that are also associated with birthweight. Growth trajectory DEmiR associated mRNAs. Bioinformatic targets of Intensity- and size-associated DEmiRs with an FDR < 0.05 were collected from the microRNA Data Integration Portal (mirDIP)20. In order to enrich our targets with true microRNA-target pairs, we utilized total RNA abundance, assayed from 199 placentae using RNAseq in the RICHS cohort (https://doi.org/10.15139/S3/FUC5EW). mRNA transcripts were considered putative targets of trajectory DEmiRs if they were detectable in RICHS placenta samples. Using these criteria, we found 1,273 putative miR-155 targets, 1,256 let-7c targets, targets, 38 miR-629 targets, 168 miR-876 targets, 747 miR-216a targets, and 114 miR-let-7d targets. DEmiR mRNA targets were used in pathway analysis. For each DEmiR, putative target genes were tested for pathway overrepresentation with consensuspathdb (CPDB), against all of the genes that passed QC in the RICHS whole transcriptome RNA-seq analysis21. The most significant pathways are listed in Table 3. CPDB integrates pathways from 12 databases, meaning that similar results can be reported across sources. To further prioritize significantly overrepresented pathways, we generated term frequency matrices for all pathway terms. To assess the microRNA target genes leading the enrichments, a second term frequency matrix was made from the microRNA target genes present in the significant pathways. From these analyses, we found that FGFR1–4 and IGF/R signaling pathways were most frequent among significant miR-155 pathways. The most frequent miR-155 target genes were PIK3CA and PIK3R1. EGF and EGFR pathways were the most frequent among let-7a significant pathways, with MAPK1, PIK3CA and PIK3R1 as the most frequent gene targets. Among mir-629 pathways, PTEN was the most frequent pathway, with TNRC6C and AGO1 and AGO4 the most common gene targets. For miR-876–5p, a microRNA of interest in the intensity analysis (FDR = 0.07) BMP, SMAD and TGF/beta signaling were the most frequent pathways, with SMAD2, TGFBR1 and ACVR1 and 2b the most frequent target genes. For interesting microRNA, miR-216a (FDR=0.054), regulation of MECP2 was most frequent among pathways, with miR-216a targets CALM1–3 as the most frequent genes. Let-7d-3p, which was identified as a microRNA of interest in the size analysis (FDR = 0.054), did not have targets enriched in any pathway. When targets of positively-associated growth intensity DEmiRs (Fig. 3) were pooled for pathway analysis, we found that the most frequent pathway terms were FGFR1–4 and the most frequent gene targets were PIK3CA and PIK3R1. DISCUSSION In this study, we have described the microRNAs from human placenta that associate with growth trajectory from birth to five years old. We used a shape invariant model with random effects to generate two parameters that describe children’s growth intensity and average size during the observation period. We found evidence of microRNAs that vary with both growth parameters (DEmiRs). We narrowed bioinformatically predicted microRNA targets to only those in which the targeted mRNA was stably expressed in term placenta in the RICHS cohort. These putative DEmiR targets were used in pathway over-representation analysis. Placental function, which underlies successful pregnancy and may have lasting influence, may be dictated by cellular dynamics – the balance of cell proliferation and differentiation among the terminal placental trophoblast lineages22. Recent evidence has suggested that upstream progenitor cells, with the ability to differentiate into cytotrophoblasts, syncytiotrophoblasts and extravillous trophoblasts are present in placenta at term23. Diminished abundance of these progenitor cells corresponds to placental dysfunction, like pre-eclampsia23. The formation of the placenta relies on the maintenance and proliferation of human trophoblast stem cells, guided, in part by WNT and EGFR signaling24. In mice, this maintenance of stemness is reliant on the presence of FGF signaling25, however, this may or may not be the case in human placentae24. IGF is also important for survival and proliferation of trophoblast stem cells22. In our analysis, we see evidence that the EGFR (miR-155, let-7c), FGFR (miR155) and IGFR (let-7c, miR-155) signaling pathways are influenced by growth trajectory microRNAs (Fig. 4). Multipotent villous cytotrophoblasts fuse to form the epithelial, multinucleated syncytiotrophoblast, which facilitates exchange of gases, nutrients and waste for the growing embryo, as well as acting as an endocrine organ to balance the needs of the mother and fetus26. Syncytialization is mediated by cAMP and rising intracellular Ca+, as well as continued EGF signaling and Activin A24,27. In this analysis, growth trajectory microRNAs are predicted to target calmodulin (miR-216a), EGFR (miR-155, let-7c) pathways, as well as Activin A (miR-876; Fig. 4). Cytotrophoblasts undergo a process similar to the epithelial-to-mesenchymal transition to form the invasive extravillous trophoblast that connects the placenta with the maternal decidua and myometrium to establish maternal blood supply26. Signaling through NOTCH1/2 and TGFβ family members (BMP2, Activins) mediate differentiation to the invasive extravillous cytotrophoblast28–30. The role of the TFG-beta superfamily in trophoblast differentiation is complicated, as many of the pathway mechanisms overlap31, yet TGF-beta1/2/331 and NODAL32 inhibit the invasive phenotype and favor syncytialization while BMP2 and Activin A/B/AB all favor the invasive phenotype28,29. In this analysis, we found evidence that growth trajectory associated microRNAs target components of the NOTCH1/2 (miR-629) and TGFβ superfamily (miR-876) signaling cascades (Fig. 4). Although these processes described above were primarily described in first trimester placentae and cell culture, the placental cytotrophoblasts continue to maintain the syncytiotrophoblast and extravillous trophoblasts to term23. The discovery of trophoblast progenitor cells in term placenta suggests that some of the signaling pathways relevant in early gestation, remain important later in gestation. Within this assumption, our findings suggest a potential role for microRNAs to influence the cellular dynamics of placenta at term, which in turn relates to the plasticity and efficiency of the placenta to support fetal growth23,33,34. This initial growth may prime the neonate’s metabolism for early growth patterns35. However, it is also possible that some of the growth factors under microRNA influence have specific functions at term that are in addition to or exclusive of their functions in early gestation. For instance, while EGF signaling guides trophoblast maintenance, proliferation and differentiation in early gestation, it may stimulate the release of hormones to the maternal and fetal circulations at term22. Growth trajectory-associated microRNAs have also been associated with placental characteristics in other studies. In cultured extravillous trophoblasts, miR-155 inhibits cell proliferation by down-regulating cyclin D1/p2736. In cultured cytotrophoblasts, Let-7c is associated with reduced proliferation potential and syncytialization37,38. Let-7c is associated with the WNT/β-catenin signaling pathway in other progenitor cell types39. Our results suggest that placental microRNAs effect signaling cascades central to trophoblast proliferation, differentiation and function. Most importantly, our results underscore the importance of placental function and the intrauterine environment in establishing early growth trends. However, our findings should be interpreted within the context of this study’s limitations. This is an observational study in which RNA was assayed from term placentae. We cannot conclude that our results are representative of microRNA associations throughout development. Further, we cannot establish that DEmiR abundances directly cause differences in growth trajectory. We used DESeq2 to identify associations between miRNA expression and childhood growth, where childhood growth was determined using child-specific estimates of size and intensity derived using SITAR. In DESeq2, microRNA abundances (dependent variable) are regressed on size or intensity (independent variable), allowing us to examine the association of early childhood growth on placental microRNA expression. Although the models employed in DESeq2 are temporally reversed in terms of what is being modeled as dependent and independent variables, DESeq2 represents the best choice for modeling gene expression data as it accounts for the over-dispersion of RNA-sequencing count data. While the estimates generated by these models may be less intuitive and temporally reversed from our hypothesis, the associations between placental microRNA expression with growth trajectory patterns ascertained using such models are nevertheless valid. We adjusted for likely confounders in our study, but cannot rule out the possibility that unmeasured or residual confounding remains in our analysis. Potential confounders are maternal BMI, gestational weight gain and pre-eclampsia. Sensitivity analysis suggests that the addition of these variables to our models would have little to no effect on our conclusions, though some of our top findings are sensitive to one or both. To limit unknown statistical confounding (e.g. differing cellular composition between individuals or population stratification), our models are adjusted using surrogate variable analysis. This is a data-driven approach that may incorrectly estimate confounding elements, adding variability to our model. Recent research indicates that SVA is one of the more robust and reliable methods in studies such as ours40. Lastly, the cohort utilized in this study consisted predominantly of healthy white mothers from a rural New England region of the United States, potentially limiting the generalizability of our findings. To our knowledge, this is the first study to examine the relationships between human placental microRNAs and early childhood growth trajectory. In this analysis, we found that growth trajectory associated placenta microRNAs target genes involved in signaling pathways central to the formation, maintenance and function of placenta. These results suggest that placental cellular dynamics remain critical to infant growth to term and are under the control of microRNAs. Our results contribute to the existing body of research suggesting that the placenta plays a key role in programming health in the offspring. Supplementary Material 1 FINANCIAL SUPPORT: This work was supported by the National Institutes of Health (NIEHS R24ES028507, R01ES025145, P30ES019776, NIMHD R01MD011698 and NICHD K99HD104991). DATA AVAILABILITY RICHS total RNA-seq raw reads have been deposited at the NCBI database of Genotypes and Phenotypes (dbGaP) (phs001586). RICHS and NHBCS microRNA count matrices (https://doi.org/10.15139/S3/FUC5EW) and covariate data (https://doi.org/10.15139/S3/O9KYGB) are available at Dataverse. Fig. 1. Participation in weight observation collection. Weights were collected at up to 14 separate time points for each child (x-axis). With the exception of the 1-month (1m) measure, missingness rate (y-axis) was low, meaning that observations at each measurement (obsage) remained high despite missing data after 12 months (12m, Nage). Fig. 2. NHBCS Growth Curves. Unadjusted growth curves are plotted for all participants in this analysis (N = 238). The mean growth curve, calculated by SITAR, is plotted as a dashed line. The growth curves representing the minimum and maximum average size are plotted in blue and red, respectively. Deviations in average size appear as vertical shifts from the mean curve. The growth curves representing the minimum and maximum growth intensities are plotted in cyan and purple, respectively. Deviations in growth intensity appear as rotations (counter/clockwise) of the mean curve. Fig. 3. Differential expression analysis results. microRNAs with FDR<0.05 in either analysis are listed on the y-axis. Their log2 fold change for a one percent change in either growth intensity (green) or average size (purple) is on the x-axis. 95% confidence intervals are illustrated with either solid lines. Point size is proportional to −log10(P-value), such that larger points represent smaller p-values. Fig. 4. The potential roles of growth trajectory microRNAs in the cellular dynamics of placental trophoblasts. A terminal placental villous is illustrated in the center of the figure, representing the involved placental cell types from which microRNAs in our study could arise: fetal endothelial cells (FEC), cytotrophoblasts (CTB), syncytiotrophoblasts (STB) and extravillous trophoblasts (EVT).Growth trajectory microRNAs are listed (FDR<0.05 in black, FDR = 0.05–0.1 in gray) along with their influential targets in the processes we predict they may influence (trophoblast stem maintenance, proliferation and differentiation to the syncytiotrophoblast (STB) or extravillous trophoblast (EVT) terminal lineage). microRNAs and their putative targets in the central blue or outer red areas are predicted to encourage or inhibit the given process, respectively. Created with BioRender.com. Table 1. Study Cohort Characteristics Intensitya (n = 235) Sizeb (n = 230) MATERNAL CHARACTERISTICS Age - mean (range) 31 (18 – 45) 31 (18 – 45) Education (>high school) - % (n) 91 (206) 90 (208) Parity - mean (range) 1 (0 – 4) 1 (0 – 4) Existing Diabetes 0.4% (1) 0.4% (1) Gestational Diabetes 5% (11) 5% (12) Chronic hypertension 4% (10) 4% (10) Gestational hypertension 3% (6) 3% (6) Pre-eclampsia 2% (4) 2% (4) Pre-pregnancy BMI - mean (range) 26 (17 – 46) 26 (17 – 46) Gestational weight gain category c Lowd - % (n) 7% (16) 6.6% (15) Normale - % (n) 26% (59) 25.7% (58) Highf - % (n) 67% (155) 67.7% (153) INFANT CHARACTERISTICS Race (white) - % (n) 100% (235) 100% (235) Gestational age (wks) - mean (range) 40 (31 – 42) 39 (31 – 42) Birthweight (g) - mean (range) 3464 (1380 – 4572) 3468 (1380 – 4572) Birthweight group SGAg - % (n) 4% (9) 3% (8) AGAh - % (n) 86% (206) 88% (202) LGAi - % (n) 10% (20) 9% (20) Sex (Female) - % (n) 49% (116) 49% (112) SITAR parameter - mean (range) 0 (−9 – 12) 0 (−37 – 31) a The differential expression analysis to find microRNAs that associate with the SITAR Intensity parameter used 235 NHBCS samples (discussed in Methods section). b The differential expression analysis to find microRNAs that associate with the SITAR Size parameter used 230 NHBCS samples (discussed in Methods section). c NHBCS statistics for gestational weight gain were based on the 230 samples with available measures in the Intensity parameter analysis and 226 for the size analysis. d Low – Gestational weight gain below recommendation for pre-pregnancy BMI category22 e Normal – Gestational weight gain within recommendation for pre-pregnancy BMI category22 f High – Gestational weight gain above recommendation for pre-pregnancy BMI category22 g SGA – Infants born with a birthweight percentile ≤ 1023 h AGA – Infants born with a birthweight between the 10th and 90th percentiles23 i LGA – Infants born with a birthweight percentile ≥ 9023 Table 2. Growth trajectory correlates Variable Analysis Estimate Error P-value Pre-eclampsia Intensity 3.78 1.76 0.03 Parity Intensity −0.64 0.22 4×10−3 Gestational weight gain category (low v normal) Intensity 2.10 0.99 0.03 Gestational age (wks) Intensity −1.07 0.14 3×10−13 Birthweight percentile Intensity −0.06 0.01 1×10−11 Maternal education (>high school) Size −0.45 0.22 0.04 Primigravida Size 0.32 0.15 0.03 Gestational weight gain category (high v normal) Size 0.4 0.15 9×10−3 Birthweight percentile Size 0.01 2×10−3 7×10−8 Table 3. Top significant pathways for growth trajectory differentially expressed microRNAs microRNA Analysis Analysis FDR Pathway Pathway FDR % pathway genes as targets hsa-miR-155–5p Intensity 1.1×10−4 FLT3 Signaling 4×10–3 42 hsa-let-7c-5p Intensity 0.01 EGF-EGFR Signaling 2×10−5 47 hsa-miR-629–3p Intensity 0.04 Signaling by NOTCH 6×10−3 21 hsa-miR-876–5p Intensity 0.07 BMP2 signaling TGF-beta 0.04 11 hsa-miR-216a-5p Size 0.054 EGFR1 3×10−3 11 IMPACT: We found that growth trajectory associated placenta microRNAs target genes involved in signaling pathways central to the formation, maintenance and function of placenta; suggesting that placental cellular dynamics remain critical to infant growth to term and are under the control of microRNAs. Our results contribute to the existing body of research suggesting that the placenta plays a key role in programming health in the offspring. This is the first study relate molecular patterns in placenta, specifically microRNAs, to early childhood growth trajectory. CATEGORY OF STUDY: This article is being presented as an original research article, categorized as a Population Study. DISCLOSURE STATEMENT: The authors declare they have no competing interests or personal relationships that would potentially influence the work presented in this paper. ETHICAL STANDARDS: All participants provided written, informed consent and all protocols were approved by the IRBs at the Women & Infants Hospital of Rhode Island, Dartmouth College and Emory University, respectively. ==== Refs REFERENCES 1. Barker DJP & Thornburg KL Placental programming of chronic diseases, cancer and lifespan: a review. Placenta 34 , 841–845 (2013).23916422 2. Red-Horse K Trophoblast differentiation during embryo implantation and formation of the maternal-fetal interface. J. Clin. Invest 114 , 744–754 (2004).15372095 3. 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PMC010xxxxxx/PMC10192449.txt	==== Front 0100714 6400 Pediatr Res Pediatr Res Pediatric research 0031-3998 1530-0447 36396698 10.1038/s41390-022-02379-z nihpa1847231 Article Changes in Depressive and Anxiety Symptoms during COVID-19 in children from the PROGRESS Cohort McGuinn Laura A. a Rivera Rivera Nadya a Osorio-Valencia Erika b Schnaas Lourdes b Hernandez-Chavez Carmen b DeFelice Nicholas B. a Harari Homero a Klein Daniel N. c Wright Rosalind J. ad Téllez-Rojo Martha Maria e Wright Robert O. a Rosa Maria José a Tamayo-Ortiz Marcela f a Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY b National Institute of Perinatology, Mexico City, Mexico c Department of Psychology, Stony Brook University, Stony Brook, NY d Kravis Children’s Hospital, Department of Pediatrics, Division of Pediatric Pulmonology, Icahn School of Medicine at Mount Sinai, New York, NY e Center for Nutrition and Health Research, National Institute of Public Health, Cuernavaca, Morelos, Mexico f Occupational Health Research Unit, Mexican Institute of Social Security (IMSS), Mexico City, Mexico Author contributions: We confirm that all coauthors have made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and final approval of the version to be published. Address correspondence to: Laura A. McGuinn, Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1057, New York, NY 10029, laura.mcguinn@mssm.edu, 212-824-7058. 3 11 2022 18 11 2022 18 5 2024 10.1038/s41390-022-02379-zhttp://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms Background We assessed associations between maternal stress, social support, and child resiliency during the COVID-19 pandemic in relation to changes in anxiety and depression symptoms in children in Mexico City. Methods Participants included 464 mother-child pairs from a longitudinal birth cohort in Mexico City. At age 8–11 (pre-COVID, 2018–2019) and 9–12 (during-COVID, May-Nov 2020) depressive symptoms were assessed using the child and parent-reported Children’s Depressive Inventory. Anxiety symptoms were assessed using the child-reported Revised Manifest Anxiety Scale. Linear regression models were used to estimate associations between maternal stress, social support, and resiliency in relation to changes in depressive and anxiety symptoms. We additionally assessed outcomes using clinically relevant cut-points. Models were adjusted for child age and sex, and maternal socioeconomic status and age. Results Higher continuous maternal stress levels during the COVID-19 pandemic were associated with increases in depressive symptoms (β: 0.72; 95% CI: 0.12, 1.31), and higher odds of clinically relevant depressive and anxiety symptoms in the children. Conclusion Maternal stress during the pandemic may increase mental health symptoms in pre-adolescent children. Additional studies are needed that examine the long-term pandemic-related impacts on mental health throughout the adolescent years. Category: Population study ==== Body pmcIntroduction As the coronavirus disease 2019 (COVID-19) pandemic spread across the globe, several population-level interventions went into place. In Mexico City, the first confirmed case was in February 2020, with school closures and social distancing measures following shortly after in March. Though effective in reducing transmission, these preventative measures have contributed to social isolation and loneliness among several populations,1 leading to the new onset of or potentially further exacerbating mental health symptoms.2 The pandemic has posed a particular threat to the mental health of children, adolescents, and their caregivers.3,4 Of the existing cross-sectional and longitudinal studies on the mental health impacts of COVID-19-related stressors in children, several have found increases in depressive and anxiety symptoms5,6.7 Previous studies have additionally shown associations with maternal stress and child mental health;8,9 however, the majority have focused on prenatal stress and long-term impacts. Maternal stress may have a heightened short-term impact during the pandemic due to home confinement and social isolation measures. The impact of protective factors such as social support additionally remains poorly understood. This is a major research gap as maternal social isolation has been linked to adverse health outcomes in the child including depression.3,10 The impact of pandemic-related stressors on child mental health remains even less studied in low and middle-income countries, such as Mexico. This is a critical gap given that up to 40% of adolescents in Mexico City may have a mental health condition.11 A recent study in Brazil found impacts of the pandemic on anxiety and depressive symptoms in children with those from vulnerable populations most impacted.12 One recent study looked at well-being of Mexican and Chilean adolescents during the pandemic and found overall higher prevalence of languishing in adolescents.13 We take a socio-ecological approach for assessing pandemic-related impacts on mental health symptoms in children.14 This framework considers that it is a complex interplay between the individual, family, community, and society. The main objective of our study was to assess associations between maternal stress and social support and changes in anxiety and depression symptoms in children from a birth cohort in Mexico City from before to during the pandemic. We additionally aimed to assess sex differences in the associations. We hypothesized that a) child mental health symptoms would increase, b) maternal stress would be related to higher number of symptoms, while maternal social support would be related to fewer, c) and given differences in mental health symptoms by sex,15 that these associations would differ by child sex. Methods Study Population We used data from the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) birth cohort in Mexico. Pregnant women were recruited between 2007 and 2011 at 12–24 weeks’ gestation in primary care clinics of the Mexican Social Security Institute. Women were eligible if they were ≥18 years, planned to live in Mexico City, <20 weeks gestation, had no medical history of heart or kidney disease, and did not consume alcohol daily.16 Of the 948 women that delivered a live birth and agreed to follow-up, 500 returned for both the pre- and post-COVID visit, and 464 of those women had complete data (Supplemental Figure 1). Participant characteristics did not differ for those included and those in the original sample (Supplemental Table 1). Protocols were approved by the institutional review boards at the Icahn School of Medicine at Mount Sinai, Harvard School of Public Health, and Mexican National Institute of Public Health. All women provided informed consent and children provided assent. Outcome Measures Mothers and children completed the pre-pandemic in-person assessments between 2018–2019. Mother-child pairs completed the telephone-based assessments during COVID between May-November 2020. Both pre- and post-pandemic assessments were administered in a standardized format by trained psychologists. Symptoms of anxiety and depression were assessed in children before and during the pandemic using the Spanish versions of the Children’s Depression Inventory (CDI-2) and Revised Children’s Manifest Anxiety Scale (RCMAS-2). Though both the CDI17 and RCMAS18 have shown high validity, these screening tools do not diagnose depression or anxiety, but instead provide an indication of severity of symptoms. Children’s Depression Inventory. The CDI is a validated17 instrument developed to evaluate symptoms of depression in 7–17 year olds.19 The short form of the children’s version of the CDI-2 (CDI-C) contains 12 items; the parent-report version (CDI-P) contains 17 items. For both versions, items were summed to create a total raw score. Raw scores on the CDI-P ranged from 0–37 (Cronbach’s alpha = 0.8 for pre-COVID, 0.8 for COVID). Raw scores on the CDI-C ranged from 0–21 (Cronbach’s alpha = 0.6 for pre-COVID, 0.6 for COVID). Raw scores were converted to standardized T-scores based on normative samples.19 We analyzed T-scores as continuous measures, with higher scores indicating more severe symptoms. We additionally dichotomized scores using cut-off values recommended by the manual (≥65). Revised Children’s Manifest Anxiety Scale. The RCMAS-2 is a validated18 self-report instrument developed to measure the nature and degree of anxiety in 6–19 year olds. The RCMAS-2 short form has 12 items rated as yes/no. Higher scores indicate greater symptoms. Individual items on the RCMAS-2 were summed to create a total raw score ranging from 0–10 (Cronbach’s alpha = 0.6 for pre-COVID and 0.70 for the COVID assessment). Raw total anxiety scores were converted to standardized T-scores based on normative samples. We analyzed scores as continuous and also dichotomized scores based on the manual (≥60). Exposure Measures Maternal negative life events (NLE). Maternal stress was measured before and during the pandemic using data from the Spanish version of the validated20 Crisis in Family Systems (CRISYS)21 questionnaire. This 64-item questionnaire assesses the occurrence of stressful life events across several domains during the prior 6 months. Mothers rated the life event as positive, negative, or neutral. Studies demonstrate increased vulnerability when experiencing events across multiple domains.22 Therefore, the number of domains with one or more events endorsed as negative were summed to create a NLE domain score (range 0–11), with higher scores indicating greater stress, as done in prior research.23,24 Social support. Maternal social support from family, neighbors, and friends was assessed before and during the pandemic using the Spanish version of the Social Support Network (SSN) Scale. The SSN scale was previously validated in Mexican populations.25 Mothers rated their degree of agreement with each item on the SSN based on 4 levels scored from 1 (strongly disagree) to 4 (strongly agree). Social support scores ranged from 7–20 in our population, with higher scores indicating greater support. The Cronbach alpha was 0.89 for both the pre-pandemic and pandemic SSN scale. Resiliency scale. Children’s resiliency was assessed using the Resiliency scale from the Behavioral Assessment System for Children (BASC-2).26 The Spanish version of the BASC-2 was administered to mothers prior to COVID – this assessment was not administered during the pandemic, and thus we only assessed impacts with this measure in sensitivity analyses. The Resiliency scale includes 10 items and measures the ability of the child to overcome stress and adversity. Raw scores were converted to standardized T-scores based on normative samples.26 Covariates Covariate information was obtained from standardized questionnaires. The program DAGitty was used to construct our directed acyclic graph in order to identify the minimally sufficient adjustment set (Supplemental Figure 2).27 The final adjustment set included child’s age (before and during COVID), child’s sex, maternal age (before and during COVID), and maternal SES prior to COVID. Thirteen variables derived from questionnaire results were used to classify study participants into six levels based on the SES index.28 We further collapsed this into lower, medium, and higher SES. Statistical Analyses Paired t tests were used to assess changes in T-scores from before to during COVID. We chose paired t tests for this analysis since measurements were taken from the same individual. McNemar’s test was used to assess changes in clinically elevated symptoms. We first estimated changes in depressive and anxiety symptoms by subtracting the continuous baseline total score from the score during the pandemic. Linear regression models were then used to assess the impact of continuous measures of maternal stress, social support, and changes in depressive and anxiety symptoms. Depressive and anxiety scores were also dichotomized at clinically relevant cut-points to see the impact of exposures on odds of more severe mental health symptoms during the pandemic. For dichotomized outcomes we used logistic regression models and odds ratio (OR) and 95% CIs were reported. In secondary analyses, we additionally assessed associations between child resiliency and mental health symptoms for those with resiliency measures available (N=392). We assessed if associations differed by child sex by using an augmented product term approach.29 We specified a model that included product terms between sex and all covariates – this model is equivalent to a fully stratified model. From this model we were able to evaluate the sex-exposure product term; a p<0.10 cut-off was used to indicate significant effect measure modification by child sex.29 All statistical analyses were conducted using Stata Version 17.0. Results Table 1 provides sample descriptive characteristics of the study population for before and during COVID. Children were on average 11.1±1.1 years (min: 8.9, max: 12.8) at the COVID visit; there was an even distribution of females and males. Mothers were on average 39 years and primarily of lower SES. Average maternal-reported NLE were slightly lower during COVID compared to before (3.2 vs. 2.9). In our study population, COVID visit assessments occurred between May-October 2020; maternal-reported stress levels were higher for those assessed in later months (Supplemental Table 2). Overall, the mean anxiety T-score was comparable to the age-standardized population (i.e. means around 50); however, scores were slightly higher for both the child and parent-reported depressive symptom T-scores (Table 1). Table 2 presents the mean differences in child and parent-reported depressive symptom and child-reported anxiety symptom T-scores from before to during COVID. Overall, depressive symptoms increased from before to during COVID, for both child (1.18, 95% CI: 0.13, 2.23) and parent-reported measures (1.76, 95% CI: 0.96, 2.56) (Table 2). These differences were more prominent for girls, children from lower SES families, and those with less social support. On average, anxiety levels slightly decreased from before to during COVID, particularly for boys. The percentage of females reporting depressive symptoms almost doubled from before to during COVID, for both child and parent-reported symptoms (Supplemental Table 3). Anxiety symptoms did not significantly change. Self-reported outcome measures were in general moderately correlated across measures and visits (Supplemental Figure 3). Correlations between self and parent-reported depressive symptoms ranged from 0.18 (pre-COVID) to 0.39 (during COVID). Table 3 presents the results for associations between continuous measures of maternal stress and social support during COVID-19 and changes in child depressive and anxiety symptoms. Higher maternal stress during the pandemic was associated with increases in parent and child-reported depressive scores. For every one-unit increase in maternal stress scores, child depressive scores increased by about 0.7 points (b: 0.72, 95% CI: 0.12, 1.31). We observed similar findings for parent-reported depressive symptoms (b: 0.77, 95% CI: 0.30, 1.23), but not with child-reported anxiety (Table 3). We additionally did not observe any overall associations between maternal social support and changes in depressive or anxiety symptoms. (Table 3). Next, we assessed associations with dichotomized outcomes in order to assess associations with clinically relevant depressive any anxiety symptoms during the pandemic. Higher maternal stress during the pandemic was associated with higher odds of clinically elevated depressive (OR: 1.19, 95% CI: 1.03, 1.37) and anxiety (OR: 1.19, 1.02, 1.39) symptoms (Table 4). There was a significant sex interaction for child-reported depressive and anxiety symptoms. For instance, for child-reported anxiety symptoms, we observed associations in girls (OR: 1.36, 95% CI: 1.12, 1.66), but not boys (OR: 0.92, 95% CI: 0.69, 1.22) (p-interaction: 0.03) (Table 4). Children of mothers with higher social support had lower odds of clinically elevated parent-reported depressive symptoms (Table 4). We additionally assessed the role of child resiliency prior to COVID on changes in child anxiety and depressive symptoms for a subset of children with these measures available. We observed inconsistent findings for change scores, with non-significant decreases for child-reported measures and increases for parent-reported depressive symptoms (Table 3). In dichotomized models, we saw a protective effect of child resiliency, with fewer depressive and anxiety symptoms for those children with higher resiliency (Tables 4). Specifically, there was a decreased odds of clinically elevated child (OR: 0.94, 95% CI: 0.91, 0.97) and parent-reported (OR: 0.89, 95% CI: 0.85, 0.93) depressive symptoms for every one-unit increase in child resiliency T-scores. Discussion In this investigation of maternal stress and social support during the pandemic in relation to child mental health, we leveraged a comprehensive assessment of anxiety and depressive symptoms pre- and post-pandemic that included both child and parent-reported measures. Similar to previous studies,30,31 we observed low-to-moderate correlations between child and parent-reported depressive symptoms. We additionally observed a higher prevalence of depressive symptoms for the child-reported compared to the parent-reported measures. This is consistent with other studies that have reported higher mental health symptoms for child-reported measures. A recent meta-analysis found the pooled prevalence of clinically significant depressive and anxiety symptoms to be around 0.25 and 0.21, respectively.32 Our clinically elevated depressive symptom prevalence was 0.19 and 0.16 for anxiety symptoms. Overall, we found that higher maternal stress during the pandemic was associated with increases in child and parent-reported depressive symptoms and child-reported anxiety symptoms. A few recent studies have found consistent results with associations seen between COVID-related stressors and changes in mental health.33–36 Recent reviews have found the strongest associations with anxiety and depressive symptoms in youth.7 While we did not address COVID-stress directly, our results are consistent with the literature regarding stressors during COVID on child mental health outcomes. Research has shown that maternal social support may reduce the harmful impacts of stress by altering the perception of the situation.37 This is particularly important during the pandemic, as a greater perceived connection to family, friends, and the community may buffer against pandemic-related stressors and impacts from social isolation. In the current study, maternal-reported social support was associated with fewer parent-reported child mental health symptoms – though overall associations were inconsistent with maternal social support measures. It could be that child reported social support from friends is more important during the pandemic. We unfortunately did not have this information for the current study but will measure it in the future. We additionally found associations between child resiliency and fewer reported mental health symptoms. This is consistent with previous findings on child resilience during other major life stressors and provides support for promoting child resilience in the face of novel major life stressors.38 The proportion of children experiencing clinically elevated depressive symptoms increased from before to during COVID-19. This may in part be due to increases in mental health symptoms with increasing age of the children. We accounted for this by controlling for age at both assessments. These differences were primarily driven by girls, with the proportion of girls experiencing significant mental health symptoms almost doubling from before to during the pandemic. We found slight decreases in continuous anxiety symptoms from before to during the pandemic, particularly for boys. We hypothesize that this finding may be related to decreases in social anxiety symptoms from reduced social interactions during the pandemic. We also observed differences of the maternal NLE-child anxiety association by sex, with associations only seen in girls. Several recent studies have shown higher levels of depression and anxiety in female youth during the pandemic,15,33 and increased symptoms of loneliness and social media use.39 Thus, females may be both more impacted by the pandemic in general and also by family-related stressors. In Mexico City, the first confirmed COVID case was in February 2020, with school closures and social distancing measures following shortly after in March. Our assessment occurred during May – November 2020, so captures pandemic-related stressors during the early wave of the pandemic in Mexico City. During this early period, COVID cases peaked around July 2020 and continued for several months through the fall. Thus, our assessments were conducted when COVID cases were considerably high in Mexico City. Although cases were high throughout this time, there may be other factors that would have changed throughout this time from May – November 2002. We assessed changes in outcome symptoms by assessment month and observed no apparent differences. Our study is not without limitations. We had no direct measure of how the pandemic affected the mother or child or whether other individuals in the family had contracted COVID-19. Additionally, we assessed symptoms in children using screening tools and acknowledge that these tools do not diagnose depression or anxiety, but instead provide an indication of severity. Cronbach’s alphas ranged from 0.6 – 0.8 for our outcome measures. While we acknowledge that these are on the lower side, these are acceptable ranges for internal consistency.40 We also acknowledge the potential impact of unmeasured confounders. Maternal SES was only available at baseline, yet the economic standing of many families likely changed during the pandemic. Economic standing was part of the stress questionnaire, thus adjusting for change in SES would likely remove some of the variance we were interested in capturing. We also did not have information on whether the child felt they had adequate social support or suffered undue economic distress during the pandemic. Finally, we acknowledge the loss to follow-up in our study. We evaluated close to 600 participants at visits prior to and during COVID; however, participants were only included in the analysis if they had complete data for both visits. Our study has several strengths. We leveraged data from a longitudinal prospective birth cohort study to assess the association between both maternal-reported stress and social support in relation to child mental health outcomes. Our study incorporated outcome data measured prior to and during the pandemic, and thus we were able to assess changes in mental health symptoms in the same cohort of children. Our results showed similar findings across respondents, thus giving strength to the evidence for an association with mental health outcomes. We additionally controlled for time-varying confounders, including child age. Finally, our main analyses used a dimensional outcome assessment approach and showed subclinical effects on mental health.41 Conclusion The COVID-19 pandemic has disrupted nearly all aspects of life, creating unique stressors and placing under-resourced populations at a potential increased risk of mental health conditions. Thus, under these unprecedented times, where the most effective way to prevent the virus from spreading is social distancing, we need to also consider the impact these policies may have on the stagnation of children’s development and the likelihood this may lead to mental health symptoms. The findings from our study highlight the need for additional resources and programs for parents, clinicians, and mental health providers to be able to provide support for children going through similar events to reduce mental health impacts in this population, as well as increased screening of mental health symptoms. Emphasis should be placed on promoting social support and children’s resilience as children transition through these early years, particularly in the face of a novel major life stressor. Finally, PROGRESS is continuing to follow up participants - future analyses will continue to assess support, resilience, and mental health outcomes in children, with a particular emphasis on long-term pandemic-related impacts throughout the adolescent years. Supplementary Material 1 Funding: This work was supported by the NIH [grant numbers T32HD049311, R01ES013744, R01ES021357, P30ES023515, R00ES027496, R24ES028522, and K99ES032480]. Data availability statement: The datasets generated during and/or analyzed during the current study are not publicly available due to privacy concerns, but a limited dataset may be available from the corresponding author on reasonable request. Table 1. Distribution (Mean ± SD and min, max) of Time-varying Confounders, Exposures, and Outcomes in the PROGRESS Study Population Before COVID (n=464) During COVID (n=464) Mean ± SD Min, Max Mean ± SD Min, Max Child’s age 9.7 ± 0.7 8.1, 12.1 11.1 ± 1 8.9, 12.8 Maternal age 37.9 ± 6 28.3, 53.1 39.3 ± 6 29.3, 54.3 Exposures Total maternal negative life events 3.2 ± 2 0, 9 2.9 ± 2 0, 8 Social support 17.5 ± 3 5, 20 17.2 ± 2 7, 20 Child resiliency 46.6 ± 9 21, 69 --- --- Child mental health symptoms CDI child reported 53.4 ± 9 40, 90 54.6 ± 10 40, 90 CDI parent reported 51.4 ± 9 35, 88 53.1 ± 10 35, 86 RCMAS-2 50.9 ± 8 33, 73 50.0 ± 8 36, 73 Note. CDI = Children’s Depression Inventory; NLE = negative life events; RCMAS = Revised Children’s Manifest Anxiety Scale; SD = standard deviation; SES = socioeconomic status. Table 2. Mean Differences (95% CI) in CDI-2 Depressive and RCMAS-2 Anxiety Symptoms Scores from Before to During COVID N (%) Depressive symptoms - child report (CDI-C) Depressive symptoms - parent report (CDI-P) Anxiety symptoms - child report (RCMAS) Overall 464 1.18 (0.13, 2.23)* 1.76 (0.96, 2.56)* −0.86 (−1.66, −0.06)* Child sex Male 236 (51) −0.07 (−1.47, 1.34) 1.06 (−0.07, 2.18) −1.53 (−2.64, −0.41)* Female 228 (49) 2.48 (0.93, 4.02)* 2.50 (1.36, 3.63)* −0.17 (−1.32, 0.98) Child age at COV ≤9 89 (19) −0.53 (−2.95, 1.89) 2.57 (0.71, 4.44)* 1.02 (−0.99, 3.03) 10 123 (27) 0.94 (−1.15, 3.04) 2.64 (1.07, 4.21)* −1.38 (−2.74, −0.03)* 11 144 (31) 0.42 (−1.27, 2.12) 1.18 (−0.26, 2.62) −1.51 (−3.02, −0.01)* 12 108 (23) 3.87 (1.52, 6.22)* 0.87 (−0.79, 2.53) −0.95 (−2.62, 0.72) Maternal SES Lower 179 (39) 1.29 (0.09, 3.12)* 1.07 (−0.26, 2.41) −1.53 (−2.83, −0.23)* Medium 222 (48) 1.63 (0.19, 3.07)* 2.18 (1.04, 3.32)* 0.17 (−0.97, 1.31) Higher 63 (14) −0.71 (−3.33, 1.90) 2.25 (0.09, 4.42)* −2.59 (−4.80, −0.37)* Total maternal negative life events (COV) a High (>3) 164 (35) 2.83 (1.02, 4.64)* 2.83 (1.38, 4.28)* 0.73 (−1.53, 1.99) Low (≤3) 300 (65) 0.28 (−1.00, 1.56) 1.18 (0.23, 2.13)* −1.73 (−2.75, −0.71)* Family social support (COV) b Low (≤17) 241 (52) 1.88 (0.33, 3.42)* 2.14 (1.01, 3.28)* 0.05 (−1.09, 1.18) High (>17) 223 (48) 0.43 (−0.98, 1.83) 1.35 (0.23, 2.49)* −1.84 (−2.97, −0.72)* Child resiliency c Low (≤46) 202 (52) 1.96 (0.24, 3.68)* 3.44 (2.21, 4.66)* 0.18 (−1.13, 1.49) High (>46) 190 (48) −0.17 (−1.62, 1.29) 0.96 (−0.25, 2.18) −1.74 (−2.85, −0.63)* Note. CDI-C = Children’s Depression Inventory child reported; CDI-P = Children’s Depression Inventory parent reported; CI = confidence interval; NLE = negative life events; RCMAS = Revised Children’s Manifest Anxiety Scale (child reported); SES = socioeconomic status. a Maternal negative life events assessed using the Crisis in Family Systems- Revised survey b Maternal family/friends social support assessed using the Social Support Network scale c Child resiliency assessed using the parent-reported BASC-2 resiliency T-score measure * indicates p<0.05 Table 3. Linear regression results for associations between continuous maternal reported negative life events, maternal social support, and child resiliency in relation to continuous CDI-2 depressive and RCMAS-2 anxiety symptoms in the child CDI-2 depressive symptoms (child report) CDI-2 depressive symptoms (parent report) RCMAS-2 anxiety symptoms (child report) N b (95% CI) p-int b (95% CI) p-int b (95% CI) p-int Maternal negative life events* Overall 464 0.72 (0.12, 1.31) 0.77 (0.30, 1.23) 0.43 (−0.03, 0.90) Males 236 0.48 (−0.39, 1.36) 0.69 (−0.01, 1.39) 0.47 (−0.21, 1.15) Female 228 0.85 (0.02, 1.67) 0.56 0.86 (0.24, 1.48) 0.71 0.39 (−0.25, 1.03) 0.85 Maternal social support Overall 464 −0.30 (−0.77, 0.17) −0.28 (−0.65, 0.10) −0.19 (−0.55, 0.17) Males 236 −0.24 (−0.90, 0.41) −0.44 (−0.98, 0.10) 0.07 (−0.42, 0.56) Female 228 −0.29 (−0.99, 0.40) 0.92 −0.16 (−0.70, 0.37) 0.45 −0.41 (−0.94, 0.11) 0.18 Child resiliency Overall 392 −0.11 (−0.25, 0.02) 0.13 (0.03, 0.24) −0.06 (−0.16, 0.04) Males 197 −0.08 (−0.26, 0.09) 0.14 (0.00, 0.28) −0.12 (−0.26, 0.02) Female 195 −0.12 (−0.33, 0.08) 0.46 0.12 (−0.05, 0.28) 0.81 0.03 (−0.12, 0.19) 0.30 Note. CDI-C = Children’s Depression Inventory child reported; CDI-P = Children’s Depression Inventory parent reported; p-int = p-value for sex X exposure interaction, RCMAS = Revised Children’s Manifest Anxiety Scale (child reported). All analyses were adjusted for child age, child sex, maternal SES, and maternal age. * also adjusted for pre-COVID negative life events Table 4. Adjusted logistic regression results for associations between continuous maternal reported negative life events, social support, child resiliency, and depressive and anxiety symptoms dichotomized at clinically significant cut-points N CDI-2 C Odds ratio (95% CI) p-int CDI-2 P Odds ratio (95% CI) p-int RCMAS-2 C Odds ratio (95% CI) p-int Maternal negative life events Overall 464 1.19 (1.03, 1.37) 1.50 (1.27, 1.77) 1.19 (1.02, 1.39) Males 236 0.97 (0.75,1.26) 1.65 (1.27, 2.13) 0.92 (0.69, 1.22) Female 228 1.30 (1.08, 1.56) 0.07 1.43 (1.15, 1.78) 0.42 1.36 (1.12, 1.66) 0.03 Maternal social support Overall 464 0.93 (0.83, 1.05) 0.83 (0.73, 0.94) 0.92 (0.81, 1.05) Males 236 0.88 (0.72, 1.08) 0.82 (0.68, 0.99) 0.93 (0.75, 1.15) Female 228 0.98 (0.84, 1.14) 0.41 0.81 (0.67, 0.97) 0.89 0.93 (0.79, 1.09) 0.97 Child resiliency Overall 392 0.94 (0.91, 0.97) 0.89 (0.85, 0.93) 0.97 (0.93, 1.00) Males 197 0.93 (0.88, 0.98) 0.89 (0.84, 0.94) 0.95 (0.89, 1.01) Female 195 0.96 (0.91, 1.00) 0.35 0.88 (0.82, 0.94) 0.81 0.97 (0.93, 1.01) 0.51 Note. CDI-C = Children’s Depression Inventory child reported; CDI-P = Children’s Depression Inventory parent reported; p-int = p-value for sex X exposure interaction, RCMAS = Revised Children’s Manifest Anxiety Scale (child reported). All analyses are adjusted for child age, child sex, maternal SES, and maternal age. Impact: In this longitudinal cohort study of children in Mexico City, we observed that depressive symptoms were higher from before to during the pandemic. Maternal stress surrounding the pandemic may increase mental health symptoms in pre-adolescent children. Child resiliency may help to protect against pandemic related stressors. Conflict of Interest: The authors have no conflicts of interest relevant to this article to disclose. Consent statement: All women provided informed consent and children provided assent. ==== Refs References 1 Brooks SK The Psychological Impact of Quarantine and How to Reduce It: Rapid Review of the Evidence. 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PMC010xxxxxx/PMC10227180.txt	==== Front 0100714 6400 Pediatr Res Pediatr Res Pediatric research 0031-3998 1530-0447 36446920 10.1038/s41390-022-02373-5 nihpa1845764 Article Preschool Neurodevelopment in Zika Virus-Exposed Children Without Congenital Zika Syndrome Mulkey Sarah B. 123 Peyton Colleen 4 Ansusinha Emily 1 Corn Elizabeth 1 Arroyave-Wessel Margarita 1 Zhang Anqing 1 Biddle Cara 13 Gutierrez Corina 5 Sorkar Andrea 5 Cure Andres 5 Cure Daniela 5 du Plessis Adre J. 123 DeBiasi Roberta L. 137 Msall Michael E. 6 Cure Carlos 5 1 Children’s National Hospital, Washington, DC 2 Department of Neurology, The George Washington, University School of Medicine and Health Sciences, Washington, DC 3 Department of Pediatrics, The George Washington, University School of Medicine and Health Sciences, Washington, DC 4 Department of Physical Therapy and Human Movement Sciences, Northwestern University, Chicago, IL 5 BIOMELab, Barranquilla, Colombia 6 University of Chicago Medicine Kennedy Research Center on Intellectual and Neurodevelopmental Disabilities, Chicago I 7 Department of Microbiology, Immunology and Tropical Medicine, and The George Washington University School of Medicine and Health Sciences, Washington, DC Author Contributions: Dr. Mulkey conceptualized and designed the study, developed data collection instruments, trained the study team, reviewed study data, interpreted study data and results of data analyses, drafted the initial manuscript, and reviewed and revised the manuscript. Dr. Peyton conceptualized and designed the study, developed data collection instruments, trained the study team, reviewed study data, interpreted study results, and reviewed and revised the manuscript. Ms. Ansusinha and Ms. Corn developed data collection instruments, trained the study team, reviewed study data, carried out initial analyses, interpreted study results, drafted the manuscript tables, and reviewed and revised the manuscript. Ms. Arroyave-Wessel helped design the study and translated data collection instruments, helped train the study team, oversaw the use of Telehealth for the study activities and reviewed and revised the manuscript. Dr. Zhang oversaw the development of the data collection database, analyzed and interpreted study data, reviewed and revised the manuscript and tables. Dr. Biddle, Dr. du Plessis, Dr. DeBiasi, and Dr. Msall helped with the conceptualization and design of the study, provided additional insight into data interpretation, and critically reviewed the manuscript for important intellectual content. Dr. Gutierrez, Ms. Sorkar, Mr. A. Cure, Dr. D. Cure developed the plan logistics of child evaluations, recruited and evaluated the children, were trained in study evaluations, reviewed study data, and reviewed and revised the manuscript. Dr. C. Cure conceptualized and designed the study, oversaw the recruitment and evaluations of the children, reviewed study data, and critically reviewed the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. Corresponding author: Sarah B. Mulkey, MD, PhD, Children’s National Hospital, Prenatal Pediatrics Institute, 111 Michigan Ave., NW, Washington, DC 20010, SBMULKEY@childrensnational.org, Phone: (202) 476-5815; Fax: (202) 476-5897. 11 11 2022 30 11 2022 30 5 2024 10.1038/s41390-022-02373-5http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms Background: Children with in-utero Zika virus (ZIKV) exposure without congenital Zika syndrome (CZS) are at risk for abnormal neurodevelopment. Preschool-age outcomes for children with antenatal ZIKV exposure have not yet been established. Methods: Children with in-utero ZIKV exposure and nonexposed controls had neurodevelopmental evaluations at age 3–5 years in Sabanalarga, Colombia. Cases did not have CZS and were previously evaluated prenatally through age 18 months. Controls were born before ZIKV arrival to Colombia. Neurodevelopmental assessments included Pediatric Evaluation of Disability Inventory (PEDI-CAT), Behavior Rating Inventory of Executive Function (BRIEF-P), Bracken School Readiness Assessment (BSRA), and Movement Assessment Battery for Children (MABC). Family demographics and child medical history were recorded. Results: Fifty-five ZIKV-exposed children were evaluated at mean age 3.6 years and 70 controls were evaluated at 5.2 years. Family demographics were similar between groups. BRIEF-P t-scores were higher for cases than controls in shift and flexibility domains. Cases had lower PEDI-CAT mobility t-scores compared to controls. There was no difference in MABC between groups. In 11% of cases and 1% of controls, parents reported child mood problems. Conclusions: Children with in-utero ZIKV exposure without CZS may demonstrate emerging differences in executive function, mood, and adaptive mobility that require continued evaluation. ==== Body pmcIntroduction Children exposed to the Zika virus (ZIKV) in utero during the ZIKV epidemic, have aged into early childhood. Congenital Zika Syndrome (CZS) describes the severe phenotype of infants with multiple neurological abnormalities resulting in complex ongoing medical needs.1–3 Although many children with antenatal ZIKV exposure do not have CZS at birth,4 early neurodevelopmental outcome studies suggest a risk for neurodevelopmental delays in the first two years of life.5,6 There is a need to understand the neurologic and neurodevelopmental outcomes in children with the full spectrum of congenital ZIKV exposure. Several studies demonstrated lower-than-expected developmental performance in motor and language domains, highlighting the need for follow-up in these areas.5,6 Due to uncertainty regarding neurodevelopment in ZIKV exposed infants, the Centers for Disease Control and Prevention (CDC) recommended routine follow-up through early childhood.7 Since the ZIKV epidemic occurred relatively recently from 2015–2017, long-term child outcome data have not yet been documented. Thus, the international healthcare community remains on a steep learning curve as many critical questions about ZIKV and its long-term consequences remain unanswered. In 2016, we developed an international collaboration to evaluate ZIKV-infected pregnant women with serial prenatal imaging.8 Infants from this well-characterized Colombian cohort were seen for early neurodevelopmental evaluations.5 Building upon our prior study that found lower-than-expected multi-domain assessment scores in the children to age 18 months, we sought to determine outcomes prior to school entry. The objectives of this study were to determine whether children exposed to ZIKV in-utero who do not have CZS have abnormal neurodevelopmental outcomes at preschool age. We hypothesized that the ZIKV-exposed children would have lower multi-domain developmental assessments compared to non-ZIKV exposed controls. Methods Participants We performed a prospective cohort study of ZIKV-exposed children and non-ZIKV exposed control children in Atlántico Department, Colombia. Seventy children with antenatal ZIKV exposure without CZS from our longitudinal cohort established in pregnancy were eligible and aged three to four years.8 Children were normocephalic at birth, had normal sequential fetal ultrasonography and magnetic resonance imaging examinations, no clinical findings of CZS at birth, and at least one neurodevelopmental evaluation up to 18 months of age as part of an early outcome study.5,8 Their mothers had symptomatic ZIKV infection in pregnancy, resided in an area of endemic ZIKV transmission, and had laboratory confirmation of ZIKV, thus meeting the CDC clinical criteria for probable ZIKV infection.5,8 We prospectively enrolled 70, four- and five-year-old children from Atlántico Department, Colombia without antenatal ZIKV-exposure as controls. All controls were born prior to April 1, 2016. The eligibility birth date was selected to enroll controls close in age to exposed cases but born before emergence of ZIKV circulation in Colombia, ruling out possibility of exposure to asymptomatic maternal ZIKV infection during at least the first half of gestation. Children were excluded as a control if their mother reported an infectious disease during pregnancy (i.e., Zika, Dengue, Chikungunya), if they had a chronic medical condition, history of seizures, abnormal hearing or vision not corrected by lenses, developmental concerns expressed by their caregiver, received therapy for developmental delays, had a behavioral or psychological condition, or were born preterm (≤36 weeks). This study received approval from the Children’s National Hospital Institutional Review Board, Washington, D.C. and the Institutional Review Committee and Independent Committee on Research Ethics (CIRCIE), Barranquilla, Colombia. Women provided written informed consent for their child’s study participation. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. This study is registered on ClinicalTrials.gov, NCT04398901. Setting The ZIKV-exposed children were recruited by in-person contact at their home or by phone and live in or near Sabanalarga in the Atlántico Department, Colombia (Figure 1). Children were scheduled for visits between December 3, 2020, and February 18, 2021. Control children were recruited by door-to-door meetings with families in Sabanalarga by research staff. In some cases, twins or similarly aged cousins were enrolled. Visits for controls occurred between January 28, 2021, and February 18, 2021. The visits occurred at a local school due internet connection and availability of adequate space for activities. ZIKV Outcome Toolbox Neurodevelopment was assessed by the ZIKV Outcome Toolbox (Table 1) containing items selected specifically for this study based on the multiple domains assessed, availability in Spanish, and possibility of observational assessments of child motor function. The Toolbox includes parental questionnaires and standardized child evaluations. The Pediatric Evaluation of Disability Inventory (PEDI-CAT) is a computer-based questionnaire that measures the functional domains of daily activities, mobility, social-cognitive, and responsibility (Pearson Q-global).9 The Behavior Rating Inventory of Executive Function (BRIEF-P) is a questionnaire to assess executive function (PAR, Inc.).10,11 Parents also completed the Parenting Stress Index (PSI-4) (PAR, Inc.), questionnaires on the family and home environment and their child’s medical history. Socioeconomic status was evaluated by parental occupation and education level. Mothers of children with ZIKV-exposure were queried about feelings of stigmatization due to a diagnosis of ZIKV in pregnancy. A research coordinator read the questions to the parent when needed based on literacy level. Children were evaluated by the Bracken School Readiness Assessment (BSRA) and the Movement Assessment Battery for Children-Second Edition (MABC) (Pearson). The BSRA measures a child’s knowledge of five areas: colors, letters, numbers/counting, sizes/comparison, and shapes. The MABC evaluates manual dexterity, aiming and catching, and balance. For the MABC manual dexterity items of posting coins and stringing beads, six coins and beads were used for all children. Some children refused to complete all or some parts of the assessments, in which case evaluations were not scoreable. Child weight, height, and head circumference were measured, and body mass index (BMI) was calculated. Telehealth Training and Observation of Child Activities Due to the COVID-19 pandemic and inability for the U.S. study team to travel to Colombia, training was completed by Zoom telehealth (Figure 1).12 The Colombian team demonstrated learned skills by live telemedicine connection with similar aged children of their own. Telehealth connections were used during study visits for live observation of child activities and remote recording (Figure 1). Two laptops with telehealth connections captured child performance: one capturing BSRA and seated MABC activities, and the other standing MABC activities. Both laptops directly recorded video to hard drives. The videos were used for MABC and BSRA scoring, and observational assessments. Statistical Analysis Data were entered into a Research Electronic Data Capture (REDCAP) database.13 Pearson’s Q-global reported PEDI-CAT scores based on age. The BRIEF-P, PSI-4, and MABC scores were scaled for age per test manuals. As MABC manual dexterity standard scores reflect child performance using 12 coins/beads at age 5, local norms were developed for the use of 6 coins/beads irrespective of age. Z-scores were generated from control data of 5-year-olds for “posting coins” and “threading beads”. These Z-scores were then attached to a standard score based on test manual norming. For BRIEF-P, a t-score of ≥65 was considered clinically significant. BSRA results were reported using raw scores only due to lack of Spanish edition norms. Scores were compared using Mann-Whitney or t-test depending on data’s normality, which was determined by the Kolmogorov-Smirnov test. For significant P-values, 95% confidence intervals were reported using Hodges-Lehmann method. Multiple regression evaluated associations between PEDI-CAT Mobility, BRIEF-P Shift, and BSRA Sizes and Comparison scores for cases with gestational age at ZIKV exposure, BMI, and sex. For controls, multiple regression evaluated for associations between PEDI-CAT Mobility, BRIEF-P Shift, and BSRA Sizes and Comparison scores with BMI, sex, maternal education, oldest child, and number of children in the home. Data were analyzed using SAS for Windows version 9.4 (SAS Institute Inc., Cary, NC). Two-sided test with a significance level of .05 was used. Results Demographics: Fifty-five of 70 (79%) children with in utero ZIKV exposure (cases) were evaluated at a mean (SD) of 3.6 (0.4) years of age (Table 2). Fifteen cases (21%) declined participation due to COVID-19 concerns, moved out of the region, or could not be contacted. Their mothers had ZIKV during the first and second trimesters of pregnancy, with fetal ZIKV exposure at a mean of 7.9 (4.3) gestational weeks. Seventy controls without ZIKV exposure were evaluated at 5.2 (0.2) years of age. Questionnaires: Most mothers (50/55, 91%) with ZIKV during pregnancy reported that worry about ZIKV did not affect interactions with their child. During pregnancy, 13 (24%) mothers said they felt different than other pregnant people due to their ZIKV diagnosis. Twelve (22%) parents of ZIKV-exposed children reported worry about their child’s health compared to 5 (7%) parents of control children, (95% CI 1.4 to 26.8, P = .03). In six (11%) cases and one (1%) control, parents reported child mood problems (95% CI 0.8 to 18.5, P = .02). There was higher report of child vision problems in cases than controls, 6% vs. 0%, respectively, (95% CI −0.6 to 11.9, P = .08) and no difference in receipt of rehabilitation therapy. Thirty-three (60%) of the ZIKV-exposed children (all < 5 years of age) were reported to be attending daycare with the remaining cared for by family members or friends. Of control participants, 59 (84%) had begun primary school at the time of their evaluation. The results of the ZIKV Outcome Toolbox questionnaires are in Table 3. The PEDI-CAT t-scores for cases were lower in mobility (P < .001) and responsibility (P < .001) reflecting lower reported child function in these domains, but higher in social/cognitive (P = .021) and daily activities (P < .001) compared to controls. The BRIEF-P t-scores were higher for cases than controls in shift (95% CI 0 to 8, P = .049) and flexibility (95% CI 0 to 9, P = .047), but there was no difference for percent clinically elevated (t-score ≥65). The PSI-4 score overall (95% CI 0 to 20, P = .043) and difficult child domain (95% CI 0 to 20, P = .029) were elevated for cases over controls. Child evaluations (Table 4): Twenty-three cases and five controls did not have MABC scores due to refusal of some or all MABC sections. Having a refusal was associated with younger age (95% CI 0.12 to 0.51 years, P = .002). Among the 32 cases and 65 controls who completed the MABC, there was no difference in manual dexterity, aiming and catching, balance, or total age-adjusted standard scores. By MABC score zones of green, amber, and red, the cases had 30 (94%), 0 (0%), and 2 (6%) children in each zone and the controls had 50 (77%), 6 (9%), and 9 (14%) children in each zone, respectively, and this distribution was not different between cases and controls (Fisher Exact P = .09). The BSRA scores reflect low mastery of school readiness concepts for cases and controls (Table 4). There was no association between gestational age of ZIKV-exposure, sex, and BMI with the outcomes of PEDI-CAT Mobility, BRIEF-P Shift, and BSRA Sizes and Comparison scores by multiple regression. For the controls, the number of children in the home was associated with the BRIEF-P shift score (P = .045), but maternal education level, sex, BMI, and being the oldest child in the home were not associated with the PEDI-CAT Mobility, BRIEF-P Shift, and BSRA Sizes and Comparison scores. Discussion This study provides continued prospective longitudinal neurodevelopmental assessments of a well-characterized cohort of children with confirmed antenatal ZIKV exposure, without CZS at birth. These children showed overall progress in neurodevelopmental skills at preschool age and appear to be doing well. However, we detected some differences in developmental domains that require continued evaluation. Follow-up was achieved in 79% of children since the prenatal period, representing one of the longest longitudinal follow-up cohorts of ZIKV-exposed children worldwide.5,8 Compared to controls, children with antenatal ZIKV exposure showed differences in areas of executive function and parental report of mobility, responsibility, and temperament. Direct evaluation of motor skills, however, showed comparable case and control performance. While parents of ZIKV-exposed children expressed worry over their child’s health, reported child medical conditions mostly reflected common childhood conditions and injuries. The findings provide insight into neurodevelopment of children with antenatal ZIKV exposure who do not have the severe sequelae of CZS, and can guide child neurodevelopmental follow-up into school-age. Our study is enhanced by a non-ZIKV exposed control cohort of children from the same Colombian community. Parental occupations for cases and controls were primarily in manual labor positions and there was a similar range of educational attainment, with many parents having incomplete schooling. Attention to sociodemographic similarity between cases and controls is important as home and neighborhood environments influence child development.14,15 Many studies of outcomes for infants and children with ZIKV exposure are limited by the lack of a control cohort,6,16–22 including our prior studies.5,8 During an infectious epidemic, especially when infections may be asymptomatic and laboratory diagnosis complex, the ability to identify non-exposed controls can be difficult. Any child born in Colombia during ZIKV endemicity could be ZIKV-exposed, so we included only controls with older birthdates. Controls were a mean of 1.4 years older than cases, and direct comparison of raw scores will only be possible when the cases reach the same age. However, many assessments were scaled for age, thus limiting the effect of age on our results, and highlighting our priority of selecting non-exposed over same-aged controls. The benefits of the ZIKV Outcome Toolbox used in this study include that it can be performed in under one hour and yield results in multiple developmental domains, it is cost-effective, does not require extensive experience, and can be used in a community low-resource setting. The Toolbox worked well but required assistance of the research team for questionnaire completion since some parents had low literacy. A major advantage of the Toolbox was that the child BSRA and MABC evaluations could be recorded and livestreamed via Zoom Telehealth connections with the U.S. research team. In the future, it may be better to only include the BSRA for children aged four or older, as young age likely influenced refusals to sit for the assessment. Executive function is vulnerable to early life insults due to the protracted window of development of the fronto-striatal brain region,23 and encompasses working memory, planning, and organization, which are skills for academic and life success.11 At preschool-age, executive function begins to emerge. While we found higher BRIEF-P scores for the domains of shift and flexibility for cases compared to controls, these differences were not in the clinically elevated range. As children are still relatively young, evaluation at older ages is necessary. Interestingly, parents of cases reported higher child mood problems, also reflected by the PSI-4. These elements of lower executive function skills, mood and behavior problems seem to correspond with lower responsibility scores on PEDI-CAT among ZIKV-exposed cases. Assessments of motor function have demonstrated lower scores for ZIKV-exposed children in prior studies and is an area of vulnerability due to the long maturational time course of the motor pathways.6,20,22,24 Abnormality of movement in infants with in utero ZIKV exposure may predict two-year cognitive, language, and motor outcomes.24 In our ZIKV-exposed cases, we previously showed lower mobility scores on the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA) with increasing age from 6 to 20 months, demonstrating specific concern about future neuromotor development.5 In this study we evaluated child mobility using the PEDI-CAT and MABC.5 The PEDI-CAT mobility scores were lower for cases than controls, but the average t-score was normal for both. This difference in parental reported mobility between cases and controls may reflect either lower adaptive motor skills for cases or may represent a limitation of using PEDI-CAT for inter-age comparison. Not all children completed the MABC assessment due to refusal of all or some of the test, therefore our findings may overestimate motor abilities by scoring only those who completed the evaluation. However, for those scored, the fine and gross motor MABC scores provide some reassurance that ZIKV-exposed children are progressing similarly to their neighborhood peers. Colombian children’s exposure to early school concepts is variable and depends upon the home environment and teaching by caregivers. We found that knowledge of school readiness concepts was low in the ZIKV-exposed cases; this is likely multifactorial and cannot be ascribed to ZIKV-exposure at this time. The children have been mostly at home for the past year due to the COVID-19 pandemic and quarantines within their community. The controls, who are older, had higher knowledge of colors, numbers, and letters, likely due to more time for educational experiences. Direct comparison of raw scores on the BSRA for cases at a similar age to controls, will be necessary to understand any difference in attainment of school readiness skills. We found that parents of the ZIKV-exposed children reported higher difficulty in parenting. The parents of both groups completed the PSI-4 questionnaire at a similar period of the SARS CoV-2 pandemic which maybe a time of increased stress for families.26 Whether the results reflect higher stress and difficulty in parenting 3–4-year-old children, the cases, versus 4–5-year-old children, the controls, or reflects more difficult children among the ZIKV-exposed, is not known at this time. The study has several limitations. Some children did not complete all assessments and were unable to be scored. Whether the behavior of refusal for assessments represents a difference in executive function skills, self-esteem, shyness, or lack of knowledge will require future evaluations. The study did not collect current education-related effects of the SARS CoV-2 pandemic. The impact of reduced preschool experiences due to the pandemic should be considered in the context of the study results.25 As controls were older than case participants, investigators were not blinded during the child evaluations. It is unclear whether the impact of lost schooling and community closures due to the pandemic had a greater influence on one age group over the other. In addition, the exclusion criteria for controls were defined in order to preclude enrollment of children with known developmental delays so the control cohort may not be representative of the population as a whole. Additionally, it should be noted that parent-rating forms may be influenced by the parents’ perceptions or increased worry about their child’s development, due to inability to be blinded to ZIKV exposure status. In the PEDI-CAT, scores for cases are higher than those for controls in some domains. This fact may reflect an inability to compare scores between age groups, or parent reporting bias. As such, further study to allow for direct age comparison is necessary. Conclusion Children with in-utero ZIKV exposure without CZS appear to be making progress in neurodevelopmental skills. These children may need additional support for early executive function skills and school readiness concepts as they prepare to enter school. Longitudinal follow-up upon school entry along with more comprehensive neuropsychological assessments to evaluate cognitive and emotional development can help determine the long-term special needs of children born during the ZIKV epidemic. Funding: This work was supported by the Thrasher Research Fund. SBM has additional funding from the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number R01HD102445, and a contract with the U.S. Centers for Disease Control and Prevention, for work on Zika virus separate from this study. CP receives support from National Center for Advancing Translational Sciences, Grant KL2TR001424. Data availability statement The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Figure. 1 Colombia Zika Child Outcomes Study Process We harnessed novel telemedicine advancements to allow for remote coordination of neurodevelopmental evaluations. Live video and telehealth Zoom allowed for the U.S. team to train Colombian research staff in Barranquilla, Colombia, as well as monitor and score assessments of children on-site in Sabanalarga, Colombia. Table 1: ZIKV Outcome Toolbox ZIKV Outcome Toolbox item Assessment type Domains assessed Time (min) Special features Socioeconomic, Medical History Parent questionnaire Medical health, environment, safety 10 Completed with help of trained team member PEDI-CAT Parent questionnaire Daily activities Mobility Social-cognitive Responsibility 10 Computerized questionnaire completed with help of trained team member BRIEF-P Parent questionnaire Executive function 10 Completed with help of trained team member PSI-4 Parent questionnaire Parental stress 10 Completed with help of trained team member BSRA-3 In-person child assessment School readiness 15 Telehealth live monitored and video-recorded MABC-2 In-person child assessment Fine and gross motor 20 Telehealth live monitored and video-recorded Abbreviations: BRIEF-P: Behavior Rating Inventory of Executive Function – Preschool; BSRA-3: Bracken School Readiness Assessment – Third Edition; PEDI-CAT: Pediatric Evaluation of Disability Inventory Computer Adaptive Test; PSI-4: Parenting Stress Index – Fourth Edition; MABC-2: Movement Assessment Battery for Children – Second Edition Table 2: Demographic, Socioeconomic, and Health Characteristics of ZIKV-exposed Children and Non-Exposed Controls Characteristic ZIKV-Exposed Children (N=55) Non-Exposed Controls (N=70) P-value Male sex (n [%]) 24 (44) 34 (49) .594a Years of age at visit (median [IQR]) 3.8 (0.7) 5.2 (0.4) <.001b BMI (mean [SD]) Male 17.0 (2.9) 14.8 (1.1) .002c Female 15.4 (1.7) 15.3 (1.4) .635c Education-level mother (n [%]) .858a All or some primary 5 (9) 8 (11) All or some secondary 41 (75) ;48 (69) Technical school 8 (15) 10 (14) None 1 (2) 2 (3) University 0 (0) 0 (0) NR 0 (0) 2 (3) Education-level father (n [%]) .386a Primary school 7 (13) 15 (21) All or some secondary 40 (73) 42 (60) Technical school 3 (6) 3 (4) University 0 (0) 3 (4) None 2 (4) 1 (1) NR 3 (6) 6 (9) Most common occupation types (n) Type 1 Shopkeeper (12) Taxi driver (15) Type 2 Construction worker (8) Various trades (15) Type 3 Various trades (7) Construction worker (7) Type 4 Taxi driver (4) Shopkeeper (4) Type 5 Fisherman (4) Independent worker (4) Principal sustainer (n [%]) .537a Mother 5 (9) 6 (9) Father 40 (73) 57 (81) Both 2 (4) 2 (3) Other or NR 7 (15) 5 (7) Child education (n [%])d Attend daycare 33 (60) Attend primary school 59 (84) Number of children in home (median, IQR) (n=55, 69)e 2 (1) 3 (2) .215b Participant oldest child in home (n [%]) (n=54, 68) 19 (35) 25 (36) 1a Child medical history (n [%]) Parent worried about child’s health (n=55, 65) 12 (22) 5 (7) .036a Vision problem (n=53, 70) 3 (6) ;0 (0) .077a Hearing problem (n=54, 70) 1 (2) 2 (3) 1a Growth problem (n=54,70) 2 (4) 0 (0) .181a Received therapy (n=55, 69) 2 (4) 1 (1) .584a Behavior problems (n=55, 67) 4 (7) 2 (3) .408a Mood problems (n=54, 68) 6 (11) 1 (1) .043a a Fisher’s Exact Test b Mann-Whitney U test c Student’s t-test d Sabanalarga schools using remote learning modality at the time of assessments due to the COVID-19 pandemic e sample size for individual items indicated as (n = [n ZIKV-exposed], [n controls]) Abbreviations: BMI-Body mass index; NR-No response Table 3: ZIKV Outcome Toolbox Parental Questionnaires: BRIEF-P, PEDI-CAT, PSI Assessment ZIKV-exposed children (N=55) Non-exposed controls (N=70) P-value BRIEF-P t-score (mean [SD])/(median)[IQR] Inhibit 57.4 (12.0) 56.0 (11.7) .511a Shift 52.0 (18) 46.0 (15) .049b Emotional control 51.0 (15.5) 46.0 (17) .165b Working memory 54.1 (14.6) 55.0 (10.5) .689a Plan/organize 51.8 (14.5) 52.3 (11.1) .849a ISCI 55.2 (13.6) 53.6 (11.5) .186a FI 51(14.5) 45 (18) .047b EMI 51(17) 48 (17.3) .624b GEC 56(19.5) 50 (20) .230b PEDI-CAT t-score (median [IQR]) Daily activities 47 (7) 42 (7) <.001b Mobility 48 (12) 77 (1) <.001b Social/cognitive 46 (12) 38 (14) 0.021b Responsibility 15 (29) 60 (37) <.001b PSI (median [IQR]) Parental distress 46 (52) 32 (42) .085b Parent-child dysfunctional interaction 32 (44) 28 (36) .120b Difficult Child 34 (44) 26 (32) .029b Total Score 40 (50) 28 (36) .043b a Student’s t-test (P < 0.05) b Mann-Whitney U test (P < 0.05) Abbreviations: BRIEF-P: Behavior Rating Inventory of Executive Function – Preschool; EMI: Emergent Metacognition Index; FI: Flexibility Index; GEC: Global Executive Composite; IQR: Interquartile Range; ISCI: Inhibitory Self-Control Index; PEDI-CAT: Pediatric Evaluation of Disability Inventory – Computerized Adaptive Test; PSI: Parenting Stress Index; SD: Standard deviation Table 4. ZIKV Outcome Toolbox Child Assessments: MABC-2 and BSRA-3 Assessment ZIKV-exposed children (N=55) Non-exposed controls (N=70) P-value MABC standard score (mean [SD])/(median [IQR])d Manual Dexterity (n = 43, 69)a 22.8 (7.8) 24.3 (6.5) .282b Aiming and Catching (n=41, 69) 20.6 (6.3) 20.7 (4.8) .951b Balance (n= 36, 66) 31.0 (9.8) 32.5 (10) .275c Overall Score (n= 32, 65) 75 (15.4) 75 (14.8) .992b BSRA raw score (mean [SD]) (n=50, 69) Colors (of 10) 2.5 (3) 6.2 (4) -- Letters (of 15) 1.2 (2) 1.5 (2.4) -- Numbers & Counting (of 18) 1.2 (2.3) 4.7 (5.5) -- Sizes & Comparisons (of 22) 5.0 (3.4) 7.4 (3.8) -- Shapes (of 20) 3.9 (2.5) 5.9 (3.1) -- Total (of 85) 13.9 (9.8) 25.8 (13.9) -- a MABC scorable sample size for each assessment indicated as (n = [n ZIKV-exposed], [n controls]) b Student’s t-test (p <0.05) c Mann-Whitney U test (p <0.05) d nonparametric data represented as (median [IQR]) Abbreviations: BSRA: Bracken School Readiness Assessment; MABC: Movement Assessment Battery for Children Impact Preschool neurodevelopmental outcome in children with in-utero Zika-virus exposure is not yet known, since the Zika virus epidemic occurred in 2015–2017 and these children are only now entering school age. 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PMC010xxxxxx/PMC10232675.txt	==== Front 0100714 6400 Pediatr Res Pediatr Res Pediatric research 0031-3998 1530-0447 36456690 10.1038/s41390-022-02399-9 nihpa1851388 Article Associations between socioeconomic gradients and racial disparities in preadolescent brain outcomes Isaiah Amal 12* Ernst Thomas M. 345 Liang HuaJun 3 Ryan Meghann 3 Cunningham Eric 3 Rodriguez Pedro J. 3 Menken Miriam 3 Kaschak Dianne 3 Guihen Ciara 3 Reeves Gloria 6 Lever Nancy 6 Edwards Sarah M. 6 Chang Linda 3457* 1 Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, MD 21201 2 Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD 21201 3 Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD 21201 4 Department of Medicine, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96813 5 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205 6 Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21201 7 Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201 Author contributions: Dr. Isaiah conceptualized and designed the study, performed statistical analysis, drafted the initial manuscript, and reviewed and revised the manuscript. Drs. Chang, Cloak, and Ernst conceptualized and designed the study, the data collection instruments, supervised data collection, and reviewed and revised the manuscript. Drs. Edwards, Liang, Lever, and Reeves; Ms. Guihen, Kaschak, Ryan, and Mr. Rodriguez performed data collection, and critically reviewed and revised the manuscript for important intellectual content. * Contributed equally as co-senior authorsCorrespondence to: Amal Isaiah, MD, PhD, Departments of Otorhinolaryngology—Head and Neck Surgery and Pediatrics, University of Maryland School of Medicine, 16 S Eutaw St, Ste 500, Baltimore, MD 21201, United States of America, Phone: 410-328-5837, aisaiah@som.umaryland.edu 8 1 2023 01 12 2022 01 6 2024 10.1038/s41390-022-02399-9http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms Objective: To determine the extent to which socioeconomic characteristics of the home and neighborhood are associated with racial inequalities in brain outcomes. Methods: We performed a cross-sectional analysis of the baseline dataset (v.2.0.1) from the Adolescent Brain and Cognitive Development Study (ABCD). Cognitive performance was assessed using the National Institutes of Health Toolbox (NIH-TB) cognitive battery. Standard socioeconomic indicators of the family and neighborhood were derived from census-related statistics. Cortical morphometric measures included MRI-derived thickness, area, and volume. Results: 9,638 children were included. Each NIH-TB cognitive measure was negatively associated with household and neighborhood socioeconomic characteristics. Differences in cognitive scores between Black or Hispanic children and other racial groups were mitigated by higher household income. Most children from lowest-income families or residents in impoverished neighborhoods were Black/Hispanic. These disparities were associated with racial differences in NIH-TB measures and mediated by smaller cortical brain volumes. Conclusion: Neighborhood socioeconomic characteristics are associated with racial differences in preadolescent brain outcomes and mitigated by greater household income. Household income mediates racial differences more strongly than neighborhood-level socioeconomic indicators in brain outcomes. Highlighting these socioeconomic risks may direct focused policy-based interventions such as allocation of community resources to ensure equitable brain outcomes in children. ==== Body pmcBackground Different levels of prosperity confer varied experiences for brain development.1 Maladaptive processes in the brain are linked proximally to exposures associated with the household (e.g., household income) and more distally from neighborhood-level characteristics (e.g., crime). Given that race and socioeconomic status are potentially confounded in their associations with public health outcomes in the United States,2 dissecting these relationships illuminate avenues for economic and social justice interventions.3 Recent neuroimaging studies facilitated a better understanding of the associations between environmental influences and children’s brain structure.4 However, the effects of socioeconomic status on brain structure and function may be non-uniform across racial/ethnic groups.5,6 Therefore, isolating specific socioeconomic characteristics of the household and community that contribute to brain-related outcomes could address the gaps in our understanding of the sequelae of racial inequalities.7 The Adolescent Brain and Cognitive Development (ABCD) Study is the largest study of brain development in children to date.8 Using the baseline dataset, we sought to identify the specific socioeconomic characteristics of household and community associated with potential adverse brain outcomes. Methods Research Sample We used the baseline ABCD dataset v.2.0.1 collected from 11,875 9–10-year-old ‘typically-developing’ children from 21 sites throughout the United States (https://abcdstudy.org/study-sites). The study was approved by the central Institutional Review Board (University of California, San Diego), with reliance from local institutions. We accessed the data from the National Institutes of Mental Health Data Archive following a data use agreement. The recruitment strategy replicated a multi-stage probability sample derived from a national distribution of the enrolled sites, and the children were primarily recruited from local schools.9 The sample size ensures adequate power to detect small to medium effects for exploratory analyses while accounting for ~10% attrition over the study duration.9 Race and ethnicity were self-selected with potential overlap in the original ABCD study. We used the same categorization, which has also been utilized in other ABCD studies that combined race and ethnic groups. Cognitive Assessments The National Institutes of Health Toolbox for Assessment of Neurological and Behavioral Function® (NIH-TB) cognitive battery, administered on an iPad, included seven test modules within the domains of executive function, episodic visual memory, immediate verbal recall, language, processing speed, working memory, and cognitive control/attention.10 Full descriptions of the tasks were published.10,11 The current study included uncorrected scores from the Oral Reading Recognition test and the composite outcomes Fluid Composite (from the Flanker, Dimensional Change Card Sort, Picture Sequence Memory, List Sorting, and Pattern Comparison tests), Crystallized Composite (Picture Vocabulary and Oral Reading Recognition tests) and Total Cognition Composite (from all seven domains). Magnetic resonance imaging Unless contraindicated, children underwent magnetic resonance imaging (MRI) using a Siemens Prisma® (Siemens Medical Solutions, Malvern, PA), General Electric Discovery™ MR750 (GE Healthcare, Chicago, IL), or Philips Achieva (Koninklijke Philips, Amsterdam, Netherlands) scanner. Standard adult coils provided high resolution images harmonized using the following settings: T1-weighted: MP-RAGE with 256×256 matrix size, 176 slices, 1 mm resolution in all axes, TR=6.31 ms, TE=2500 ms and TI=1060 ms; flip angle=8 deg; 2-fold parallel imaging; multiband off.12 Cortical thickness, area, and volume were calculated using a Freesurfer-based pipeline13 using the Destrieux atlas,14 which parcellated 74 cortical and subcortical brain regions/hemisphere. Cortical effect size maps were generated using Nilearn.15 Area Deprivation Index (ADI) and related neighborhood indices ADI ranks a census block using the theoretical domains of income, education, employment, and housing quality. Originally created by the Health Resources and Services Administration, these parameters were extended to the Census-block level by Kind et al.16 ADI percentile score ranks a neighborhood according to the American Community Survey data (2011–2015). The ABCD dataset also includes measures of housing, unemployment, education, and income. Due to collinearity (Fig. S1), we applied a feature selection algorithm using the approach of Zuber and Strimmer17 that orders the predictors using the empiric Correlation-Adjusted coRelation (CAR) scores that canonically orders predictors. Statistical Analysis All analyses were carried out in R version 3.6 (https://cran.r-project.org/) using packages lme4 (version 1.1) for mixed effects models, emmeans for estimation of marginal effects (version 1.4), lavaan (version 0.6) for fitting mediation models, and ggplot2 (version 3.3) for plotting. Linear Mixed Effects Models The format of the mixed effects models pre-specified for ABCD analysis is: Outcome=predictor+covariates+(1∣site or scanner ID/family ID)+ϵ The mixed effects models incorporate the random effects (1\|site/family ID) arising from the recruitment sites, scanners, and a nesting term for family ID to account for siblings; the error term, ϵ, accounts for subject-level variability. The fixed effects included age, the biological sex at birth, and the approximate years of parental education. Pre-tax income classes were stratified to <$50,000, $50,000-$100,000, and >$100,000. The contribution of each predictor was assessed by measuring the change in proportion of variance (R2) through the addition of the variable to the baseline, covariates-only model. The 4 NIH Toolbox measures and 148 models of cortical parcellations were incorporated into mixed effects models and effect sizes calculated for each. The P values for all cortical morphometric models were corrected for false discovery rate (FDR) of 0.05.18 Marginal effects and pairwise comparisons were calculated following Tukey adjustment. Test statistics for all mixed effects models are provided in Data files 1-3. Mediation Analysis Serial mediation analysis used two putative mediating variables representing intermediate pathways for racial differences in cognitive and brain structural outcomes. The mediator, m1, was represented by total pre-tax household income, a proximal estimate of financial security. The variable, m2, included five neighborhood-derived socioeconomic mediators identified from variable selection. Race was dichotomized. The outcome comprised the 4 NIH-TB scores and 151 cortical volumes using the Destrieux atlas (148 regions and 3 global measures). We hypothesized an overall model in which the predictor first contributes to m1 and subsequently to m2, either via m1 or independently. The serial mediation model implemented using lavaan19 jointly modeled three regression equations as below: m1∼β1(race) m2∼β2m1+(race) cognition∼β1β2m2+m1+d(race)+age+sex+education+site The two indirect effects pathways linked to mediators m1 and m2 are calculated separately as β1 and β2. Model criteria were a Comparative Fit Index of at least 0.9, a Root Mean Square Error of Approximation <0.8, a Tucker Lewis Index >0.95, and a standardized root mean square residual <0.08.20 Age, biological sex at birth, years of education, and enrollment site (or scanner serial number) served as covariates. The parameters extracted from the models meeting the criteria were their coefficients and the multiplicity-adjusted P value. Mediator coefficients were calculated using 1000 bootstrap iterations and comprised an additional comparison of the two mediators. The parameters derived from models meeting these thresholds incorporated the coefficients, the Z value representing the ratio of the coefficients to its standard errors, and the associated P values. Test statistics for mediation models are provided in Data files 4-5. Results Participant Characteristics and Neighborhood Indices Complete datasets existed for 9,638 children aged 9–10 years. More than half (5,297; 55%) were White, 13% (1,272) Black and 20% (1,879) Hispanic (Table 1). Boys comprised slightly more than half (5,064; 53%). Almost a third (2,971; 31%) of the families earned $100,000-$200,000 in annual pre-tax income. The most common category of highest caregiver education status was a college degree (2,819; 29%). Girls performed better than boys on Total Cognition (difference, 0.7 points; 95% CI, 0.3–1.0, P<0.001), especially for Fluid Composite (1.2 points; 95% CI, 0.8–1.6, P<0.001). Five neighborhood socioeconomic indicators were identified by variable selection (Fig. S1). Larger Cortical and Subcortical Brain Volumes predict better Cognitive Performance Each of the NIH-TB scores was predicted by cortical and subcortical volumes (Fig. 1, S2). The total subcortical gray matter volume showed the strongest prediction for the Crystallized Composite score, which represents accumulated knowledge and skills. However, brain volumes showed only weak associations with the Fluid Composite score, which reflects problem solving and reasoning abilities. ADI and Household Income are Associated with Cognitive Performance and Brain Volumes Higher ADI percentile predicted poorer Total Cognition Composite score and smaller total cortical volume in the children from low (<$50,000), middle ($50,000-$100,000), or high income (>$100,000) tiers (Fig. 2A,2B). The moderating impact of household income on the negative associations among ADI ranking, cognitive outcomes (Fig. 2C,D), and cortical volumes (Fig. 2E,F), further illustrates the protective effect of household financial security across all brain outcomes. These observations extend to other neighborhood parameters (Fig. S3). Racial differences in socioeconomic indices and their associations with cognition and brain volumes Racial/ethnic groups were stratified by ADI ranking (Fig. 3A) and household income levels (Fig. 3B). Of the 664 children (6.9%) from the most impoverished neighborhoods (ADI>90th percentile), 482 (72.6%) were Black/Hispanic and only 92 (13.8%) were White. Conversely, three times more White children lived in the most affluent areas (ADI<10th percentile; n=1,297; White, 782 [60.3%]) than Black/Hispanic children (265 [20.4%]). These disparities were also observed for household income, as most White children belonged to households earning over $200,000 in annual pre-tax income (n=1,096; White, 830 [75.7%]; Black/Hispanic, 98 [8.9%]). Conversely, Black/Hispanic children constituted most households earning less than $5,000 (n=343, Black/Hispanic, 275 [80.3%]; White, 98 [8.9%]). These disparities reflected the negative associations between ADI percentile and NIH-TB Total Cognition Composite score (Fig. 3C) and total cortical volume (Fig. 3D). Most Black and Hispanic children comprised the lower bound of the relationships between household income and Total Cognition Composite (Fig. 3E) or total cortical volume (Fig. 3F). Similar exposure-outcome relationships were replicated for Crystallized and Fluid Composite scales (Fig. S4) and extended further to the negative associations of every other neighborhood parameter with cognitive measures, as well as cortical and subcortical volumes (Figs. S5, S6). While higher income families were more likely to reside in more affluent neighborhoods, more Black and Hispanic children live in lower income communities even within the highest household income tier (Fig. S7). The pair-wise comparisons for various racial groups (Fig. S8) demonstrate that these differences were greatest for Black and White children. Higher household income mitigates racial group differences in cognitive test scores While the Total Cognition Composite score was 7.3 points (95% CI, 6.5–8.1 points) lower in Black children compared to White children in the same (<$50,000) income tier, this difference in Composite score diminished by ~40% to 4.4 points (95% CI, 3.0–5.8 points) among children in the highest income tier (>$100,000). Greater household income also attenuated group differences in reading scores, for which the difference of 3.7 points (95% CI, 2.0–4.4 points) between Black and White Children in the lowest income tier was fully offset in the high-income group with a difference of 1.3 points (95% CI, 0.0–2.3 points). Similar income-dependent group differences were also observed between Hispanic and other children. Direct and Indirect Effects of Socioeconomic Indices on Total and Regional Brain Volumes Community and household socioeconomic indicators were compared by determining the change in variance (ΔR2) associated with the addition of each variable to the covariates-only model. The direct effects of ADI percentile, percentage of the population with at least a high school level education, percentage of single parent households, and median household income showed the strongest negative associations with total and regional brain volumes [P<0.001 following adjustment for false discovery (Q)]. These effects, shown in Fig. 4A, were most pronounced for total cortical volume (ΔR2=1.7%, Q<10−37) and regionally for the superior frontal gyrus (ΔR2=1.3%, Q < 10−26), superior temporal sulcus (ΔR2=1.1%, Q<10−21), and middle temporal gyrus (ΔR2 =1.1%, Q<10−21). We used a mediation model to identify the unique contributions of household income and neighborhood indices towards the observed racial differences in regional cortical volumes (Fig. 4B). The superior frontal gyrus demonstrated the greatest regional mediation effect associated with household income (Z=7.48, Q<0.001). Neighborhood-level racial disparities were associated with the volumes of the left cuneus (e.g., % single parent households, Z=7.86, Q<0.001), supramarginal gyrus (% unemployed, Z=6.02, Q<0.001), and right parietooccipital sulcus (% with at least high school education, Z=5.30, Q<0.001). The unique contributions of household income were comparable with neighborhood indices for regional cortical volumes but noticeably stronger for cognitive outcomes (Fig. 4C). Discussion We observed that socioeconomic indices may influence cognitive scores and total and regional brain volumes in the preadolescents enrolled in the ABCD study. Significant neighborhood-level racial disparities were associated with smaller cortical volumes that are involved in multimodal sensory processing, including information integration and comprehension. While household income associations were comparable with neighborhood indices for regional cortical volumes, household income was noticeably stronger for cognitive outcomes, emphasizing a potentially greater role in brain development. These findings also highlight the disadvantage faced by most Black and Hispanic children via their disproportionate associations with lower income and residence in impoverished neighborhoods during a critical period of brain development. While these disparities were ameliorated by rising household income, the Black-White gap in the associations with community socioeconomic hazards persists even within the highest income tier. This residual gap may result from other unmeasured environmental influences such as food insecurity21 and the prevalence of crime.22 Improved cognitive performance in children with larger subcortical and cortical volumes are generally consistent with those found in the Pediatric Imaging, Neurocognition, and Genetics study, in which greater cortical surface area correlated with better cognitive performance on the NIH Toolbox.4 Similarly, another study showed lower cortical volumes in infants predicted greater burden of problem behaviors three years later.23 While one study showed that lower cortical volume may explain as much as 20% of the variance in achievement deficits by children from lower income families,23 in our study, which adjusted for socioeconomic variables, morphometric measures only explained a small proportion of the variance related to cognitive measures, thereby reinforcing a potential greater role of home- and neighborhood-level socioeconomic indicators on brain development. The consistent associations between neighborhood socioeconomic indices and cognitive measures in our study concur with previous reports.7,24–28 Although the negative associations between socioeconomic indicators and brain morphometric measures were attributable primarily to the prefrontal cortex,25 the current study included subcortical structures such as the amygdala and hippocampus that regulate emotional, memory and learning processes. The relative immunity provided by higher household income against adverse brain outcomes even in impoverished neighborhoods could be explained by additional educational resources (e.g., private schools, tutors) and better nutrition accessible by children from wealthier families.23,29 The current study illustrates significant racial disparities in exposure to home- and neighborhood-level socioeconomic indicators in a large preadolescent sample that approximates the racial and socioeconomic diversity of the United States. Due to the sensitivity regarding racial disparity on cognition,30,31 little contemporary research has addressed the relationship between race and brain outcomes. The nature versus nurture debate often triggered much controversy, although the availability of more reliable data on confounders could challenge previous conclusions regarding heritability as being the principal determinant of brain outcomes.32 High-quality evidence has emerged in recent years illuminating findings that delineate the role of socioeconomic factors on brain development. A recent large study based on the UK Biobank comprising over 20,000 adults showed that while genetic effects appear to be stronger in some brain regions (e.g., prefrontal cortex, insula), environmental factors are likely more influential in other brain regions (e.g., cerebellum, lateral temporal).33 Another study that evaluated the role of socioeconomic adversities in brain development, racial influences on the relationship between socioeconomic status and brain outcomes appeared to be negligible;34 however, the limited sample size impacts its generalizability. Brain development in-utero appears to be impacted by socioeconomic status of the mother, which is especially novel, given that imaging of the fetal brain precludes the confounding impact of postnatal exposure.35 Other studies have extended these assessments to relationships among race, socioeconomic disparities, and brain pathology. More recently, children with brain tumors and exposure to greater socioeconomic adversity appeared to perform more poorly over time in multiple cognitive domains following radiotherapy when compared to those exposed to less adversity.36 In the current study, Black and Hispanic children were more likely to reside in impoverished neighborhoods and belong to low-income families, which contributed to the observed racial differences in brain outcomes. Previous studies also demonstrated lower returns for socioeconomic indicators such as parental education and household income among minorities based on the ABCD dataset.37,38 While some of these findings are replicated in the current study, our findings further indicate that higher household income ameliorated racial differences in cognitive assessments. For example, Black-White differences in Reading scores were eliminated by rising household income, supporting the trajectory of income-dependent improvement in the racial differences in cognitive outcomes that parallels the alleviation in economic inequality since desegregation.28 Furthermore, stressful adversities related to the environment are operational via multiple mechanistic pathways; hence, some of these negative brain outcomes may be dominated by exposure to stress.39 We identified several potential mediators related to racial differences in brain outcomes. For the associations between neighborhood-level socioeconomic indicators and brain outcomes, the most pronounced mediation effects were related to the regional volumes of the superior frontal gyrus, superior temporal sulcus, and middle temporal gyrus, which are neural substrates for higher cognitive functions, working memory, language, and multimodal sensory integration.40,41 For household income, the strongest mediation effects spanned the volumes of the left cuneus, the supramarginal gyrus, and the right parietooccipital sulcus, which are brain regions for multimodal sensory processing, information integration and comprehension.42,43,44 These results suggest that household and community resources may impact brain development through different mechanistic pathways. While the current study as well as others illustrate that both socioeconomic status and stress may be influenced by systemic racism creating barriers to education and work opportunities, other factors and causal pathways may exist that additionally propagate ethnoracial cognitive outcomes.39 Our study has several strengths. The common protocol for data collection and central processing of data and harmonization standards minimized the procedural variability. The large and diverse cohort enrolled across the United States enabled evaluation of the socioeconomic variables. The protective effects of household income on brain development in the presence of environmental adversities may also generalize to specific exposures, e.g., lead.45 The persistence of neighborhood-level disparities among Black and Hispanic children following stratification by income tier highlights the need for additional policy-related efforts to ensure equitable brain development and learning opportunities. This study extends prior reports4,25 that described the socioeconomic impact on brain development, by elucidating how this socioeconomic context shapes and contributes to racial differences in brain outcomes. The principal limitation of our study is its cross-sectional nature which cannot imply causal relationships. While reverse causality, i.e., inferior brain outcomes may lead to socioeconomic disparities (social selection), is also possible, the prevailing evidence46 favors the premise of exposure to socioeconomic adversity increases the risk of adverse brain outcomes (social causation), especially in preadolescence.6 This is further supported by the vulnerability of the heritable aspects of brain size and intelligence to environmental stressors via an ensemble of epigenetic mechanisms.47 Second, while these results are derived from a large and diverse sample, the participants were recruited primarily from urban academic institutions; hence, the results may not be generalizable to children from rural areas. The ABCD cohort is also skewed towards over-representation of families with higher household income and education than the national data.48 Third, these children’s past residences or socioeconomic status were not assessed, which may also influence brain outcomes. Fourth, racial and ethnic groups were self-selected and may overlap, be incorrect, or unknown in some instances—categorization of the groups reflected the original variable in the ABCD dataset, which has been used in other studies. Finally, other unmeasured potential confounders arising from both household and neighborhood include, but are not limited to genetic variability, detailed aspects of birth and illnesses that were unlisted in the ABCD dataset, domestic violence, differences in culture, parenting skills, healthcare accessibility, and cost of living. While the current study focuses on the neurobiological aspects of racial differences in brain outcomes in the ABCD dataset, the results also underscore areas for policy-level intervention that could mitigate the observed disparities. Given that the findings are from preadolescents in whom early exposure to adversities may account for some or all the differences, interventions such as public assistance are likely the first line of approach. Results reflecting this have been promising, as shown by the Baby’s First Years study which randomized mothers to receive low or nominal cash gifts.49 Neurobiologically favorable brain activity in brain areas of children detected by electroencephalography demonstrated neuroplasticity and environmental adaptation. These results highlight a promising area of social intervention for improved childhood brain outcomes.50 In addition, there is a strong need to include screening for unaddressed social needs such as housing, employment, education, and food, which could potentially be challenged by increased need for resources for screening and referral.51 Addressing these risk measures could facilitate normative neurodevelopment across the socioeconomic spectrum.52 Conclusions Socioeconomic characteristics of the home and the neighborhood are negatively associated with children’s brain outcomes. Greater household income ameliorates racial differences in brain outcomes in a large, national sample. Household income also mediates racial differences in brain outcomes more strongly than neighborhood-level socioeconomic indicators. While unmeasured confounders could account for some racial differences in brain outcomes, delineation of how household- and neighborhood-level factors interact as shown here provide avenues for policymaking, with the greater goal of more equitable child development. Supplementary Material 1851388_Sup_Data_file_1 1851388_Sup_Data_file_2 1851388_Sup_Data_file_3 1851388_Sup_Data_file_4 1851388_Sup_Data_file_5 1851388_Sup_Info Acknowledgments Data used in the preparation of this article were obtained from the Adolescent Brain Cognitive DevelopmentSM (ABCD) Study (https://abcdstudy.org), held in the NIMH Data Archive (NDA). This is a multisite, longitudinal study designed to recruit more than 10,000 children age 9–10 and follow them over 10 years into early adulthood. The ABCD Study® is supported by the National Institutes of Health and additional federal partners under award numbers U01DA041048, U01DA050989, U01DA051016, U01DA041022, U01DA051018, U01DA051037, U01DA050987, U01DA041174, U01DA041106, U01DA041117, U01DA041028, U01DA041134, U01DA050988, U01DA051039, U01DA041156, U01DA041025, U01DA041120, U01DA051038, U01DA041148, U01DA041093, U01DA041089, U24DA041123, U24DA041147. A full list of supporters is available at https://abcdstudy.org/federal-partners.html. A listing of participating sites and a complete listing of the study investigators can be found at https://abcdstudy.org/consortium_members/. ABCD consortium investigators designed and implemented the study and/or provided data but did not necessarily participate in analysis or writing of this report. This manuscript reflects the views of the authors and may not reflect the opinions or views of the NIH or ABCD consortium investigators. The ABCD data repository grows and changes over time. The ABCD data used in this report came from 10.15154/1523037. Instructions on how to create an NDA study are available at https://nda.nih.gov/training/modules/study.html). Financial Support: The ABCD Study® is supported by the National Institutes of Health and additional federal partners under award numbers U01DA041048, U01DA050989, U01DA051016, U01DA041022, U01DA051018, U01DA051037, U01DA050987, U01DA041174, U01DA041106, U01DA041117, U01DA041028, U01DA041134, U01DA050988, U01DA051039, U01DA041156, U01DA041025, U01DA041120, U01DA051038, U01DA041148, U01DA041093, U01DA041089, U24DA041123, U24DA041147. A full list of supporters is available at https://abcdstudy.org/federal-partners.html. Figure 1. Associations between cortical morphometric variables and cognitive outcomes. (A-D) show the relationship between total cortical volume and predicted cognitive outcomes measured by the National Institutes of Health Toolbox,™ including the composite measures of Total Cognition, Crystallized and Fluid, and the additional outcome measure of Reading. As cortical volume is the product of cortical surface area and thickness, most of the variance in these relationships was accounted for by total cortical surface area (E-H) with minimal to no contribution from the average cortical thickness (I-L). The color gradient of the hexagonal bins is proportional to the number of childrefor a given predictor-outcome combination. The model fit was measured by the change in overall variance (R2) following addition of the predictor variable to the baseline, covariates-only mixed effects model that included age, sex, education and the family ID nested within the scanner serial number. * < 0.0001; < 0.001; * < 0.05 Figure 2. Socioeconomic indices are negatively associated with cognitive performance and total cortical volume in preadolescents (n = 9,638). (A) Higher Area Deprivation Index (ADI) percentile, a composite measure of neighborhood disadvantage, predicted lower Total Cognition Composite score, derived from the National Institutes of Health Toolbox™ (NIH-TB) in the Adolescent Brain Cognitive Development Study. (B) Greater ADI percentile ranking also predicted lower cortical gray matter volume. The size of the bubbles represents the proportion of children within each income tier and stratified by ADI decile. Low, middle- and high-income groups in the ABCD study earn less than $50,000, $50,000 to $100,000, and more than $100,000, respectively. Both models incorporate the predicted marginal values from a multilevel model incorporating age, sex, and the caregiver’s education as fixed effect covariates. The site and scanner serial number are included as random effects while nesting the family ID. The gray shading represents the 95% confidence interval for the predicted relationship. The model fit is shown by the change in the proportion of variance (R2) by addition of the predictor variable to the baseline, covariates-only model. (C) and (D) represent the magnitude of the relationship between each predictor (vertices) and NIH-TB outcomes using the same mixed effects models for low- and high-income groups, respectively. (E) and (F) demonstrate the relationship between the same predictors and brain morphometry outcomes for low- and high-income groups. Abbreviations: % ≥ HS, the percentage of the population with at least high school education; % Unemp, the unemployed civilian labor force aged ≥ 16 years. Figure 3. Racial differences in associations between neighborhood disadvantage and brain outcomes. (A) shows a proportional area plot demonstrating the percentage of children within each racial or ethnic group categorized as White, Black, or Hispanic, and Other for each level of Area Deprivation Index (ADI) percentile ranking. (B) similarly demonstrates the stratified representation across income deciles. Black and Hispanic children were more likely to be resident in the most deprived neighborhoods while their families earned the lowest. (C) represents the relationship between ADI percentile ranking and the predicted marginal values of the National Institutes of Health Toolbox™ (NIH-TB) Total Cognition Composite score with the race/ethnicity highlighted in color. (D) shows the relationship between ADI percentile and predicted total cortical volume. (E) shows the relationship between log-transformed total pre-tax household income and the predicted NIH-TB Total Cognition Composite score, while (F) demonstrates similar relationship between household income and total cortical volume. All models incorporate both fixed (age, sex, and parental education level) and random effects (family ID nested within each site for the NIH-TB scores or within each scanner for total cortical volumes). Figure 4. Comparison of the direct and indirect effects from mediation models of associations between socioeconomic indices and regional brain volumes. (A) shows the direct effect measured by the change in overall variance (R2) in regional cortical volume following addition of the socioeconomic variable to the covariates-only model containing age, sex, race and education as fixed effects, and scanner as a random effect (Q<0.001). The strongest and most widespread negative associations were between household income and regional cortical volumes. (B) compares the averaged indirect effects of household income and neighborhood indices associated with racial differences in regional cortical volumes. The effect size maps average the critical Z values associated with the neighborhood and household income mediation effects following incorporation of the degrees of freedom for the mediation models. The regional effects are shown by the Z value for each region of interest following incorporation of a threshold for criticality based on the degrees of freedom and Q<0.001. Race was coded as Black/Hispanic versus others. Prominent regional effects are labeled. The outline of the mediation framework for the assessment of the contribution of two indirect effects to the racial disparities (Black or Hispanic versus others) in National Institutes of Health Toolbox™ (NIH-TB) composite measures and cortical volumes (regional and total). (C) shows split violin plots compare the kernel densities of magnitudes of the mediation effects (β) and Z scores (Z) of neighborhood characteristics (orange) with that of household income (magenta) on 148 regional cortical volumes derived from the Destrieux atlas (cortical) and 4 NIH-TB (cognitive) scores. While the two mediation effects were similar for regional cortical volumes, the household income was a stronger mediator of racial inequalities in cognitive outcomes. SFG, superior frontal gyrus; STG, superior temporal gyrus; SFG, superior frontal gyrus. Table 1. Baseline characteristics of the Adolescent Brain Cognitive Development Study (v2.0.1, n = 9,638). Categorical variables are described by number (%) and continuous variables by mean (standard deviation). Sex refers to the biological sex at birth. Race/ethnicity was self-selected by the primary caregiver. Variable Value Age (months) 119.0 ± 7.5 Sex Female 4574 (47.5) Male 5064 (52.5) Race/ethnicity White 5297 (55.0) Black 1272 (13.1) Hispanic 1879 (19.5) Asian 187 (0.2) Other 1003 (10.4) Total household income before taxes (US Dollars) < 5,000 343 (3.5) 5,000–12,000 369 (3.8) 12,000–16,000 240 (2.5) 16,000–25,000 456 (4.7) 25,000–35,000 583 (6.1) 35,000–50,000 823 (8.5) 50,000–75,000 1344 (13.9) 75,000–100,000 1413 (14.7) 100,000–200,000 2971 (30.8) >200,000 1096 (11.4) Highest education status of the caregiver < High school graduate 384 (4.0) High school graduate 728 (7.6) High school/General Educational Development 931 (9.7) Some college/associate 2819 (29.3) Bachelor’s degree 2817 (29.3) Master’s degree 1948 (20.1) Professional/doctoral degree 623 (6.5) Impact: Neighborhood socioeconomic characteristics are associated with racial differences in preadolescent brain outcomes and mitigated by greater household income. Household income mediates racial differences more strongly than neighborhood-level socioeconomic indicators in brain outcomes. Highlighting these disparities related to socioeconomic risks may direct focused policy-based interventions such as allocation of community resources to ensure equitable brain outcomes in children. Category of Study: Original Research—Population Study Conflict of interest: The authors have no conflicts of interest relevant to this article to disclose. Consent statement: The study protocol was approved by the local as well as the constituent member Institutional Review Boards of the ABCD study. Parents of all children gave written consent to participate in the study. ==== Refs References 1. Shonkoff JP , Boyce WT , McEwen BS . Neuroscience, molecular biology, and the childhood roots of health disparities: building a new framework for health promotion and disease prevention. JAMA. 2009 Jun 3;301 (21 ):2252–9.19491187 2. 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PMC010xxxxxx/PMC10238677.txt	==== Front 0100714 6400 Pediatr Res Pediatr Res Pediatric research 0031-3998 1530-0447 36463364 10.1038/s41390-022-02404-1 nihpa1851387 Article Prematurity associated wheeze: Current knowledge and opportunities for further investigation Crist Anna P. 12 Hibbs Anna Maria 13 1 Rainbow Babies and Children’s Hospital, Cleveland, OH 2 Cleveland Clinic Children’s, Cleveland, OH 3 Case Western Reserve University School of Medicine, Cleveland, OH Author Contributions: APC drafted and revised the article. AMH contributed to conception, revisions, and final approval of the published version. Corresponding author: Anna Crist, Cleveland Clinic Children’s Department of Neonatology, Mail Code M31, 9500 Euclid Avenue, Cleveland, OH 44195, 216-440-7912, crista@ccf.org 5 12 2022 03 12 2022 03 6 2024 10.1038/s41390-022-02404-1http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms Prematurity-associated wheeze is a common complication of preterm birth, with significant impact on the health and healthcare utilization of former preterm infants. This wheezing phenotype remains poorly understood and difficult to predict. This review will discuss the current state of the literature on prematurity associated wheeze. We will discuss etiology and pathophysiology, and offer two conceptual models for the pathogenesis of this complex condition. This review will also identify current methods of ascertainment, and discuss the strengths and limitations of each. We will explore research-backed approaches to prevention and management, and finally suggest both pre-clinical and clinical avenues for investigation. An in-depth understanding of prematurity-associated wheeze will aid clinicians in its diagnosis and management, and inspire scientists to pursue much-needed further study into causes and prevention of this common and impactful condition. ==== Body pmcIntroduction Prematurity has long been recognized to affect lung function throughout childhood and into preteen years1–3. Literature in the post-surfactant era has described a high incidence of long-term respiratory morbidity in infants with and without a diagnosis of BPD, including moderate and late preterm infants1,3–6. In these infants, wheezing is a dominant respiratory symptom throughout early childhood7. In 2021, around 10% of births – over half a million infants – were preterm8. Rates of recurrent wheeze within the first year of life vary from 19% in moderate to late preterm infants to as high as 56% of extremely preterm infants9–12. Recurrent early childhood wheeze is associated with significant healthcare costs6,13, and respiratory complications account for the plurality of healthcare utilization in the first years of life in preterm infants5,14,15. Despite the prevalence and socio-economic impact of prematurity-associated wheeze, it remains a poorly understood phenotype. The etiology and pathophysiology of wheeze, as well as environmental influences and approaches to prevention, are subject to ongoing research. Ascertaining prematurity-associated wheeze can be nebulous, and methods of ascertainment are largely limited to questionnaire-based assessment in both clinical and research settings. Long term outcomes are difficult to predict as the prematurity-associated wheeze phenotype shares features with both asthma and bronchopulmonary dysplasia but does not necessarily progress into asthma or other long-term respiratory morbidity. As recognition for the impact of prematurity-associated wheeze grows, so do opportunities for further investigation into this morbidity that affects tens of thousands of children nationwide. Epidemiology and Etiology Wheeze is a common prematurity-associated respiratory morbidity. The association between gestational age and childhood wheeze was recognized in the early 1990s16,17. In the first published prospective study of wheezing in very preterm infants, Elder et al. (1996) found a 14.5% incidence of wheeze requiring bronchodilator treatment within the first year of life, as compared to 3.2% in a term control group18. A 2014 meta-analysis by Been, et al found that preterm infants are more likely to experience wheeze than term infants, with an odds ratio of 1.71 (CI 1.57–1.87)1. Similarly, in a retrospective analysis of a population-based birth cohort study, Kotecha et al. identified an odds ratio of 1.6 for early wheeze in preterm as compared to term infants3. The pathophysiology and risk factors behind prematurity-associated wheeze can be summarized through two distinct but not mutually-exclusive conceptual pathways (figure 1). In the first “lung injury” pathway, wheeze is part of a process that begins with a premature lung and subsequent injury to that lung, followed by a period of recovery that is characterized by persistent but gradually improving clinical lung disease, one symptom of which is prematurity-associated wheeze. In an alternative pathway, there need not be any initial clinically apparent lung injury. Instead, wheeze is a result of ongoing, often silent, developmental perturbations that cause a change in the developmental trajectory of the lung. Both pathways account for a number of risk factors for prematurity-associated wheeze, which are summarized in Table 1. Lung Injury The causal pathways for prematurity-associated wheeze are complex, and many of the most well-described associations in the existing literature support a “lung injury” model of prematurity-associated wheeze. Infants born preterm, particularly during the canalicular or early saccular stages of lung development, experience subsequent impaired alveolar development resulting in alveolar simplification19. Birth at these early stages of lung development may contribute to a later wheezing phenotype. Been, et al. demonstrated a dose-dependent effect of gestational age on wheeze, with a 6% decrease in odds of wheeze for each additional week increase in gestational age up to 40 weeks1. Immature lung parenchyma alone, however, likely does not explain the entire picture of prematurity-associated wheeze. The sequelae of preterm birth, including positive pressure ventilation, hypoxic and hyperoxic stress, and infection and inflammation, result in increased airway reactivity via alterations in lung parenchyma, neural pathways, and smooth muscle function20,21. Indeed, infants with a diagnosis of BPD, a condition pathologically characterized by large, simplified alveoli, dysmorphic capillaries, and interstitial fibroproliferation19, may be at an independently increased risk for later asthma and wheeze7,22,23. In the PROP study, Keller et al. demonstrated an association between severity of BPD and post-prematurity respiratory disease (PRD, a composite respiratory outcome), but noted that BPD was imperfectly predictive of this outcome – 40% of infants with no or mild BPD experienced PRD, and 21% of infants with BPD had no PRD22. Thus, mechanisms beyond BPD alone likely explain premature infants’ predisposition toward wheeze. Maternal chorioamnionitis has been implicated as a mediator of wheeze. Dessardo et al. (2017) found that the histologic finding of maternal chorioamnionitis, especially when associated with fetal inflammatory response syndrome (FIRS), was associated with increased odds of early childhood wheeze (OR 5.63, 95% CI 2.42–13.05)24. However, in term infants, chorioamnionitis is not associated with later wheeze25, suggesting that the development of the preterm lung is especially vulnerable to derangement in the setting of inflammation. Ventilator-associated lung injury contributes to inflammation and airway remodeling, and has long been implicated in prematurity-associated respiratory morbidity. Multiple pre-clinical models of barotrauma have demonstrated interruptions to the lung interstitium leading to subsequent inflammation and airway remodeling21. Recent advances in non-invasive mechanical ventilation have greatly reduced such ventilator-associated lung injury. However a 2017 longitudinal follow-up study by Doyle, et al. showed no improvement in oxygen requirement at 36 weeks corrected PMA, and worsened FEV1 at 8 years of age when comparing a 2005 cohort of infants to earlier cohorts who had received more invasive ventilation26. In a mouse model, one week of CPAP exposure increased airway reactivity as compared to unexposed controls27. Thus, although non-invasive ventilation is undoubtedly a boon to the respiratory health of the preterm population, its effects on prematurity associated wheeze remain uncertain, and may have long term consequences that are not yet fully understood. Hyperoxia likely contributes to increased airway smooth muscle reactivity. Preterm infants encounter a number of hyperoxic exposures in the NICU, largely iatrogenic in nature. A number of animal models suggest that hyperoxia leads to dysregulation of smooth muscle neuroepithelial function, resulting in excessive airway constriction21. In vivo models of fetal airways demonstrate that hyperoxia may also lead to airway remodeling via increased extracellular matrix deposition and proliferation of airway smooth muscle28,29. Interestingly, a mouse model of mild (40% FiO2) versus severe (70% FiO2) hyperoxia demonstrated that only mild hyperoxia was associated with an increase in methacholine-induced airway hyperreactivity30. Conversely, intermittent hypoxia has also been implicated as a contributor to prematurity-associated wheeze. In translational models, mouse models of alternating hypoxia followed by hyperoxia result in airway hyperreactivity in excess of that caused by hyperoxia alone31. These models have a clinical correlate in the episodes of hypoxia followed by over-correction and mild to moderate rebound hyperoxia that have been demonstrated to occur in the NICU setting32. Overall, preterm infants are vulnerable to episodes of hypoxia and hyperoxia, and both factors likely contribute to airway hyperreactivity and wheeze. One retrospective cohort study found that children receiving asthma medications at two years of age were exposed to both higher cumulative oxygen in the first three days of life, and had more frequent intermittent hypoxemic events33. Prospective studies have associated high cumulative oxygen exposure within the first three days of life with increased symptomatic airway disease at twelve months corrected gestational age both in VLBW infants without BPD and ELBW infants with and without BPD34,35. Developmental Perturbation It has become increasingly clear that even moderate and late-preterm infants experience significant alterations in lung function that influence respiratory morbidity later in life5,11,36–38. The prevalence of wheeze in moderate and late preterm infants, including those with minimal to no clinically apparent lung disease at birth, suggests a “developmental perturbation” model of prematurity-associate wheeze in which early exposures continue to affect lung growth and function long after birth hospitalization. Literature suggests that premature infants without BPD, including those born moderately- or late-preterm, are at increased risk of early childhood wheeze1,36,39. For example, Been, et al. (2014) found that moderate preterm infants are more likely to wheeze than term infants, with an adjusted odds ratio of 1.37 (95% CI 1.17–1.62)1. Pulmonary function studies in moderate and late-preterm infants have demonstrated alterations in lung function even in infants without clinical lung disease at birth. McEvoy, et al. (2013) found that term-corrected infants born at 33–36 weeks without clinical lung disease had increased airway resistance, reduced compliance, and lower expiratory flow ratio than term matched controls37. These early perturbations in lung function may represent sequelae of exposures prior to and during birth hospitalization, such as maternal smoking, oxygen exposure at delivery, and treatment with microbiome-altering therapies. Viral illness, particularly respiratory syncytial virus (RSV), has been identified as a contributor to prematurity-associated wheeze. Premature infants are both more susceptible to contracting RSV and more likely to develop wheeze as a consequence – a “two hit” model in which both factors together contribute to the ultimate outcome of wheeze40. One study of infants enrolled in the Prematurity and Respiratory Outcomes Program (PROP) found that some infants born less than 29 weeks retain a “fetal” immunologic phenotype characterized by persistently low CD31+CD4+ T-cells. This arrest in immune maturation is associated with a 3.5-fold increase in post-prematurity respiratory disease, and may increase vulnerability to post-discharge respiratory morbidity including RSV41. In one prospective cohort of healthy preterm infants born at 32–35 weeks, children who were hospitalized with RSV during infancy demonstrated four-fold adjusted odds of wheeze at the age of six42. Observational studies such as this are unable to distinguish whether RSV is a direct causal factor in prematurity associated-wheeze, or simply the initial wheezing trigger in infants with an underlying predisposition to wheeze. However, trials of RSV prevention seem to suggest that the former is true. In a randomized placebo-controlled trial of palivizumab prophylaxis versus placebo, palivizumab treatment reduced total wheezing days by 61% in healthy preterm infants. The authors hypothesized that RSV causes direct pulmonary epithelial damage as well as alterations in immune-response patterns leading to long-term airway hyperresponsiveness43. Environmental exposures may also play a role in the development of prematurity-associated wheeze. In a prospective study by Robison, et al., maternal smoking during pregnancy was associated with nearly four-fold odds of recurrent wheeze in premature infants (OR 3.8, 95% CI 1.8–8.0) but not in term infants. Postnatal secondhand smoke exposure also has an impact – another prospective study of VLBW infants found that living with a smoker was associated with increased likelihood of needing acute care for wheeze or trouble breathing by 12 months corrected gestational age, with an adjusted odds ratio of 2.62 (95% CI 1.22–15.94). The same study identified exposure to pests as a risk factor for needing acute care for respiratory illness (OR 4.41, 95% CI 1.22–15.94)44. These exposures, as with RSV, likely follow a “two-hit” model of disease. Several other environmental pollutants, including benzene, SO2, nitrogen oxides, and CO, have been associated with asthma exacerbations in term children but not in premature infants specifically45–47. It has not yet been determined whether the effects of these exposures might be amplified in the vulnerable preterm lung, or whether they are associated with prematurity-associated wheeze. Finally, social determinants of health, including racial disparities, appear to affect the lung health of preterm infants. In one retrospective analysis of 400 extremely low gestational age infants, infants of Black mothers had nearly three-fold odds of wheeze compared to infants of non-Black mothers (OR 2.9, 95% CI 1.9–4.5)48. In the PROP cohort, extremely preterm Black infants were found to have a lower rate of BPD than white infants but paradoxically had a higher rate of post-prematurity respiratory disease in the first year of life22,49. Moreover, Black infants are 50% more likely to be born preterm than non-black infants50. A 1997 study by David and Collins demonstrated that the incidence of low-birth weight infants of U.S. born Black women was nearly twice that African-born black women, whose birth-weight patterns were more closely related to U.S. born white women51. These groundbreaking findings indicated that effect of Black race on preterm birth rate is unlikely to be genetic; but may instead represent an accumulation of unmeasured environmental influences such as racial discrimination, institutionalized segregation, education gaps, and income inequality, as well as increased toxic exposures and environmental stress that ultimately lead to worsened birth outcomes for Black infants52. Ascertainment of wheeze Research on prematurity-associated wheeze requires sensitive and specific methods of ascertaining wheeze and airway reactivity in a preterm-born population. There is variability in the definition of prematurity-associated wheeze amongst existing literature, with some studies relying on parent-completed questionnaires, physician report, or asthma diagnosis for outcome ascertainment1. Questionnaire-based assessment of wheeze is commonly used and convenient. Studies in both term-born and preterm infants routinely use the phrase “wheezing or whistling in the chest,” which is used in questionnaires such as the American Thoracic Society (ATS) child questionnaire and the International Study of Asthma and Allergies in Children (ISAAC) 53,54. This definition of wheeze, along with parental reports of medically attended respiratory illnesses and medications prescribed, is routinely used in multi-center NHLBI trials such as D-WHEEZE, SUPPORT, and NO-CLD to characterize long-term respiratory outcomes in preterm infants9,55,56. Boggs, et al. demonstrated good test-retest reliability and convergent validity for a number of questionnaire items including “wheezing or whistling in the chest” in a cohort of preterm infants without BPD57. Infant pulmonary function testing has increasingly been used in research settings to assess lung function and predict later respiratory outcomes. Such testing has been well validated and standardized by the ATS and European Respiratory Society (ERS)58–60. Unfortunately, many forms of pulmonary function testing in infants require sedation and/or highly specialized equipment, making it difficult to access outside of research settings, and impractical for largescale clinical use or epidemiological studies61. Spirometry, for example, despite being a mainstay of diagnosis and monitoring of interventions in pediatric wheeze and asthma62–64, requires sedation and external mechanical compression of an infant’s abdomen and thorax to effectively quantify forced expiratory volumes59. Several non-invasive methods, such as the single-breath occlusion technique, forced oscillometry, and electromagnetic inductance plethysmography, allow for pulmonary function testing in non-sedated infants and have increasingly been employed in the former preterm population37,38,58,61,65,65–70. These methods are particularly useful in exploring mechanisms of prematurity-associated lung disease and assessing degree of fixed airway obstruction. However, these modalities are limited in their ability to capture airway reactivity in prematurity-associated wheeze. Furthermore, infants are preferential nose-breathers with small caliber upper airways, and increase in upper airway resistance precludes measurement of lower airway resistance or lung function during acute viral illness61 – precisely when many infants experience wheezing episodes. Thus, while pulmonary function testing captures valuable information about underlying lung function, it is not a surrogate for of the lived experience of infants with prematurity-associated wheeze. Prevention and Management Prevention of prematurity associated wheeze begins prior to birth and continues throughout infancy. The strategies discussed below are summarized in Table 2. Prenatal Prevention Prevention of preterm birth is the gold standard in decreasing prematurity-associated wheeze and other respiratory morbidities. Approximately one-quarter of preterm births are provider-initiated71. Between 1981 and 2003 there was a notable trend toward increased preterm deliveries, particularly of late preterm infants72, which prompted initiatives toward decreasing iatrogenic preterm deliveries. Between 2004 and 2013, provider-initiated preterm deliveries declined, especially amongst Black mothers73; however, since that time, preterm deliveries have continued to increase, largely driven by late-preterm births71. Causes of spontaneous preterm birth are multifactorial and often overlap with causes of prematurity-associated wheeze; for example, maternal smoking74. Preterm birth is associated with many other modifiable maternal risk factors such as pre-pregnancy weight, smoking, and interpregnancy interval, highlighting the importance of pre-pregnancy provider counseling. Vaginal progesterone is a well-supported intervention to decrease the risk of preterm birth in the setting of short cervix or prior preterm delivery71. Beyond prevention of preterm birth, there are several modifiable prenatal risk factors for prematurity-associated wheeze. Maternal smoking increases preterm birth and increases odds of preterm infants developing BPD (OR 1.16, 95% CI 1.02–1.33)74,75. In one prospective cohort, there was a joint effect of prematurity and maternal smoking on early childhood recurrent wheezing, with an odds ratio of 3.8 (95% CI 1.8–8.0) and a significant interaction between the two factors76. Smoking cessation has been shown to reduce preterm delivery77. For mothers unable to quit smoking during pregnancy, a randomized controlled trial of vitamin C supplementation demonstrated that vitamin C may attenuate some of the negative effects of smoking. Infants whose mothers were randomized to vitamin C supplementation had decreased wheezing by one year of age (RR 0.56, 95% CI 0.33–0.95)78. This study did not examine premature infants specifically; however preterm infants were not excluded. Perinatal interventions Several modern trials aimed at reducing the incidence of BPD have also examined wheezing outcomes. The Breathing Outcomes Study was a prospective secondary trial to the SUPPORT trial56, and found that intubation and surfactant administration offered no protective benefit against wheeze within the first two years of life when compared to early CPAP alone (ARR 0.90, 95% CI 0.68–1.19)79. McEvoy, et al. (2017) examined the impact of a rescue dose of antenatal steroids on respiratory outcomes and found no difference in wheezing frequency in the first year of life (OR 0.65, 95% CI 0.24–1.75)80. Other interventions have suggested improvement in long term pulmonary outcomes. In a 1 year follow-up to the NO CLD trial, infants randomized to receive inhaled nitric oxide received medications for wheezing, but there was no reduction in parental report of wheezing or hospitalization9. In a 2003 study by Davis et al, preterm infants treated with intratracheal recombinant human superoxide dismutase showed a 36% reduction in asthma medication use at 1 year of life as compared to placebo group (p = 0.05), despite no difference in BPD rates81. However, in most of these studies wheezing and other long term respiratory morbidities were secondary outcomes. There is a need for trials of neonatal interventions that directly target prematurity associated wheezing as a primary outcome. Post-discharge considerations Adequate nutrition and growth appear to play a key role in post-natal lung development and prevention of prematurity associated wheeze. In a secondary analysis of data from the Infant Health and Development program, Belfort et al. found an increase in odds of asthma at 8 years of age with increasing BMI from term to 4 months of age82. A retrospective analysis of a Welsh cohort revealed that rapid infant weight gain was associated with increased wheeze in preterm infants (OR 1.22, 95% CI 1.02–1.45) and that this association was especially pronounced in infants less than or equal to 32 weeks gestation (OR 5.04, CI 3.36–7.54)83. In term infants, higher adiposity is associated with increased wheeze84. Thus, providers caring for premature infants should be cautioned against the assumption that “all weight gain is good weight gain”, and breastfeeding should be encouraged, as it has been shown to increase lean mass and decrease adiposity in preterm infants85. There may be additional benefits to breastfeeding in prematurity associated wheeze. Breastfeeding is associated with reduced risk of developing BPD86–88. In a prospective birth cohort study by Oddy, et al., infants who were breastfed for less than six months had two-fold adjusted odds of medically attending wheezing illness as compared to infants who breastfed for more than six months (OR 2.07, 95% CI 1.47–2.90)89. This study, however, did not specifically examine preterm infants. A longitudinal study by Verduci et al. demonstrated a dose-dependent effect of breastfeeding, with a 15% reduction in odds of recurrent wheeze with each month of exclusive breastfeeding90. Few studies have specifically examined breastfeeding and prematurity-associated wheeze. In an analysis of preterm infants in the UK Millenium Cohort Study, Kotecha, et al. found a weak association between any breastfeeding and reduction in early wheeze (OR 0.676, 95% CI 0.457–1.00). The specific effects of breastfeeding on prematurity associated wheeze remain uncertain, but breastfeeding should nevertheless be highly encouraged in this population due to its benefits across multiple organ systems. Vitamin supplementation, particularly vitamin D, may play a role in prevention prematurity-associated wheeze. In a cohort of “healthy” preterm infants without BPD, multivitamin exposure was associated with increased wheeze in Black infants (OR 2.15, 95% CI 0.97–4.75), but decreased wheeze in non-Black infants (OR 0.43, 95% CI 0.19–0.96)10. The D-Wheeze randomized control trial sought to elucidate the effects of vitamin D specifically in Black infants born preterm, and found that sustained vitamin-D supplementation through 6 months corrected age was associated with a reduction in recurrent wheeze as compared to infants randomized to a diet-limited vitamin D supplementation strategy (RR 0.66, 95% CI 0.47–0.94). Immunization and RSV prophylaxis are crucial in preventing viral illnesses that may contribute to prematurity-associated wheeze. Palivizumab is a monoclonal antibody to RSV, and is administered monthly via 5 intramuscular doses given seasonally beginning in November. The most current American Academy of Pediatrics policy recommends palivizumab use in the first year of life in infants less than 29 weeks gestation at birth, infants less than 32 weeks with BPD, and other high risk infants (e.g. those with congenital heart disease and immunocompromised infants) 91. Multiple studies have shown that RSV prophylaxis is associated with reduced odds of early childhood wheeze42,92,93. Unfortunately, the high cost of this medication precludes its use in older preterm infants who are also vulnerable to RSV and subsequent wheeze. Several RSV vaccines still in development, as well as new, more stable monoclonal antibodies, show promise in providing protection against this virus for a larger population of infants94–96. Management Of course, not all prematurity-associated wheeze can be prevented, and in such cases proper management is key. Prematurity-associated wheeze involves mechanisms distinct from atopic wheeze and thus management strategies cannot necessarily mirror those used in asthma and other allergic wheeze. In a study by Baraldi et al. (2005), exhaled nitric oxide concentrations in BPD survivors were much lower than asthmatic controls despite similar degrees of airflow limitation of pulmonary function testing, suggesting absence of the eosinophilic inflammation appreciated in the asthmatic airway97. In the D-Wheeze study of vitamin D supplementation in infancy, Hibbs et al. found low rates of positive antigen panels in both treatment and control groups despite relatively high rates of recurrent wheeze in both groups55. However, a 2018 meta-analysis of 28 studies suggests that preterm infants do exhibit bronchial hyperresponsiveness – more so than their term counterparts - in response to both methacholine challenge and exercise tests98. Moreover, both family and personal history of atopy is associated with increased risk of recurrent wheeze in preterm infants99. Overall, in the absence of clinical evidence of allergic inflammation, it is unclear whether the prematurity-associated wheeze phenotype is responsive to the same medications used to manage allergic asthmatic wheeze. Several clinical studies have explored role of bronchodilators and inhaled corticosteroids in prematurity-associated wheeze. A systematic review of bronchodilator use in former preterm children ages 5 and up showed short-term improvements in FEV1; however, the study authors identified no studies that assessed multiple doses, and only one study that evaluated long-term responsiveness100. Several studies of inhaled corticosteroids suggest little to no effectiveness in prematurity-associated wheeze. One randomized-controlled trial of fluticasone showed no improvement in respiratory symptoms in infants with chronic lung disease, but the study was stopped early due to low recruitment101. Another study of budesonide in school-aged preterm children showed no improvement in respiratory symptoms scores102. Despite questions of efficacy, asthma medications are frequently used in former preterm infants. A questionnaire-based study by Edwards, et al. found that 33.3% of very preterm infants reported use of any inhaler medication, compared to 11.9% of term infants (OR 3.7, 95% CI 2.9–4.7), and that moderately preterm and late preterm infants also had elevated rates of inhaler use (OR 1.8, 95% CI 1.4–2.4; OR 1.8, 95% CI 1.6–3.5, respectively)103. In the PROP cohort of infants less than 29 weeks gestational age, 14.2% reported corticosteroid use and 31% reported active bronchodilator use by 1 year corrected age104. Overall, data on the effectiveness of inhaled medications for treatment of prematurity-associated wheeze are quite limited, and although these medications may be useful in a small subset of patients, they are likely over-prescribed and over-used in the preterm population. Pediatricians caring for former preterm infants should remain vigilant for signs of prematurity-associated wheeze, encourage avoidance of environmental pollutants including second hand smoke, monitor nutrition and growth, promote vaccination and provide synagis referral where applicable, and consider use of asthma medications on an individualized basis with close monitoring for medication response or lack thereof. Outcomes Prematurity-associated wheeze is typically understood to be an affliction of early childhood, but some children may continue to show signs of wheeze well into school-age years. Kotecha, et al. defined four different wheezing phenotypes in a UK cohort of preterm born children: no/infrequent, early, persistent, and late wheeze. Preterm infants demonstrated a predominance of early wheeze (wheeze reported at 3 years or age but disappearing by 7 or 11 years of age), and persistent wheeze (wheeze persisting through 11 years of age), but rates of late wheeze (wheeze developing at 7 years or beyond) were similar to that of term-born children. The wheeze phenotypes of very preterm children were similar to those of late preterm born children3. Prematurity-associated wheeze, though biologically distinct from asthma, may predispose to an asthma diagnosis later in life. A Spanish prospective study identified recurrent wheeze in early childhood as a risk factor for asthma at 8 years of age in late preterm infants105. Similarly, a Finnish cross-sectional study found an association between preterm birth and asthma diagnosis, with a 2-fold higher risk for those preterm infants previously hospitalized with bronchiolitis106. It remains unclear whether prematurity-associated wheeze is predictive of respiratory morbidity in teenage years and adulthood. Adult BPD survivors appear to have increased wheeze and asthma as compared to term controls, as well as reduced exercise tolerance and persistent PFT abnormalities7. However, adult outcomes of infants with prematurity-associated wheeze but no BPD diagnosis have not been studied. Regardless, former preterm adults should follow a standard lung health regimen including exercise, smoking avoidance or cessation, and immunizations. Opportunities for further study As the field of neonatology matures, focus has shifted from optimizing survival to optimizing long-term patient outcomes. The scale and impact – both individually and on a health systems level – of prematurity associated wheeze make it an ideal target for efforts to improve quality of life for former preterm infants. To start, further mechanistic and prevention studies are needed to better understand the mediators of prematurity associated wheeze. How might the neonatologist optimize care in the NICU to mitigate factors that may contribute to future wheeze? The role of non-invasive ventilation in airway reactivity is a potential target for inquiry. Continuous positive airway pressure (CPAP) establishes functional residual capacity, prevents apnea, and reduces need for invasive ventilation in preterm infants with RDS107. However, animal models suggest that CPAP may contribute to airway hyperreactivity27, and, as previously discussed, progression toward non-invasive means of ventilation has not been associated with long-term improvements in FEV126. Both translational models of CPAP administration and prospective clinical trials focused on long-term respiratory outcomes are needed to fully understand the role of CPAP on prematurity-associated wheeze. Similarly, the effects of oxygen exposure are a target for continued research. Pre-clinical models have explored the impact of both hyperoxia and hypoxia, but further mechanistic research is needed. In infants, prospective studies of intermittent hypoxia and hyperoxia are needed to better understand the impact of both exposures. Similarly, randomized controlled trials may aid in determining optimal oxygen titration strategies to avoid either hypoxia or rebound hyperoxia. Attention should also be turned to nutritional support of the preterm infant, specifically the role of human milk in preventing prematurity-associated wheeze. The full extent of human milk’s biologic activity is only beginning to be understood. Components such as cytokines, microbiota, and mRNA may contribute to lung health via immunologic and epigenetic mechanisms that are yet to be described108. Development of better early predictors of prematurity-associated wheeze will aid in mechanistic studies. BPD has long been used as a surrogate for future respiratory morbidity as it is typically diagnosed at 36 weeks post-menstrual age109,110 and is therefore a practical short term study outcome. Although BPD is associated with increased odds of wheeze, there is a sizeable population without BPD that is nevertheless afflicted by prematurity-associated wheeze. Jensen et al. (2019) applied BPD criteria to 2,677 infants in the Neonatal Research Network and found that the “optimal” definition of BPD is indeed associated with long-term outcomes, but that there remains a high degree of respiratory morbidity in the “no BPD” group, and conversely, a large minority of infants with BPD but without wheeze110. In a 2018 systematic review of large, multicenter RCTs by Corwin, et al., the authors found that BPD outcomes did not consistently predict the effect of the studies’ interventions on longer-term outcomes. Therefore, while BPD is undoubtedly an outcome of interest, it falls short in serving as a surrogate for long-term respiratory outcomes. A more sensitive short-term surrogate for long-term respiratory outcomes, especially wheeze, would aid in developing future outcomes studies. Validation and standardization of respiratory questionnaires for evaluation of long-term outcomes in premature infants is an equally important area for further research. Such a tool would also prove useful in the identification and monitoring high-risk premature infants throughout childhood. Conclusion In conclusion, prematurity-associated wheeze is a common respiratory morbidity of prematurity and affects infants with and without clinically apparent lung disease in the neonatal period. While the pathophysiology of wheeze is, in part, due to the lung injury and remodeling typically associated with preterm birth, a growing understanding of the effects of ongoing (and often silent) developmental perturbations points toward a “two hit” model of disease in which a vulnerable lung plus environmental exposures results in the wheezing phenotype. Further research is needed into prediction and ascertainment of prematurity-associated wheeze as well as prevention and management. Funding: AMH receives funding from the NHLBI: K24HL143291 Figure 1: Two conceptual theories for the development of prematurity-associated wheeze. The upper graph represents the “lung injury” model of prematurity-associated wheeze, in which an infant is born with clinically apparent lung disease followed by a period of recovery during which wheeze may manifest. The lower graph represents a “developmental perturbation” model of disease, wherein the infant is born without clinically apparent disease but experiences ongoing perturbations which culminate in a disease state. Table 1: Risk factors for prematurity-associated wheeze Prenatal • Maternal smoking during pregnancy • Chorioamnionitis Postnatal • Gestational age • Intermittent hypoxia • Oxygen exposure • Bronchopulmonary dysplasia Environmental • Respiratory syncytial virus • Secondhand smoke • Pest exposure • Environmental pollutants* Social/Family • Family history of atopy • Maternal Black race * Not studied specifically in preterm infants Table 2: Preventive strategies for prematurity-associated wheeze Prenatal • Primary prevention of preterm birth • Vitamin C in pregnancy for mothers who smoke* Postnatal • Human milk feeding • Adequate growth • RSV prophylaxis • Vitamin D supplementation * Not studied specifically in preterm infants Impact: There is no recent, concise review on the current state of research on prematurity-associated wheeze, which is a rapidly evolving area of study This article highlights causal models of wheeze, methods of ascertainment, management strategies for the clinician, and opportunities for further research for the physician scientist Competing interests: The authors of this study report no competing interests ==== Refs 1. 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Oddy WH Breast feeding and respiratory morbidity in infancy: a birth cohort study. Arch. Dis. Child. 88 , 224–228 (2003).12598384 90. Verduci E , Banderali G , Peroni D , Lassandro C & Radaelli G Duration of exclusive breastfeeding and wheezing in the first year of life: A longitudinal study. Allergol Immunopathol (Madr) 45 , 316–324 (2017).27836323 91. COMMITTEE ON INFECTIOUS DISEASES AND BRONCHIOLITIS GUIDELINES COMMITTEE Updated Guidance for Palivizumab Prophylaxis Among Infants and Young Children at Increased Risk of Hospitalization for Respiratory Syncytial Virus Infection. Pediatrics 134 , 415–420 (2014).25070315 92. Olicker A Have Changing Palivizumab Administration Policies Led to More Respiratory Morbidity in Infants Born at 32–35 Weeks? J Pediatr 171 , 31–37 (2016).26724119 93. Simões EAF The effect of respiratory syncytial virus on subsequent recurrent wheezing in atopic and nonatopic children. J Allergy Clin Immunol 126 , 256–262 (2010).20624638 94. Abbasi J RSV Vaccines, Finally Within Reach, Could Prevent Tens of Thousands of Yearly Deaths. JAMA 327 , 204–206 (2022).34964806 95. Griffin MP Single-Dose Nirsevimab for Prevention of RSV in Preterm Infants. N Engl J Med 383 , 415–425 (2020).32726528 96. Hammitt LL Nirsevimab for Prevention of RSV in Healthy Late-Preterm and Term Infants. N Engl J Med 386 , 837–846 (2022).35235726 97. Baraldi E , Bonetto G , Zacchello F & Filippone M Low Exhaled Nitric Oxide in School-Age Children with Bronchopulmonary Dysplasia and Airflow Limitation. Am J Respir Crit Care Med 171 , 68–72 (2005).15477497 98. Kotecha S , Clemm H , Halvorsen T & Kotecha SJ Bronchial hyper-responsiveness in preterm-born subjects: A systematic review and meta-analysis. Pediatr Allergy Immunol 29 , 715–725 (2018).30014518 99. Simões MCRDS Recurrent wheezing in preterm infants: Prevalence and risk factors. J Pediatr (Rio J) 95 , 720–727 (2019).30031764 100. Kotecha SJ Effect of bronchodilators on forced expiratory volume in 1 s in preterm-born participants aged 5 and over: a systematic review. Neonatology 107 , 231–240 (2015).25721674 101. Beresford MW , Primhak R , Subhedar NV & Shaw NJ Randomised double blind placebo controlled trial of inhaled fluticasone propionate in infants with chronic lung disease. Arch Dis Child Fetal Neonatal Ed 87 , F62–63 (2002).12091296 102. Pelkonen AS , Hakulinen AL , Hallman M & Turpeinen M Effect of inhaled budesonide therapy on lung function in schoolchildren born preterm. Respir Med 95 , 565–570 (2001).11453312 103. Edwards MO Management of Prematurity-Associated Wheeze and Its Association with Atopy. PLoS One 11 , e0155695 (2016).27203564 104. Ryan RM Respiratory Medications in Infants <29 Weeks during the First Year Postdischarge: The Prematurity and Respiratory Outcomes Program (PROP) Consortium. J Pediatr 208 , 148–155.e3 (2019).30857774 105. Morata-Alba J , Romero-Rubio MT , Castillo-Corullón S & Escribano-Montaner A Respiratory morbidity, atopy and asthma at school age in preterm infants aged 32–35 weeks. Eur J Pediatr 178 , 973–982 (2019).31001655 106. Garcia-Garcia ML Impact of Prematurity and Severe Viral Bronchiolitis on Asthma Development at 6–9 Years. J Asthma Allergy 13 , 343–353 (2020).32982322 107. Ho JJ , Subramaniam P & Davis PG Continuous positive airway pressure (CPAP) for respiratory distress in preterm infants. Cochrane Database Syst Rev 10 , CD002271 (2020).33058208 108. Christian P The need to study human milk as a biological system. Am J Clin Nutr 113 , 1063–1072 (2021).33831952 109. Ehrenkranz RA Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 116 , 1353–1360 (2005).16322158 110. Jensen EA The Diagnosis of Bronchopulmonary Dysplasia in Very Preterm Infants. An Evidence-based Approach. Am J Respir Crit Care Med 200 , 751–759 (2019).30995069
PMC010xxxxxx/PMC10239788.txt	==== Front 0100714 6400 Pediatr Res Pediatr Res Pediatric research 0031-3998 1530-0447 36470964 10.1038/s41390-022-02398-w nihpa1849528 Article Risk of seizures in neonates with hypoxic-ischemic encephalopathy receiving hypothermia plus erythropoietin or placebo Glass Hannah C. 23 Wusthoff Courtney J. 45 Comstock Bryan A. 6 Numis Adam L. 12 Gonzalez Fernando F. 2 Maitre Nathalie 7 Massey Shavonne L. 8 Mayock Dennis E. 9 Mietzsch Ulrike 9 Natarajan Niranjana 10 Sokol Gregory M. 11 Bonifacio Sonia L. 12 Van Meurs Krisa P. 12 Thomas Cameron 13 Ahmad Kaashif A. 14 Heagerty Patrick J. 6 Juul Sandra E. 9 Wu Yvonne W. 12 1 Department of Neurology and Weill Institute for Neuroscience, University of California San Francisco, San Francisco, CA 2 Department of Pediatrics; UCSF Benioff Children’s Hospital, University of California San Francisco, San Francisco, CA 3 Department of Epidemiology & Biostatistics; University of California San Francisco, San Francisco, CA 4 Department of Neurology, Stanford University, Palo Alto, CA 5 Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University, Palo Alto, CA 6 Department Biostatistics, University of Washington, Seattle, WA 7 Department of Pediatrics, and Emory + Children’s Pediatric Institute, Emory University, Atlanta GA 8 Departments of Neurology and Pediatrics, Children’s Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 9 Department of Pediatrics, Division of Neonatology, University of Washington School of Medicine, Seattle Children’s Hospital, Seattle, WA 10 Department of Neurology, University of Washington School of Medicine, Seattle, WA 11 Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 12 Division of Neonatal and Developmental Medicine, Stanford University School of Medicine and Lucile Packard Children’s Hospital Stanford, Palo Alto, CA 13 Department of Pediatrics, University of Cincinnati and Division of Neurology, Cincinnati Children’ Hospital Medical Center; Cincinnati, OH 14 Pediatrix Neonatology of San Antonio Author Contributions Kaashif A. Ahmad assisted with study design, as well as data acquisition, analysis, and interpretation; critically revised the manuscript, and approved the final version to be published. Sonia L. Bonifacio assisted with study design, as well as data acquisition, analysis, and interpretation; critically revised the manuscript, and approved the final version to be published. Bryan A. Comstock performed analysis, and interpretation; critically revised the manuscript, and approved the final version to be published. Hannah C. Glass designed the study, assisted with data analysis and interpretation, drafted and finalized the manuscript. Fernando F. Gonzalez assisted with study design, critically revised the manuscript, and approved the final version to be published. Patrick J. Heagerty assisted with study design, and data analysis and interpretation; critically revised the manuscript and approved the final version to be published. Sandra E. Juul assisted with study design, critically revised the manuscript, and approved the final version to be published. Nathalie Maitre assisted with data acquisition and interpretation; critically revised the manuscript, and approved the final version to be published. Shavonne L. Massey assisted with data acquisition, critically revised the manuscript, and approved the final version to be published. Dennis E. Mayock assisted with study design, data acquisition, critically revised the manuscript, and approved the final version to be published. Ulrike Mietzsch assisted with data acquisition, critically revised the manuscript, and approved the final version to be published. Adam L. Numis assisted with study design, as well as data acquisition, analysis, and interpretation; critically revised the manuscript, and approved the final version to be published. Gregory M. Sokol contributed to data acquisition, analysis, and interpretation; critically revised the manuscript, and approved the final version to be published. Cameron Thomas assisted with data acquisition, critically revised the manuscript and approved the final version to be published. Krisa P. Van Meurs assisted with acquisition of data, critically revised the manuscript, and approved the final version to be published. Niranjana Natarajan critically revised the manuscript and approved the final version to be published. Yvonne W. Wu assisted with the study design, analysis, and interpretation of data, critically revised the manuscript, and approved the final version to be published. Courtney J. Wusthoff assisted with study design, as well as with data acquisition, analysis, and interpretation; critically revised the manuscript, and approved the final version to be published. Address correspondence to: Hannah C. Glass, MDCM, MAS, 675 Nelson Rising Lane, Box 0663, San Francisco, CA 94143, Hannah.Glass@ucsf.edu, 415-476-1000 12 11 2022 05 12 2022 05 6 2024 10.1038/s41390-022-02398-whttp://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms Background An ancillary study to the High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial of for neonates with hypoxic-ischemic encephalopathy (HIE) and treated with therapeutic hypothermia examined the hypothesis that neonates randomized to receive erythropoietin (Epo) would have a lower seizure risk and burden compared with neonates who received placebo. Methods Electroencephalograms (EEGs) from 7/17 HEAL trial centers were reviewed. Seizure presence was compared across treatment groups using a logistic regression model adjusting for treatment, HIE severity, center, and seizure burden prior to first dose. Among neonates with seizures, differences across treatment groups in median maximal hourly seizure burden were assessed using adjusted quantile regression models. Results Forty-six of 150 (31%) of neonates had EEG seizures (31% in Epo vs 30% in placebo, p=0.96). Maximal hourly seizure burden after study drug was not significantly different between groups (median 11.4 for Epo, IQR: 5.6, 18.1 vs median 9.7, IQR: 4.9, 21.0 minutes/hour for placebo). Conclusion In neonates with HIE treated with hypothermia who were randomized to Epo or placebo, we found no meaningful between-group difference in seizure risk or burden. These findings are consistent with overall trial results, which do not support Epo use for neonates with HIE undergoing therapeutic hypothermia. ==== Body pmcIntroduction Neonatal encephalopathy due to hypoxia-ischemia, or hypoxic-ischemic encephalopathy (HIE), is the most common cause of seizures in neonates.1,2 Erythropoietin (Epo), long been known as a proerythropoietic agent, has more recently been explored as a neuroprotective agent because of its nonhematopoietic functions including neurotrophic and neuroprotective effects.3 Epo has also been shown to reduce the severity of both acute and late seizures in animal models of HIE.4–7 Despite the anti-convulsant effect of Epo in pre-clinical models of HIE,4–7 the United States Food and Drug Administration (FDA) drug label information for Epo warns of a possible pro-convulsant effect based on older trials in adults with renal disease.8–10 It is unclear whether this warning should apply to neonates, as human neonatal studies were previously limited by small cohort sizes and lack of gold standard continuous video-EEG monitoring (cEEG) to diagnose seizures.11,12 The recent High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) multicenter, randomized trial of Epo vs. placebo for neuroprotection in neonates with moderate/severe HIE who receive therapeutic hypothermia showed no meaningful difference between groups in the rate of death or disability at age two to three years.13 However, the primary study did not assess differences in timing and severity of electrographic seizure burden between study groups. We leveraged the HEAL trial to examine a sub-set of neonates who were evaluated with cEEG throughout cooling and rewarming to examine the hypothesis that neonates who receive Epo have a lower risk and burden of acute provoked seizures after study drug administration as compared to neonates who receive placebo. Methods Study Design. We conducted an ancillary study of the HEAL randomized trial of Epo vs. placebo for neuroprotection in neonates with moderate/severe HIE who received therapeutic hypothermia (NCT02811263)13 to study neurophysiology measures. Epo or placebo treatment was allocated 1:1 and administered at five time points: within 24 hours of birth (day 1), and at days 2, 3, 4, and 7 days after birth at the same time of day. Details of the study protocol have been previously published.14 We included participants enrolled at the seven HEAL enrollment sites (Supplementary Table 1) that performed cEEG throughout cooling and rewarming according to American Clinical Neurophysiology Society (ACNS) guidelines15 as part of routine clinical care. De-identified EEG tracings were collected for central review and inclusion in this ancillary study called HEAL-EEG. The HEAL trial and cEEG data collection were approved by the Institutional Review Board at each participating site and neonates were studied after informed parental consent. Inclusion and Exclusion Criteria. Neonates were eligible if they met all four study criteria: 1) born at ≥36 weeks’ gestation; 2) one or more signs of perinatal depression including Apgar score <5 at 10 minutes; cardiorespiratory resuscitation received beyond 10 minutes of age; pH <7.00 or base deficit ≥15 mmol/L in a cord or infant arterial or venous gas obtained within 60 minutes of age; 3) moderate or severe encephalopathy defined as ≥3 of 6 modified Sarnat criteria present at 1 to 6 hours of age; and 4) passive or active therapeutic hypothermia started within 6 hours of birth. Exclusion criteria were birthweight <1800 grams, head circumference <30 cm, genetic or congenital condition affecting neurodevelopment, hematocrit >65.0%, considering redirection of care, encephalopathy attributed to a postnatal event, guardian with diminished capacity, or unlikely to be followed due to unstable social situation.13,14 Additional HEAL-EEG specific inclusion criteria were: 1) cEEG recorded without interruption throughout cooling and rewarming (except for neonates who died during the neonatal admission), and 2) EEG quality sufficient for interpretation by neurophysiologist review. Measurements. Maternal and neonatal demographics and clinical characteristics were determined based on medical chart review. Timing and dose of antiseizure medication (ASM) administration were extracted from the medication administration record. Seizure treatment agent and timing were determined by the treating physician(s). Encephalopathy was classified as moderate or severe based on the number of abnormal Sarnat elements in the moderate and severe categories; if equal numbers were present, severity classification was decided based on level of consciousness category.14 EEG Acquisition and Interpretation. Continuous EEG was recorded using a minimum of 8 electrodes and 10–20 electrode placement modified for the neonate per local clinical practice. Complete recordings were de-identified and stripped of video, then collected for central review by two board-certified clinical neurophysiologists (ALN and CJW). Files were reviewed in the order they were received for centralized review using Persyst software with neurophysiologists able to adjust montages as desired for interpretation. Neurophysiologists were blinded to treatment group, local interpretation, and outcomes. Each neurophysiologist independently reviewed the files; discrepancies were resolved by consensus. Kappa statistic was used to compare agreement in the observed rate of neonates with EEG seizures or status epilepticus and Pearson correlation coefficient was used to assess inter-rater reliability on total minutes of seizure burden. Inter-rater reliability for seizure identification was almost perfect (Kappa=0.82) and for status epilepticus was substantial (Kappa=0.78).16 Inter-rater reliability for overall minutes of seizure burden among neonates with identified seizures was also very high (Pearson r=0.96). Outcome Measures. Seizures were defined as a sudden, abnormal EEG event with a repetitive and evolving pattern with a minimum 2μV peak-to-peak voltage and duration of at least 10 seconds.17 Status epilepticus was defined as the summed duration of seizures comprising ≥50% of any 1-hour epoch of recording.17 Only electrographic seizures were considered; clinically-detected seizures were not considered for this ancillary study. Primary outcome. EEG maximal hourly seizure burden (in minutes per hour) after Epo administration among neonates with seizures. EEG maximal hourly seizure burden was determined using a sliding one hour time window throughout the course of the EEG recording. Pre-specified secondary outcomes. 1) Response to initial dose of ASM with complete response defined as no further seizures present >30 minutes after adequate loading dose of an ASM (phenobarbital >20mg/kg, levetiracetam >40mg/kg, or fosphenytoin >20mg/kg) until the end of the recording, 2) Overall seizure burden (minutes of seizure per minutes of cEEG recording) 3) Seizure period (time from the onset of the first seizure to the end of the last seizure), and 4) Presence of status epilepticus. Analysis. Given this was a select sub study population the baseline characteristics and measurements were first compared between treatment groups using Chi-square tests for categorical variables and Wilcoxon rank sum tests for continuous variables. The maximum hourly seizure burden was defined as the maximum number of seizure minutes over any 60-minute window within time periods (Tj) for j = 0 (before study drug dose 1), j=1 (between study drug doses 1 and 2), or j=2 (between study drug doses 2 and 3). Baseline seizures rates were expected to be similar due to randomization, therefore statistical inference focused on the first and second dose time periods. To estimate the adjusted relative risk (aRR) of seizure burden between groups, we used a Poisson regression model with robust standard errors to allow for overdispersion. The regression model adjusted for sex, recruitment site, HIE severity (moderate or severe), maximum hourly seizure burden observed prior to the first study drug dose, and a log offset log(Tj) to account for variable lengths of cEEG observation time overall or between study drug doses. For secondary binary outcomes measures (any seizures, complete response to initial loading dose of ASM, status epilepticus), we used a log-logistic regression model to calculate relative risks comparing treatment groups adjusting for sex, recruitment site, HIE severity, and any seizure observed prior to the first study drug dose. Seizure period was defined as the median hours from the first to the last observed seizure and median percentage of total cEEG time with observed seizures were compared between treatment groups using quantile regression (R “quantreg” package). Group differences in medians and 95% confidence intervals (CI) were adjusted for HIE severity and log cEEG observation time. All analyses were conducted using R software version 4.0.2 (Vienna, Austria).18 Power and Sample Size. To test the hypothesis that Epo reduces both the proportion of neonates with seizures and seizure burden, we assumed a priori that approximately 50% of placebo-treated neonates would have seizures at a median burden of 4.0 minutes/hour (IQR: 2.0–7.0).19,20 We used simulations to generate data under various scenarios and to assess power for each outcome assuming that Tj is approximately 24 hours. To mimic seizure data, we used a zero inflated model composed of two parts: the probability of no seizures and the seizure burden among those with seizures. For simulation analyses (n=10,000 replications) we used a generalized linear model regression Wald test with alpha=0.05 based on a generalized linear model function assuming a log link and quasi-Poisson family and considered a variety of over-dispersion parameters. We sought to evaluate n=150 neonates with cEEG, as a sample size of 70 subjects/group provided at least 80% power to detect a treatment effect under three scenarios: 1) a test of whether treatment reduces both the probability of any seizures and the burden of seizures by 25% (a common rate ratio of 0.75), 2) treatment effect associated only with a relative risk of 0.53 for the presence of any seizures, but no reduction in burden among subjects with seizures, and 3) no treatment effect on the percent of subjects with seizures, but the seizure burden is reduced by 40% (rate ratio 0.60) among subjects with seizures. Results Patients. Of 500 neonates included in the modified intention to treat analysis of the HEAL trial, born between January 25, 2017 and October 9, 2019, 235 (47%) participants were enrolled at one of the seven HEAL-EEG centers (Supplementary Table 1). One hundred and eighty-five of 235 (79%) of cEEGs were reviewed for background and seizure burden, to reach the prespecified sample size of 150 recordings with adequate quality for inclusion (37 were excluded for low quality tracing, 15 from the Epo and 22 from the placebo group Figure 1). Twenty-three cEEGs were not reviewed as there were sufficient high-quality tracings to achieve the pre-specified sample size. There were no meaningful differences in characteristics between infants selected for cEEG review compared to those that were not reviewed (Supplemental Table 2). The first dose of Epo was administered at a median 18.5 (IQR 13.1–22.3) hours. Twenty of 150 neonates (13%) died, six of whom had the cEEG removed prior to completing the 72-hour monitoring period. Table 1 describes baseline characteristics of neonates who received Epo (n=83) and placebo (n=67). There were no significant differences between groups in maternal characteristics, pregnancy and delivery complications, infant characteristics (including severity of encephalopathy), or EEG monitoring. Seizures and seizure treatment. Electrographic seizures occurred in 46/150 (31%, Table 2). There was no significant difference in the percentage of neonates experiencing seizures between the Epo and placebo groups (26/83, 31% vs. 20/67, 30%; aRR = 1.04; 95% CI = 0.60 – 1.80). Among the 140 neonates who received the first study drug dose after the start of cEEG monitoring, 30 (21%) had seizures before study drug administration, with similar rates comparing the Epo (23%) and placebo (20%) groups. The percentage of neonates with seizures after study drug dosing was also similar across treatment groups. Thirty-four of 150 neonates (27%) had seizures between the first and second doses of study drug, with a similar rate for the Epo (19/83, 23%) and placebo (15/67, 22%) groups, and 16/150 (11%) had seizures after the second dose of study drug, with similar rates across the Epo (11/83, 13%) and placebo (5/67, 7.5%) groups. Anti-seizure medications were administered to 30/83 (36%) of neonates who received Epo and 36/67 (54%) neonates who received placebo (aRR=0.60, 95% CI = 0.40–0.89; p=0.01). Primary outcome. Among neonates with seizures, there was no meaningful difference in the median maximal hourly seizure burden after administration of the first dose of study drug between study groups (Epo: 11.4, IQR 5.6, 18.1 minutes per hour compared with placebo: 9.7, IQR 4.9, 21.0 minutes per hour; adjusted difference= −0.2; 95% CI= −6.3 – 5.6; Table 3). Seizure timing by treatment group is presented in Figure 2. In a sensitivity analysis excluding the six children who died and had incomplete cEEG data, median maximal hourly seizure burden was unchanged (median 11.6, IQR 5.6, 17.4 minutes per hour in the Epo group and median 10.4, IQR 4.9, 21.5 minutes per hour in the placebo group). Secondary outcomes. Among the 43 (29%) of neonates that received a loading dose of ASM, 13 (30%) had a complete response. A lower complete response was observed in neonates treated with Epo (5/24, 21%) compared to placebo (8/19, 42%), but the difference was not significant after adjustment for HIE severity and baseline seizure burden prior to first study drug dose (aRR 0.78, 95% CI 0.27 – 2.26). Among the 46 neonates with seizures, total minutes of observed seizure burden was higher in the Epo group (median=63.8; IQR= 28.5, 146.5) compared to the placebo group (median=31.5; IQR= 23.4, 77.1; adjusted difference=34.0; 95% CI= 2.81 – 67.4; Table 3). However, when considering the total cEEG recording time, the percentage of time with seizures was not significantly different between the Epo group (median=1.2%; IQR= 0.5%, 3.5%) and placebo group (median=0.6%; IQR= 0.4%, 1.3%; adjusted difference= 0.2%; 95% CI= −0.4% - 0.8%). In a sensitivity analysis excluding the six children who died and had incomplete EEG data, the observed seizure burden was similar (median 63.2, IQR 25.5, 81.2) minutes for the Epo group and (median 32.5, IQR 25.5, 81.2) minutes for the placebo group. The median period over which a neonate had seizures was 16.3 hours (IQR 6.2, 25.2) and was not significantly different between groups (median 20.2 hours, IQR 8.4, 33.1 hours for Epo and median 14.9 hours, IQR=3.9, 21.0 hours for placebo; adjusted difference = 2.5; 95% CI= −3.3 – 11.6). Status epilepticus was present in 10/46 (22%) of neonates with seizures and occurred more frequently among neonates treated with Epo (9/26, 35%) compared to those treated with placebo (1/20, 5.0%), but was not significantly different after adjustment for pre-treatment seizure burden and HIE severity (aRR = 2.84; 95% CI = 0.56 – 14.39). Discussion Among neonates who received cEEG monitoring within the HEAL randomized, controlled trial of erythropoietin (Epo) vs placebo plus hypothermia for moderate or severe encephalopathy presumed due to hypoxic-ischemic encephalopathy (HIE), 31% had electrographic seizures and there was no significant difference between study groups. Maximal hourly seizure burden, overall timing and duration of seizures, as well as response to antiseizure medication treatment were not significantly different after receiving Epo as compared with placebo. These findings are not consistent with preclinical studies, where Epo has been shown to reduce the severity of acute and late seizures in animal models of HIE.4–7 Proposed mechanisms for the anti-seizure effects of Epo include microglial activation, reduced inflammation, decreased neuronal death and ectopic granule cell generation, as well as enhanced hippocampal Epo receptor expression (especially following status epilepticus).4–7,21–24 In a study of kainic acid and hypoxia-induced seizures, the latency to seizure onset doubled and duration of seizures dropped by 50% in the Epo-treated animals.6 There are several possible reasons why our data are not aligned with results from animal research. In the HEAL trial, Epo was delivered in combination with hypothermia, while in animal models, it was delivered without cooling. Both Epo and hypothermia may act through similar mechanisms and target similar points in the injury cascade, including reduced apoptotic, inflammatory, and excitotoxic injury.25 Epo may not confer additional benefit beyond hypothermia when used in combination. However, the results of the current study do not exclude the possibility that Epo alone could have anti-seizure properties. Other explanations for our negative findings could include suboptimal timing of administration (specifically administration of Epo early in the injury cascade), or suboptimal dosing of Epo. FDA labeling for Epo warns of a possible pro-convulsant effect based on older trials in adults with renal disease and hypertension,8–10 but there is limited active research in neonates at risk for seizures. Although we found no significant increase in seizure risk after Epo administration, several important measures indicated potentially worse seizures in the Epo group (e.g., total seizure duration, overall maximal hourly seizure burden, seizure period, and status epilepticus), and the overall gestalt of the swimmer plots is one of higher seizure burden in the Epo group. Possible explanations for worse seizures in the Epo group include chance (i.e., failure to randomize into two groups with equal likelihood of seizures), less robust ASM treatment in the Epo group, or a true increase in seizure burden related to Epo or its side effects. Importantly, there was no apparent pro-convulsant effect of Epo among neonates with HIE who were treated with hypothermia: differences by treatment group were not significant after adjusting for pre-treatment seizure burden. Prior studies highlight the importance of pre-treatment seizure burden on apparent efficacy of a study drug. For instance, a randomized, controlled trial of bumetanide for acute provoked neonatal seizures had an important imbalance in pre-treatment seizure burden, which limited the study’s ability to detect a treatment effect and led the study authors and an international working group to recommend that future trials of ASMs should take measures to balance baseline seizure severity between the study groups.26,27 Finally, we cannot exclude small differences between groups. Although we present data from a large, randomized controlled, double-blind trial of Epo vs placebo for neonates with HIE with central review of cEEG recorded throughout cooling and rewarming, our data are not without limitations. First, the rate of EEG-detected seizures (31%) was lower than anticipated and lower than most previously published studies (34% - 65%)20,28,29. The lower seizure rate could have limited the power to detect significant differences between groups. The reason for lower seizure frequency may be related to improved obstetric care and resuscitation, rapid onset of hypothermia, or other neuroprotective measures to prevent secondary brain injury and overall lower frequency of severe encephalopathy at treating sites. Second, seizure identification and treatment were at the discretion of the local care team; the study was not designed to address interactions between Epo treatment and ASM. It is, therefore, possible that the lack of Epo effects were related to unknown confounding interactions. However, randomization and adjustment for site in our analysis should have mitigated potential confounding. The reasons for differences in ASM use between groups is not known and may relate to treatment of clinically suspected versus electrographic only seizures. Third, we reached our a priori sample size of 150 before reviewing all available cEEGs and before achieving a sample size of 70 in each group. Finally, the parent study excluded families with an unstable social situation, which may limit the generalizability of study results. Conclusions In this large cohort of neonates with encephalopathy due to HIE who were randomized to Epo or placebo plus hypothermia and who received cEEG monitoring per ACNS guidelines throughout cooling and rewarming, we found no meaningful differences in key measures of seizure burden or response to treatment in the Epo group. These findings are consistent with overall trial results, which do not support adjunct use of Epo for neonates with HIE undergoing therapeutic hypothermia. The overall proportion of children with seizures was lower that prior studies. Although Epo combined with hyothermia showed no benefit in seizure reduction, this study provides new important information about the contemporary risk of seizures during hypothermia. We also add to the literature about seizure timing and burden in neonates with HIE. Future studies will address EEG background activity for long-term prognosis in neonates with HIE. Supplementary Material 1 Acknowledgements The authors would like to thank Dr. Taeun Chang (1971-2022) for her tireless contributions to this work, site investigators Drs. John Flibotte and Lori Billinghurst, as well as the Clinical Research Coordinators at each study site. Funding The study was funded by NIH/NINDS R01NS104322, U01NS092764, and U01NS092553. Adam L. Numis, MD, received grant support during the study period from NINDS K23NS105918. Data Availability Statement HEAL Trial Data-sharing plan We will prepare and share a final research data set that the accepted primary pragmatic trial publication is based upon. The final data set will be structured to maximize future scientific value while protecting patient and health system privacy. The UW DCC will remove or de-identify all 18 HIPAA-specified direct identifiers. The aim of our data sharing policy is strive for the least restrictive plan possible while providing appropriate protection for participant privacy, health system privacy, and scientific integrity. Within 9 months of the end of the final year of funding, a final study data set will be accessible via a supervised private data enclave managed by the National Institute of Neurological Disorder and Stroke (NINDS) at: https://www.ninds.nih.gov/Current-Research/Research-Funded-NINDS/Clinical-Research/Archived-Clinical-Research-Datasets. The shared data set will contain all data collected under both the HEAL Trial protocol and HEAL ancillary studies. Access will be limited to registered users who submit proposed specific questions or analysis plans and sign a data use agreement according to NINDS guidelines. “Supervised” indicates that individual requests are reviewed to protect the intellectual property rights of the project investigative team by restricting external development of manuscripts using the study data that substantially overlap with those that are already in development by study investigators. Figure 1. CONSORT diagram for seven sites participating in the HEAL-EEG ancillary study. Figure 2. Swimmer plot of 46 neonates with seizures with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia and treated with erythropoietin (Epo, panel A) or placebo (panel B) who received continuous video-EEG throughout hypothermia and rewarming. Vertical lines indicate that a seizure was observed. Panel C: Density plot of neonates with seizure in the previous hour of EEG recording. Table 1. Baseline clinical and electroencephalogram (EEG) characteristic of 150 neonates with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia and treated with erythropoietin or placebo who received continuous video-EEG throughout hypothermia and rewarming. Total N=150 Erythropoietin N=83 Placebo N=67 p-value* Maternal Characteristics, n (%) Race 0.59 White 104 (69%) 58 (70%) 46 (69%) Black 18 (12%) 8 (9.6%) 10 (15%) Asian 15 (10%) 8 (9.6%) 7 (10%) Other 13 (8.7%) 9 (11%) 4 (6.0%) Hispanic ethnicity 33 (22%) 16 (19%) 17 (25%) 0.37 Age (years), mean (SD) 30.1 (6.6) 30.8 (6.9) 29.3 (6.3) 0.16 Education, high school or less 58 (39%) 33 (40%) 25 (37%) 0.76 Parity = 1 (including subject) 91 (61%) 52 (63%) 39 (58%) 0.58 Pregnancy and Delivery Complications, n (%) Maternal chorioamnionitis or fever 28 (19%) 15 (18%) 13 (19%) 0.84 Maternal pre-eclampsia or eclampsia 16 (11%) 8 (10%) 8 (12%) 0.65 Gestational diabetes 14 (9.3%) 6 (7.2%) 8 (12%) 0.32 Maternal obesity (BMI >30) 25 (17%) 15 (18%) 10 (15%) 0.61 Sentinel eventa 48 (32%) 26 (31%) 22 (33%) 0.85 Cesarean section delivery 99 (66%) 57 (69%) 42 (63%) 0.33 Infant Characteristics Female, n (%) 65 (43%) 33 (40%) 32 (48%) 0.44 Birth weight (grams), mean (SD) 3411 (558) 3354 (542) 3481 (573) 0.14 Gestational age (weeks), mean (SD) 39.2 (1.5) 39.1 (1.4) 39.3 (1.4) 0.26 5-minute Apgar score, median (IQR) 3 (2, 4) 3 (2, 4) 4 (2, 5) 0.26 Lowest pHb, mean (SD) 6.9 (0.2) 6.9 (0.2) 6.9 (0.2) 0.79 Worst base deficitb, mean (SD) 17.6 (6.1) 17.1 (5.6) 18.2 (6.6) 0.54 Severe encephalopathyc, n (%) 33 (22%) 19 (23%) 14 (21%) 0.77 cEEG Monitoring cEEG starting hour after birth, median (IQR) 8.4 (6.4, 10.3) 7.9 (6.5, 9.7) 9.0 (6.3, 10.7) 0.26 Hours of cEEG, median (IQR) 89.3 (79.7, 98.0) 89.7 (77.9, 98.1) 88.6 (80.5, 97.9) 0.98 Initial cEEG background pattern Normal 70 (47%) 35 (42%) 35 (52%) 0.36 Excessively discontinuous 43 (29%) 25 (30%) 18 (27%) Severely abnormal 36 (24%) 23 (28%) 13 (19%) Cannot determine (excess artifact at onset of recording) 1 (0.7%) 0 (0%) 1 (1.5%) EEG seizures observed prior to 1st dose of study drug, n (%) 30/140 (21%) 18/79 (23%) 12/61 (20%) 0.66 SD standard deviation; BMI body mass index; IQR interquartile range; cEEG continuous video electroencephalogram * P values calculated using Chi-square tests for categorical variables and Wilcoxon rank sum tests for continuous variables. a Sentinel event = placental abruption, shoulder dystocia, uterine rupture, or prolapsed cord. b Lowest pH and worst base deficit among cord arterial, cord venous, and arterial blood gas samples taken before 60 minutes of age. c Severe encephalopathy as defined by modified Sarnat score. Table 2. Seizures and anti-seizure medications (ASM) of 150 neonates with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia and treated with erythropoietin or placebo who received continuous video-EEG throughout hypothermia and rewarming. Total N=150 Erythropoietin N= 83 Placebo N=67 aRR (95% CI)* P value * Seizures and Seizure Timing N (%) with EEG seizures** 46 (31%) 26 (31%) 20 (30%) 1.04 (0.60, 1.80) 0.88 With moderate encephalopathy 29/117 (25%) 16/64 (23%) 13/53 (24%) 0.98 (0.41, 2.34) With severe encephalopathy 17/33 (52%) 10/19 (53%) 7/14 (50%) 1.03 (0.62, 1.72) After 1st dose of study drug 40 (27%) 22 (27%) 18 (27%) 0.88 (0.44, 1.76) 0.72 Between 1st and 2nd dose of study drug 34 (23%) 19 (23%) 15 (22%) 0.88 (0.45, 1.73) 0.71 After 2nd dose of study drug 16 (11%) 11 (13%) 5 (7.5%) 1.12 (0.41, 3.07) 0.83 ASM Administration N (%) administered ASM 66 (44%) 30 (36%) 36 (54%) 0.60 (0.40, 0.89) 0.01 Phenobarbital 64 (43%) 29 (35%) 35 (52%) 0.62 (0.41, 0.93) 0.02 Levetiracetam 33 (22%) 12 (15%) 11 (16%) 0.73 (0.34, 1.60) 0.44 Phenytoin/Fosphenytoin 13 (8.7%) 7 (8.4%) 6 (9.0%) 1.06 (0.39, 2.88) 0.91 Other (midazolam, lorazepam, topiramate) 65 (43%) 34 (41%) 31 (46%) 0.91 (0.61, 1.34) 0.62 aRR adjusted relative risk; EEG electroencephalogram; ASM anti-seizure medication * Adjusted relative risks and P values based upon generalized (binary) logistic regression model and adjusts for treatment, HIE severity, and recruitment site. ** Logistic regression models additionally adjusted for the maximum seizure minutes/hour observed prior to first study drug dosing, and a log offset log(Tj) to account for variable lengths of cEEG observation time overall or between study drug doses. Table 3. Seizures and anti-seizure medications 46 neonates with hypoxic-ischemic encephalopathy and confirmed EEG seizures while undergoing therapeutic hypothermia and treated with erythropoietin or placebo who received continuous video-EEG throughout hypothermia and rewarming. Total with Seizures N=46 Erythropoietin and Seizures N=26 Placebo and Seizures N=20 Adjusted Group Comparison (95% CI) Seizures and Seizure Timing Total seizure duration in minutes, median (IQR)* 51.4 (26.6, 100.3) 63.8 (28.5, 146.5) 31.5 (23.4, 77.1) 34.0 (2.81, 67.4) Prior to the 1st study drug dose 8.1 (0, 35.3) 21.0 (0, 70.3) 3.1 (0, 18.3) 16.8 (0.6, 30.3) Between 1st and 2nd dose of study drug 17.4 (1.4, 44.9) 18.0 (1.4, 44.9) 17.4 (5.9, 38.8) 0.2 (−8.2, 15.2) After 2nd dose of study drug 0 (0, 7.5) 0 (0, 16.7) 0 (0, 0.7) 0 (0, 0.6) Maximal EEG seizure burden (minutes/hour), median (IQR)* 16.1 (10.3, 32.7) 19.7 (10.6, 38.1) 15.0 (10.4, 22.7) 8.8 (−2.6, 18.6) Prior to the 1st study drug dose 9.9 (0.0, 25.8) 16.2 (0.0, 34.4) 7.7 (0.0, 11.4) 8.1 (2.5, 17.6) After 1st dose of study drug 10.8 (5.2, 20.0) 11.4 (5.6, 18.1) 9.7 (4.9, 21.0) −0.2 (−6.3, 5.6) Between 1st and 2nd dose of study drug 7.9 (0.6, 18.1) 7.9 (0.6, 15.7) 8.2 (3.5, 21.0) 0.3 (−8.9, 4.4) After 2nd dose of study drug 0.0 (0.0, 3.7) 0.0 (0.0, 5.7) 0.0 (0.0, 0.4) 0 (0, 0.2) Status epilepticus at any time during the recording, n (%)** 10 (22%) 9 (35%) 1 (5.0%) 2.84 (0.56, 14.39) Hours from start of first seizure to end of last seizure, median (IQR)* 16.3 (6.2, 25.2) 20.2 (8.4, 33.1) 14.9 (3.9, 21.0) 2.5 (−3.3, 11.6) Percentage of cEEG recording time with observed seizures, median (IQR)* 1.0 (0.5, 1.7) 1.2 (0.5, 3.5) 0.6 (0.4, 1.3) 0.2 (−0.4, 0.8) Between 1st and 2nd dose of study drug 0.6 (0.0, 1.3) 0.5 (0.0, 1.1) 0.6 (0.2, 1.5) 0.2 (−0.6, 0.3) After 2nd dose of study drug 0 (0, 0.1) 0 (0, 0.4) 0 (0, 0.0) 0 (0, 0) Complete response to ASM >=30 minutes after first loading dose of anti-seizure medication, n (%)* 13/43 (30%) 5/24 (21%) 8/19 (42%) 0.78 (0.27, 2.26) Received ≥2 ASM to treat neonatal seizures, n (%)* 23 (50%) 12 (46%) 11 (55%) 1.18 (0.49, 2.88) IQR interquartile range; cEEG continuous video electroencephalogram; ASM anti-seizure medication * Group differences in median hourly seizure burden, percentage, and hours of seizure burden were adjusted for treatment, HIE severity, maximum seizure minutes/hour observed prior to 1st study drug dose, and a log offset log(Tj) to account for variable lengths of cEEG observation time overall or between study drug doses Relative risk of status epilepticus is based upon generalized (log) logistic regression adjusting for treatment, HIE severity, and maximum seizure minutes/hour observed prior to first study drug dosing. * Relative risks for other dichotomous variables adjust for treatment, HIE severity, recruitment site, maximum seizure minutes/hour observed prior to first study drug dosing, and for a log offset log(Tj) to account for variable lengths of cEEG observation time overall or between study drug doses. Impact: In the HEAL trial of erythropoietin (Epo) vs placebo for neonates with encephalopathy presumed due to hypoxic-ischemic encephalopathy (HIE) who were also treated with therapeutic hypothermia, electrographic seizures were detected in 31%, which is lower than most prior studies. Epo did not reduce the proportion of neonates with acute provoked seizures (31% in Epo vs 30% in placebo) or maximal hourly seizure burden after study drug (median Epo: 11.4, IQR 5.6, 18.1 for Epo vs median 9.7, IQR 4.9, 21.0 minutes/hour for placebo). There was no anti- or pro-convulsant effect of Epo when combined with therapeutic hypothermia for HIE. Competing Interests Kaashif A. Ahmad has nothing to disclose. Sonia L. Bonifacio has nothing to disclose. Bryan A. Comstock has nothing to disclose. Hannah C. Glass has nothing to disclose. Fernando F. Gonzalez has nothing to disclose. Patrick J. Heagerty has nothing to disclose. Sandra E. Juul has nothing to disclose. Nathalie Maitre has nothing to disclose. Shavonne L. Massey has nothing to disclose. Dennis E. Mayock has nothing to disclose. Ulrike Mietzsch has nothing to disclose. Niranjana Natarajan has nothing to disclose. Adam L. Numis has nothing to disclose. Gregory M. Sokol has nothing to disclose. Cameron Thomas has nothing to disclose. Krisa P. Van Meurs has nothing to disclose. Yvonne W. Wu has nothing to disclose. Consent Statement Neonates were studied after informed parental consent. ==== Refs References 1 Glass HC Contemporary Profile of Seizures in Neonates: A Prospective Cohort Study. J Pediatr 174 , 98–103 e101, doi:10.1016/j.jpeds.2016.03.035 (2016).27106855 2 Ronen GM , Penney S & Andrews W The epidemiology of clinical neonatal seizures in Newfoundland: a population-based study. J Pediatr 134 , 71–75, doi:10.1016/s0022-3476(99)70374-4 (1999).9880452 3 Juul S Erythropoietin in the central nervous system, and its use to prevent hypoxic-ischemic brain damage. Acta paediatrica 91 , 36–42, doi:10.1111/j.1651-2227.2002.tb02904.x (2002).12477263 4 Yang J Erythropoietin preconditioning suppresses neuronal death following status epilepticus in rats. Acta Neurobiol Exp (Wars) 67 , 141–148 (2007).17691221 5 Nadam J Neuroprotective effects of erythropoietin in the rat hippocampus after pilocarpine-induced status epilepticus. Neurobiol Dis 25 , 412–426, doi:S0969–9961(06)00259–2 [pii]10.1016/j.nbd.2006.10.009 (2007).17166730 6 Mikati MA , El Hokayem JA & El Sabban ME Effects of a single dose of erythropoietin on subsequent seizure susceptibility in rats exposed to acute hypoxia at P10. Epilepsia 48 , 175–181, doi:10.1111/j.1528-1167.2006.00900.x (2007).17241225 7 Chu K Erythropoietin reduces epileptogenic processes following status epilepticus. Epilepsia 49 , 1723–1732, doi:EPI1644 [pii]10.1111/j.1528-1167.2008.01644.x (2008).18479396 8 Brown AL , Tucker B , Baker LR & Raine AE Seizures related to blood transfusion and erythropoietin treatment in patients undergoing dialysis. BMJ 299 , 1258–1259, doi:10.1136/bmj.299.6710.1258 (1989).2513901 9 Beccari M , Romagnoni M & Sorgato G Seizures in dialysis patients treated with recombinant erythropoietin. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 10 , 423–424 (1995).7792048 10 Edmunds ME Seizures in haemodialysis patients treated with recombinant human erythropoietin. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 4 , 1065–1069 (1989).2517327 11 Wu YW Erythropoietin for neuroprotection in neonatal encephalopathy: safety and pharmacokinetics. Pediatrics 130 , 683–691, doi:10.1542/peds.2012-0498 (2012).23008465 12 Baserga MC Darbepoetin administration to neonates undergoing cooling for encephalopathy: a safety and pharmacokinetic trial. Pediatr Res 78 , 315–322, doi:10.1038/pr.2015.101 (2015).25996892 13 Wu YW Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns. N Engl J Med 387 , 148–159, doi:10.1056/NEJMoa2119660 (2022).35830641 14 Juul SE High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL): A Randomized Controlled Trial - Background, Aims, and Study Protocol. Neonatology 113 , 331–338, doi:10.1159/000486820 (2018).29514165 15 Shellhaas RA The American Clinical Neurophysiology Society’s Guideline on Continuous Electroencephalography Monitoring in Neonates. J Clin Neurophysiol 28 , 611–617, doi:10.1097/WNP.0b013e31823e96d7 (2011).22146359 16 Landis JR & Koch GG The measurement of observer agreement for categorical data. Biometrics 33 , 159–174 (1977).843571 17 Tsuchida TN American clinical neurophysiology society standardized EEG terminology and categorization for the description of continuous EEG monitoring in neonates: report of the American Clinical Neurophysiology Society critical care monitoring committee. J Clin Neurophysiol 30 , 161–173, doi:10.1097/WNP.0b013e3182872b24 (2013).23545767 18 R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, URL https://www.R-project.org/. 2020). 19 Lynch NE The temporal characteristics of seizures in neonatal hypoxic ischemic encephalopathy treated with hypothermia. Seizure 33 , 60–65, doi:10.1016/j.seizure.2015.10.007 (2015).26571073 20 Glass HC Risk factors for EEG seizures in neonates treated with hypothermia: a multicenter cohort study. Neurology 82 , 1239–1244, doi:10.1212/WNL.0000000000000282 (2014).24610326 21 Bahcekapili N Erythropoietin pretreatment suppresses seizures and prevents the increase in inflammatory mediators during pentylenetetrazole-induced generalized seizures. Int J Neurosci 124 , 762–770, doi:10.3109/00207454.2013.878935 (2014).24397543 22 Yoo JY Neuroprotective effects of erythropoietin posttreatment against kainate-induced excitotoxicity in mixed spinal cultures. J Neurosci Res 87 , 150–163, doi:10.1002/jnr.21832 (2009).18711747 23 Montero M Comparison of neuroprotective effects of erythropoietin (EPO) and carbamylerythropoietin (CEPO) against ischemia-like oxygen-glucose deprivation (OGD) and NMDA excitotoxicity in mouse hippocampal slice cultures. Exp Neurol 204 , 106–117, doi:10.1016/j.expneurol.2006.09.026 (2007).17157835 24 Garzon F NeuroEPO Preserves Neurons from Glutamate-Induced Excitotoxicity. J Alzheimers Dis 65 , 1469–1483, doi:10.3233/JAD-180668 (2018).30175978 25 Wassink G Recombinant erythropoietin does not augment hypothermic white matter protection after global cerebral ischaemia in near-term fetal sheep. Brain Commun 3 , fcab172, doi:10.1093/braincomms/fcab172 (2021). 26 Soul JS A Pilot Randomized, Controlled, Double-Blind Trial of Bumetanide to Treat Neonatal Seizures. Ann Neurol 89 , 327–340, doi:10.1002/ana.25959 (2021).33201535 27 Soul JS Recommendations for the design of therapeutic trials for neonatal seizures. Pediatr Res 85 , 943–954, doi:10.1038/s41390-018-0242-2 (2019).30584262 28 Wusthoff CJ Electrographic seizures during therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy. J Child Neurol 26 , 724–728, doi:10.1177/0883073810390036 (2011).21447810 29 Nash KB Video-EEG monitoring in newborns with hypoxic-ischemic encephalopathy treated with hypothermia. Neurology 76 , 556–562, doi:10.1212/WNL.0b013e31820af91a (2011).21300971
PMC010xxxxxx/PMC10281215.txt	==== Front Rev Mal Respir Rev Mal Respir Revue Des Maladies Respiratoires 0761-8425 1776-2588 SPLF. Published by Elsevier Masson SAS. S0761-8425(23)00201-2 10.1016/j.rmr.2023.06.005 Article Original Mesures d’hygiène pour les Explorations Fonctionnelles Respiratoires (EFR) après la pandémie de COVID-19 – Résultats d’une enquête nationale auprès de 28 centres hospitaliers en 2023 Survey on hygiene practices after the COVID-19 pandemic in EFR departments.Günther S 1 Bancal C 2 Plantier L 3⁎ pour le Groupe Fonction de la SPLF 1 Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Européen Georges-Pompidou, Unité d’Explorations Fonctionnelles Respiratoires et du sommeil, Université de Paris Cité, Paris, France 2 Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Bichat, service d’Explorations Fonctionnelle, secteur respiratoire, France 3 Service de Pneumologie et Explorations Respiratoires, CHRU de Tours, CEPR/INSERM UMR1100, Université de Tours, France ⁎ Auteur correspondant: Service de Pneumologie et Explorations Respiratoires, CHRU de Tours, CEPR/Inserm UMR1100, Université de Tours, 2 Bd Tonnellé, 37044 Tours Cedex 9, France 20 6 2023 20 6 2023 25 4 2023 8 6 2023 © 2023 SPLF. Published by Elsevier Masson SAS. All rights reserved. 2023 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. Résumé Lors de la pandémie de COVID-19, des recommandations strictes d’hygiène applicables à la réalisation des explorations fonctionnelles respiratoires (EFR) et à l’exercice (EFX) ont été publiées, dont la pertinence dans le contexte post-pandémique de 2023 peut être discutée. Dans l’hypothèse que les centres experts aient adapté leurs pratiques par rapport à ces recommandations, une enquête a été conduite du 8 au 21 février 2023 auprès de 28 services hospitaliers français pratiquant des EFR et EFX. Dans leur grande majorité, les centres ne pratiquaient pas de limitation des indications (96%) et ne demandaient pas de certificat de vaccination/rétablissement (93%) ni de test diagnostique préalable (89%). Le port du masque chirurgical par le patient et les soignants ainsi que l’utilisation de filtres antimicrobiens étaient unanimement respectés, alors que seuls 36% des centres déclaraient l’utilisation de masques filtrants FFP2. La désinfection des mains des soignants était déclarée par 96% des centres. La majorité des centres déclaraient le respect d’un temps de pause (75%) et la désinfection des surfaces des appareils (89%) entre deux patients. En dehors des quelques aménagements cités, les pratiques rapportées par les centres experts de l’EFR et EFX en 2023 semblaient proches de celles en cours avant l’épidémie de COVID-19. During the COVID-19 pandemic, airborne transmission of lung disease was a cause for major concern, and scientific societies published strict hygiene guidelines for pulmonary function tests (PFT) and cardiopulmonary exercise testing (CPET). These guidelines led to a major decrease in patient access to PFT and CPET, and their relevance in the 2023 post-pandemic context may be called into question. Under the hypothesis that PFT/CPET expert centers have modified their practices in accordance with the applicable guidelines, a survey was conducted from the 8th through the 23rd of February 2023 in 28 French PFT/CPET hospital departments. An overwhelming majority of the centers (96%) did not limit indications for PFT/CPET, and requested neither a vaccination or recovery certificate (93%) nor a negative diagnostic test (89%). While the use by patients and caregivers of surgical masks and antimicrobial filters was unanimously adopted, only 36% of centers declared that FFP2/N95-filtering face masks were worn. Disinfection of caregivers' hands was carried out by 96%, and a majority of centers reported break time (75%) and disinfection of equipment surfaces (89%) between the testing of two patients. In conclusion: Aside from a few modifications, the practices reported by PFT/CPET French expert centers in 2023 were close to those in force prior to the COVID-19 epidemic. Keywords Spirometry walk test infection prevention Liste des abréviations CHU Centre hospitalier universitaire CPET Cardiopulmonary exercise testing COVID-19 Coronavirus 2019 DLCO Capacité de diffusion du monoxyde de carbone EFR Explorations Fonctionnelles Respiratoires EFX Explorations Fonctionnelles à l’exercice ERS European Respiratory Society PFT Pulmonary function tests RT-PCR Réaction en chaîne par polymérase à transcription inverse SNIP Sniff nasal inspiratory pressure SPLF Société de Pneumologie de Langue Française ==== Body pmc
PMC007xxxxxx/PMC7102747.txt	==== Front Rev Fr Allergol (2009) Rev Fr Allergol (2009) Revue Francaise D'Allergologie (2009) 1877-0312 1877-0320 Elsevier Masson SAS. S1877-0320(09)00022-0 10.1016/j.reval.2009.01.021 Article Virus et sensibilisation Virus and sensitizationBrouard J. ⁎ Nimal D. Bessière A. Service de pédiatrie, hôpital Clemenceau, CHU de Caen, avenue Clemenceau, BP 95182, 14033 Caen cedex 5, France ⁎ Auteur correspondant. 11 3 2009 4 2009 11 3 2009 49 3 140142 Copyright © 2009 Elsevier Masson SAS. All rights reserved. 2009 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. Les virus respiratoires peuvent, en se répliquant aussi bien au niveau de l’épithélium respiratoire supérieur qu’inférieur, induire des sifflements. La plupart des études cliniques soulignent qu’une symptomatologie sifflante secondaire à l’atteinte par un virus respiratoire durant la prime enfance est liée à un risque ultérieur d’asthme. Les virus peuvent induire une exacerbation asthmatique par un effet direct sur sa cible principale, l’épithélium, mais aussi d’une réaction immuno-inflammatoire médiée par voie systémique. Par ailleurs, des études ont également montré des résultats discordants dans la capacité d’une infection virale d’induire des réponses allergiques significatives. Est-ce le virus l’initiateur de l’asthme allergique ou les sifflements viro-induits le révélateur d’enfants déjà prédisposés à l’atopie en raison d’anomalies préexistantes pulmonaires et/ou de la réponse immunitaire ? Respiratory viruses are able to replicate in both the upper and lower respiratory epithelium, thus inducing wheezing. Most clinical studies suggest that wheezing illnesses due to respiratory viruses in early childhood are linked to a risk for asthma. Viruses may induce asthma exacerbations through direct effects on their main target, the respiratory epithelium, as well as via a systemic immune-inflammatory reaction. On other hand, studies have also yielded conflicting results in regard to the ability of viral infection to enhance subsequent allergic responses. Do early viral illnesses cause allergic asthma or viral wheezing episodes serve to reveal children who are already predisposed to this disease on basis of an abnormal lung physiology and/or immune response? Mots clés Asthme Atopie Virus Keywords Respiratory viral infection Children Asthma Atopy Allergy ==== Body pmcUn virus peut être impliqué de différentes façons à une expression clinique sifflante : sibilances associées aux infections respiratoires de la prime enfance, exacerbations aiguës chez l’asthmatique, induction d’une sensibilisation allergique. 1 Sibilances associées aux infections respiratoires du nourrisson La cohorte de Tucson a permis de préciser l’épidémiologie virale en population générale des infections respiratoires basses. Sur 1246 enfants, 519 ont eu au moins une infection respiratoire basse avant l’âge de trois ans diagnostiquée et prise en charge par un médecin [1]. L’épidémiologie pour les enfants ayant bénéficié des investigations virologiques (472 enfants sur les 519) confirme la prédominance virale puisque 43,9 % des prélèvements retrouvaient le virus respiratoire syncytial (VRS), 14,4 % les VPI, 14,4 % un virus différent des deux premiers, chez 27,7 % des enfants aucun virus ne fut identifié lors de l’épisode infectieux. Mais cette épidémiologie varie selon les méthodes diagnostiques utilisées, les saisons, l’âge et le niveau de l’atteinte des voies aériennes qui peut prédominer sur le tractus respiratoire supérieur ou s’étendre sur le tractus respiratoire inférieur. Les sifflements viro-induits dont l’intensité nécessite un recours hospitalier n’ont pas la même signification selon le virus en cause (Tableau 1 ). Le VRS est bien l’agent majeur de bronchiolites hospitalisées, les rhinovirus lorsqu’ils induisent une expression clinique évoquant ce diagnostic est prédictif d’un asthme ultérieur probablement en raison d’un terrain immuno-allergique déjà particulier, chez le sujet sain le rhinovirus reste l’agent étiologique principal du rhume banal et rarement d’une détresse respiratoire intense.Tableau 1 Étude prospective comparative, au cours de l’hiver 2003–2004, de l’épidémiologie virale lors d’infections respiratoires associées à un syndrome obstructif expiratoire chez le nourrisson (bronchiolites aiguës et exacerbations asthmatiques). Tableau clinique Bronchiolites Exacerbation inaugurale d’un asthme du nourrisson p Nombre d’aspirations nasales 298 61 Âge moyen en mois (± D.S.) 5 (± 4) 10,5 (± 5,5) Épidémiologie virale (%) V. Respiratoire syncytial 54,3 25,7 < 0,001 Rhinovirus 29,0 44,6 < 0,01 V. Influenza 3,7 8,1 NS Adénovirus 0,9 4,0 NS V. Parainfluenza 2,6 0,0 NS Entérovirus 1,1 4,0 0,06 Coronavirus 3,5 8,1 NS Métapneumovirus 4,9 5,5 NS Laboratoire de virologie du CHU de Caen, Professeur F. Freymuth. Technique d’identification par biologie moléculaire : 91,5 % de recherche virale positive. 2 Virus initiateur de l’asthme ? Cette relation est retrouvée avec le VRS (OR = 3,0) et s’accentue avec le rhinovirus (OR = 6,6) : 63 % des nourrissons de moins d’un an ayant sifflé lors de la saison hivernale continueront à le faire à trois ans, alors que 20 % de ceux qui n’ont pas sifflé durant leur première année le feront à l’âge de trois ans [2]. Ces données issues de la cohorte américaine Childhood Origins of Asthma (COAST) ont été confirmées par un suivi prolongé à six ans, les infections respiratoires par rhinovirus responsables de respiration sifflante au cours de la petite enfance constituent le facteur prédictif le plus significatif de développement d’un asthme [3]. L’analyse des données indique que les infections par le rhinovirus seul, qu’elles interviennent la première, la deuxième ou la troisième année, augmentent de manière significative le risque d’asthme à six ans : celui-ci est multiplié respectivement par 2,7 ; 6,5 ; 31,7. Les infections par VRS seul ne sont pas associées à un risque accru d’asthme lorsqu’elles surviennent au cours de la première et de la deuxième année. En revanche, au cours de la troisième année, les infections par VRS uniquement multiplient le risque d’asthme par 9,9. Ces résultats se retrouvent dans l’évaluation du risque d’asthme en cas d’infections conjointes par VRS et rhinovirus (risque respectivement : 2,7 ; 12,6 ; 25,6). 3 Infection virale initiatrice de l’allergie ? Divers résultats suggèrent que les antibiothérapies précoces, le plus souvent prescrites pour en réalité une atteinte virale, pourraient majorer les risques atopique et asthmatique ultérieur des enfants. Il est aussi possible comme l’ont suggéré d’autres études que le recours fréquent aux antibiotiques chez les enfants appelés à devenir allergiques et/ou asthmatiques ne soit que le reflet d’un terrain génétique prédisposant ces enfants à la fois à un risque accru d’infections et d’atopie et ne soit pas la cause directe de leurs allergies et/ou de leur asthme. On peut en rapprocher l’étude de Bisgaard et al. qui souligne une corrélation entre une colonisation bactérienne précoce trachéale chez les nourrissons qui développeront ultérieurement un asthme [4]. Il y a peu d’argument pour penser qu’une infection virale précoce induise directement une atopie. Une méta-analyse retenant des critères stricts de la bronchiolite à VRS, excluant les études portant sur les enfants âgés de plus d’un an et celles ne disposant pas de preuve virologique, souligne que les sifflements récurrents ne sont ni en rapport avec une élévation ultérieure du risque atopique, ni liés à une fréquence plus élevée des antécédents familiaux d’atopie [5]. Cependant, une étude suédoise souligne une augmentation conjointe de l’asthme et de l’atopie (avec une positivité des tests cutanés et des IgE). Cela serait un argument en faveur d’un mécanisme de démarrage commun de ces deux phénomènes. Dans cette étude, 47 enfants hospitalisés pour bronchiolite sévère à VRS ont été suivis. À l’âge de 13 ans, ces enfants ont plus de manifestations asthmatiques par rapport aux témoins (43 % vs 8 %). Cette population va aussi avoir plus de signes d’atopie, de rhinoconjonctivites allergiques (39 % vs 15 %), de prick-tests positifs (50 % vs 28 %) ainsi que des IgE sériques (45 % vs 26 %), également avec ce recul de 13 ans [6]. Une interprétation différente peut être opposée : les nourrissons non hospitalisés lors d’une épidémie hivernale à VRS ont de fait un facteur protecteur non identifié du risque de développer ultérieurement un asthme ou une allergie. Les taux de la protéine cationique des éosinophiles, du macrophage-inflammatory protein-1a (MIP-1a) et de l’IL-4 sont dans certaines études significativement plus élevés dans les secrétions nasales des nourrissons infectés par des virus respiratoires divers que dans les secrétions nasales des enfants témoins non infectés [7]. Ces résultats suggèrent que les infections virales des voies respiratoires orientent les réponses immunitaires locales vers des réponses du type TH2-prédominant, susceptibles de favoriser les risques de sensibilisation par les aéroallergènes présents dans l’environnement des jeunes enfants. Dans une étude prospective de 455 enfants à risque élevé d’atopie et/ou d’asthme, suivis de la naissance jusqu’à l’âge de deux ans, Lee et al. montrent que les prévalences des sensibilisations aux allergènes courants et de l’asthme sont positivement corrélées avec le portage viral des enfants pendant les deux premières années de vie [8]. Les virus les plus relevants sont les virus para-influenzae et le VRS. L’hypothèse selon laquelle ce serait un terrain atopique préexistant qui pourrait être responsable de l’augmentation de la fréquence des infections et non l’inverse, est étayée par les résultats d’une étude prospective où le risque d’asthme persistant à l’âge de cinq ans a été augmenté chez les enfants ayant présenté des bronchiolites aiguës virales, mais seulement lorsque ces enfants avaient des prick-tests positifs à un ou plusieurs aéroallergènes et/ou trophallergènes avant l’âge de deux ans [9]. L’asthme et l’atopie sont a priori des entités différentes avec des composantes génétiques distinctes même s’ils sont épidémiologiquement souvent liés. L’influence des infections virales peut être de compréhension délicate lors d’une augmentation conjointe d’incidence. L’influence des mécanismes liés à l’hôte mais également aux cascades physiopathologiques différentes selon le virus en cause nécessite la poursuite des études afin d’envisager de nouvelles pistes thérapeutiques. ==== Refs Références 1 Stein R.T. Sherill D. Morgan W.J. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years Lancet 354 1999 541 545 10470697 2 Lemanske R.F. Jr. Jackson D.J. Gangnon R.E. Rhinovirus illnesses during infancy predict subsequent childhood wheezing J Allergy Clin Immunol 116 2005 571 577 16159626 3 Jackson D.J. Gangnon R.E. Evans M.D. Roberg K.A. Anderson E.L. Pappas T.E. Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children Am J Respir Crit Care Med 178 2008 667 672 18565953 4 Bisgaard H. Hermansen M.N. Buchvald F. Loland L. Halkjaer L.B. Bønnelykke K. Childhood asthma after bacterial colonization of the airway in neonates N Engl J Med 357 2007 1487 1495 17928596 5 Kneyber M.C.J. Steyerberg E.W. de Groot R. Moll H.A. Long-term effects of respiratory syncytial virus (RSV) bronchiolitis in infants and young children: A quantitative review Acta Paediatr 89 2000 654 660 10914957 6 Sigurs N. Gustafsson P.M. Bjarnason R. Severe respiratory syncytial virus bronchiolitis in infancy and asthma and allergy at age 13 Am J Respir Crit Care Med 171 2005 137 141 15516534 7 Kristjansson S. Bjarnarson S.P. Wennergren G. Palsdottir A.H. Arnadottir T. Haraldsson A. Respiratory syncytial virus and other respiratory viruses during the first 3 months of life promote a local TH2-like response J Allergy Clin Immunol 116 2005 805 811 16210054 8 Lee K.K. Hegele R.G. Manfreda J. Wooldrage K. Becker A.B. Ferguson A.C. Relationship of early childhood viral exposures to respiratory symptoms, onset of possible asthma and atopy in high risk children: The Canadian asthma primary prevention study Pediatr Pulmonol 42 2007 290 297 17245731 9 Kusel M.M. de Klerk N.H. Kebadze T. Vohma V. Holt P.G. Johnston S.L. Early life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma J Allergy Clin Immunol 119 2007 1105 1110 17353039
PMC007xxxxxx/PMC7102790.txt	==== Front Rev Fr Allergol (2009) Rev Fr Allergol (2009) Revue Francaise D'Allergologie (2009) 1877-0312 1877-0320 Elsevier Masson SAS. S1877-0320(14)00045-1 10.1016/j.reval.2014.01.018 Article Collectivités : lieu de rencontre virale Day-care centers: Sites of viral contactBrouard J. a⁎c Vabret A. bc Dina J. bc Lemercier H. a a Service de pédiatrie, CHU de Caen, avenue Côte-de-Nacre, 14033 Caen, France b Laboratoire de virologie, CHU de Caen, avenue Clemenceau, 14033 Caen, France c EA 4655 U2RM, équipe E3 : « virologie respiratoire comparée », 14032 Caen, France ⁎ Auteur correspondant. 20 2 2014 4 2014 20 2 2014 54 3 173178 Copyright © 2014 Elsevier Masson SAS. All rights reserved. 2014 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. La répétition des épisodes infectieux chez les nourrissons placés précocement en collectivités est une évidence. Leur tropisme sur la sphère respiratoire et l’appareil digestif l’est également. Leur probable retentissement au long cours est difficile à évaluer par la rareté des études prospectives. Le risque infectieux est lié en partie au type de structure de garde, ce risque est important dans les premiers mois de fréquentation et conditionne les récidives ultérieures. Les liens de causalité entre infection virale et asthme sont complexes. Les infections virales augmentent le risque d’asthme mais le statut asthmatique augmente aussi le risque de réponses sévères à une infection virale. Alors que les infections acquises dans cet environnement sont majoritairement virales, leur répétition conduit à une utilisation excessive des antibiotiques d’où une pression de sélection microbienne et un retentissement sur le microbiome digestif voire respiratoire. It is well known that young infants attending day-care centers are subjected to repeated infectious episodes, with a tendency to involve the respiratory and gastrointestinal tracts. Their long-term impact is difficult to assess because there are few relevant prospective studies. The risk of infection is influenced in part by the structure of the day-care center, and it is more important in the early months of attending and linked to later recurrent infectious episodes. Causal links between viral infection and asthma are complex. Viral infections increase the risk of asthma exacerbation but the presence of asthma also increases the risk of severe responses to a viral infection. While infections acquired in this environment are mainly viral, their recurrence can lead to excessive use of antibiotics which promote antimicrobial resistance with an impact on the digestive or respiratory microbiota. Mots clés Crèche Infections respiratoires Virus Nourrisson Résistance bactérienne aux antibiotiques Keywords Day-care center Respiratory infections Viruses Infants Antimicrobial resistance ==== Body pmc1 Introduction Ces dernières décennies ont vu des modifications profondes de nature socio-économique et familiale conduisant à un développement du recours aux modes de garde extrafamiliaux. En France, plus d’un enfant sur deux de moins de trois ans est gardé régulièrement hors de sa famille ; en 2001 environ 250 000 enfants de 3 mois à 3 ans ont fréquenté une crèche : deux tiers au sein d’une crèche collective, un tiers dans une crèche familiale. Actuellement l’ensemble des programmes électoraux pour les municipales abordent le besoin de créer 250 000 places supplémentaires d’accueil pour les nourrissons. L’accueil dans ces structures concerne les enfants sains mais parfois aussi d’enfants porteurs de pathologies notamment infectieuses, le risque de contamination interhumaine est alors important heureusement limité par la mise en place préventive d’une organisation sanitaire adéquate. Les infections respiratoires virales ne donnent lieu qu’à des affections modérées et limitées dans le temps qui s’inscrivent dans l’éducation immunitaire du nourrisson. Cependant la plupart des études épidémiologiques soulignent l’association entre la symptomatologie sifflante secondaire à une agression virale durant la petite enfance et le risque ultérieur de développement d’un asthme. 2 Quelles infections sont particulièrement en cause en collectivités de nourrissons ? En fonction des principales manifestations cliniques qu’ils provoquent, on peut classer ces virus selon leur tropisme : respiratoire, intestinal ou hépatique, cutané ou systémique. Les virus qui infectent le système digestif sont excrétés dans les selles, ceux qui infectent le système respiratoire sont excrétés dans les sécrétions respiratoires (mucus du nez, gouttelettes de la salive ou des éternuements), le cytomégalovirus est excrété dans la salive et dans les urines, le risque de transmission infectieuse par une morsure d’enfant est minime mais pas nulle pour certains virus [1]. La transmission des germes s’effectue de façon soit directe (contacts main-bouche, inhalation ou ingestion de gouttelettes émises lors de la toux ou de l’éternuement), soit indirecte transmis par des intermédiaires (objets, mains du personnel, surfaces souillées) (Tableau 1 ). Il est possible de prévenir dans une très grande mesure ces transmissions par des mesures d’hygiène simple. Les mouchoirs en papier jetés immédiatement après usage seront utilisés pour le mouchage ; lors des épidémies hivernales, surtout dans le secteur de nourrissons n’ayant pas acquis la marche, le port du masque chirurgical par le personnel et les parents sera favorisé. Dans le cas des maladies infectieuses légères ne nécessitant pas une prise en charge thérapeutique conséquente, l’exclusion de ces enfants malades n’a qu’un impact mineur sur l’incidence d’infections chez les autres enfants, en effet l’enfant est contagieux avant que la maladie ne se déclare. Le maintien ou l’exclusion de la collectivité doit se faire sur la base des besoins de l’enfant malade, de son confort, de la charge thérapeutique, du diagnostic de certaines viroses très contagieuses (rougeole, phase éruptive de la varicelle). Les vaccins jouent un rôle de premier plan dans la prévention de nombreuses maladies contagieuses de l’enfant en bas-âge. Non seulement la vaccination protège directement les individus vaccinés, mais elle protège également l’ensemble du groupe, en limitant les possibilités de transmission de l’agent infectieux.Tableau 1 Principaux virus et leur mode de transmission dans une collectivité. Mode de transmission Virus Transmission féco-orale Adénovirus entérique, Astrovirus, Entérovirus, Hépatite A, Norovirus, Rotavirus, Transmission respiratoire aérienne Influenza, Rougeole, Varicelle-Zona Transmission respiratoire « gouttelettes » Adénovirus, Influenza, Oreillon, Parvovirus B19, Rhinovirus, Rougeole, Rubéole, virus respiratoire syncytial Transmission respiratoire par contact Entérovirus, Para-influenza, Rhinovirus, virus respiratoire syncytial Transmission par contact direct personne à personne, contact avec les liquides biologiques ou contact par objet contaminé Conjonctivite virale, Cytomégalovirus, Hépatite B, Herpès simplex, Varicelle-Zona, VIH 3 Quelques données épidémiologiques 3.1 Le lien entre fréquence des infections et mode de garde est attesté par les études épidémiologiques Les collectivités d’enfants constituent un cadre propice à la transmission des agents infectieux. De nombreuses études épidémiologiques sont issues d’équipes Anglo-Saxonnes, Américaines ou Scandinaves, leurs conclusions ne peuvent être transposables directement à notre pays. Il existe d’importantes différences d’organisation : les « day-care centers » américains accueillent les enfants jusqu’à l’âge de 6 ans, les pays scandinaves bénéficient d’une législation du congé parental très favorable au maintien à domicile durant plus d’un an et à la poursuite de l’allaitement maternel (Danemark congé parental d’une durée de 64 semaines ; Suède congé parental entièrement rémunéré d’une durée de 480 jours) et leurs résultats sont sensibles aux biais car se réfèrent à des effectifs limités d’enfants de moins d’un an. Seules trois grandes enquêtes prospectives françaises sont disponibles sur les infections acquises en collectivité par des enfants d’âge préscolaire. Deux études effectuées dans la région de Lyon [2], [3] : la première « Santé-Enfant-Crèche » réalisée entre 1988 et 1989 recensant l’ensemble des infections contractées par les enfants fréquentant 3 types de crèches (grande crèche collective, petite crèche collective et crèche familiale) comparés à des enfants gardés au domicile familial durant une période de 8,5 mois ; la seconde conduite de novembre 2004 à mai 2005 estimant l’incidence en crèche des gastroentérites à rotavirus et son coût. Une étude a été effectuée dans les crèches municipales parisiennes analysant, sur une cohorte suivie de septembre 2000 à juin 2001, les facteurs organisationnels associés à la répétition des épisodes infectieux [4]. Dans l’enquête Santé-Enfant-Crèche [1], les infections les plus fréquentes ont été par ordre de fréquence décroissant : les infections des voies aériennes supérieures (VAS) (rhinopharyngites 49,9 % des cas, otites 21,3 % et laryngites 9,6 %) et les diarrhées (19 % des cas). Ce classement se retrouve aussi en Europe et aux États-unis [5], [6]. L’étude Santé-Enfant-Crèche souligne également que l’incidence globale des infections varie notablement en fonction du mode de garde de l’enfant, un enfant gardé en collectivité présente annuellement 4 à 6 fois plus d’infections qu’un enfant élevé au domicile. Sur une période de 8,5 mois, les enfants gardés au domicile ont présenté un nombre moyen d’épisodes infectieux égal à 0,75 contre 2,99 pour les enfants gardés en crèches familiales versus 3,47 en grandes crèches collectives et 4,51 en petites crèches collectives. Le risque de contracter des infections récidivantes a été estimé pour chaque type de garde hors du domicile, l’âge et l’ancienneté du mode de garde. Cette analyse a montré que les enfants des petites crèches collectives ont deux à trois fois plus de risque d’infections récidivantes que les enfants des crèches familiales, ce risque étant intermédiaire pour les enfants des grandes crèches collectives. Le mélange d’enfants d’âges différents au sein des petites crèches serait plus favorable à la transmission des germes et, à l’inverse, la séparation des enfants en fonction de leur classe d’âge dans les grandes crèches serait plutôt un facteur limitant la transmission des germes. Les stratégies d’orientation des bébés susceptibles d’être plus sensibles aux infections prioritairement vers des modes de garde à domicile ou les crèches familiales, sont donc argumentées [3]. Au total, 41 % des rhumes observés chez les enfants de 1 an [7] et 30 % des infections respiratoires supérieures des enfants de moins de 3 ans [8] pourraient être attribués au seul fait de fréquenter une crèche collective. En moyenne, chez les enfants préscolaires, la fréquentation d’une crèche collective multiplie par deux le risque d’infections des VAS prolongées ou récidivantes par rapport à une garde à domicile ; cet excès de risque serait limité aux enfants de moins de 2 ans. Cette incidence plus forte serait toutefois moins liée au mode de garde qu’au nombre d’enfants gardés. En effet, certains auteurs montrent que la présence à domicile de fratries plus âgées aurait autant d’impact sur le sur-risque d’infection que la fréquentation d’une garde en crèche collective [9]. 3.2 Les infections en crèches sont corrélées à leur circulation virale communautaire Le manque d’étude virologique pédiatrique « hors institution » rend compte de la faiblesse des données disponibles concernant son épidémiologie communautaire, hormis celles issues du réseau GROG (www.grog.org) sur les virus grippaux. Les épidémies virales en collectivité sont le reflet de ce qui se déroule « en ville », elles prédominent en période automno-hivernale, elles n’ont pas de spécificité particulière contrairement à l’épidémiologie bactérienne en collectivité. Une étude française a recensé l’ensemble des épidémies survenues dans 27 crèches, regroupant environ 500 enfants, au cours des années 1988–1989 et 1989–1990 [10]. Chaque année, la moitié des enfants de ces crèches ont présenté une symptomatologie épidémique présumée virale. Les manifestations cliniques de ces épidémies ont été principalement des infections respiratoires (41,4 % et 53,1 % des épisodes épidémiques) et des gastroentérites aiguës (41,4 % et 37,5 % des épisodes épidémiques). Les prélèvements virologiques effectués chez les enfants malades ont permis de documenter l’étiologie de ces infections. Quatre-vingt-dix pour cent des gastroentérites ont été d’origine virale. Les virus les plus souvent isolés ont été les rotavirus, les entérovirus et les adénovirus avec une fréquence relative variable d’une année à l’autre. L’identification virale a été étroitement associée à la symptomatologie respiratoire, elle a pu être documentée entre 60 et 65 % des cas ; parmi les virus identifiés, le virus syncytial respiratoire (VRS) a été le plus fréquemment mis en évidence (55 à 70 % des prélèvements positifs selon l’année), parfois le virus influenza a représenté 20 % des prélèvements positifs. Les virus isolés au cours des conjonctivites ont été des adénovirus. Les récentes techniques moléculaires de diagnostic virologique peuvent modifier cette épidémiologie. En Normandie, chez les nourrissons hospitalisés pour une atteinte respiratoire aiguë, le VRS est présent dans 64,1 % des cas, les rhinovirus (RV) dans 26,8 %, le métapneumovirus humain dans 7,6 % et les virus para-influenza dans 3,4 % [11]. Deux études récentes ont utilisé ces techniques moléculaires en collectivité préscolaire [12], [13]. L’une a été menée au sein de 3 crèches d’une base militaire américaine (Tacoma) auprès de 225 enfants âgés de 5 semaines à 30 mois [12]. Cent soixante-trois ont présenté une atteinte respiratoire à un âge moyen de 12 mois, dont 67 % à plus d’une reprise (455 épisodes infectieux), une identification virale lors d’une atteinte respiratoire fût retrouvée dans 84 % des cas. L’épidémiologie virologique par l’utilisation des techniques PCR fût : 30 % RV, 15 % adénovirus, 15 % bocavirus, 12 % para-influenza, 10 % VRS, 10 % coronavirus, 4 % métapneumovirus, 4 % influenza. Cette étude a également suivi la durée d’excrétion virale, la charge virale et la modification de l’épidémiologie virale après l’épisode infectieux aiguë. 3.3 La répétition des infections conduit à une utilisation excessive des antibiotiques La répétition des infections est à l’origine d’une consommation élevée d’antibiotiques. L’étude Santé-Enfant-Crèche [2] souligne que 65 % des épisodes infectieux ont motivé la prescription d’un antibiotique. Une antibiothérapie a été prescrite pour 90 % des otites et 71 % des rhinopharyngites. La plupart des études confirment le rôle de l’utilisation d’antibiotiques dans le mois ou les 2 mois précédents dans l’acquisition de pneumocoques résistants. Le jeune âge favorise le portage du pneumocoque, il varie également selon le mode de garde : 69 % chez les enfants gardés en crèche, 29 % chez les enfants gardés par une nourrice, 13 % chez ceux maintenus à domicile. Ces pneumocoques présents dans le pharynx sont soumis à la pression des antibiotiques et vont ainsi pouvoir acquérir une résistance. 3.4 La relation entre les sifflements viro-induits de la petite enfance et le développement ultérieur d’un asthme dépend du virus en cause au sein d’une population d’enfants à risque atopique Ainsi dans la cohorte américaine COAST, l’odd-ratio (OR) d’asthme ultérieur est de 3,0 si l’infection est à VRS et 6,6 lors de RV. De plus, 63 % des nourrissons de moins de un an ayant sifflé lors de la saison hivernale continueront à le faire à trois ans, alors que 20 % de ceux qui n’ont pas sifflé durant leur première année le feront à l’âge de trois ans [14]. Ces données ont été confirmées par le suivi à six ans, les infections respiratoires par RV responsables de respiration sifflante au cours de la petite enfance constituent le facteur prédictif le plus significatif de développement d’un asthme [15]. 4 Quelles conséquences ? L’immaturité immunitaire des premiers mois de vie est bien connue : de la naissance au sixième mois les nourrissons perdent progressivement les anticorps maternels transmis, en particulier les IgG 2 ; leur capacité à fabriquer des anticorps de type IgG 2, contre les polysaccharides (antigènes thymo-indépendants), qui constituent la capsule de nombre de bactéries, est limitée ; la synthèse des IgA sécrétoires paraît restreinte. Probablement lié à leur immaturité immunitaire, le portage des bactéries potentiellement pathogènes (S. pneumoniae, H. influenzae, M. catarrhalis) est plus fréquent et plus prolongé chez le nourrisson. Au cours ou au décours de l’évolution d’une rhinopharyngite, le risque de survenue d’une otite moyenne aiguë est plus important chez les enfants gardés en crèche. Enfin, les pourcentages de souches bactériennes résistantes aux antibiotiques, d’échecs de traitement des otites moyennes aiguës ou d’évolution vers une otite traînante sont plus élevés chez ces patients. 4.1 Infections respiratoires L’augmentation des infections ORL, en particulier des otites moyennes aiguës, chez les enfants vivant en crèche a été bien démontrée et l’ensemble des résultats vont dans le même sens : le risque est multiplié par 2 ou 3 pour un enfant fréquentant une crèche collective par rapport à celui vivant au domicile [16]. Une étude longitudinale des infections respiratoires aiguës en crèche sur 16 années retrouve un pic de l’incidence des infections entre l’âge de 6 et 12 mois (10 par enfant et par an) suivi d’une diminution [17]. L’augmentation de l’incidence des infections respiratoires basses est moins bien documentée, car elles sont moins fréquentes et plus difficiles à diagnostiquer avec certitude. Dans une étude cas-témoins réalisée à Atlanta, 102 enfants hospitalisés pour infections respiratoires basses ont été comparés à 199 témoins appariés sur l’âge et le sexe, la fréquentation d’une crèche collective était plus fréquemment retrouvée chez les malades que chez les témoins [9]. Moins de 10 % des infections respiratoires impliquent les voies aériennes inférieures. 4.2 Infections gastro-intestinales Selon l’enquête Santé-Enfant-Crèche [2], le risque de présenter des épisodes récidivants de diarrhées infectieuses n’est pas significativement différent d’un type de crèche à un autre probablement du fait de la grande contagiosité des germes responsables. Une étude finlandaise [7] a montré que la garde en crèche familiale n’augmentait pas le risque d’infections digestives par rapport à la garde au domicile familial, à la différence d’une garde en crèche collective associée à la survenue d’infections digestives à 1 et 2 ans avec respectivement un risque 1,76 et 1,56 fois plus élevé comparé à ceux élevés au domicile familial. Au total, les auteurs estiment que 49 % des épisodes de diarrhées de l’enfant de 1 an et 37 % de ceux des enfants de 2 ans sont attribuables à la garde en crèche collective. Une étude prospective multicentrique a été conduite en crèches municipales de la ville de Lyon de novembre 2004 à mai 2005 [3]. Trois cent deux enfants âgés de moins de 36 mois gardés au moins 4 fois par semaine ont été inclus, parmi eux, le diagnostic clinique de gastroentérite aiguë a été confirmé et validé 63 fois dont 46 % étaient dus au rotavirus (GEAR). L’âge médian des enfants avec une GEAR était de 12,2 mois. L’incidence de la GEAR a été de 2,2/100 enfants/mois chez les enfants de moins de 36 mois et a été plus élevée chez les enfants de moins de 24 mois (3,4/100 enfants/mois). Dans 85,7 % des cas de GEAR, un avis médical a été nécessaire. Dans 58,3 % des cas, au moins 1 parent a dû s’arrêter de travailler pendant 2,1 j en moyenne. Le coût direct et indirect moyen d’une GEAR en crèche a été estimé à 275,54 euros. Les recommandations vaccinales spécifiques tardent à venir en France ainsi que leur niveau de prise en charge financière. 4.3 Cytomégalovirus Les enfants de moins de 3 ans accueillis en collectivité sont particulièrement exposés aux infections à cytomégalovirus (CMV). Les infections à cytomégalovirus présentant un risque particulier pour les femmes enceintes et les immunodéprimés. Habituellement l’enfant acquiert une infection à CMV par sa mère (transmission in utero, intrapartum, allaitement maternel), cet incidence est estimée entre 10 et 50 % la première année de vie [18]. Une fois que l’enfant est infecté, son excrétion virale par les urines ou les sécrétions respiratoires se poursuit sur plusieurs mois de façon intermittente ou continue. Vingt à 70 % des enfants en crèche peuvent se trouver dans cette situation. La difficulté reste que le CMV provoque rarement une maladie cliniquement reconnaissable chez l’enfant sain et l’adulte, cependant l’atteinte fœtale in utero, même très inconstante voire rare, est redoutable lorsqu’elle survient. La non-fréquentation de la collectivité pourra être décidée si une personne de l’équipe accueillante est enceinte ou immunodéprimée. L’importance des mesures d’hygiène systématique est donc soulignée (lavage mains, masques et gants pour les gestes exposés aux liquides biologiques). 4.4 Infection virale et orientation TH2 L’analyse du profil de cytokines et de chémokines, dans les sécrétions nasopharyngées, selon le statut virologique et l’âge du nourrisson montre qu’il existe une fenêtre de vulnérabilité. Un nourrisson infecté par le VRS durant ses 3 premiers mois a des concentrations locales plus importantes d’IL-4 en comparaison à des enfants plus âgés. Ce profil TH2 est retrouvé chez les nourrissons de moins de 3 mois infectés par le virus influenza et les PIV. Ceci suggère que les virus orientent les réponses immunitaires locales vers des réponses de type TH2 chez le nourrisson. Par conséquent, la réponse immunitaire adaptative est dépendante de l’âge, le VRS n’étant pas l’unique responsable d’une orientation vers une réponse de type TH2 post-virale [19]. L’orientation TH2 favorisait une sensibilisation par des aéro-allergènes présents dans le proche environnement. Au sein d’une cohorte néonatale d’enfants à risque, une corrélation positive a été retrouvée entre la prévalence d’une sensibilisation ou d’un asthme et le portage viral dans les deux premières années de vie [20]. À l’inverse, un terrain atopique préexistant aux infections virales pourrait être responsable de l’augmentation de la fréquence des infections. Ainsi, le risque d’asthme persistant à l’âge de cinq ans semble n’être augmenté après une bronchiolite aiguë qu’en présence de tests cutanés positifs avant l’âge de deux ans [21]. L’écosystème intestinal héberge dix fois plus de micro-organisme que de cellules humaines, on découvre par ailleurs que le dogme du poumon stérile s’effondre, il est maintenu convenu que cette « flore » doit être dénommé « microbiote ». Ces micro-organismes jouent un rôle protecteur et se caractérisent par un état d’équilibre appelé eubiose. Le microbiote est propre à chaque individu, il est stable mais des événements extérieurs peuvent rompre cet équilibre : infections, modification de l’alimentation (arrêt allaitement maternel), antibiothérapie ou utilisation de probiotiques qui interférent avec le microbiote intestinal. La dysbiose est un déséquilibre du microbiote associé à des conséquences néfastes pour son hôte. Une méta-analyse avait antérieurement montré que l’utilisation de probiotiques tant thérapeutique que préventif, particulièrement Lactobacillus rhamnosus, dans les diarrhées aiguës de l’enfant avait globalement un effet bénéfique par la diminution des épisodes de GEAR. Plus récemment une prévention des infections respiratoires chez les enfants vivants en collectivité a été mise en évidence grâce à une alimentation lactée des nourrissons apportant Lactobacillus GG, la réduction significative des infections des voies aériennes supérieures a été d’un tiers et une réduction non significative des infections des voies aériennes inférieures [22]. L’étude du microbiome est un domaine de recherche foisonnant particulièrement vers la connaissance des mécanismes conduisant au développement des allergies [23]. 5 Conclusion Il existe un risque majoré de contamination interhumaine à l’origine d’infection à répétition dans les structures de garde collective plus importante que les structures familiales surtout avant un an. Cette incidence plus forte serait toutefois moins liée au mode de garde qu’au nombre d’enfants gardés et au mélange des âges. L’excès de risque infectieux diminue avec l’âge et la durée de fréquentation de la crèche, témoignant d’une augmentation des défenses immunitaires des enfants, facilitée par la vie en collectivité. Le risque d’apparition d’infections potentiellement préoccupantes est majoré chez les plus jeunes enfants, ce qui pose le problème de l’âge d’entrée en crèche collective. À côté de ces infections essentiellement virales, les enfants fréquentant des crèches sont plus souvent porteurs de pneumocoques résistants aux antibiotiques que les enfants élevés à domicile, en raison d’infections et de consommations d’antibiotiques plus fréquentes. Les infections plus fréquentes en milieu collectif sont associées à une plus grande consommation médicale et à des arrêts de travail des parents qui représentent un coût non négligeable. Une orientation des enfants à risque vers un mode de garde plus protecteur est à privilégier. Les études cliniques de prévention des infections virales sévères pourront peut-être permettre de mieux définir les liens qui unissent les infections respiratoires virales de la petite enfance et le développement d’un asthme. Déclaration d’intérêts Les auteurs n’ont pas transmis de déclaration de conflits d’intérêts. ==== Refs Références 1 Solomons H.C. Elardo R. Biting in day care centers: incidence, prevention, and intervention J Pediatr Health Care 5 1991 191 196 1865290 2 Floret D. Épidémiogie des infections de crèche. Comparaison des différents modes de garde. Impact de la pression des antibiotiques sur la résistance bactérienne Med Mal Infect 30 Suppl. 3 2000 215 220 3 Fau C. Billaud G. Pinchinat S. Lina B. Kaplon J. Pothier P. Épidémiologie et impact de la gastroentérite aiguë à rotavirus dans les crèches minicipales de la ville de Lyon – saison 2004–2005 Arch Pediatr 15 2008 1183 1192 18456480 4 Delour M. Caparros N. Rufat P. Desplanques L. Bonnefoi M.C. Patris S. Facteurs organisationnels associés à la répétition des épisodes infectieux des enfants accueillis en crèche à Paris Arch Pediatr 13 2006 1215 1221 16930964 5 Ponka A. Nurmi T. Salminen E. Nykyri E. Infections and other illness of children in day care centers in Helsinki. I: incidences and effects of home and day care center variables Infection 19 1991 230 236 1917034 6 Churchill R.B. Pickering L.K. Infection control challenges in child-care centers Infect Dis Clin North Am 11 1997 347 365 9187951 7 Louhiala P.J. Jaakkola N. Ruotsalainen R. Jaakkola J.J. Form of day care and respiratory infections among Finnish children Am J Public Health 85 1995 1109 1112 7625505 8 Fleming D.W. Cochi S.L. Hightower A.W. Broome C.V. Childhood upper respiratory tract infections: to what degree is incidence affected by day care attendance Pediatrics 79 1987 55 60 3797171 9 Anderson L.J. Parker R.A. Strikas R.A. Farrar J.A. Gangarosa E.J. Keyserling H.L. Day-care center attendance and hospitalization for lower respiratory tract illness Pediatrics 82 1988 300 308 3405658 10 Aymard M. Chomel J.J. Bordier M. Suivis des infections virales épidémiques dans les crèches du Rhône durant deux années consécutives. Infections ORL et respiratoires de l’enfant : les nouvelles voies de recherche Pediatrie 46 Suppl. 1991 22 24 1665223 11 Freymuth F. Vabret A. Dina J. Les virus des bronchiolites aiguës Arch Pediatr 17 2010 1192 1201 20558050 12 Martin E.T. Fairchok M.P. Stednick Z.J. Kuypers J. Englund J.A. Epidemiology of multiple respiratory viruses in childcare attendees J Infect Dis 207 2013 982 989 23288925 13 Bonfim C.M. Nogueira M.L. Simas P.V. Gardinassi L.G. Durigon E.L. Rahal P. Frequent respiratory pathogens of respiratory tract infections in children attending daycare centers J Pediatr (Rio J) 87 2011 439 444 22125800 14 Lemanske R.F. Jr. Jackson D.J. Gangnon R.E. Rhinovirus illnesses during infancy predict subsequent childhood wheezing J Allergy Clin Immunol 116 2005 571 577 16159626 15 Jackson D.J. Gangnon R.E. Evans M.D. Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children Am J Respir Crit Care Med 178 2008 667 672 18565953 16 Wald E.R. Guerra N. Byers C. Upper respiratory tract infections in young children: duration of and frequency of complications Pediatrics 87 1991 129 133 1987522 17 Denny F.W. Collier A.M. Henderson F.W. Acute respiratory infections in day care Rev Infect Dis 8 1986 527 532 3529308 18 Brady M.T. Infectious disease in pediatric out-of-home child care Am J Infect Control 33 2005 276 285 15947744 19 Kristjansson S. Bjarnarson S.P. Wennergren G. Respiratory syncytial virus and other respiratory viruses during the first 3 months of life promote a local TH2-like response J Allergy Clin Immunol 116 2005 805 811 16210054 20 Lee K.K. Hegele R.G. Manfreda J. Relationship of early childhood viral exposures to respiratory symptoms, onset of possible asthma and atopy in high risk children: the Canadian Asthma Primary Prevention Study Pediatr Pulmonol 42 2007 290 297 17245731 21 Kusel M.M. de Klerk N.H. Kebadze T. Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma J Allergy Clin Immunol 119 2007 1105 1110 17353039 22 Hojsak I. Snovak N. Abdović S. Szajewska H. Misak Z. Kolacek S. Lactobacillus GG in the prevention of gastrointestinal and respiratory tract infections in children who attend day care centers: a randomized, double-blind, placebo-controlled trial Clin Nutr 29 2010 312 316 19896252 23 Reynolds L.A. Finlay B.B. A case for antibiotic perturbation of the microbiota leading to allergy development Expert Rev Clin Immunol 9 2013 1019 1030 24168410
PMC007xxxxxx/PMC7102822.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(16)00058-0 10.1016/j.reval.2016.01.037 Article Les exacerbations sévères de l’asthme : quels sont les acteurs saisonniers ? Les infections virales Severe asthma exacerbations: What are the seasonal actors? Viral infectionsMordacq C. ⁎ Lejeune S. Deschildre A. Unité de pneumologie et allergologie pédiatriques, pôle de pédiatrie, hôpital Jeanne-de-Flandre, CHRU de Lille, 59037 Lille cedex, France ⁎ Auteur correspondant. 2 3 2016 4 2016 2 3 2016 56 3 205206 18 1 2016 19 1 2016 Copyright © 2016 Published by Elsevier Masson SAS. 2016 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. Mots clés Asthme Exacerbation Virus Rhinovirus Keywords Asthma Exacerbations Viral infections Rhinovirus ==== Body pmcLes exacerbations sévères sont un problème dans la prise en charge de l’asthme. En effet, indépendamment de la sévérité de l’asthme et de la pression thérapeutique, le risque de survenue d’une exacerbation persiste. Les exacerbations sévères sont responsables de nombreuses hospitalisations, d’une éviction scolaire et d’un coût élevé pour la société. Elles sont un facteur important de morbidité dans l’asthme mais également un facteur de mortalité. Parmi les facteurs déclenchant les exacerbations, les infections virales ont un rôle majeur. 1 La saisonnalité des exacerbations virales La majorité des exacerbations sévères surviennent au cours de l’automne. L’été est une saison moins propice aux exacerbations d’asthme. La fréquence des exacerbations est fortement liée aux épidémies virales, en particulier chez l’enfant [1]. Les études montrent qu’une infection virale est très fréquemment identifiée dans les voies aériennes supérieures, jusque dans 80 % des cas chez l’enfant [2], [3]. Chez l’adulte, les infections virales sont également largement impliquées dans les exacerbations sévères (60 %). Les infections à rhinovirus (RV) sont nettement prédominantes (80 %). Les autres virus impliqués sont entre autres le métapneumovirus, le virus de la grippe, le VRS, le parainfluenza virus, le coronavirus, l’adénovirus [2], [4]. Le RV de type C serait associé à des exacerbations plus sévères [4]. Le mois de septembre est particulièrement propice aux exacerbations d’asthme dans les pays du Nord, et ce en lien avec les infections virales, particulièrement les RV. Jusque 25 % des exacerbations sévères ont lieu pendant ce mois [5]. Ce pic d’exacerbations sévères est multifactoriel. Il survient peu de temps après la rentrée scolaire soit après une période d’été où la pression thérapeutique a souvent été levée ; il s’agit d’une période où l’exposition allergénique est forte. L’infection virale survient alors sur un terrain fragilisé et propice aux exacerbations. 2 Physiopathologie des exacerbations virales Le lien entre l’infection virale et les facteurs environnementaux a été mis en évidence. Il existe un effet synergique entre l’exposition allergénique et l’infection virale. Ainsi, la combinaison d’une exposition allergénique élevée et d’une infection virale augmente le risque d’hospitalisation pour une exacerbation sévère d’asthme [6]. Les mécanismes immunologiques ne sont pas complètement identifiés pour expliquer cette synergie. Torres et al. ont confirmé, in vitro, sur des cellules épithéliales bronchiques sensibilisées à l’ovalbumine, que l’exposition au virus ou au dsRNA synthétique conduit à l’amplification de la réponse Th2, par le biais de recrutement de cellules dendritiques et du récepteur TLR3 [7]. Subrata et al. ont mis en évidence un profil particulier d’activation des lymphocytes T de patients atopiques (par le biais de l’augmentation de l’expression d’un récepteur de haute affinité pour les IgE spécifiques) au cours d’une exacerbation d’asthme induite par une infection virale. La conséquence est l’activation d’une cascade inflammatoire Th2 qui va amplifier la réponse inflammatoire antivirale et déclencher l’exacerbation [8]. Plusieurs études ont étudié les mécanismes de la susceptibilité aux infections à RV dans l’asthme. Les cellules de l’immunité innée et adaptative localisées au niveau de la muqueuse respiratoire jouent un rôle essentiel dans les défenses antivirales et dans l’inflammation de l’asthme. Une infection virale des voies respiratoires induit classiquement une réponse antivirale associée à une réaction immunitaire de type Th1. Ces réponses sont liées à la production d’IFN de type I (INF-α/β) et d’IFN-γ. Chez les patients asthmatiques, la réponse sera plutôt de type Th2 [7]. Un défaut de réponse chez les asthmatiques pourrait expliquer leur susceptibilité aux infections virales, en particulier au RV. In vitro, Wark et al. ont mis en évidence un déficit de réponse immunitaire innée sur des cellules épithéliales bronchiques de patients asthmatiques. En réponse à l’infection à RV, en comparaison de cellules épithéliales bronchiques saines, ces cellules ont un défaut de production d’IFNβ. Il en résulte une augmentation de la réplication virale et défaut de lyse des cellules. Ce déficit impliquerait le défaut de production de réponse de type Th1 (IFN-γ) [9]. La même équipe a également mis en évidence un défaut d’IFN de type III (IFN-λ). L’IFN-λ est produit par les cellules épithéliales bronchiques au cours de la réponse antivirale, en réponse à l’infection à RV. La production de cet IFN a été inversement corrélée avec l’inflammation bronchique, la charge virale et la sévérité des symptômes. In vitro, un défaut de production a été identifié en réponse à l’infection, toujours en comparaison de cellules épithéliales bronchiques saines [10]. Ces anomalies, qui sont l’apanage des asthmes sévères, ne seraient pas en lien avec un défaut d’expression des récepteurs de reconnaissance virale comme le TLR3 [11]. 3 Conclusion Le lien entre infection virale et exacerbation d’asthme sévère est démontré. Les mécanismes immunologiques pouvant expliquer cette susceptibilité ne sont pas complètement identifiés. Mieux les connaître pourrait conduire à de nouvelles options thérapeutiques et adapter la prise en charge thérapeutique selon le phénotype du patient, en particulier en cas d’exacerbations fréquentes favorisées par les virus. Jusqu’à présent, peu d’études ont mis en évidence le bénéfice d’un traitement prophylactique sur la survenue des exacerbations d’asthme induites par les virus. Les biothérapies anti-IgE ou anti-IL5 ont un impact favorable sur les exacerbations [12]. Récemment, Teach et al. ont proposé l’administration d’omalizumab en prévention des exacerbations de l’automne et ont montré son efficacité en particulier en cas d’asthme sévère, avec exacerbation récente. Ils ont de plus rapporté que ce bénéfice était associé à une restauration de la production d’interféron [13]. Il parait donc important de tenir compte du facteur viral dans la prise en charge de l’asthme, d’identifier les exacerbateurs fréquents, et dans l’avenir d’intégrer ces données dans le cadre d’un traitement personnalisé ajusté au phénotype. Déclaration de liens d’intérêts Les auteurs déclarent ne pas avoir de liens d’intérêts. ==== Refs Références 1 Teach S.J. Gergen P.J. Szefler S.J. Mitchell H.E. Calatroni A. Wildfire J. Seasonal risk factors for asthma exacerbations among inner-city children J Allergy Clin Immunol 135 2015 1465 1473 25794658 2 Engelmann I. Mordacq C. Gosset P. Tillie-Leblond I. Dewilde A. Thumerelle C. Rhinovirus and asthma: reinfection, not persistence Am J Respir Crit Care Med 188 2013 1165 1167 24180448 3 Khetsuriani N. Kazerouni N.N. Erdman D.D. Lu X. Redd S.C. Anderson L.J. Prevalence of viral respiratory tract infections in children with asthma J Allergy Clin Immunol 119 2007 314 321 17140648 4 Bizzintino J. Lee W.M. Laing I.A. Vang F. Pappas T. Zhang G. Association between human rhinovirus C and severity of acute asthma in children Eur Respir J 37 2011 1037 1042 20693244 5 Johnston N.W. Johnston S.L. Duncan J.M. Greene J.M. Kebadze T. Keith P.K. The September epidemic of asthma exacerbations in children: a search for etiology J Allergy Clin Immunol 115 2005 132 138 15637559 6 Murray C.S. Poletti G. Kebadze T. Morris J. Woodcock A. Johnston S.L. Study of modifiable risk factors for asthma exacerbations: virus infection and allergen exposure increase the risk of asthma hospital admissions in children Thorax 61 2006 376 382 16384881 7 Torres D. Dieudonné A. Ryffel B. Vilain E. Si-Tahar M. Pichavant M. Double-stranded RNA exacerbates pulmonary allergic reaction through TLR3: implication of airway epithelium and dendritic cells J Immunol 185 2010 451 459 20505141 8 Subrata L.S. Bizzintino J. Mamessier E. Bosco A. McKenna K.L. Wikstrom M.E. Interactions between innate antiviral and atopic immunoinflammatory pathways precipitate and sustain asthma exacerbations in children J Immunol 183 2009 2793 2800 19620293 9 Wark P.A. Johnston S.L. Bucchieri F. Powell R. Puddicombe S. Laza-Stanca V. Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus J Exp Med 201 2005 937 947 15781584 10 Contoli M. Message S.D. Laza-Stanca V. Edwards M.R. Wark P.A. Bartlett N.W. Role of deficient type III interferon-lambda production in asthma exacerbations Nat Med 12 2006 1023 1026 16906156 11 Mordacq C. Deschildre A. Tillie-Leblond I. Dewilde A. Pichavant M. Thumerelle C. The profile of dendritic cell and T cell response is related to the viral trigger in children with severe asthma exacerbation Eur Respir J 40 56 2012 12 Ortega H.G. Liu M.C. Pavord I.D. Brusselle G.G. FitzGerald J.M. Chetta A. Mepolizumab treatment in patients with severe eosinophilic asthma N Engl J Med 371 2014 1198 1207 25199059 13 Teach S.J. Gill M.A. Togias A. Sorkness C.A. Arbes S.J. Jr. Calatroni A. Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations J Allergy Clin Immunol 136 2015 1476 1485 26518090
PMC007xxxxxx/PMC7118615.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)30310-9 10.1016/j.reval.2020.03.003 Éditorial Maladies respiratoires, allergies et infections à COVID-19. Premières nouvelles de Wuhan Respiratory diseases, allergy and COVID-19 infection. First news from WuhanKanny G. Médecine Interne, Immunologie Clinique et Allergologie, CHRU de Nancy, Laboratoire d’Hydrologie et Climatologie Médicales, Faculté de Médecine, 9 rue de la Forêt de Haye, 54505 Vandœuvre-lès-Nancy, France 1 4 2020 4 2020 1 4 2020 60 3 117118 25 3 2020 29 3 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. ==== Body pmcPlusieurs études ont attiré l’attention sur l’association entre infections virales et asthme [1]. Toutefois, il apparaît que les infections à coronavirus jouent un rôle mineur dans les exacerbations d’asthme. Nos confrères de Wuhan [2] nous informent sur l’impact de l’infection à ce nouveau virus, COVID-19 chez les personnes asthmatiques, allergiques ou porteuses de bronchopneumopathie obstructive chronique. Zhang et al. ont étudié les caractéristiques cliniques et le statut allergique de 140 patients infectés par COVID-19 hospitalisés du 16 janvier au 3 février 2020 dans un hôpital de Wuhan [2]. L’infection a été confirmée pour chacun par RT-PCR. Le diagnostic d’infection sévère se base sur la présence d’un des critères suivants:• détresse respiratoire avec une fréquence ≥ 30/mn; • saturation pulsée en oxygène ≤ 93 % au repos; • indice d’oxygénation (PaO2/FiO2) ≤ 300 mm Hg. La guérison est définie par le jour de la disparition de tous les symptômes. Parmi les 140 patients, 58 ont été classés comme sévères. Le ratio homme/femme est de 1/1. L’âge moyen des patients est de 57 ans avec des extrêmes allant de 25 à 87 ans. La majorité (70 %) avaient plus de 50 ans. L’âge moyen des patients identifiés comme sévères était de 64 ans et pour les cas non-sévères de 51,4 ans. Aucun patient ne rapportait une exposition directe avec le marché de Huanan ou des animaux sauvages. Ils s’agissaient d’infections communautaires. Trois professionnels hospitaliers étaient infectés. Parmi eux, 90 (64,3 %) avaient au moins une comorbidité : 79,3 % dans les formes sévères et 53,7 % dans celles non-sévères. Les plus fréquentes étaient l’hypertension (30 %) et le diabète (12,1 %). Une hypersensibilité médicamenteuse était rapportée par 11,4 % des patients et une urticaire par 2 patients. L’asthme ou une autre maladie allergique (rhinite, allergie alimentaire, dermatite atopique) ne sont pas rapportés par ces patients alors que la prévalence de l’asthme est estimée à 4,3 % en Chine [3] et la rhinite allergique à 17,2 % à Wuhan en 2011 [4]. La bronchopneumopathie chronique obstructive (BPCO) qui a une prévalence de 13,7 % en Chine concerne seulement 2 patients (1,4 %), ce qui est proche de la prévalence de 1,1 % rapporté par Guan et coll. [5] et celle de 3 % rapportée par Zhou et coll. [6]. Le tabagisme est actif pour 2 sujets, arrêté pour 7 autres. Ces taux sont faibles eu égard à la prévalence de la BPCO chez les sujets de plus de 40 ans en Chine qui est de 13,7 % [7] et au fait que 27,3 % des chinois sont fumeurs Les signes cliniques étaient: fièvre (91,7 %), toux (75 %), fatigue (75 %), oppression thoracique et dyspnée (36,7 %) et symptômes gastro-intestinaux à type de nausées, diarrhée, perte d’appétit, douleurs abdominales, éructations et vomissements (39,6 %). La majorité (99,3 %) présentait des images caractéristiques au scanner. La lymphopénie est présente chez 75,4 % des patients, l’éosinopénie dans 52,9 % des cas. Le taux de PCR était augmenté chez 91,9 % des patients. La faible prévalence des patients porteurs de BPCO ou fumeurs est surprenante. Cette population avait été identifiée à risque pour le Middle East respiratory syndrome coronavirus (MERS-CoV) : la cible de ce coronavirus est la dipeptidyl peptidase IV (DDP4) qui est plus exprimée dans cette population [8]. L’enzyme de conversion de l’angiotensine 2 (ECA2), très exprimée dans les cellules épithéliales des voies aériennes est identifiée comme étant le récepteur de SARS-Cov et joue un rôle crucial dans les lésions pulmonaires [9]. Elle vient également d’être identifiée comme le récepteur du COVID-19 [10]. D’autres études sont nécessaires pour étudier le rôle d’ECA2 dans la pathogénie des lésions pulmonaires induites par ce nouveau coronavirus et étudier l’expression d’ECA2 dans les cellules épithéliales des patients porteurs de BPCO et des fumeurs. Ces données préliminaires sont rassurantes. L’asthme, les maladies allergiques et la BPCO n’apparaissent pas comme étant des facteurs de risque dans cette population de patients hospitalisés. Il conviendra de confirmer ces données en population générale et en Europe. La période de confinement que nous traversons aura des effets bénéfiques pour les personnes présentant une pollinose en les exposant moins à l’air extérieur riche en pollens en cette période de l’année et à la pollution automobile qui diminue. Il conviendra cependant de veiller à la qualité de l’air intérieur de nos domiciles en évitant l’utilisation de substances volatiles irritantes ou allergisantes: fumée de tabac, produits d’entretien, parfums d’intérieur, combustions (bougies, encens avec émission de benzène…), etc. Il est conseillé d’aérer son domicile tôt le matin et à la tombée de la nuit. La Fédération française d’allergologie rappelle que les personnes allergiques doivent poursuivre la prise du traitement prescrit par leur médecin et en particulier les corticoïdes inhalés pour les asthmatiques afin que leur maladie soit bien contrôlée. Au-delà des symptômes respiratoires, il conviendra d'être particulièrement attentif à l’apparition de symptômes inhabituels tels que la fièvre, la fatigue, des céphalées, des courbatures, des troubles gastro-intestinaux, une perte de l’odorat (anosmie) et du goût (agueusie). Déclaration de liens d’intérêts L’auteur déclare ne pas avoir de liens d’intérêts. ==== Refs Références 1 Papadopoulos N.G. Christodoulou I. Rohde G. Agache I. Almqvist C. Bruno A. Viruses and bacteria in acute asthma exacerbations–A GA2LEN-DARE* systematic review Allergy 66 2011 458 468 21087215 2 Zhang J, Dong X, Cao Y, Yuan Y, Yang Y, Yan Y, et al. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy [Internet]. [cité 20 mars 2020]; Disponible sur: https://onlinelibrary.wiley.com/doi/abs/10.1111/all.14238. 3 Huang K. Yang T. Xu J. Yang L. Zhao J. Zhang X. Prevalence, risk factors, and management of asthma in China: a national cross-sectional study The Lancet 394 2019 407 418 4 Wang X.D. Zheng M. Lou H.F. Wang C.S. Zhang Y. Bo M.Y. An increased prevalence of self-reported allergic rhinitis in major Chinese cities from 2005 to 2011 Allergy 71 2016 1170 1180 26948849 5 Guan W.-J. Ni Z.-Y. Hu Y. Liang W.-H. Ou C.-Q. He J.-X. Clinical Characteristics of Coronavirus Disease 2019 in China N Engl J Med 2020 6 Zhou F. Yu T. Du R. Fan G. Liu Y. Liu Z. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study The Lancet 2020 [cité 24 mars 2020]; Disponible sur: http://www.sciencedirect.com/science/article/pii/S0140673620305663. 7 Wang C. Xu J. Yang L. Xu Y. Zhang X. Bai C. Prevalence and risk factors of chronic obstructive pulmonary disease in China (the China Pulmonary Health [CPH] study): a national cross-sectional study The Lancet 391 2018 1706 1717 8 Seys L.J.M. Widagdo W. Verhamme F.M. Kleinjan A. Janssens W. Joos G.F. DPP4, the Middle East Respiratory Syndrome Coronavirus Receptor, is Upregulated in Lungs of Smokers and Chronic Obstructive Pulmonary Disease Patients Clin Infect Dis 66 2018 45 53 29020176 9 Kuba K. Imai Y. Rao S. Gao H. Guo F. Guan B. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury Nat Med 11 2005 875 879 16007097 10 Xu X. Chen P. Wang J. Feng J. Zhou H. Li X. Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission Sci China Life Sci 63 2020 457 460 [Nancy, le 24 mars 2020] 32009228
PMC007xxxxxx/PMC7118699.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)30502-8 10.1016/j.jaad.2020.03.079 JAAD Online COVID-19, syphilis, and biologic therapies for psoriasis and psoriatic arthritis: A word of caution Kansal Naveen Kumar MD ∗ Department of Dermatology, Venereology, and Leprosy, All India Institute of Medical Sciences, Rishikesh ∗ Correspondence to: Naveen Kumar Kansal, MD, Department of Dermatology, Venereology, and Leprosy, All India Institute of Medical Sciences, Rishikesh-249203, India 1 4 2020 6 2020 1 4 2020 82 6 e213e213 © 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: I read the timely and thought-provoking article about the coronavirus disease 2019 (COVID-19) pandemic and biologic therapy for psoriasis by Lebwohl et al.1 The authors compiled research data about almost all the most commonly used biologics in dermatology and their rates of infection, upper respiratory infections, and nasopharyngitis based on current published studies. However, I would like to offer a word of caution: the article is based on trials of biologic therapies, which are the criterion standard. It should be noted that certain groundbreaking (initial) adverse effects were published in the past as case reports or letters and may not have gotten much attention if published today. One of the foremost examples is the thalidomide tragedy. The initial adverse effects of thalidomide were described by Florence2 and later, other workers reported the embryopathy adverse effects.3 More recently, Uslu et al4 described a unique case of possible reactivation of latent syphilis infection in a patient with psoriasis and psoriatic arthritis who was receiving therapy with interleukin-12/23 monoclonal antibody (ustekinumab). The authors suggested the possibility of reactivation of latent syphilis infection in their case, although they considered it unlikely. Similar reports had earlier appeared with antitumor necrosis factor-alpha therapy. The possibility that the natural progression of syphilis may have been accelerated by biologics in these cases cannot be completely excluded.5 Unlike syphilis, which is well known, the prognosis of COVID-19 cannot be predicted in individual cases (particularly in middle aged and older patients, with co-morbidities like diabetes mellitus or cardiovascular disease etc, if they are being treated with biologics). Therefore, in my opinion, the clinician must weigh the risk of loss of efficacy of a particular biologic in a responsive patient. It may be useful to consider that the patient is likely to be responsive to another biological agent when needed. Although the risk-to-benefit ratio must always be considered before discontinuing any effective medication, the unpredictable behavior of COVID-19 may be a priority at present. Patients who continue to receive therapy with biologics will need to be closely monitored as more knowledge about this infection becomes available. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 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 5 2020 1217 1218 32199889 2 Florence A.L. Is thalidomide to blame? Br Med J 2 5217 1960 1954 3 Ward S.P. Thalidomide and congenital abnormalities Br Med J 2 5305 1962 646 647 14004945 4 Uslu U. Heppt F. Sticherling M. Secondary syphilis infection under treatment with ustekinumab Clin Exp Dermatol 42 7 2017 836 838 28866870 5 Kansal N.K. Syphilis screening before initiation of immunosuppressive and biologic therapy for psoriasis and psoriatic arthritis Clin Exp Dermatol 43 7 2018 831 29775212
PMC007xxxxxx/PMC7129669.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(14)00209-7 10.1016/j.reval.2014.02.144 Pneu-17 Risque de récurrence à 1 an d’une population de nourrissons ayant présenté une bronchiolite aiguë : le poids de l’allergie familiale ? Amat F. a Petit I. b Verdan M. b Mulliez A. c Rochette E. c Henquell C. c a Hôpital Trousseau, Paris, France b CHU Estaing, Clermont-Ferrand, France c Hôpital Gabriel-Montpied, Clermont-Ferrand, France 3 4 2014 4 2014 3 4 2014 54 3 270270 Copyright © 2014 Published by Elsevier Masson SAS. 2014 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 pmcIntroduction.– Le risque de récurrence de sifflements ou d’asthme est fréquent lors d’un épisode aigu de bronchiolite. Des études précédentes ont montré que certains virus (VRS et surtout rhinovirus) étaient responsables de ces rechutes surtout chez les enfants nés de parents atopiques. Nous avons mené une enquête prospective sur une populations de nourrissons examinés lors de l’épidémie 2010–2011 [1] et avons recherché les facteurs susceptibles d’expliquer les récidives de sifflements à 1 an. Méthodes.– Cent soixante-cinq nourrissons ont participé à ce suivi à 1 an sur la base d’entretiens téléphoniques tous les 3 mois après l’épisode inaugural. Ils avaient tous bénéficié d’une enquête virologique portant des agents pneumotropes (virus respiratoire syncitial, rhinovirus A-B, C, métapneumovirus, influenzae et parainfluenzae, picornaviridae, bocavirus, adenovirus, coronavirus) d’une analyse objective de la gravité clinique initiale (score de Wang), d’une détermination de la protéine KL-6 comme marqueurs d’agression épithéliale. Nous avons considéré comme siffleurs récurrents tous les nourrissons ayant eu plus de 2 récidives dans l’année qui a suivi leur inclusion. Résultats.– Quarante-neuf nourrissons (29,69 %) ont eu plus de deux épisodes de sifflements dans la première année. En analyse univariée l’hospitalisation initiale par rapport à un suivi ambulatoire, l’existence d’un terrain allergique familial favorisent les rechutes (p = 0,05). En analyse multivariée, l’hospitalisation initiale, l’isolement d’un métapneumovirus, l’allergie familiale sont les facteurs de risques retrouvés sans atteindre la significativité (p = 0,06). Discussion.– Contrairement à d’autres études, nous n’avons pas retrouvé de relations entre l’isolement d’un VRS, d’un rhinovirus et le risque de rechutes, mais par contre avons confirmé le lien éventuel avec un terrain allergique familial. Conclusion.– Les bronchiolites aiguës du nourrisson exposent celui ci à des rechutes particulièrement la première année. Le terrain allergique familial reste une piste à explorer pour la prévention éventuelle des récidives. ==== Refs Référence 1 Amat H. Henquell C. Verdan M. Predicting the severity of acute bronchiolitis in infants: should we use a clinical score or a biomarker? J Med Virol J 9999 2013 1 9
PMC007xxxxxx/PMC7130538.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)30513-2 10.1016/j.jaad.2020.03.090 JAAD Online Rational hand hygiene during the coronavirus 2019 (COVID-19) pandemic Cavanagh Gregory BS Wambier Carlos Gustavo MD, PhD ∗ Department of Dermatology, The Warren Alpert Medical School of Brown University, Providence, Rhode Island ∗ Correspondence to: Carlos Gustavo Wambier, MD, PhD, 65 Village Square Dr, Ste 201, South Kingstown, RI 02879 5 4 2020 6 2020 5 4 2020 82 6 e211e211 © 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 enhanced preventive measures during the SARS-CoV-2 coronavirus disease 2019 (COVID-19) pandemic include proper hand hygiene. Health care workers (HCWs) may perform frequent handwashing with water and soap, leading to the potential complication of skin damage. In Lan et al's survey1 of 526 front-line COVID-19 HCWs, 74.5% reported damage to hand skin from enhanced infection prevention measures. HCWs who washed their hands more than 10 times per day reported more damage to hand skin (odds ratio, 2.17). This skin damage creates a route of entry for COVID-19, and basic skincare measures should be taken after handwashing to address this. Notably, the cell receptor for SARS-CoV-2 entry, angiotensin-converting enzyme 2 (ACE2), is abundantly present in blood vessels/capillaries of the skin, the basal layer of the epidermis, and hair follicles. ACE2 is also present in eccrine glands.2 Yan et al.3 discuss several measures that can be done to avoid hand eczema, maceration, and erosion due to PPE and handwashing during the pandemic. Qualified sanitizers with ethanol as the main component are prioritized for hand decontamination, and the application of hand cream/moisturizers on intact skin after hand washing is instructed.3 During handwashing, overly-hot water can lead to contact dermatitis and should therefore be avoided. Hypoallergenic moisturizers, gloves, and alcoholic hand sanitizers are vital to prevent hand eczema. Educational intervention about hand-eczema risk factors—such as frequent hand washing, surgical scrubbing, and prolonged glove use—was shown to promote hand-skin health among HCWs.4 Due to the risk of hand-skin damage, rational hand-hygiene measures respectful of the skin along with proper use of protective gloves and moisturizers must be instructed to HCWs during the fight against COVID-19. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Lan J. Song Z. Miao X. Skin damage among healthcare workers managing coronavirus disease-2019 J Am Acad Dermatol 82 5 2020 1215 1216 32171808 2 Hamming I. Timens W. Bulthuis M.L.C. Lely A.T. Navis G.J. van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis J Pathol 203 2004 631 637 15141377 3 Yan Y. Chen H. Chen L. Consensus of Chinese experts on protection of skin and mucous membrane barrier for healthcare workers fighting against coronavirus disease 2019 [Epub ahead of print] Dermatol Ther 2020 e13310 10.1111/dth.13310 Accessed March 13, 2020 32170800 4 Gasparini G. Carmisciano L. Giberti I. Murgioni F. Parodi A. Gallo R. “HEALTHY HANDS”. A pilot study for the prevention of chronic hand eczema in healthcare workers of an Italian University Hospital [Epub ahead of print] G Ital Dermatol Venereol 2019 10.23736/S0392-0488.19.06220-5 Accessed June 12, 2019
PMC007xxxxxx/PMC7134483.txt	==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 Published by Mosby, Inc. S0190-9622(87)70252-7 10.1016/S0190-9622(87)70252-7 Article Human immunodeficiency virus—associated vitiligo: Expression of autoimmunity with immunodeficiency? Duvic Madeleine M.D. ******1 Rapini Ronald M.D. Hoots William Keith M.D. * Mansell Peter W. M.D. ** * University of Texas Health Science Center at Houston, Medical School, The M.D. Anderson Hospital and Tumor Institute, Departments of Dermatology, Houston, TX Internal Medicine, Houston, TX * Pediatrics, Houston, TX **** Institute for Immunologic Disorders, Houston, TX 1 Reprint requests to: Dr. Madeleine Duvic, Department of Dermatology, University of Texas Medical School, 6431 Fannin, MSB 1,204, Houston, TX 77030 3 9 2008 10 1987 3 9 2008 17 4 656662 22 6 1987 Copyright © 1987 Published by Mosby, Inc. 1987 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. Persistent viral infections have been postulated to be trigger factors for the development of autoimmune disease. We report the development of vitiligo in four patients with human immunodeficiency virus (HIV)—related conditions and in one patient with hepatitis who later developed both psoriasis and acquired immunodeficiency syndrome (AIDS). Other common features were hepatitis and multiple other viral infections. Ribavirin was associated with repigmentation in one patient. Vitiligo may be an example of an autoimmune disease triggered by viral infection in a genetically predisposed host. ==== Body pmcCost of the photographs was defrayed in part by a grant from Ortho Pharmaceuticals ==== Refs References 1. Lerner AB Nordlund JJ Vitiligo; what is it? Is it important? J Am Med Assoc 239 1978 1183 1187 2. Nordlund JJ Vitiligo Thiers BH Dobson RL Pathogenesis of skin disease 1986 Churchill Livingstone New York 99 127 3. Lucky PA Nordlund JJ The biology of the pigmentary system and its disorders Dermatol Clinic 3 1985 197 216 4. Dawber RPR Clinical associations in vitiligo Postgrad Med J 46 1970 276 277 5448375 5. Dawber RPR Bleehan SS Vallance-Owen J Vitiligo and diabetes mellitus Br J Dermatol 84 1977 600 6. Cunliff WJ Hall R Newell DJ Vitiligo, thyroid disease and autoimmunity Br J Dermatol 80 1968 135 139 5646064 7. Olholm-Larsen P Kavli G Dermatitis herpetiformis and vitiligo Dermatologica 160 1980 41 44 7351269 8. Ortonne JP Perrot H Thivolet J Etude clinique et statistique d'une population de 100 vitiligos Sem hôp Paris 52 1976 679 686 188147 9. Brown AC Olkowski ZL McLaren JR Kutner MH Alopecia areata and vitiligo associated with Down's syndrome Arch Dermatol 113 1977 1296 10. Bor S Feiwel M Chanarin I Autoantibodies in vitiligo Br J Dermatol 81 1969 83 88 5767075 11. Brostoff J Bor S Feiwel M Autoantibodies in patients with vitiligo Lancet 2 1969 177 178 4183134 12. Betterle C Caretto A De Zio A Incidence and significance of organ specific autoimmune disorders (clinical, latent or only autoantibodies) in patients with vitiligo Dermatologica 171 1985 419 423 4092795 13. Howanitz N Nordlund JJ Lerner AB Bystryn JC Autoantibodies to melanocytes Arch Dermatol 117 1981 705 708 7316530 14. Grimes PE Halder RM Jones C Autoantibodies and their clinical significance in a black vitiligo population Arch Dermatol 119 1983 300 303 6601472 15. Naughton GK Eisinger M Bystryn JC Detection of antibodies to melanocytes in vitiligo by specific immunoprecipitation J Invest Dermatol 81 1983 540 542 6196421 16. Foley LM Lowe NJ Misheloff E Tiwari JL Association of HLA-DR4 with vitiligo J Am Acad Dermatol 8 1983 39 40 6600753 17. Norris DA Bystryn JC Kissinger R Direct evidence for immunologic cytotoxicity as a mechanism of human vitiligo [abstract] Clin Res 35 1987 251A 18. Tagawa Y Lymphocyte-mediated cytotoxicity against melanocyte antigens in Vogt-Koyanagi-Harada disease Jpn J Ophthalmol 22 1978 36 39 19. Nordlund JJ Albert DM Forget B Halo nevi and the Vogt-Koyanagi-Harada syndrome Arch Dermatol 116 1980 690 692 7377805 20. Gallo RC Salahuddin SZ Popovic M Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS Science 224 1984 500 503 6200936 21. Centers for Disease Control: classification system for human T-lymphotropic virus III/adenopathy associated virus infections Ann Intern Med 105 1986 234 237 3014942 22. Klatzman D Champagne E Chamaret S T lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV Nature 312 1984 767 768 6083454 23. Dagleish AG Beverly DC Clapham PR The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus Nature 312 1984 763 767 6096719 24. Gottlieb MS Schroff R Schanker HM Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency N Engl J Med 305 1981 1425 1431 6272109 25. Dwyer JM McNamara JG Sigal LH Immunological abnormalities in patients with the acquired mimunodeficiency syndrome (AIDS): a review Clin Immunol Rev 3 1984 25 129 6207972 26. Lane HC Depper JM Greene WC Qualitative analysis of immune function in patients with the AIDS evidence for a selective defect in soluble antigen N Engl J Med 313 1985 79 84 2582258 27. Fauci AS Macher AM Longo DL Acquired immunodeficiency syndrome: epidemiologic, clinical, immunologic and therapeutic considerations Ann Intern Med 100 1984 92 106 6318629 28. Mosca JD Bednarik DP Raj NBK Herpes simplex type-1 can reactivate transcription of latent human immunodeficiency virus Nature 324 1987 67 70 29. Griscelli C Durandy A Guy-Grand D A syndrome associating partial albinism and immunodeficiency Am J Med 65 1978 691 701 707528 30. Yakura H Wakisaka A Aizawa M HLA-D antigen of Japanese origin (LD-Wa) and its association with Vogt-Koyanagi-Harada syndrome Tissue Antigens 8 1976 35 42 60795 31. Koenig S Gendelman HE Orenstein JM Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy Science 233 1986 1089 1093 3016903 32. Schnittman SM Lane HC Higgins SE Direct polyclonal activation of human B lymphocytes by the acquired immune deficiency virus Science 233 1986 1084 1086 3016902 33. Kouns DM Marty DM Sharpe RW Oligoclonal bands in serum protein electrophoretograms of individuals with human immunodeficiency virus antibodies J Am Med Assoc 256 1986 2343 34. Nicholson JKA McDougal JS Spira TJ Immunoregulatory subsets of the T helper and T suppressor cell populations in homosexual men with chronic unexplained lymphadenopathy J Clin Invest 73 1984 191 201 6228564 35. Nicolson JKA McDougal JS Spira TJ Alterations of functional subsets of T helper and T suppressor cell populations in acquired immunodeficiency syndrome (AIDS) and chronic unexplained lymphadenopathy J Clin Immunol 5 1985 269 273 2931447 36. Aubock J Romani N Grubauer G Fritsch P HLA DR expression on keratinocytes is a common feature of diseased skin Br J Dermatol 114 1986 465 472 2421756 37. Basham TY Nicholoff BJ Merigan TC Morhenn VB Recombinant gamma interferon induces HLA-DR expression on cultured human keratinocytes J Invest Dermatol 83 1984 88 90 6206165 38. Basham TY Merigan TC Recombinant interferon gamma increases HLA-DR synthesis and expression J Immunol 130 1983 1492 1494 6403609 39. Suzumura A Lavi E Weiss R Silberberg DH Corona-virus infection induces H-Z antigen expression on oligodendrocytes and astrocytes Science 232 1986 991 993 3010460 40. Londei M Lamb JR Botalizzo GF Feldman M Epithelial cells expressing MHC II determinants can present antigen to cloned T cells Nature 312 1984 639 641 6334239 41. Southern P Oldstone MBA Medical consequences of persistent viral infection N Engl J Med 314 1986 359 366 3511377 42. Stricker RB Abrams DI Corash L Shuman MA Target platelet antigen in homosexual men with immune thrombocytopenia N Engl J Med 313 1985 1375 1380 2997609 43. McDevitt HO The molecular basis of autoimmunity Clin Res 34 1986 163 175 3086018
PMC007xxxxxx/PMC7134494.txt	==== Front J Am Acad Dermatol J Am Acad Dermatol Journal of the American Academy of Dermatology 0190-9622 1097-6787 Published by Mosby, Inc. S0190-9622(87)80450-4 10.1016/S0190-9622(87)80450-4 Article Abstracts 3 9 2008 10 1987 3 9 2008 17 4 662662 Copyright © 1987 Published by Mosby, Inc. 1987 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 pmc
PMC007xxxxxx/PMC7134506.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)30268-1 10.1016/j.jaad.2020.02.030 Commentary What are we doing in the dermatology outpatient department amidst the raging of the 2019 novel coronavirus? Chen Yusha MD Pradhan Sushmita PhD, MD Xue Siliang PhD, MD ∗ Department of Dermatology, West China Hospital of Sichuan University ∗ Correspondence to: Siliang Xue, PhD, MD, 37# Guoxuexiang, Chengdu 610041, China. 17 2 2020 4 2020 17 2 2020 82 4 10341034 © 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 pmcIn late December 2019, several individuals with unexplained pneumonia were reported in Wuhan, China. A novel coronavirus was subsequently identified as the causative pathogen and provisionally designated 2019 novel coronavirus (2019-nCoV).1 As of February 10, 2020, 42,638 cases of 2019-nCoV infection have been confirmed in China, with 21,675 suspected cases and 1016 deaths. There are still more than 3000 confirmed cases every day, involving people living in or visiting Wuhan, as a subsequent characteristic of human-to-human transmission. 2019-nCoV continues to spread around the world and has been reported in other countries such as the United States.2 Hospitals in all provinces and cities across China have taken effective measures to control the spread of 2019-nCoV. On January 24, 2020, the West China Hospital of Sichuan University temporarily shut the doors of its dermatology outpatient department and dermatology surgery by postponing all of the elective operations and limiting to only emergency operations. We did not, however, completely halt the services to some patients who need to visit the dermatology outpatient department during the 2019-nCoV outbreak. At the same time, to meet the medical requirements and reduce the flow of patients to the skin clinic, we began free online and telephone consultation by providing free dermatology consultations. The dermatology outpatient department in West China Hospital was scheduled to run on January 28, 2020, mainly for critical care patients. Patients who had made an advanced appointment for obtaining medical service but chose not to visit received a full refund of registration fees. The number of dermatology outpatient clinics has been drastically reduced from 8 to 4, and only 1 accompanying person is allowed to enter the clinic. People entering the outpatient and inpatient buildings must wear masks and have their body temperature monitored by professionals wearing tight protective clothing. At the entrance of the building, anyone with a fever (body temperature ≥37.3°C), travel history to Wuhan in last 2 weeks, clear contact with residents in Wuhan in last 2 weeks, or contact with people with a fever would be directly sent to the fever clinic for screening. These individuals are considered to have been exposed and are quarantined for 2 weeks, and potential exposures are also asked to quarantine themselves for 2 weeks at home. During the skin clinic, patients are not allowed to take off their masks except on indications of facial lesions. Doctors must wear masks, surgical caps, protective suits, gloves, and goggles at work; they take off their protective equipment only after their work in a designated disposable area. In other respects, educational programs and activities of West China Hospital have come to a halt; graduate students and interns are prohibited from returning to school and work. Also, West China Hospital established special psychologic intervention counseling via a telephone and network platform to help those in need and published a psychologic protection handbook for free download. It is uncertain to predict when the 2019-nCoV will end at the time of this writing. The West China hospital is still playing a powerful role in defending against the epidemic outbreak and is a microcosm of all of the countless Chinese hospitals at this moment. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Lu R. Zhao X. Li J. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding Lancet 2020 10.1016/S0140-6736(20)30251-8 2 Holshue M.L. DeBolt C. Lindquist S. First case of 2019 novel coronavirus in the United States N Engl J Med 2020 10.1056/NEJMoa2001191
PMC007xxxxxx/PMC7141633.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)30517-X 10.1016/j.jaad.2020.03.094 Dermatologic Surgery Racial differences in time to treatment for melanoma Tripathi Raghav MPH ab∗ Archibald Laura K. MD c Mazmudar Rishabh S. BS ab Conic Rosalynn R.Z. MD, PhD d Rothermel Luke D. MD, MPH ae Scott Jeffrey F. MD af Bordeaux Jeremy S. MD, MPH ab a Department of Dermatology, Case Western Reserve University School of Medicine, Cleveland, Ohio b Department of Dermatology, University Hospitals Cleveland Medical Center, Cleveland, Ohio c University of Minnesota Medical Center, Department of Dermatology, Minneapolis, Minnesota d Department of Surgery, University of Maryland Medical Center, Baltimore, Maryland e Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, Cleveland, Ohio f Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland ∗ Correspondence to: Raghav Tripathi, MPH, Department of Dermatology, University Hospitals Cleveland Medical Center, Lakeside 3500, 11100 Euclid Ave, Cleveland, OH 44106. 8 4 2020 9 2020 8 4 2020 83 3 854859 30 3 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 Longer time from diagnosis to definitive surgery (TTDS) is associated with increased melanoma-specific mortality. Although black patients present with later-stage melanoma and have worse survival than non-Hispanic white patients, the association between race and TTDS is unknown. Objective To investigate racial differences in time to melanoma treatment. Methods Retrospective review of the National Cancer Database (2004-2015). Multivariable logistic regression was used to evaluate the association of race with TTDS, controlling for sociodemographic/disease characteristics. Results Of the 233,982 patients with melanoma identified, 1221 (0.52%) were black. Black patients had longer TTDS for stage I to III melanoma (P < .001) and time to immunotherapy (P = .01), but not for TTDS for stage IV melanoma or time to chemotherapy (P > .05 for both). When sociodemographic characteristics were controlled for, black patients had over twice the odds of having a TTDS between 41 and 60 days, over 3 times the odds of having a TTDS between 61 and 90 days, and over 5 times the odds of having a TTDS over 90 days. Racial differences in TTDS persisted within each insurance type. Patients with Medicaid had the longest TTDS (mean, 60.4 days), and those with private insurance had the shortest TTDS (mean, 44.6 days; P < .001 for both). Conclusions Targeted approaches to improve TTDS for black patients are integral in reducing racial disparities in melanoma outcomes. Key words black chemotherapy disparities immunotherapy insurance melanoma mortality National Cancer Database non-Hispanic white racial stage survival time to definitive surgery time to treatment Abbreviations used ALM acral lentiginous melanoma aOR adjusted odds ratio CI confidence interval NCDB National Cancer Database NHW non-Hispanic white TTDS time from diagnosis to definitive surgery ==== Body pmc Capsule Summary • Longer time from diagnosis to definitive surgery (TTDS) is associated with increased melanoma-specific mortality; in this study, black patients had longer TTDSs for melanoma after sociodemographic factors were controlled for, and these differences persist for each insurance, stage I to III melanoma, and time to immunotherapy. • Targeted interventions to improve TTDS for black patients with melanoma are important in improving outcomes. An estimated 2.3% of Americans are diagnosed with cutaneous melanoma annually, and the national incidence of cutaneous melanoma has continued to rise over the past decade.1 It has been shown that dermatology visits reduce adverse events, mortality, and unnecessary hospitalizations for patients with melanoma.2 , 3 However, substantial disparities in access to and use of dermatologic care for patients with melanoma have been shown for a myriad of clinical and sociodemographic factors, including age, sex, rurality, provider supply, distance to dermatologic care, and poverty rate.4 , 5 Specifically, race and insurance status are associated with differences in disease-specific mortality for patients with melanoma.6, 7, 8 Black patients present with later-stage melanoma, and later-stage melanoma at diagnosis and increased time to treatment for stage I melanoma have each independently been associated with increased melanoma-specific mortality.6 , 8, 9, 10 Despite this, the association between race and time from diagnosis to definitive surgery (TTDS) is unknown. As such, our primary goal was to investigate differences in TTDS between black and non-Hispanic white (NHW) patients with melanoma. Our secondary goals were to determine differences in TTDS between black and NHW patients by melanoma stage and insurance type and to examine racial differences in stage at presentation, distance from the hospital, and time to medical treatment (immunotherapy and chemotherapy). Methods Patients with cutaneous melanoma were identified using the National Cancer Database (NCDB) from 2004 to 2015. The NCDB, produced by the American Cancer Society and the American College of Surgeons, contains data from more than 1500 accredited hospitals and more than 70% of all newly diagnosed cancer cases in the United States. Patients with American Joint Committee on Cancer pathologic stage I to IV cutaneous melanoma were included in this study. TTDS was calculated as the number of days between initial diagnosis and definitive surgical resection of the primary tumor. Patients with missing data for covariates, unknown stage, or excisional biopsy as definitive treatment (TTDS of 0 days) were excluded. Descriptive analyses were performed for initial univariate comparison of sociodemographic characteristics between racial groups using the Pearson chi-square and analysis of variance (ANOVA). The Student t test (pooled) was initially used for univariate comparison of time to immunotherapy and chemotherapy, as well as for TTDS stratified by stage and insurance type between racial groups. Multivariable logistic regression was used to evaluate the association of race with TTDS, controlling for sex, age, median household income, and insurance type. In the multivariable model, adjusted odds ratios were calculated for black patients (reference group: NHW patients). Institutional review board approval was not required for the use of this publicly available, deidentified database. All analyses were performed in the statistical software R (R Foundation, Vienna, Austria), and P less than .05 was considered significant.11 Results Our sample included 233,982 patients with cutaneous melanoma, of which 1221 (0.52%) were black and 232,761 were NHW (99.5%) (Table I ). Black and NHW patients did not differ by age (P = .07). Compared with NHW patients, black patients were more often female (P < .001) and presented with later-stage melanoma (P < .001). Median household income differed significantly by race (P < .001). Most NHW patients had a median household income of $63,000 or greater (41.9%), whereas most black patients had a median household income of less than $38,000 (32.9%). Insurance status also differed by race, with a greater proportion of black patients having Medicaid or no insurance than NHW patients (7.0% vs 2.1% and 5.7% vs 2.3%, respectively; P < .001). On average, black patients lived closer to the hospital than NHW patients (70.0% vs 61.6% living less than 20 miles from the hospital; P < .001).Table I Sample demographics∗ Characteristics NHW, n (%) Black, n (%) P value Total number of patients 232,761 1221 Age, y, n (%) <30 9609 (4.1) 37 (3.0) .072 30-39 17,358 (7.5) 94 (7.7) 40-49 31,729 (13.6) 141 (11.5) 50-59 48,272 (20.7) 273 (22.4) 60-69 52,387 (22.5) 291 (23.8) 70-79 44,031 (18.9) 243 (19.9) 80+ 29,375 (12.6) 142 (11.6) Sex, n (%) Male 134,164 (57.6) 530 (43.4) <.001 Female 98,597 (42.4) 691 (56.6) <.001 Stage of melanoma, n (%) Stage I 154,781 (66.5) 438 (35.9) <.001 Stage II 43,644 (18.8) 385 (31.5) Stage III 27,255 (11.7) 294 (24.1) Stage IV 7081 (3.0) 104 (8.5) Time to treatment, days, mean (SD) Time to definitive surgery 11.72 (24.61) 23.42 (37.43) <.001 Time to chemotherapy 100.41 (100.57) 123.36 (135.55) .100 Time to immunotherapy 108.31 (83.82) 129.79 (79.31) .012 Time to definitive surgery, days, n (%) 0-30 198,054 (85.1) 857 (70.2) <.001 31-60 27,782 (11.9) 241 (19.7) 61-90 4775 (2.1) 70 (5.7) >90 2150 (0.9) 53 (4.3) Insurance status, n (%) Not insured 5275 (2.3) 69 (5.7) <.001 Private insurance 126,858 (54.5) 533 (43.7) <.001 Medicaid 4973 (2.1) 85 (7.0) <.001 Medicare 88,760 (38.1) 484 (39.6) .280 Other government 2410 (1.0) 14 (1.1) .702 Unknown 4485 (1.9) 36 (2.9) .010 Median household income, n (%) <$38,000 24,273 (10.5) 399 (32.9) <.001 $38,000-$47,999 47,061 (20.4) 272 (22.4) $48,000-$62,999 62,747 (27.2) 287 (23.7) $63,000+ 96,540 (41.9) 255 (21.0) Distance to hospital, miles, n (%) <20 142,166 (61.6) 847 (70.0) <.001 20-39 43,934 (19.0) 170 (14.0) 40-59 17,205 (7.5) 79 (6.5) >60 27,408 (11.9) 114 (9.4) NHW, Non-Hispanic white; SD, standard deviation. ∗ Pearson chi-square for categorical variables and t test for continuous variables. Most black (70.2%) and NHW (85.1%) patients had a TTDS between 0 and 30 days. Compared to NHW patients, black patients had an increased average TTDS (23.4 days vs 11.7 days; P < .001) and increased average time to immunotherapy (129.8 days vs 108.3 days) (P = .01). There was no significant difference in time to chemotherapy between black and NHW patients (123.4 days vs 100.4 days, P = .10). Stratified by stage, black patients had an increased average TTDS for stage I, II, and III melanoma (P < .001) but not stage IV melanoma (P = .55) (Table II ). Black patients also had an increased average TTDS when stratified by insurance type (Table III ). After sex, age, income, and insurance status were controlled for, black patients were significantly more likely than NHW patients to have a TTDS between 31 and 60 days (adjusted odds ratio [aOR], 2.10; 95% confidence interval [CI], 1.74-2.34), 61 to 90 days (aOR, 3.15; 95% CI, 2.42-4.02), or more than 90 days (aOR, 5.16; 95% CI, 3.84-6.80) (P < .001 for all) (Table IV ).Table II Comparison of time to definitive surgical treatment of melanoma between racial groups by stage Melanoma stage Race Mean TTDS, days SD P value Stage I NHW 34.59 33.69 <.001 Black 45.84 42.88 Stage II NHW 37.71 37.52 <.001 Black 46.25 39.87 Stage III NHW 38.80 34.38 <.001 Black 50.78 52.34 Stage IV NHW 41.74 42.48 .548 Black 45.76 39.92 NHW, Non-Hispanic white; SD, standard deviation; TTDS, time to definitive surgical treatment. Table III Comparison of time to definitive surgical treatment of melanoma between racial groups by insurance type Insurance Race Mean TTDS (days) SD P value None NHW 39.33 37.917 .027 Black 54.8 45.835 Private NHW 34.29 32.002 <.001 Black 44.63 46.132 Medicaid NHW 42.55 35.968 .046 Black 60.41 72.707 Medicare NHW 35.77 23.269 <.001 Black 44.53 29.239 NHW, Non-Hispanic white; SD, standard deviation; TTDS, time to definitive surgical treatment. Table IV Multivariable logistic regression for time to definitive surgery of melanoma Patient demographics Adjusted odds ratio∗ (95% CI) P value Sex Male Reference — Female 1.85 (1.65-2.08) <.001 Age, years <30 Reference — 30-49 1.39 (0.99-2) .066 50-69 1.81 (1.31-2.58) .001 >70 1.51 (1.06-2.22) .029 Median household income <$38,000 Reference — $38,000-$47,999 0.34 (0.29-0.4) <.001 $48,000-$62,999 0.26 (0.22-0.3) <.001 $63,000+ 0.15 (0.12-0.17) <.001 Insurance Not insured Reference — Private insurance 0.43 (0.33-0.56) <.001 Medicaid 1.14 (0.83-1.58) .433 Medicare 0.5 (0.38-0.67) .002 Other government 0.58 (0.31-1) .927 Unknown 0.8 (0.53-1.2) .1338 Time to definitive surgical treatment, days 0-30 Reference — 31-60 2.01 (1.74-2.34) <.001 61-90 3.15 (2.42-4.02) <.001 More than 90 5.16 (3.84-6.8) <.001 CI, Confidence interval. ∗ Adjusted odds ratios are for black patients (reference: non-Hispanic white race). Discussion In this study, black patients had a longer TTDS for stages I to III melanoma and greater time to immunotherapy compared with NHW patients, and the racial differences in TTDS persisted within each insurance type. There were no racial differences in TTDS for stage IV melanoma or time to chemotherapy. Additionally, compared with NHW patients, black patients had over twice the odds of having a TTDS between 41 and 60 days, over 3 times the odds of having a TTDS between 61 and 90 days, and over 5 times the odds of having a TTDS over 90 days. These findings add to the literature by showing increased TTDSs for black patients with melanoma after sex, age, income, and insurance type were controlled for. Our data suggest that increased TTDSs in black patients with melanoma may be an independent explanatory factor for racial differences in melanoma survival, alongside factors such as later stage at presentation, biological differences in melanoma characteristics, and differences in health care use.6 , 9 , 12 Multiple unfavorable socioeconomic factors may exacerbate overall health status more than the additive effects of each of the individual factors.13 Racial differences in TTDS persisted within each insurance group, implying that insurance status does not fully account for racial TTDS disparities. We found that black patients also had increased TTDSs despite living closer to hospitals, suggesting that physical distance from the hospital is not as much of a contributor to TTDS for melanoma as for other cancers (eg, colorectal).14 A recent study of 3 high-risk surgical procedures showed that black patients lived closer to high-quality hospitals but were 25% to 58% more likely to receive surgery at low-quality hospitals than NHW patients; it is possible that a similar phenomenon exists in TTDS for melanoma.15 The quality and availability of melanoma treatment may thus be significantly different between racial groups for reasons other than travel burden. 15 Efforts to geographically centralize care for melanoma should consider that disparities may be driven by other extrinsic and intrinsic patient-level factors. Creation of a model delineating interactions between the myriad components underlying worse outcomes for black patients with melanoma, including race and insurance status, is critical in identifying targeted avenues for intervention. Difference in disease characteristics by race may also affect time to treatment for melanoma. Black patients more often present with acral lentiginous melanoma (ALM) on the lower extremities and have increased Breslow depth and stage at diagnosis for other melanoma subtypes, which portends worse prognosis.16 Several controversies exist in the treatment of ALM that are not present in the treatment of other melanoma subtypes (such as superficial spreading melanoma), including appropriate excision margins, difficulty of primary closure, efficacy of secondary intention healing, and the use of flaps and grafts.17, 18, 19, 20 Furthermore, ALM may have less susceptibility to immunotherapy because of poor immunogenicity and infrequent BRAF mutation.18 These controversies and challenges in the treatment of ALM may necessitate further planning and coordination and, thus, increase TTDS and time to treatment for melanoma in black patients; ultimately, this may further exacerbate disparities in outcomes. For a variety of cancers, including breast and colorectal, stage at presentation plays a stronger independent role in survival than race.21 , 22 When stratified by stage, black patients had increased TTDS for stages I to III melanoma but not stage IV melanoma. Racial disparities in time to treatment may thus be less prominent for melanoma that has metastasized. Immunotherapy and targeted therapy are increasingly becoming the standard of care for patients with metastatic melanoma.23 It has been shown that black patients are less likely to receive immunotherapy for metastatic melanoma and various other cancers after other sociodemographic factors are controlled for.23 , 24 Our research also adds to the growing knowledge base regarding disparities in immunotherapy by showing that black patients receive immunotherapy an average of 21.5 days later than NHW patients. As the use of immunotherapy for melanoma continues to grow, it is important to better understand and address these underlying racial disparities. Strengths of this study include the use of one of the largest cancer registries in the world with rigorous quality assurance measures, variability in geography and hospital type, and availability of several nuances of treatment and staging that are not present in state-based registries. One limitation is that patients were matched by broader age group and stage categories rather than smaller age intervals and stage subcategories. Additionally, limited information was available to further characterize the heterogeneity of chemotherapy and immunotherapy. Finally, in 2005, 48.4% of all melanomas in the United States were included in NCDB; the NCDB may not be generalizable to the entire US population given that it is a hospital-based registry, and there may be disproportionate representation of certain groups.25 Conclusion This study investigated racial differences in time to treatment for melanoma using a large hospital-based administrative health care database. Black patients had longer TTDS for melanoma than NHW patients after other sociodemographic factors were controlled for, and racial differences in TTDS persisted after stratification by insurance type and melanoma stage. Ultimately, it is important to better understand the various components underlying worse outcomes for black patients with melanoma. Targeted approaches to improve TTDSs for black patients with melanoma are integral in reducing racial disparities in melanoma outcomes. Raghav Tripathi had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Noone A.M. Howlader N. Krapcho M. SEER Cancer Statistics Review, 1975-2015 2017 National Cancer Institute Bethesda, MD 2 Arakaki R.Y. Strazzula L. Woo E. Kroshinsky D. The impact of dermatology consultation on diagnostic accuracy and antibiotic use among patients with suspected cellulitis seen at outpatient internal medicine offices JAMA Dermatol 150 10 2014 1056 25143179 3 Roetzheim R.G. Lee J.-H. Ferrante J.M. The influence of dermatologist and primary care physician visits on melanoma outcomes among Medicare beneficiaries J Am Board Fam Med 26 6 2013 637 647 24204060 4 Stitzenberg K.B. Thomas N.E. Dalton K. Distance to diagnosing provider as a measure of access for patients with melanoma Arch Dermatol 143 8 2007 991 998 17709657 5 Buster K.J. Stevens E.I. Elmets C.A. Dermatologic health disparities Dermatol Clin 30 1 2012 53 59 22117867 6 Dawes S.M. Tsai S. Gittleman H. Barnholtz-Sloan J.S. Bordeaux J.S. Racial disparities in melanoma survival J Am Acad Dermatol 75 5 2016 983 991 27476974 7 Adamson A.S. Zhou L. Baggett C.D. Thomas N.E. Meyer A.-M. Association of delays in surgery for melanoma with insurance type JAMA Dermatol 153 11 2017 1106 1113 28979974 8 Kooistra L. Chiang K. Dawes S. Gittleman H. Barnholtz-Sloan J. Bordeaux J. Racial disparities and insurance status: an epidemiologic analysis of Ohio melanoma patients J Am Acad Dermatol 78 2018 998 1000 29138060 9 Conic R.Z. Cabrera C.I. Khorana A.A. Gastman B.R. Determination of the impact of melanoma surgical timing on survival using the National Cancer Database J Am Acad Dermatol 78 1 2018 40 46 29054718 10 Baranowski M.L.H. Yeung H. Chen S.C. Gillespie T.W. Goodman M. Factors associated with time to surgery in melanoma: an analysis of the National Cancer Database J Am Acad Dermatol 81 4 2019 908 916 31163238 11 R Core Team. R: a language and environment for statistical computing. Available at: https://www.r-project.org/. Accessed January 1, 2020. 12 Tripathi R. Knusel K.D. Ezaldein H.H. Scott J.F. Bordeaux J.S. Association of demographic and socioeconomic characteristics with differences in use of outpatient dermatology services in the United States JAMA Dermatol 154 11 2018 1286 1291 30267073 13 Shen J.J. Cochran C.R. Mazurenko O. Racial and insurance status disparities in patient safety indicators among hospitalized patients Ethn Dis 26 3 2016 443 452 27440986 14 Massarweh N.N. Chiang Y.J. Xing Y. Association between travel distance and metastatic disease at diagnosis among patients with colon cancer J Clin Oncol 32 9 2014 942 948 24516014 15 Dimick J. Ruhter J. Sarrazin M.V. Birkmeyer J.D. Black patients more likely than whites to undergo surgery at low-quality hospitals in segregated regions Health Aff 32 6 2013 1046 1053 16 Mahendraraj K. Sidhu K. Lau C.S.M. Mcroy G.J. Chamberlain R.S. Smith F.O. Malignant melanoma in African-Americans a population-based clinical outcomes study involving 1106 African-American patients from the Surveillance, Epidemiology, and End Result (SEER) database (1988-2011) Medicine (Balitmore) 96 15 2017 e6258 17 Nakamura Y. Teramoto Y. Sato S. Yamamoto A. Current surgical management of acral lentiginous melanoma Melanoma—Current Clinical Management and Future Therapeutics 2015 Intech London 18 Nakamura Y. Fujisawa Y. Diagnosis and management of acral lentiginous melanoma Curr Treat Options Oncol 19 8 2018 42 29951919 19 Jung J.Y. Roh H.J. Lee S.H. Nam K. Chung K.Y. Comparison of secondary intention healing and full-thickness skin graft after excision of acral lentiginous melanoma on foot Dermatologic Surg 37 9 2011 1245 1251 20 Bello D.M. Chou J.F. Panageas K.S. Prognosis of acral melanoma: a series of 281 patients Ann Surg Oncol 20 11 2013 3618 3625 23838913 21 Deshpande A.D. Jeffe D.B. Gnerlich J. Iqbal A.Z. Thummalakunta A. Margenthaler J.A. Racial disparities in breast cancer survival: an analysis by age and stage J Surg Res 153 1 2009 105 113 19084242 22 Lai Y. Wang C. Civan J.M. Effects of cancer stage and treatment differences on racial disparities in survival from colon cancer: a United States population-based study Gastroenterology 150 2016 1135 1146 26836586 23 Haque W. Verma V. Butler E.B. Teh B.S. Racial and socioeconomic disparities in the delivery of immunotherapy for metastatic melanoma in the United States J Immunother 42 6 2019 228 235 30985445 24 Oliver T. Pezzi T.A. Pezzi A.E. Immunotherapy disparities in metastatic melanoma J Clin Oncol 37 15 suppl 2019 9525 25 Bilimoria K.Y. Stewart A.K. Winchester D.P. Ko C.Y. The National Cancer Database: a powerful initiative to improve cancer care in the United States Ann Surg Oncol 15 3 2008 683 690 18183467
PMC007xxxxxx/PMC7144601.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)30522-3 10.1016/j.jaad.2020.03.099 JAAD Online The use of Janus kinase inhibitors in the time of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Peterson Danielle MD Damsky William MD, PhD King Brett MD, PhD ∗ Department of Dermatology, Yale School of Medicine, New Haven, Connecticut ∗ Correspondence to: Brett King, MD, PhD, 333 Cedar St, LCI 501, PO Box 208059, New Haven CT 06510 9 4 2020 6 2020 9 4 2020 82 6 e223e226 © 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: During the time of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, questions arise regarding patients being treated with immunomodulatory therapies. In particular, is there an increased risk of acquiring the infection or experiencing a worse outcome from SARS-CoV-2? Although this exact question is presently unanswerable, we can look at safety data from clinical trials to try to understand patient susceptibility to different infections. Others have addressed this in the context of biologic1 or classical small molecule therapy,2 but the risk of Janus kinase inhibitor (JAKi) treatment has not been addressed. In light of the growing off-label use of JAKis in dermatology in addition to pharmaceutical industry-sponsored clinical trials of JAKis for alopecia areata, atopic dermatitis, vitiligo, and other conditions, dermatologists need data to better understand the risks of JAKi treatment so they can best manage and counsel their patients during this unique time. We analyzed and collated adverse events data from JAKi clinical trials. In particular, we focused on infections and pulmonary toxicities observed across the different United States Food and Drug Administration-approved JAKi for their Food and Drug Administration-approved indications. When available, data from phase II or III clinical trials for dermatologic indications was included. Table I summarizes the rates of various infections, including upper respiratory infections, nasopharyngitis, and influenza, for JAKi-treated groups vs placebo groups. Overall, rates of infectious events are only mildly increased in JAKi-treated patients. We also collated pulmonary toxicities of JAKis to identify potential risks of worsening severe respiratory disease from SARS-CoV-2, and such toxicities are all but absent.Table I Rate of infections with Janus kinase inhibitors in randomized, double-blind, placebo-controlled trials over 8 to 24 weeks' duration JAK inhibitor specificity JAK inhibitor name DX Treatment groups (No. patients) Total infections, No. (%) Serious infections, No. (%) URI, No. (%) UTI, No. (%) NP, No. (%) HSV, No. (%) Zoster, No. (%) Influenza, No. (%) Reported pulmonary toxicity∗ JAK1/3 Tofacitinib RA Placebo (n = 122) Tofacitinib 5 mg bid (n = 243) Tofacitinib 10 mg bid (n = 245) Study duration 12 weeks (Fleischmann et al, N Engl J Med, 2012;367(6):495-507.) NR 0 0 1 (<1) 6 (5) 11 (5) 8 (3) 3 (3) 4 (2) 10 (4) 2 (2) 4 (2) 5 (2) NR One case 4 (3) 2 (1) 4 (2) CR: PAH (Habib et al, J Clin Rheumatol, 2018.) UC OCTAVE 1 Placebo (n = 122) Tofacitinib 10 mg bid (n = 476) (∼45%-50% on steroids) Study duration 8 weeks OCTAVE 2 Placebo (n = 112) Tofacitinib 10 mg bid (n = 429) (∼45%-50% on steroids) Study duration 8 weeks (Sandborn et al, N Engl J Med, 2017;376(18):1723-1736.) 19 (16) 111 (23) 17 (15) 78 (18) 0 6 (1) 0 1 (<1) NR NR 0 0 0 0 9 (7) 34 (7) 4 (4) 21 (5) NR NR 1 (<1) 3 (<1) 0 2 (<1) NR NR JAK1/2 Baricitinib AD BREEZE-AD1 Placebo (n = 249) Baricitinib 1 mg qd (n = 127) Baricitinib 2 mg qd (n = 123) Baricitinib 4 mg qd (n = 125) Study duration 16 weeks BREEZE-AD2 Placebo (n = 244) Baricitinib 1 mg qd (n = 124) Baricitinib 2 mg qd (n = 123) Baricitinib 4 mg qd (n = 123) Study duration 16 weeks (Simpson et al, Br J Dermatol, March 2020, bjd.18898.) NR NR NR NR 6 (2) 1 (1) 3 (2) 4 (3) 5 (2) 6 (5) 5 (4) 4 (3) 4 (2) 1 (1) 2 (2) 4 (3) 3 (1) 0 0 2 (2) 26 (10) 22 (17) 12 (10) 12 (10) 30 (12) 13 (11) 16 (13) 10 (8) 3 (1) 7 (6) 4 (3) 9 (7) 11 (5) 6 (5) 7 (6) 5 (4) 1 case Blinded 2 cases blinded NR NR NR RA RA-BEAM phase 1 Placebo (n = 488) Baricitinib 4 mg qd (n = 487) Adalimumab 40 mg q2wk (n = 330) (100% on MTX) Study duration 24 weeks (Taylor et al, N Engl J Med, 2017;376(7) 652-662.) 134 (27) 176 (36) 110 (36) 7(1) 5 (1) 2 (<1) 14 (3) 15 (3) 13 (4) 0 1 (<1) 0 0 1 (<1) 0 NR 2 (<1) 7 (1) 4 (1) 4 (<1) 12 (2) 5 (2) Ruxolitinib MF COMFORT I Ruxolitinib 15 or 20 mg bid (n = 155) Placebo (n = 151) Study duration 24 weeks (Verstovsek et al, J Hematol Oncol, 2017;10 (1):55.) NR NR 34 (22) 15 (10) 31 (20) 7 (5) 14 (9) 9 (6) 6 (4) 2 (1) 16 (10) 1 (1) 8 (5) 0 CR: ARDS (Kerget et al, Respir Med Case Rep, 2017;22:243-245; †Herman et al, Ann Am Thorac Soc, 2014;11(7):1145-1148; †Beauverd, Samii, Int J Hematol, 2014;100(5):498-501.) †CR: Pleural effusion (Tefferi and Pardanani, Mayo Clin Proc, 2011;86(12):1188-1891.) ‡CR: PAH (Low et al, Haematologica, 2015;100(6):e244-245.) JAK1 Upadacitinib AD Placebo (n = 40) Upadacitinib 7.5 mg qd (n = 42) Upadacitinib 15 mg qd (n = 42) Upadacitinib 30 mg qd (n = 42) Study duration 16 weeks (Guttman-Yassky et al, J Allergy Clin Immunol, 2020;145(3):877-884.) 8 (20) 22 (52) 18 (43) 17 (41) 0 2 (5) 1 (2) 0 4 (10) 7 (17) 5 (12) 5 (12) NR 1 (3) 2 (5) 4 (10) 3 (7) NR 0 0 0 0 0 3 (7) 0 0 NR RA SELECT-BEYOND Placebo (n = 169) Upadacitinib 15 mg qd (n = 164) Upadacitinib 30 mg qd (n = 165) (∼70% of all groups on MTX, 50% on steroids) Study duration 12 weeks (Genovese et al, Lancet, 2018;391(10139):2513-2124.) 51 (30) 54 (33) 55 (33) 0 1 (1) 4 (2) 13 (8) 13 (8) 10 (6) 10 (6) 15 (9) 9 (5) 11 (7) 7 (4) 9 (5) NR 1 (1) 1 (1) 4 (2) 0 0 0 NR AD, Atopic dermatitis; ARDS, acute respiratory distress syndrome; bid, twice daily; CR, case report; DX, diagnosis; HSV, herpes simplex virus; JAK, Janus kinase; MF, myelofibrosis; MTX, methotrexate; NP, nasopharyngitis; NR, not reported; PAH, pulmonary arterial hypertension; q2wk, every other week; qd, once daily; RA, rheumatoid arthritis; URI, upper respiratory infection; UTI, urinary tract infection; Zoster, varicella-zoster virus. ∗ www.pneumotox.com. † Indicates adverse events as a result of abrupt discontinuation of Janus kinase therapy. ‡ Exacerbation of pre-existing condition. To understand the infection data, an understanding of the mechanism and pharmacokinetics of JAKis is helpful (Fig 1 , A). Cytokines can drive autoimmunity when their activity is exaggerated. JAKis, which are taken orally 1 to 2 times per day, largely impact pathogenically elevated cytokine activity, with relative sparing of normal cytokine activity because drug concentrations are subtherapeutic for part of the day (Fig 1, B).3 Therefore, the immune response to infection is grossly intact.Fig 1 Janus kinase (JAK) inhibitors (JAKi) block the activity of cytokines. (A) Greater than 50 cytokines signal via the JAK-signal transducer and activator of transcription proteins (STAT) pathway and rely entirely on the kinase activity of JAK proteins to transmit their signals. JAK inhibitors block the activity of activated JAK proteins downstream of cytokine receptor signaling and thus prevent downstream activation of STAT proteins. (B) JAK inhibitors are oral medications dosed 1 to 2 times per day. The levels of drug in the plasma fluctuate throughout the day. During peak plasma levels a portion, but not all, of a particular cytokine's activity is inhibited. In practice, in this therapeutic range, pathologically elevated cytokine activity is targeted while normal cytokine function is relatively spared. Throughout the day, the plasma concentration is also frequently subtherapeutic. The specific range varies for individual cytokines and the specificity of the JAK inhibitor. Upon cessation of the drug, the effect dissipates rapidly. Discontinuation of JAKis in the setting of initial infection, such as with SARS-CoV-2, may be beneficial given the role of JAK-signal transducer and activator of transcription proteins (STAT)-dependent type I (α/β) and type II (γ) interferons in antiviral immunity. The biologic effects of JAKis dissipate rapidly with cessation of the drug, given their short half-lives. The potential role of JAKi treatment for patients with cytokine release syndrome of severe SARS-CoV-2 infection is more complex and an area of active investigation. While anecdotal, we are aware of 3 patients (2 women and 1 man) in their 20s in our care who are taking JAKis for alopecia areata, of whom 2 have tested positive for SARS-CoV-2, and 1 very likely has it (per symptoms). All 3 have had uneventful courses and are recovering after cessation of treatment. In this time of the SARS-CoV-2 pandemic, we must be as informed as possible regarding the risks of the treatments we prescribe our patients. Of course, shared decision making reigns supreme, but without data we, as physicians, will be unable to provide our patients the guidance they rely on us for. Funding sources: This work was supported by the Ranjini and Ajay Poddar Fund for Dermatologic Diseases Research (Dr King). Dr Damsky is supported by the 10.13039/100001582 Dermatology Foundation . Conflicts of interest: Dr Damsky has received research funding from 10.13039/100004319 Pfizer , but it did not support this work, and is a consultant for Eli Lilly. Dr King is an investigator for Concert Pharmaceuticals Inc, Eli Lilly and Company, and Pfizer Inc, is a consultant to and/or has served on advisory boards for Aclaris Therapeutics, Arena Pharmaceuticals, Bristol-Meyers Squibb, Concert Pharmaceuticals Inc, Dermavant Sciences, Eli Lilly and Company, and Pfizer Inc, and is on speaker's bureau for Pfizer Inc, Regeneron, and Sanofi Genzyme. Dr Peterson has no conflicts of interest to declare. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 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 5 2020 1217 1218 32199889 2 Price K.N. Frew J.W. Hsiao J.L. Shi V.Y. COVID-19 and immunomodulator/immunosuppressant use in dermatology J Am Acad Dermatol 82 5 2020 e173 e175 32224277 3 Clark J.D. Flanagan M.E. Telliez J.-B. Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases J Med Chem 57 12 2014 5023 5038 24417533
PMC007xxxxxx/PMC7146692.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)30542-9 10.1016/j.jaad.2020.04.003 JAAD Online Reply to: “Skin damage among health care workers managing coronavirus disease-2019” Oranges Teresa MD, PhD ab∗ Janowska Agata MD a Dini Valentina MD, PhD a a Wound Healing Research Unit, Department of Dermatology, University of Pisa, Pisa, Italy b Dermatology Unit, Department of Pediatrics, Anna Meyer Children's University Hospital, Florence, Italy ∗ Correspondence to: Teresa Oranges, MD, PhD, Department of Dermatology, University of Pisa, Via Roma 67, 56126 Pisa, Italy 10 4 2020 6 2020 10 4 2020 82 6 e233e234 © 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 article “Skin damage among health care workers managing coronavirus disease-2019” written by Lan et al.1 The main skin problems in health care managing COVID-19 and using medical devices are the hand eczema and the skin damage affecting the nasal bridge, cheek, and forehead. Lan et al1 reported that the health care workers who wore medical devices for more than 6 hours showed higher risks of skin damage, with desquamation in more than 60% of cases, and other signs, such as erythema, maceration, and ulcers, in a smaller percentage of cases. This skin damage may cause itching and pain1 and further impair the quality of life among health care workers. The World Health Organization recommends performing correct hand hygiene with alcohol-based hand rub (preferred in case of not visibly soiled hands) or water and soap, in particular, before touching a patient, before any clean or aseptic procedure, after exposure to body fluid, after touching a patient, and after touching a patient's surroundings.2 The frequent hand hygiene, the use of antiseptics, and wearing of double-layers of gloves for a long time may cause the hand eczema. At the sites of application of masks, goggles, and facial shield, pressure injuries may develop, from grade 1 (nonblanchable erythema) to grade 2/3 (erosion or ulceration). The medical device–related pressure injuries may occur on any anatomic location where the medical device is in contact with the skin and particularly where the skin is over bony prominences, such as the forehead, the nasal bridge, and the zygomatic arch. The University of Pisa (Italy) Wound Healing Unit proposes the topical management of the skin areas at risk of pressure injuries in terms of cleansing, prevention, and treatment (Table I ).Table I Topical management of pressure injuries in the health care worker using medical devices (masks, goggles and facial shield) Pressure injuries Topical management Cleansing (grade 2/3) Saline solution Polyhexamethylene biguanide (PHMB) Prevention • Before wearing medical devices Barrier film spray Prevention • After medical devices removal Omental lipids cream/emulsion Nonadherent dressings (soft silicone/paraffin) Grade 1∗ Barrier film (spray/sheet) Nonadherent dressings (soft silicone/paraffin) Grade 2/3∗ Extra-thin hydrocolloid Thin polyurethane silicone foam Scar/hyperpigmentation prevention∗ Silicone cream/sheet Photoprotection SPF 50+ (cream/spray/emulsion) SPF, Sun protection factor. ∗ Apply after removing medical devices. The no-sting barrier film spray has shown good efficacy in the management of the skin surrounding chronic wounds, with a significant reduction of the transepidermal water loss values.3 We suggest the use of this product before wearing the medical devices, because the alcohol-free liquid dries quickly after skin application and forms a protective, transparent, and conformable long-lasting barrier film. The use of topical products containing purified omental lipids will help in improving skin barrier function, repairing the epithelial cell membrane, and increasing microcirculation.4 These products are also useful to prevent the development of pressure injuries and may be used after removing the medical devices as well the nonadherent dressings (soft silicone/paraffin). Some authors described the use of thin hydrocolloid dressing to prevent pressure injuries on the nasal bridge in case of acute noninvasive ventilation.5 Nonadherent dressings (soft silicone/paraffin) and extra-thin hydrocolloid may theoretically also be used before the medical devices are worn, but further studies are needed to certify that these advanced dressings do not alter the safety of the devices. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Lan J. Song Z. Miao X. Skin damage among health care workers managing coronavirus disease-2019 J Am Acad Dermatol 82 5 2020 1215 1216 32171808 2 World Health Organization & WHO Patient Safety WHO guidelines on hand hygiene in health care: First Global Patient Safety Challenge—clean care is safer care. Geneva: World Health Organization Available at: https://apps.who.int/iris/handle/10665/4410 2009 3 Dini V. Salibra F. Brilli C. Romanelli M. Instrumental evaluation of the protective effects of a barrier film on surrounding skin in chronic wounds Wounds 20 9 2008 254 257 25941849 4 Romanelli M. Dini V. Milani M. Topical purified omental lipid formulations in the prevention of skin ulcers: a narrative review J Wound Care 28 5 2019 284 290 31067163 5 Bishopp A. Oakes A. Antoine-Pitterson P. Chakraborty B. Comer D. Mukherjee R. The preventative effect of hydrocolloid dressings on nasal bridge pressure ulceration in acute non-invasive ventilation Ulster Med J 88 1 2019 17 20 30675073
PMC007xxxxxx/PMC7146700.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)30558-2 10.1016/j.jaad.2020.04.018 Infographics A dermatologic manifestation of COVID-19: Transient livedo reticularis Manalo Iviensan F. MD a∗ Smith Molly K. MD b Cheeley Justin MD ac Jacobs Randy MD d a Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia b Pariser Dermatology Specialists, Norfolk, Virginia c Department of Medicine, Emory University School of Medicine, Atlanta, Georgia d University of California Riverside School of Medicine, Riverside, California ∗ Reprint requests: Iviensan Manalo, MD, Department of Dermatology, Emory University School of Medicine, 1525 Clifton Rd, Ste 100, Atlanta, GA 30329. 10 4 2020 8 2020 10 4 2020 83 2 700700 © 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 pmc Infographic 1 Dermatologic manifestations of COVID-19-positive patients published thus far. Supplemental Material available via Mendeley at https://doi.org/10.17632/kgb87k7863.1. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable.
PMC007xxxxxx/PMC7151252.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)30554-5 10.1016/j.jaad.2020.04.014 JAAD Online Reply to: “Biologics for psoriasis during COVID-19 outbreak” Murrell Dedee F. MA, BMBCh, MD, FRCP a Rivera-Oyola Ryan MS b∗ Lebwohl Mark MD b a Department of Dermatology, St George Hospital, University of New South Wales, Sydney, Australia b The Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai Hospital, New York, New York ∗ Correspondence to: Ryan Rivera-Oyola, MS, The Kimberly and Eric J. Waldman Department of Dermatology, 5 E 98th St, 5th Floor, New York, NY, 10029 10 4 2020 6 2020 10 4 2020 82 6 e219e219 © 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 Di Lernia1 for his commentary on the stratification planning of dermatology patients on biologics that has been adopted in Italy. Because there are many patients on biologics and on immunosuppressants for psoriasis, hidradenitis, atopic dermatitis, pemphigoid, pemphigus, and other conditions in Italy and other countries hit by the COVID-19 pandemic, hopefully, we will soon have more information about whether the rate of respiratory decompensation in this population is greater or less than expected. Until then, all we can do is to make educated recommendations. Those advocated by Dr Di Lernia1 are logical. Suggestions that biologic therapies may abrogate the severe pneumonitis that kills many are hopeful but are as speculative as suggestions made by others that biologics might worsen the course of COVID-19 infection. Because many biologics have long half-lives, it is neither practical nor logical to cease these over a few weeks while this pandemic is upon us, because it is likely to last months. Furthermore, recent studies have shown that a significant portion of individuals affected by COVID-19 will be asymptomatic carriers and that even those who eventually develop symptoms can transmit the virus to others before developing symptoms.2 , 3 In light of this, the Centers for Disease Control and Prevention announced the voluntary wearing of nose and mouth coverings, and we recommend that all patients taking biologics wear such coverings or masks when outside the home and practice social distancing. Currently, there is evidence that supports the accuracy and cost-effectiveness of teledermatology.4 Telehealth is now accepted in many countries by insurers to mitigate exposures for these patients.5 Funding sources: None. Conflicts of interest: Dr Murrell is an employee of St George Hospital, has been an investigator/advisor for Novartis, Sun Pharma, Janssen, and AbbVie, and is also the director of a clinical trial center for dermatologic diseases. Dr Lebwohl is an employee of Mount Sinai Hospital, receives research funds from 10.13039/100006483 AbbVie , 10.13039/100002429 Amgen , Eli Lilly, 10.13039/100005205 Janssen Research & Development , LLC, Novartis, Ortho Dermatologics, and UCB, Inc, and has been the principal investigator for numerous clinical trials but has no personal financial gain. Mr Rivera-Oyola has no relevant conflicts of interest to disclose. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Di Lernia V. Biologics for psoriasis during COVID-19 outbreak J Am Acad Dermatol 2020 10.1016/j.jaad.2020.04.004 2 Bai Y. Yao L. Wei T. Presumed asymptomatic carrier transmission of COVID-19 JAMA 2020 3 Rothe C. Schunk M. Sothmann P. Transmission of 2019-nCoV infection from an asymptomatic contact in Germany N Engl J Med 382 10 2020 970 971 32003551 4 Lee J.J. English J.C. 3rd Teledermatology: a review and update Am J Clin Dermatol 19 2 2018 253 260 28871562 5 Villani A. Scalvenzi M. Fabbrocini G. Teledermatology: a useful tool to fight COVID-19 J Dermatolog Treat 2020 1 3
PMC007xxxxxx/PMC7151396.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)30528-4 10.1016/j.jaad.2020.03.103 JAAD Online Reply to: “COVID-19, syphilis, and biologic therapies for psoriasis and psoriatic arthritis: A word of caution” Lebwohl Mark MD a Rivera-Oyola Ryan MS a∗ Murrell Dedee F. MA, BMBCh, MD, FRCP, FACD b a Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mt Sinai Hospital, New York, New York b Department of Dermatology, St. George Hospital, University of New South Wales, Sydney, Australia ∗ Correspondence to: Ryan Rivera-Oyola, The Kimberly and Eric J. Waldman Department of Dermatology, 5 E 98th St, 5th Floor, New York, NY, 10029 10 4 2020 6 2020 10 4 2020 82 6 e215e215 © 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 Kansal1 from the All India Institute of Medical Sciences for her pertinent comments in response to our publication on the use of biologic agents for psoriasis patients in the current COVID-19 pandemic.2 Certainly, there are other diseases for which screening could be considered in particular populations before starting a biologic, such as syphilis, as Dr Kansal makes a point about in her study. Strongyloides and leprosy are others. These screening tests apply to all immunosuppressants, not just biologic immunomodulators. There will always be exceptions to the clinical trial data, but even with 10 to 20 years of real-world data reporting of many of these biologics, we have not seen alarming rates of influenza or other viral infections in the non-tumor necrosis factor inhibitor classes of biologics that would warrant advice to discontinue treatment. There are several reasons why biologic agents are different from traditional immunosuppressive drugs such as methotrexate or cyclosporine. They are very targeted and do not affect the entire immune system. Most relevant to our current times, many do not impact host defenses against viral infection. For example, individuals born with deficiencies in molecules like interleukin 17 or p40 are prone to chronic mucocutaneous candidiasis or to mycobacterial and salmonella infections.3 , 4 They do not have increased rates of viral infections. Moreover, the skin itself is a vector for spreading COVID-19, and the impact of active skin disease on transmission is unknown. In addition, there has been speculation that reducing overall inflammation in patients with COVID-19 infection protects against the deadly pneumonia that has caused the demise of so many.5 Finally, we know that dupilumab, in addition to treating atopic dermatitis, which in itself can be debilitating, also treats asthma, which could be a complicating factor in COVID-19 infection. To be clear, we cannot know the long-term impact of biologic agents on patients with suspected or confirmed COVID-19 until more time passes and we have more data. For now, the most medical organizations, including the American Academy of Dermatology, the National Psoriasis Foundation, and the International Eczema Council, among others, have advocated not discontinuing biologics in patients who are not infected. Of course, these agents should be discontinued in patients with active infection. Funding sources: None. Conflicts of interest: Dr Lebwohl is an employee of Mount Sinai, receives research funds from 10.13039/100006483 AbbVie , 10.13039/100002429 Amgen , Eli Lilly, 10.13039/100005205 Janssen Research & Development , LLC, 10.13039/100004336 Novartis , Ortho Dermatologics, and 10.13039/100011110 UCB , Inc, and has been the principal investigator for numerous clinical trials but has no personal financial gain. Dr Murrell is an employee of St George Hospital, has been an investigator/advisor for Novartis, Sun Pharma, Janssen and AbbVie, and is also the director of a clinical trial center for dermatologic diseases. Ryan Rivera-Oyola has no relevant conflicts of interest. IRB approval status: Not applicable. ==== Refs References 1 Kansal N.K. COVID-19, syphilis, and biologic therapies for psoriasis and psoriatic arthritis: a word of caution J Am Acad Dermatol 82 2020 e213 32246966 2 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 5 2020 1217 1218 32199889 3 Puel A. Cypowyj S. Marodi L. Abel L. Picard C. Casanova J.L. Inborn errors of human IL-17 immunity underlie chronic mucocutaneous candidiasis Curr Opin Allergy Clin Immunol 12 6 2012 616 622 23026768 4 Altare F. Jouanguy E. Lamhamedi S. Doffinger R. Fischer A. Casanova J.L. Mendelian susceptibility to mycobacterial infection in man Curr Opin Immunol 10 4 1998 413 417 9722917 5 Conti P. Ronconi G. Caraffa A. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies J Biol Regul Homeost Agents 34 2 2020
PMC007xxxxxx/PMC7151475.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)30612-5 10.1016/j.jaad.2020.04.035 JAAD Online Reply to: “Various forms of skin rash in COVID-19: Petechial rash in a patient with COVID-19 infection” Joob Beuy PhD a∗ Wiwanitkit Viroj MD b a Sanitation 1 Medical Academic Center, Bangkok, Thailand b Dr DY Patil University, Pune, India, and Hainan Medical University, Haikou, China ∗ Correspondence to: Beuy Joob, PhD, Sanitation 1 Medical Academic Center, Bangkok 10330, Thailand 10 4 2020 8 2020 10 4 2020 83 2 e143e143 © 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 appreciate the additional information from Jimenez-Cauhe et al1 on our report on a skin rash in a patient with COVID-19.2 Jimenez-Cauhe et al1 showed a clinical picture of a skin rash at the axilla of a patient. As a new emerging virus infection, the dermatologic presentation is an interesting clinical feature. The skin rash in our previous publication that looked like the skin rash in dengue copresented with thrombocytopenia in a patient with COVID-19.2 Nevertheless, there is also the possibility that there might be other forms of COVID-19 skin rashes. In a previous report on a classical coronavirus infection, the rash appeared to be recurrent; “target-like purpuric plaques” was reported as another clinical presentation.3 In the present clinical case by Jimenez-Cauhe et al,1 the rash might be a coincidence or an actual COVID-19–induced skin rash. Whether the lesion described by Jimenez- Cauhe et al1 is related to the pathophysiologic process of COVID-19 or not should be further studied. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 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 2 2020 e141 e142 32283233 2 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 3 Chesser H. Chambliss J.M. Zwemer E. Acute hemorrhagic edema of infancy after coronavirus infection with recurrent rash Case Rep Pediatr 2017 2017 5637503 28243478
PMC007xxxxxx/PMC7151476.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)30608-3 10.1016/j.jaad.2020.04.032 Infographics Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is likely to be androgen mediated Wambier Carlos Gustavo MD, PhD a∗ Goren Andy MD b a Department of Dermatology, The Warren Alpert Medical School of Brown University, Providence, Rhode Island b Applied Biology, Inc, Irvine, California ∗ Correspondence and reprint requests to: Carlos Gustavo Wambier, MD, PhD, Rhode Island Hospital, 593 Eddy St, APC, 10th Floor, Providence, RI 02903. 10 4 2020 7 2020 10 4 2020 83 1 308309 © 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 Key words 5-α reductase ACE2 androgen receptor androgenetic alopecia angiotensin converting enzyme 2 COVID-19 dutasteride finasteride human skin retinoids antiandrogen therapy SARS-CoV-2 TMPRSS2 transmembrane protease serine 2 Abbreviations used ACE2 angiotensin converting enzyme 2 COVID-19 coronavirus disease 2019 SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 TMPRSS2 transmembrane protease, serine 2 ==== Body pmcCoronavirus disease 2019 (COVID-19) pandemic fatalities are rare before adrenarche/puberty (<10 years of age), and the vulnerability of males to severe disease1 has been constantly reported over the past months of pandemic. The first biologic step required for potential infectivity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the priming of the spike proteins by transmembrane protease, serine 2 (TMPRSS2). Although other proteases have been described to activate the spikes in vitro, only TMPRSS2 activity is regarded as essential for viral spread and pathogenesis in the infected hosts.2 TMPRSS2 may also cleave angiotensin converting enzyme 2 (ACE2) for augmented viral entry.3 Androgen receptor activity has been considered a requirement for the transcription of the TMPRSS2 gene because no other known TMPRSS2 gene promoter has been described in humans to date.4 , 5 Male vulnerability may be further enhanced by X-linked inheritance of genetic polymorphisms (androgen receptor and ACE2 genes loci are in chromosome X). Obvious dermatologic signs of hyperactivation of androgen receptors are pattern reduction of density of scalp hair, increased density of facial and chest hair, acne, and oily skin. Theoretically, the hyperandrogenic phenotype might correlate with COVID-19 increased viral load, increased viral dissemination, and severity of lung involvement (Infographic 1 ).Infographic 1 Androgen-mediated COVID-19. Studies are still required for epidemiologic conclusions. Acknowledging the importance of androgens during the COVID-19 pandemic may offer another targeted therapy for trials, with androgen suppression to reduce host vulnerability when infection risk is high. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. ==== Refs References 1 Shi Y. Yu X. Zhao H. Wang H. Zhao R. Sheng J. Host susceptibility to severe COVID-19 and establishment of a host risk score: findings of 487 cases outside Wuhan Crit Care 24 1 2020 108 32188484 2 Hoffmann M. Kleine-Weber H. Schroeder S. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor Cell 2020 1 10 3 Heurich A. Hofmann-Winkler H. Gierer S. Liepold T. Jahn O. Pohlmann S. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein J Virol 88 2 2014 1293 1307 24227843 4 Lucas J.M. Heinlein C. Kim T. The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis Cancer Discov 4 11 2014 1310 1325 25122198 5 National Institutes of Health TMPRSS2 transmembrane serine protease 2 [Homo sapiens (human)] Gene ID: 7113 Updated March 13, 2020. Available at: https://www.ncbi.nlm.nih.gov/gene/7113
PMC007xxxxxx/PMC7151529.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)30606-X 10.1016/j.jaad.2020.04.030 JAAD Online Adalimumab for treatment of hidradenitis suppurativa during the COVID-19 pandemic: Safety considerations Blaszczak Alecia PhD a Trinidad John C.L. MD, MPH a∗ Cartron Alexander M. BS b a Division of Dermatology, The Ohio State University College of Medicine, Columbus, Ohio b Department of Dermatology, University of Maryland School of Medicine, Baltimore, Maryland ∗ Correspondence and reprint requests to: John C. L. Trinidad, MD, MPH, The Ohio State University College of Medicine, Division of Dermatology, 540 Officenter Pl, Ste 240, Columbus, OH 43230 10 4 2020 7 2020 10 4 2020 83 1 e31e31 © 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: With the peak of coronavirus disease 2019 (COVID-19) expected to occur in many regions of the United States in the coming weeks to months, physicians and patients alike are concerned about the use of immunosuppressive, biologic agents given the increased infection risk. A recent Letter to the Editor highlighted the risk of total infections, upper respiratory tract infections, and nasopharyngitis in patients with psoriasis on immunomodulating biologic therapy.1 Similar to psoriasis, hidradenitis suppurativa (HS) is an inflammatory skin disease managed effectively with biologic agents when disease burden is high. Adalimumab, a tumor necrosis factor-α inhibitor, is currently the only United States Food and Drug Administration (FDA)-approved drug for moderate to severe HS. Compared with patients with psoriasis, patients with HS generally require higher doses of adalimumab, especially during treatment initiation.2 Although current data are not available for COVID-19 risk in patients with HS, data from the Efficacy and Safety Study of Adalimumab in Treatment of Hidradenitis Suppurativa (PIONEER) I and II phase 3 clinical trials may provide important insight into the risk of infectious complications in this unique patient population.3 Table I highlights the risk of total infections, upper respiratory tract infections, and pharyngitis in patients with HS on adalimumab vs placebo from the data published in the PIONEER I and II trials.3 In patients with HS taking adalimumab, there is a modest increased risk of total infections and nasopharyngitis by 2.5%, on average, with no difference in the risk of upper respiratory tract infections. These results demonstrate that, in general, there was minimal difference between rates of respiratory infections in patients with HS on adalimumab vs placebo.Table I Risks of total infections, upper respiratory infections, and nasopharyngitis in hidradenitis suppurativa patients taking adalimumab vs placebo∗ Trial Patients, No. Total infections, No. (%) Upper respiratory tract infections, No. (%) Nasopharyngitis, No. (%) Adalimumab Placebo Adalimumab Placebo Adalimumab Placebo Adalimumab Placebo PIONEER I 152 153 40 (26) 32 (21) 4 (2.6) 5 (3.3) 16 (10.5) 9 (5.9) PIONEER II 163 163 37 (23) 36 (22) 9 (5.5) 8 (4.9) 10 (6.1) 9 (5.5) Total 315 316 77 (24) 68 (21.5) 13 (4.1) 13 (4.1) 26 (8.2) 18 (5.7) ∗ Data from period 1 of the Efficacy and Safety Study of Adalimumab in Treatment of Hidradenitis Suppurativa (PIONEER) I and II trials. Much like data regarding the effect of immunosuppressive drugs on patients with psoriasis, extrapolating data from the PIONEER I and II trials to susceptibility to coronavirus infection is difficult. Nonetheless, dermatologists may use these data to make informed treatment decisions for patients with HS during the ongoing COVID-19 pandemic. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. ==== Refs References 1 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 5 2020 1217 1218 32199889 2 United States Food and Drug Administration Adalimumab [package insert] 2015 Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125057s394lbl.pdf. Accessed April 27, 2020 3 Kimball A.B. Okun M.M. Williams D.A. Two phase 3 trials of adalimumab for hidradenitis suppurativa N Engl J Med 375 5 2016 422 434 27518661
PMC007xxxxxx/PMC7160444.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)30478-3 10.1016/j.jaad.2020.03.056 JAAD Online Use of systemic immunomodulatory therapies during the coronavirus disease 2019 (COVID-19) pandemic Shah Payal BS Zampella John G. MD ∗ Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York ∗ Correspondence to: John G. Zampella, MD, FAAD, The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, Preston Robert Tisch Center for Men's Health, 555 Madison Ave, New York, NY 10022 31 3 2020 6 2020 31 3 2020 82 6 e203e204 © 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 anticipation the American Academy of Dermatology's recent publication, “Guidance on the Use of Biologic Agents During COVID-19 Outbreak.”1 Although the immunopathophysiology behind these guidelines remains to be investigated, existing concepts may elucidate which agents require extra precautions to mitigate coronavirus disease 2019 (COVID-19) morbidity. A key aspect of risk mitigation is prevention of SARS-CoV-2 infection in at-risk populations. Current evidence suggests that these populations include older adults, those with serious chronic medical conditions, and immunosuppressed patients with prior or active cancer.2 , 3 Whether this last group includes patients receiving biological and small-molecule therapies remains to be seen. Nevertheless, the therapeutic efficacy of immunosuppressive and immunomodulatory medications is critical to the management of inflammatory and autoimmune conditions in dermatology. Indeed, understanding the physiology and mechanisms of these agents can aid in discussion with patients. CD4+ T-cell immunity is critical to host defense against viral pathogens. Antiviral T-cell responses are initiated with the uptake of viral antigen in infected tissue, activation of T cells by viral recognition and pathogen signaling, and cytokine polarization toward a T-helper (Th) type-1 profile via interleukin (IL) 12 and type 1 interferon.4 Importantly, Th17, Th2, and regulatory (Treg) T-cell populations may also be generated to some degree to combat infection against certain viral pathogens. It stands to reason that the use of biologic therapies known to modulate and blunt Th1 responses, including tumor necrosis factor-α inhibitors, abatacept (CTLA-4 inhibitor), and ustekinumab (IL-12/23 inhibitor), may specifically require more stringent precautions to diminish risk of infection and prioritization of alternative therapeutic agents when possible.5 The effect of IL-17 inhibitors and dupilumab (IL-4 blockade), which predominately impair Th17 pathways and Th2 pathways, respectively, on SARS-CoV-2 remains unknown and, for now, also warrants caution. Additionally, the use of nonbiologic systemic therapies, such as cyclosporin, azathioprine, and methotrexate, warrants similar precautions because their therapeutic mechanisms create a state of generalized immunosuppression in the host. Clinical data also paradoxically suggest that further deterioration in infected patients may be the result of a proinflammatory state created by cytokine storm.2 Similar pathogenesis was implicated in the disease biology of SARS-CoV and MERS-CoV infections. Specifically, higher concentrations of GCSF, IP10, MCP1, MIP1A, and tumor necrosis factor α were found in patients requiring intensive care unit admission compared with those with infection that did not require intensive care unit admission, suggesting a possible association between cytokine storm and disease severity.2 The cytokine storm immunopathology of SARS-CoV-2 suggests that a subset of immunosuppressive therapies may begin to play a protective role in infected patients. By inhibiting the intensity of the cytokine storm, immunosuppressants may prevent lung tissue damage and further clinical deterioration. Directly counteracting the cytokine storm with glucocorticoids and anti–IL-6 treatment is under active investigation in China.2 Anti–IL-17 therapy was similarly investigated to combat morbidity of the influenza A (H1N1) virus pandemic in 2009, and a similar mechanism may become important in SARS-CoV-2.6 As clinical evidence is collected to inform evidenced-based guidelines for the management of COVID-19, dermatologists should use their clinical judgement, the existing American Academy of Dermatology guidelines, and an understanding of pathophysiology to determine the appropriate risks/benefits of using systemic immunomodulating therapies. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 American Academy of Dermatology Guidance on the use of biologic agents during COVID-19 outbreak Available at: https://assets.ctfassets.net/1ny4yoiyrqia/PicgNuD0IpYd9MSOwab47/023ce3cf6eb82cb304b4ad4a8ef50d56/Biologics_and_COVID-19.pdf 2 Huang C. Wang Y. Li X. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Lancet 395 10223 2020 497 506 31986264 3 Liang W. Guan W. Chen R. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China Lancet Oncol 21 3 2020 335 337 32066541 4 Swain S.L. McKinstry K.K. Strutt T.M. Expanding roles for CD4(+) T cells in immunity to viruses Nat Rev Immunol 12 2 2012 136 148 22266691 5 Ma W.-T. Yao X.-T. Peng Q. Chen D.-K. The protective and pathogenic roles of IL-17 in viral infections: friend or foe? Open Biol 9 7 2019 190109 31337278 6 Li C. Yang P. Sun Y. IL-17 response mediates acute lung injury induced by the 2009 pandemic influenza A (H1N1) virus Cell Res 22 3 2012 528 538 22025253
PMC007xxxxxx/PMC7161488.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)30657-5 10.1016/j.jaad.2020.04.044 Research Letter Varicella-like exanthem as a specific COVID-19–associated skin manifestation: Multicenter case series of 22 patients Marzano Angelo Valerio MD ab∗ Genovese Giovanni MD ab Fabbrocini Gabriella MD c Pigatto Paolo MD d Monfrecola Giuseppe MD c Piraccini Bianca Maria MD e Veraldi Stefano MD ab Rubegni Pietro MD f Cusini Marco MD a Caputo Valentina MD g Rongioletti Franco MD h Berti Emilio MD ab Calzavara-Pinton Piergiacomo MD i a Dermatology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy b Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Italy c Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Italy d Clinical Dermatology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy e Department of Dermatology, University of Bologna, Italy f Dermatology Unit, Department of Medical, Surgical and Neurosciences, University of Siena, Italy g Unit of Pathology, Grande Ospedale Metropolitano Niguarda, Milan, Italy h Unit of Dermatology, Department of Medical Sciences and Public Health, Cagliari, Italy i Department of Dermatology, University of Brescia, Italy ∗ Reprint requests: Angelo Valerio Marzano, MD, Dermatology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Pace, 9, 20122, Milano, Italia 16 4 2020 7 2020 16 4 2020 83 1 280285 © 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: COVID-19, an infection due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that may cause interstitial pneumonia and respiratory failure, has currently taken on pandemic proportions.1 The COVID-19 outbreak emerged in Wuhan, China, and rapidly spread to Europe, particularly to Italy,2 where, as of April 27, 2020, a total of 199,414 people have tested positive.3 Two recent publications have brought attention to COVID-19–associated cutaneous manifestations.4 , 5 Joob and Wiwanitkit4 reported on a dengue-like petechial rash in a patient with COVID-19 from Thailand. Recalcati5 described 18 out of 88 patients with COVID-19 hospitalized in Lecco Hospital (Lombardy region, Italy) who developed erythematous rash (n = 14), widespread urticaria (n = 3), or varicella-like vesicles (n = 1). During the Italian outbreak, we have observed a varicella-like papulovesicular exanthem as a rare but specific COVID-19–associated skin manifestation. Eight Italian dermatology units collected clinical data from patients with COVID-19 (microbiologically proven by nasopharyngeal swab) and no history of new medications in the previous 15 days who developed varicella-like lesions. Demographic and clinical features of the 22 patients are summarized in Table I . The median age was 60 years, and 72.7% of patients (n = 16/22) were male. Most patients (n = 17/22; 77.3%) came from Lombardy, currently the worst-hit region in Italy, and the remaining patients came from Piedmont (n = 1), Emilia-Romagna (n = 1), Toscana (n = 1), Lazio (n = 1), and Campania (n = 1). The median latency time from systemic symptoms to exanthem was 3 days (range, -2 to 12 days). The median duration of skin manifestations was 8 days (range, 4-15 days). Lesions were scattered in most patients (n = 16; 72.7%), and they were diffuse in 6 (27.3%) patients. Predominance of vesicles was observed in 12 (54.5%) patients. No variations in the papulovesicular presentation were observed in our case series. The trunk was always involved, in some cases in association with the limbs (n = 4; 18.2%) (Fig 1 , A-D). No facial or mucosal involvements were scored. Itching, which was generally mild, was reported in 9 (40.9%) patients. In all patients who underwent skin biopsy (n = 7), histologic findings were consistent with viral infection (Fig 1, E and F).Table I Demographic and clinical data of patients with varicella-like exanthem associated with COVID-19 ID Sex Age, years Hometown Systemic symptoms' onset Positive result on nasopharyngeal swab Skin lesions Skin symptoms Latency time, days Duration, days Localization Systemic symptoms Negative result on nasopharyngeal swab Course 1 M 75 Rome February 19, 2020 March 4, 2020 Diffuse papulovesicular lesions (predominance of papules) No itching 12 5 Trunk Fever, asthenia, hypogeusia, hyposmia Yes Resolution 2 M 57 Milan February 20, 2020 February 22, 2020 Diffuse papulovesicular lesions (predominance of vesicles) Mild itching 5 4 Trunk Fever, cough, coryza, headache, hyposmia, hypogeusia, weakness Yes Resolution 3 M 59 Milan February 28, 2020 March 2, 2020 Scattered papulovesicular lesions (predominance of papules) Mild itching 7 15 Trunk Fever, cough, pharyngodynia, headache, weakness Yes Resolution 4 F 56 Brescia February 28, 2020 March 2, 2020 Scattered papulovesicular lesions (predominance of vesicles) Pain 3 15 Trunk Fever, cough, coryza, headache, weakness Yes Resolution 5 M 28 Bologna March 1, 2020 March 10, 2020 Diffuse papulovesicular lesions started (predominance of papules) Itching 4 7 Trunk Fever, cough Yes Resolution 6 M 45 Biella March 1, 2020 March 6, 2020 Scattered papulovesicular lesions (predominance of papules) No itching 6 10 Trunk Fever, diarrhea, nausea Yes Resolution 7 M 72 Brescia March 1, 2020 March 14, 2020 Scattered papulovesicular lesions (predominance of vesicles) No itching Unknown NA Trunk, limbs Fever, cough, coryza, headache, dyspnea No Active disease 8 M 83 Cremona March 2, 2020 March 10, 2020 Scattered papulovesicular lesions (predominance of vesicles) No itching 2 5 Trunk Fever, dyspnea No Active disease∗ 9 M 61 Milan March 2, 2020 March 5, 2020 Diffuse papulovesicular lesions (predominance of vesicles) Mild itching 2 4 Trunk Fever, cough, dyspnea, coryza, headache, weakness // Death 10 M 29 Brescia March 3, 2020 March 10, 2020 Scattered papulovesicular lesions (predominance of vesicles) Mild itching 1 12 Trunk Fever, cough, weakness Yes Resolution 11 M 65 Brescia March 3, 2020 March 16, 2020 Scattered papulovesicular lesions (predominance of papules) Burning 2 13 Trunk Fever, cough, dyspnea, coryza, headache, weakness No Active disease 12 M 44 Brescia March 8, 2020 March 16, 2020 Scattered papulovesicular lesions (predominance of vesicles) Burning, itching 3 8 Trunk Fever, cough, coryza, headache, weakness No Resolution 13 M 75 Cremona March 8, 2020 March 16, 2020 Scattered vesicular lesions (predominance of vesicles) No itching 0 8 Trunk, limbs Fever, dyspnea // Death 14 F 51 Brescia March 8, 2020 March 17, 2020 Scattered papulovesicular lesions (predominance of vesicles) Pain 4 8 Trunk Fever, cough, dyspnea, coryza, headache, weakness No Active disease 15 F 62 Brescia March 9, 2020 March 18, 2020 Scattered papulovesicular lesions (predominance of papules) Burning 2 11 Trunk Fever, cough, coryza, headache, weakness No Improvement 16 M 25 Siena March 10, 2020 March 17, 2020 Diffuse papulovesicular lesions (predominance of vesicles) Itching 5 6 Trunk, limbs Cough, hyposmia, hypogeusia No Resolution 17 F 90 Cremona March 12, 2020 March 20, 2020 Scattered papulovesicular lesions (predominance of vesicles) No itching 1 6 Trunk Fever, cough, dyspnea, coryza, headache, weakness No Active disease 18 F 69 Brescia March 12, 2020 March 20, 2020 Scattered papulovesicular lesions (predominance of papules) No itching Unknown NA Trunk Fever, cough, dyspnea, coryza, hyposmia, hypogeusia, headache, weakness No Active disease 19 M 65 Naples March 13, 2020 March 20, 2020 Diffuse papulovesicular lesions (predominance of papules) Mild itching -2 9 Trunk Fever, cough No Improvement 20 M 80 Brescia March 14, 2020 March 22, 2020 Scattered papulovesicular lesions (predominance of vesicles) No itching Unknown NA Trunk, limbs Fever, dyspnea // Death 21 M 43 Milan March 15, 2020 March 23, 2020 Scattered papulovesicular lesions (predominance of vesicles) Mild itching 0 11 Trunk Fever, myalgia No Active disease 22 F 8 Milan March 15, 2020 March 24, 2020 Scattered papulovesicular lesions (predominance of papules) No itching 3 7 Trunk Fever, cough No Resolution F, Female; ID, identification; M, male; NA, not available; //, not applicable. ∗ Patient with acute respiratory distress symptoms in intensive care unit. Fig 1 A-D, Papulovesicular exanthem on the trunk in 4 patients with COVID-19. A-C, In 3 patients, predominance of papules is seen. D, In another patient mainly presenting with vesicles, exanthem resolution with crusts is evident; E, Basket-wave hyperkeratosis; slightly atrophic epidermis; and vacuolar degeneration of the basal layer with multinucleate, hyperchromatic keratinocytes and dyskeratotic cells. Note the absence of inflammatory infiltrate. (Hematoxylin-eosin stain; original magnification: ×4.) F, Close-up image with atrophic epidermis, vacuolar alteration with disorganized keratinocytes lacking orderly maturation, and enlarged and multinucleate keratinocytes with dyskeratotic (apoptotic) cells. (Hematoxylin-eosin stain; original magnification: ×20). The most common systemic symptom was fever (n = 21/22; 95.5%), followed by cough (n = 16; 72.7%), headache (n = 11; 50%), weakness (n = 11; 50%), coryza (n = 10; 45.5%), dyspnea (n = 9; 40.9%), hyposmia (n = 4; 18.2%), hypogeusia (n = 4; 18.2%), pharyngodynia (n = 1; 4.5%), diarrhea (n = 1; 4.5%), and myalgia (n = 1; 4.5%). Death occurred in 3 (13.6%) patients. Ours is the first series on this varicella-like exanthem as a specific COVID-19–associated cutaneous picture, unlike the nonspecific cutaneous manifestations such as erythematous rash or urticaria reported by Recalcati.5 Its typical features are frequent trunk involvement, usually scattered distribution, and mild/absent pruritus, the latter being in line with most viral exanthems but unlike true varicella. Lesions generally appear 3 days after systemic symptoms and disappear by 8 days, without leaving scarring. A limitation of our study was missing histologic evaluation in some cases. Moreover, demonstration of SARS-CoV-2 presence by polymerase chain reaction in lesional skin was not possible because of specific primer unavailability. If further studies validate our findings, this early skin manifestation will represent a useful clue for suspecting COVID-19 in asymptomatic/paucisymptomatic patients. The authors wish to thank the following collaborators for their help in data collection and patient treatment: Marica Annunziata, Cristiana Colonna, Massimo Ghislanzoni, Raffaele Gianotti, Chiara Moltrasio, Gianluca Nazzaro, Emanuela Passoni, Marina Picca, Gaetano Rizzitelli, and Diego Tosi. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Because of the retrospective nature of the study, only a notification to the ethical committee of the principal investigator center (Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy) was requested. All patients gave written informed consent for publishing the clinical images. ==== Refs References 1 Zhu N. Zhang D. Wang W. China novel coronavirus investigating and research team A novel coronavirus from patients with pneumonia in China, 2019 N Engl J Med 382 8 2020 727 733 31978945 2 Livingston E. Bucher K. Coronavirus disease 2019 (COVID-19) in Italy [Epub ahead of print] JAMA 2020 10.1001/jama.2020.4344 3 Dipartimento della Protezione Civile. Comunicato stampa: Coronavirus: la situazione dei contagi in Italia, Available at: http://www.protezionecivile.gov.it/media-comunicazione/comunicati-stampa/-/content-view/view/1265583. Accessed April 27, 2020. 4 Joob B. Wiwanitkit V. COVID-19 can present with a rash and be mistaken for Dengue J Am Acad Dermatol 82 2020 e177 32213305 5 Recalcati S. Cutaneous manifestations in COVID-19: a first perspective [Epub ahead of print] J Eur Acad Dermatol Venereol 2020 10.1111/jdv.16387 Accessed April 27, 2020
PMC007xxxxxx/PMC7161494.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)30663-0 10.1016/j.jaad.2020.04.050 Letter from the Editors Big data and cutaneous manifestations of COVID-19 Grant-Kels Jane M. MD a Sloan Brett MD ab Kantor Jonathan MD cd Elston Dirk M. MD e∗ a Department of Dermatology, University of Connecticut, Farmington, Connecticut b Department of Dermatology, Connecticut Veterans Affairs, Newington, Connecticut c Department of Dermatology and Center for Global Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania d Florida Center for Dermatology, P.A., Saint Augustine, Florida e Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, South Carolina ∗ Correspondence to: Dirk M. Elston, MD, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, MSC 578, 135 Rutledge Ave, 11th Floor, Charleston, SC 29425-5780. 16 4 2020 8 2020 16 4 2020 83 2 365366 © 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 pmcIn this issue of the JAAD, Freeman et al1 discuss the new COVID registry launched by the American Academy of Dermatology with the support of the International League of Dermatological Societies. Big data has tremendous potential to answer key questions about manifestations of the infection, the influence of pre-existing disease and immunomodulating therapy, and the potential protective or negative effects of other drugs administered for the treatment of chronic diseases. Without such data, we can only guess at the effects of biologics, antimalarials, and other agents. Registries have tremendous potential to produce valuable data that could never be gleaned from single institutions. We applaud the tremendous effort that went into the creation of this valuable tool. Also in this issue, authors report on the range of dermatologic manifestations associated with COVID-19. Dermatologists are experts in the diagnosis of viral exanthems and play an important role in the response to the pandemic. In addition to secondary findings associated with disseminated intravascular coagulation and other thrombotic events, a viral exanthem may occur in infected patients. In one report, 20% of infected patients had a skin manifestation, and, of that group, 44% presented with a rash at the onset.2 The cutaneous manifestations of COVID-19 that have been reported are highly variable and include eruptions that are petechial,3 erythematous, urticarial, vesicular (varicelliform or chicken pox-like), and annular (in review). Manifestations resembling perniosis have been reported in children, and an eruption similar to dengue fever (white islands on a sea of red) can occur. Transient livedo eruptions have also been reported, and some manifestations may correlate with a greater risk of thrombosis.4 Images may be somewhat difficult to obtain because there is a reasonable concern that using a camera in an infected patient's room might result in the camera becoming a potential fomite, but some high-quality images are available, and the JAAD family of journals (JAAD, JAAD Case Reports, and JAAD International) are helping make these widely available. Elsevier has made all COVID-related articles open access to help all health care workers in the fight against the pandemic, and a link to the COVID article collection appears in red on the JAAD homepage. A graphical abstract highlighting the range of COVID-19 rashes appears in this issue of the journal, and we will continue to highlight dermatologic aspects of the disease and other scientific data relevant to practicing dermatologists. Dermatologists have contributed data on the sterilization and reuse of personal protective equipment, occupational injury, and optimizing telemedicine platforms to provide care in a virtual environment. We welcome original submissions that present new data to assist in the global response to the pandemic and will provide expedited review and rapid dissemination of these important manuscripts. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Freeman E.E. McMahon D.E. Fitzgerald M.E. The American Academy of Dermatology COVID-19 registry: crowdsourcing dermatology in the age of COVID-19 J Am Acad Dermatol 83 2020 509 510 32305438 2 Recalcati S. Cutaneous manifestations in COVID-19: a first perspective J Eur Acad Dermatol Venereol 34 2020 e212 e213 32215952 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 Otto M.A. Skin manifestations are emerging in the coronavirus pandemic. The Hospitalist Available at: https://www.the-hospitalist.org/hospitalist/article/220183/coronavirus-updates/skin-manifestations-are-emerging-coronavirus-pandemic Accessed April 29, 2020
PMC007xxxxxx/PMC7161526.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)30662-9 10.1016/j.jaad.2020.04.049 Commentary United States Cutaneous Lymphoma Consortium recommendations for treatment of cutaneous lymphomas during the COVID-19 pandemic Zic John A. MD a∗ Ai Weiyun MD b Akilov Oleg E. MD, PhD c Carter Joi B. MD d Duvic Madeleine MD e Foss Francine MD f Girardi Michael MD g Gru Alejandro A. MD h Kim Ellen MD i Musiek Amy MD j Olsen Elise A. MD k Schieke Stefan M. MD l Shinohara Michi MD m Zain Jasmine M. MD n Geskin Larisa J. MD o∗ a Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee b Division of Hematology/Oncology, University of California San Francisco, San Francisco, California c Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania d Department of Dermatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire e Department of Dermatology, MD Anderson Cancer Center, Houston, Texas f Division of Hematology/Oncology, Yale-New Haven Medical Center, New Haven, Connecticut g Department of Dermatology, Yale-New Haven Medical Center, New Haven, Connecticut h Department of Pathology, University of Virginia School of Medicine, Charlottesville, Virginia i Department of Dermatology, University of Pennsylvania Perelman Center for Advanced Medicine, Philadelphia, Pennsylvania j Division of Dermatology, Washington University in Saint Louis, St Louis, Missouri k Department of Dermatology, Duke University School of Medicine, Durham, North Carolina l Department of Dermatology, University of Wisconsin-Madison, Madison, Wisconsin m Department of Dermatology, University of Washington Medical Center, Seattle, Washington n Division of Hematology and Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, California o Department of Dermatology, Columbia University Irving Medical Center, New York, New York ∗ Correspondence to: John A. Zic, MD, Vanderbilt Dermatology, One Hundred Oaks 719 Thompson Lane, Suite 26300, Nashville, TN 37204-3609. ∗ Larisa Geskin, MD, 161 Fort Washington Avenue, 12th Floor, New York, NY 10032. 16 4 2020 8 2020 16 4 2020 83 2 703704 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 cutaneous lymphoma high-risk mycosis fungoides Sézary syndrome Abbreviations used MF mycosis fungoides PC primary cutaneous UV ultraviolet ==== Body pmcEvidence suggests that patients with malignancy1 and older age have a higher risk of severe events including death2 , 3 due to COVID-19.4 Patients with primary cutaneous lymphoma tend to be older and to receive immunosuppressive therapy long term for disease control. Because both the cutaneous lymphoma and the type of immunosuppressive treatment can contribute to the development of more severe complications from COVID-19, we propose strategies for treating patients with primary cutaneous lymphomas by dividing both into low-, intermediate-, and high-risk categories (see recommendations for individual therapies in Supplemental Table I; available via Mendeley at doi:10.17632/7f3jvhw74s.1). Cutaneous lymphomas Low risk Pagetoid reticulosis, acral CD8+ T-cell lymphoma, CD4+ pleomorphic small/medium T-cell lymphoproliferative disorder, lymphomatoid papulosis, and mycosis fungoides (MF) stage IA, MF stage IB (patch only or limited body surface area), primary cutaneous (PC) marginal zone or PC follicle center B-cell lymphoma. Intermediate-low risk Primary cutaneous anaplastic large cell lymphoma, folliculotropic MF, granulomatous MF, granulomatous slack skin, MF stages IB (extensive patches/plaques) and IIA (reactive lymphadenopathy), subcutaneous panniculitis-like–cell lymphoma. Intermediate-high risk MF stages IIB (tumors) and III (erythrodermic), PC diffuse large B-cell lymphoma (not leg type). High risk Sézary syndrome; MF stage IV or transformed; primary cutaneous gamma-delta T-cell lymphoma; CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma; extranodal natural killer/T-cell lymphoma; PC diffuse large B-cell lymphoma, leg type. Therapies Low risk Topical retinoids, mechlorethamine gel or ointment, topical steroids with or without occlusion, imiquimod, home narrowband ultraviolet (UV) B phototherapy, heliotherapy, oral antibiotics, oral antipruritics, dilute vinegar or bleach soaks/baths, and aggressive moisturization. Intermediate risk Oral retinoids (bexarotene, acitretin, isotretinoin), methotrexate, oral steroids, vorinostat, and interferons (alpha or gamma). High risk Pralatrexate, romidepsin, mogamulizumab, brentuximab, gemcitabine and other chemotherapies. Skin radiotherapy, photopheresis, and office-based UV therapy are high risk because of travel. Low-risk therapies that can be used at home should be continued for all patients. The risks of travel and exposure likely outweigh the benefit of in-office treatments such as UV light therapy and total body electron beam radiation therapy. Home-based narrowband UVB phototherapy and heliotherapy can be continued or initiated. For patients with low-risk disease, only low-risk therapies are recommended. Intermediate-risk therapies may be continued, but dose adjustments may be advised on an individual basis. The least frequent laboratory monitoring possible should be performed to limit exposure while ensuring patient safety. Initiation of these therapies may be postponed using low-risk bridge therapies in the short term. Increase in or initiation of a retinoid or interferon should be considered in cases that necessitate the removal of other high-risk therapies. High-risk therapies, in addition to their inherent risks, may require travel to the clinic or hospital. These should be used only in the highest-risk patients, and the additional risks of therapy-related travel should be considered. Infusion regimens may be adjusted to increase treatment intervals. Romidepsin and mogamulizumab may be considered on an individual basis with extended intervals and lower doses. Allogeneic stem cell transplant and treatment with cyclophosphamide, hydroxyrubicin, vincristine, prednisone (CHOP), alemtuzumab, and fludarabine are strongly discouraged during the pandemic because they often lead to significant cytopenias that are known risk factors for COVID-19 complications.2 , 3 Consider alternative lower-risk therapies whenever possible. Telemedicine visits should be used to avoid unnecessary exposure, except for critical in-person evaluation and/or therapy. We must dynamically adjust treatment plans to provide optimal care for our patients with lymphoma while protecting them from COVID-19 complications. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Liang W. Guan W. Chen R. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China Lancet Oncol 21 2020 335 337 32066541 2 Yang J. Zheng Y. Gou X. Prevalence of comorbidities and its effects in coronavirus disease 2019 patients: a systematic review and meta-analysis Int J Infect Dis 2020 10.1016/j.ijid.2020.03.017 [e-pub ahead of print] 3 Wang T. Du Z. Zhu F. Comorbidities and multi-organ injuries in the treatment of COVID-19 Lancet 395 10228 2020 e52 32171074 4 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 72314 cases from the Chinese Center for Disease Control and Prevention JAMA 2020 10.1001/jama.2020.2648 [e-pub ahead of print]
PMC007xxxxxx/PMC7162762.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)30658-7 10.1016/j.jaad.2020.04.045 From the Academy The American Academy of Dermatology COVID-19 registry: Crowdsourcing dermatology in the age of COVID-19 Freeman Esther E. MD, PhD ab∗ McMahon Devon E. BA a Fitzgerald Matthew E. DrPH c Fox Lindy P. MD d Rosenbach Misha MD e Takeshita Junko MD, PhD, MSCE e French Lars E. MD f Thiers Bruce H. MD c Hruza George J. MD, MBA c 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 American Academy of Dermatology, Schaumburg, Illinois d Department of Dermatology, University of California–San Francisco, San Francisco, California e Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania f Department of Dermatology, University Hospital, Munich University of Ludwig Maximilian, Munich, Germany ∗ Correspondence to: Esther Freeman, MD, PhD, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114. 17 4 2020 8 2020 17 4 2020 83 2 509510 11 4 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. ==== Body pmcThere have been increasing reports of dermatologic manifestations of COVID-19. The first case series of dermatologic manifestations included 18 Italian patients with erythematous, urticarial, and vesicular rashes, often on the trunk.1 Other reports include drug hypersensitivity,2 urticaria,2 a petechial rash mimicking dengue,3 and acro-ischemia.4 It is important to further characterize dermatologic manifestations of COVID-19 to understand the relationship between the virus and skin and to determine whether cutaneous manifestations of COVID-19 may assist with early disease detection. To date, collecting cases of dermatologic manifestations of COVID-19 has been challenging given their relative infrequency and the rapid spread of COVID-19. Dermatologists are relying on informal networks, including social media, to share cutaneous manifestations of the disease. To rapidly and centrally collate these cases from a global network and inform colleagues on the front lines combatting the virus, the American Academy of Dermatology (AAD) COVID-19 Task Force has launched an online COVID-19 dermatology registry. This registry was inspired by a similar registry created by the COVID-19 Global Rheumatology Alliance.5 The registry's primary purpose is to rapidly collect COVID-19 cutaneous manifestations to enable prompt dissemination of the findings to the dermatology community and front-line health care workers. Given early reports of COVID-19 disparities across racial and socioeconomic groups in the United States, we encourage submission of COVID-19 cases across all ages, races, and socioeconomic statuses. A secondary objective is to report how COVID-19 affects patients with pre-existing dermatologic conditions, particularly those receiving immunosuppressive therapies. We expect that these results will generate ideas for further epidemiologic studies on COVID-19 in dermatology. The registry is available online through the AAD website at www.aad.org/covidregistry. The International League of Dermatological Societies is collaborating with the AAD on this registry with the aim of extending its reach internationally. Cases can be entered by any health care worker, including nondermatologists and non–AAD members, from around the world. Data entry takes 5 to 7 minutes and requires no patient protected health information. Patient demographics, new-onset dermatologic conditions in the setting of COVID-19, dermatologic and medical history, and the patient's COVID-19 diagnosis and treatment are requested. COVID-19 diagnosis may be based on clinical suspicion alone or laboratory confirmation. The registry was reviewed by the Partners Healthcare (Massachusetts General Hospital) institutional review board. Data are housed securely through Partners REDCap, and is not housed at the AAD. We recognize the limitations of such a registry, including selective reporting, duplicate case entries, and lack of a denominator, that preclude us from accurately estimating incidence or prevalence. This registry does not replace rigorous epidemiologic studies. However, we believe this registry will allow the global community to rapidly share observations without the institutional or national boundaries that often limit scientific collaboration. Ultimately, the success of this international effort depends on the active participation of all health workers caring for patients with COVID-19. Together, we hope to use this registry to compile a more complete and representative case series of potential dermatologic manifestations of COVID-19 and outcomes of established dermatology patients who develop COVID-19. The authors would like to thank the COVID-19 Global Rheumatology Alliance for sharing their experience with registry development. We would also like to thank staff at the 10.13039/100001934 American Academy of Dermatology for their logistical and administrative support. We also appreciate comments from Drs Kenneth Katz, Matthew Mansh, and Adewole Adamson regarding collecting demographic information in the registry. We thank Megan Wenger for her assistance with REDCap. Funding sources: None. Disclosure: Drs Freeman, Fox, Rosenbach, Takeshita, and Hruza are part of the American Academy of Dermatology COVID-19 Ad Hoc Task Force. Dr French is president of the International League of Dermatological Societies. Dr Thiers is the President of the American Academy of Dermatology. Devon McMahon and Matthew Fitzgerald have no conflicts of interest to declare. Reprints not available from the authors. ==== Refs References 1 Recalcati S. Cutaneous manifestations in COVID-19: a first perspective [Epub ahead of print] J Eur Acad Dermatol Venereol 2020 10.1111/jdv.16387 Published online March 26, 2020 2 Zhang J.J. Dong X. Cao Y.Y. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China [Epub ahead of print] Allergy 2020 10.1111/all.14238 Published online February 19, 2020 3 Joob B. Wiwanitkit V. COVID-19 can present with a rash and be mistaken for dengue J Am Acad Dermatol 82 2020 e177 32213305 4 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 2020 E006 32220276 5 Robinson P.C. Yazdany J. The COVID-19 Global Rheumatology Alliance: collecting data in a pandemic [Epub ahead of print] Nat Rev Rheumatol 2020 1 2 10.1038/s41584-020-0418-0 31784724
PMC007xxxxxx/PMC7162783.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)30659-9 10.1016/j.jaad.2020.04.046 JAAD Online COVID-19 and racial disparities Shah Monica BSc a∗ Sachdeva Muskaan BHSc a Dodiuk-Gad Roni P. MD bcd a Faculty of Medicine, University of Toronto, Ontario, Canada b Division of Dermatology, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada c Department of Dermatology, Ha'emek Medical Center, Afula, Israel d Ruth and Bruce Rappaport Faculty of Medicine, Technion Institute of Technology, Haifa, Israel ∗ Correspondence to: Monica Shah, BSc, Faculty of Medicine, University of Toronto, 1 King's College Cir, Toronto, ON M5S 1A8 17 4 2020 7 2020 17 4 2020 83 1 e35e35 © 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: Epidemiologic evidence of age- and sex-related differences for COVID-19 suggest that males and older adults with underlying health conditions including hypertension, obesity, chronic lung disease, diabetes, and cardiovascular disease have increased vulnerability to COVID-19.1 To date, the literature is very limited on data exploring racial disparities.1 On April 8, 2020, the Centers for Disease Control and Prevention published surveillance data of laboratory-confirmed COVID-19–associated hospitalizations in 14 US states.1 Although 18% of individuals in the catchment population were African American, among those with data on race/ethnicity (n = 580), 33.1% were African American, suggesting that African Americans may be disproportionately affected by COVID-19.1 These data are consistent with government statistics from cities in the United States showing similar racial disparities. In Chicago, Illinois, African Americans account for only 14.6% of the state's population; however, as of April 9, 2020, 51.5% of COVID-positive patients and 67.3% (n = 132) of those who died were African American.2 Furthermore, in Michigan, although 33% of patients diagnosed with COVID-19 as of April 9, 2020, were African American, this population makes up only approximately 14.1% of the state population.3 Ethnic minority groups may have greater risk of infection due to comorbidities, including hypertension in African American populations.4 Moreover, African Americans are more likely to live in densely populated neighbourhoods of lower socioeconomic status, which may lead to increased exposure from closer contact between individuals, less equitable health care access, and lower rates of COVID-19 testing. Additionally, the US Bureau of Labour Statistics reported that only 19.7% of African American employees can work from home, compared with 29.9% of white employees.5 African Americans may be more likely to work in occupations included in the essential workforce, such as transportation and food service. Moreover, on April 8, 2020, Oliver Brooks, the President of the National Medical Association representing African American physicians and their patients in the United States, stated, “Many of these jobs also do not provide healthcare coverage, so we are underinsured or uninsured during a health crisis. When adding the underlying health risk factors of heart disease, diabetes, and asthma, the African American population is at the epicenter of this current health crisis.”4 To gain a thorough understanding of the epidemiology of COVID-19 and to ensure targeted health education and equitable allocation of health care system resources for more vulnerable populations, studies on the race-specific prevalence of COVID-19 and outcomes are crucial. We call for higher-priority assessment of racial and ethnic disparities in COVID-19, which may reduce morbidity and mortality among African Americans. As Brooks stated, “There is still time, but time is running out.”4 Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Garg S. Kim L. Whitaker M. Hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019—COVID-NET, 14 states, March 1–30, 2020 MMWR Morb Mortal Wkly Rep 69 2020 458 464 32298251 2 City of Chicago. Latest data Available at: https://www.chicago.gov/city/en/sites/covid-19/home/latest-data.html 3 State of Michigan Coronavirus: Michigan data Available at: https://www.michigan.gov/coronavirus/0,9753,7-406-98163_98173---,00.html 4 National Medical Association COVID-19 underscores wealth and health disparities in the African American community. Available at: https://www.nmanet.org/news/500673/COVID-19-Underscores-Wealth-and-Health-Disparities-in-the-African-American-Community.htm 2020 5 US Bureau of Labour Statistics Economic news release Available at: https://www.bls.gov/news.release/flex2.t01.htm 2019
PMC007xxxxxx/PMC7172896.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)30687-3 10.1016/j.jaad.2020.04.072 JAAD Online Invited response to the comment on “Dermatology residents and the care of COVID-19 patients” Grant-Kels Jane M. MD ∗ Dermatology Department, University of Connecticut, Farmington, Connecticut Department of Dermatology, the University of Florida, Gainesville, Florida ∗ Correspondence to: Jane M. Grant-Kels, MD, UConn Dermatology Department, 21 South Rd, Farmington, CT 06032 21 4 2020 7 2020 21 4 2020 83 1 e51e51 © 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: I am greatly appreciative to Dr Basil Patel for his comments1 on the dermatoethics piece, “Dermatology residents and the care of COVID-19 patients.”2 As someone who is intimately involved with dermatology residents at 2 universities, I am personally very aware of residents' concerns and fears regarding this pandemic. I will address each of the issues raised by Dr Patel. Although the fatality rate for those aged 20 to 49 years is lower, I recognize that any risk, when it is personal, is terrifying. I did not mean to imply that fear was not appropriate. Your assertion that theoretically upholding the Hippocratic Oath should make the fatality rate irrelevant has some merit. Although physicians, as you state, do not need to be martyrs, they need to fulfill their professional responsibility the same as a fireman running into a burning building. There is now personal protective equipment that reduces the infectivity rate substantially, if worn properly, which should be reassuring. I agree that having personal protective equipment available is crucial. Peggy Noonan penned an editorial in the Wall Street Journal published April 11-12, 2020. She reflected upon the “ …selflessness of doctors and nurses, for instance, and how they do their jobs because it's a calling. This tells us what bravery looks like, but also what a vocation is, and how a vocation is a spiritual event.”3 I am very sensitive to the fact that many residents are young with spouses and children. The risk of returning home after caring for infectious patients is something I did not mention but was acutely aware of. The need to be concise and conform to the word limit of a letter prevented me from raising this issue. Finally, you raised the issue of power dynamics and that residents have little leverage. This implies that attendings are not fulfilling their obligation to care for these infectious patients. Emergency department and hospital attendings (many of whom, at many hospitals, include called-up dermatology attendings) are potentially jeopardizing their well-being just as you are. I hope that all are pitching in during this national emergency, not out of fear that their contract will not be renewed but “to fulfill the key human desire to be part of something—‘to be part of Team Humanity,’ to be useful.”3 I am pleased that you are proud to be helping your community, and I am confident your community is grateful to you. Those at the front line caring for these patients are heroes. This pandemic has tested all of us. I am hopeful that out of this trial we will grow as physicians and human beings. Thank you for your service. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the author. ==== Refs References 1 Patel B. Comment on “Dermatology residents and the care of COVID-19 patients.” J Am Acad Dermatol 83 1 2020 e49 32330631 2 Stoj V. Grant-Kels J.M. Dermatology residents and the care of COVID-19 patients J Am Acad Dermatol 82 6 2020 1572 1573 32259536 3 Noonan P. A Holy Week Amid a National Tribulation. The Wall Street Journal; April 9, 2020 Available at: https://www.wsj.com/articles/a-holy-week-amid-a-national-tribulation-11586474599
PMC007xxxxxx/PMC7185594.txt	==== Front Rev Fr Allergol (2009) Rev Fr Allergol (2009) Revue Francaise D'Allergologie (2009) 1877-0312 1877-0320 Elsevier Masson SAS. S1877-0320(12)00420-4 10.1016/j.reval.2012.11.007 Article Original L’analyse virologique des aspirations nasopharyngées reflète-t-elle l’infection respiratoire basse chez l’enfant ? Étude en PCR multiplex Does the nasopharyngeal samples virological analysis reflect the lower respiratory tract infection in children population? A PCR multiplex studyKoenig-Zores C. a⁎ Stoll-Keller F. b Ammouche C. c Donato L. a a Service de réanimation néonatale et pédiatrie 2, pôle médicochirurgical de pédiatrie, hôpital de Hautepierre, hôpitaux universitaires de Strasbourg, avenue Molière, 67098 Strasbourg, France b Service de virologie, pôle de biologie, hôpitaux universitaires de Strasbourg, 67000 Strasbourg, France c Service de réanimation médicochirurgicale pédiatrique, pôle médicochirurgical de pédiatrie, hôpital de Hautepierre, hôpitaux universitaires de Strasbourg, avenue Molière, 67098 Strasbourg, France ⁎ Auteur correspondant. 20 12 2012 3 2013 20 12 2012 53 2 5964 22 10 2012 21 11 2012 Copyright © 2012 Elsevier Masson SAS. All rights reserved. 2012 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. Les infections respiratoires sont un problème de santé publique. Leur cause en est majoritairement virale chez le jeune enfant. La mise au point de techniques de détection par biologie moléculaire a permis d’en élargir le spectre virologique. L’objectif de notre travail est d’évaluer la corrélation entre les résultats des prélèvements effectués par aspiration rhinopharyngée et par lavage bronchoalvéolaire. Trente enfants présentant une symptomatologie d’infection respiratoire basse ont ainsi été prélevés aux deux sites au cours d’une même séance. Les échantillons ont été analysés par Polymerase chain reaction (PCR) virale multiplex (xTAG™ RVP). Une corrélation forte est retrouvée entre la positivité de la PCR virale dans les voies respiratoires hautes et basses (p = 0,0002). Le virus le plus fréquemment isolé est l’entéro-rhinovirus. Ces résultats confirment que l’infection virale touche l’appareil respiratoire de façon diffuse, et suggèrent que le prélèvement par aspiration rhinopharyngée suffit au diagnostic virologique d’une infection respiratoire virale basse chez l’enfant immunocompétent. Respiratory tract infections are frequent in young children and are related to viruses in most cases. Multiplex Polymerase chain reaction (PCR) based techniques are valuable tools for describing the spectrum of such viruses. The goal of this study was to assess the correlation of virus detection in samples obtained by nasopharyngeal aspiration and by bronchoalveolar lavage. Both samples were taken at the same time in 30 children with lower respiratory tract infection, and were analyzed by multiplex virus PCR (xTAG™ RVP). A strong correlation has been found (P = 0.0002) and the most frequently isolated virus was the entero-rhinovirus spp. These results strengthen the opinion that viruses colonize both the upper and lower respiratory tract. Nasopharyngeal samples should be sufficient to the diagnosis of lower respiratory tract viral infection in immuno-competent children. Mots clés Lavage bronchoalvéolaire PCR Virus Aspiration rhinopharyngée Infection respiratoire Pédiatrie Keywords Bronchoalveolar lavage PCR Viruses Nasopharyngeal aspiration Respiratory tract infection Paediatrics ==== Body pmc1 Introduction Les virus sont responsables d’environ 80 % des infections respiratoires de l’enfant : infections hautes (rhinite, laryngotrachéite) et basses (bronchite, bronchiolite, pneumopathie). L’incidence annuelle des pneumopathies communautaires de l’enfant de moins de cinq ans est de 34 à 40 pour mille [1]. Les virus en sont principalement responsables chez les nourrissons [2]. Les nouveaux outils du diagnostic virologique permettent d’affiner les données épidémiologiques. Comparées à l’immuno-histochimie et aux cultures, les techniques de Polymerase chain reaction (PCR) mettent en évidence un spectre viral beaucoup plus large, incluant des organismes déjà connus, mais aussi des virus dits « émergents » issus le plus souvent d’une recombinaison génétique. Chez l’enfant, la méthode de prélèvement la plus largement employée est l’aspiration rhinopharyngée (ARP) à l’aide d’un dispositif stérile. L’écouvillonnage nasal a une moins bonne sensibilité pour certains virus [3]. Les virus peuvent également être recherchés par prélèvement pulmonaire notamment dans le liquide de lavage bronchoalvéolaire (LBA), par brossage endoscopique ou même par biopsie. À notre connaissance, aucune étude n’a comparé à ce jour les résultats de l’analyse virologique de l’ARP et du LBA en PCR multiplex. Notre étude a comme objectif principal d’en évaluer la corrélation chez des enfants immunocompétents, présentant une infection respiratoire basse, et chez lesquels une indication d’endoscopie bronchique a été posée. L’objectif secondaire est d’explorer l’existence ou non d’un portage viral chez les patients présentant une symptomatologie d’asthme. 2 Patients et méthodes Cette étude a été menée de janvier 2008 à avril 2010 dans les hôpitaux universitaires de Strasbourg principalement en hospitalisation de jour, mais également en réanimation pédiatrique. 2.1 Critères d’inclusion Les enfants inclus dans l’étude devaient présenter une symptomatologie respiratoire chronique pour laquelle une bronchofibroscopie était requise : bronchopneumopathie traînante, asthme mal contrôlé, et où le diagnostic d’infection bronchique était optiquement porté au cours de l’examen. Parmi les 30 patients inclus, sept avaient un asthme déjà diagnostiqué au moment de l’examen et au moins trois d’entre eux ont eu des symptômes d’hyperréactivité bronchique dans les mois qui ont suivi. 2.2 Critères d’exclusion Aucun enfant porteur ou suspect de l’une des affections suivantes n’a été inclut dans l’étude :• déficit immunitaire, constitutionnel ou acquis ; • maladie génétique de l’arbre respiratoire (mucoviscidose, dyskinésie ciliaire primitive) ; • syndrome polymalformatif ; • infection nosocomiale ; • d’un corps étranger inhalé. 2.3 Déroulement de l’examen La fibroscopie bronchique a été réalisée en ambulatoire ou en hospitalisation si nécessaire, après obtention de l’accord des parents. Vingt minutes avant l’examen, l’enfant a reçu une prémédication par voie intrarectale (sulfate d’atropine et benzodiazépine à courte durée d’action). Chez l’enfant de plus d’un an, une sédation complémentaire par protoxyde d’azote inhalé a été délivrée au masque pendant toute la durée de l’examen. Le geste a été complété par une anesthésie locale à la lidocaïne. 2.4 Modalités de prélèvement L’endoscopie, réalisée par voie naso-trachéale, est précédée d’une pulvérisation nasale de lidocaïne. Dans notre protocole habituel cette pulvérisation est suivie d’une aspiration nasopharyngée visant à éliminer l’excédent de lidocaïne. Dans le présent travail, le produit de cette aspiration a été collecté pour étude virologique. Après exploration de l’arbre bronchique, le LBA a été effectué dans le territoire le plus suspect ou dans la bronche lobaire moyenne en cas d’infection diffuse. Trois à cinq seringues de 1 mL/kg de sérum physiologique stérile ont été injectées successivement par le canal opérateur, puis ré-aspirées et homogénéisées sur flacon piège. Des échantillons ont été envoyés aux laboratoires pour analyses virologique, cytologique et bactériologique. 2.5 Analyse virologique Les deux prélèvements ont été acheminés dans un milieu de transport spécifique (universal transport medium [UTM-RT, milieu de transport universel]) au laboratoire de virologie où a été réalisée une PCR multiplex pour la détection d’un panel de virus respiratoires1 . Il s’agit d’un test qualitatif de recherche d’acide nucléique viral permettant la détection simultanée et l’identification de plusieurs virus à tropisme respiratoire à partir d’aspirations ou de sécrétions rhinopharyngées ou de LBA. Les virus recherchés par cette technique sont l’influenza A, H1, H3 et H5, l’influenza B, le virus respiratoire syncytial (VRS) de type A et B ; la para-influenza 1, 2, 3,4, le Coronavirus (CoV) NL63, OC43, HKU1, 229E, SARS, le métapneumovirus humain (MPV), l’adénovirus et l’entéro-rhinovirus (cette technique ne pouvant différencier ces deux Picornavirus). 2.6 Analyse statistique Les données sont traitées à l’aide du logiciel Statistica 8.02 . Les résultats sont exprimés en variables qualitatives et leur association est mesurée en analyse de corrélation (Spearman R) ainsi qu’en régression logistique. Les comparaisons sont faites en X 2 ou en probabilité unilatérale de Fisher en cas d’effectifs théoriques insuffisants. Le seuil de significativité est fixé pour un risque α inférieur à 5 %. 3 Résultats 3.1 Population étudiée Trente enfants âgés de 11 [1–122] mois et pesant 8,8 [3,4–36] kg ont été inclus (médianes et extrêmes). Le sex-ratio est de 1. Pour plus de la moitié d’entre eux, l’indication de fibroscopie a été posée devant un tableau d’infection bronchopulmonaire traînante ; un tiers des cas présentait un asthme mal contrôlé ; les autres étaient majoritairement explorés dans le cadre d’une pathologie œsophagienne ou laryngée avec symptômes respiratoires. Les fibroscopes utilisés étaient : Olympus® BFXP40/XP60/XP160 (diamètre : 2,8 mm) chez 21 sur 30 enfants, Olympus® 3C30/3C160 (diamètre : 3,6 mm) chez neuf sur 30 patients3 . 3.2 Microbiologie 3.2.1 Positivité des prélèvements Vingt-cinq sur 30 (83 %) prélèvements ont permis d’identifier un ou plusieurs virus et/ou bactéries pouvant être associés à la symptomatologie. Une identification mixte, virale et bactérienne, est trouvée dans 16 sur 30 (53 %) cas (bactéries par ordre de fréquence : Haemophilus influenzae, Streptococcus pneumoniae et Staphylococcus aureus). 3.2.2 Analyse virologique des aspirations rhinopharyngées (ARP) La PCR multiplex est positive dans 15 sur 30 (50 %) des cas, et a permis de mettre en évidence 16 virus (Fig. 1 ). Le virus le plus largement mis en évidence est l’entéro-rhinovirus chez 11 sur 30 (37 %) des enfants soit 11 sut 15 (73 %) des PCR virales multiplex positives. On ne note qu’un seul cas de co-infection virale (entéro-rhinovirus et CoV).Fig. 1 Résultats des Polymerase chain reaction (PCR) virales au niveau des deux sites de prélèvement. Le diagramme à barres représente le nombre de fois (en ordonnée) où les différents virus (en abscisse) ont été identifiés par PCR selon le site de prélèvement : en bleu, aspirations rhinopharyngées (ARP) ; en jaune, lavage bronchoalvéolaire (LBA). Les camemberts indiquent la proportion de chaque virus dans les produits d’ARP (à gauche) et dans le liquide de LBA (à droite). 3.2.3 Analyse virologique du liquide de lavage bronchoalvéolaire (LBA) Seize sur 30 (53 %) des prélèvements étaient positifs à au moins un virus, et ont mis en évidence 18 virus (Fig. 1). Le virus le plus souvent identifié est l’entéro-rhinovirus chez 13 sur 30 (43 %) des enfants soit 13 sur 16 (81 %) des PCR multiplex virales positives. Les autres virus sont retrouvés en égales proportions mais bien inférieures à celle de l’entéro-rhinovirus un sur 16 (6 %). On note deux co-infections virales : entéro-rhinovirus/CoV et entéro-rhinovirus/métapneumovirus. 3.2.4 Association entre positivité de la Polymerase chain reaction (PCR) au niveau de l’aspiration rhinopharyngée (ARP) et du lavage bronchoalvéolaire (LBA) Tous virus confondus, la positivité de la PCR multiplex effectuée au niveau des ARP est significativement corrélée à sa positivité sur le LBA (Spearman R = 0,63 ; p = 0,00017) (Fig. 2 ). En régression logistique, l’ARP positive fournit un bon modèle prédictif pour un LBA positif (OR 26 ; Wald-Chi2 = 10,7 ; p = 0,001).Fig. 2 Concordance entre la positivité de la Polymerase chain reaction (PCR) virale haute et basse. Abscisse : nombre de virus révélés par la PCR multiplex : 0 (aucun), un et deux. Prélèvements concordants (diagonale) : 12 cas avec aspirations rhinopharyngées (ARP) et lavage bronchoalvéolaire (LBA) négatifs ; 12 cas où l’ARP et le LBA montrent un virus ; un cas avec deux virus. Prélèvements discordants (marges) : deux ARP sont isolément positives ; trois LBA sont isolément positifs. 3.2.5 Corrélation spécifique par virus La positivité de la PCR pour l’entéro-rhinovirus au niveau des ARP est statistiquement corrélée à celle du LBA (Spearman R = 0,73 ; p = 0,00001) (Fig. 3 ). La signature moléculaire des virus influenza B, virus respiratoire syncytial A et B et du CoV a été identifiée de manière concordante dans quatre paires de prélèvements. Cinq prélèvements discordants entre les deux sites ont été mis en évidence. Trois PCR virales multiplex ne sont positives qu’au niveau du LBA. L’entéro-rhinovirus est impliqué dans tous les cas, dont une fois en association avec un métapneumovirus (Fig. 1).Fig. 3 Concordance entre la positivité de la Polymerase chain reaction (PCR) entéro-rhinovirus haute et basse. Abscisse : PCR négative (0) ou positive (1) pour la recherche d’entéro-rhinovirus en PCR. Prélèvements concordants (diagonale) : 16 cas avec aspirations rhinopharyngées (ARP) et lavage bronchoalvéolaire (LBA) négatifs ; dix cas où l’ARP et le LBA montrent un entéro-rhinovirus. Prélèvements discordants : une ARP est isolément positive ; trois LBA sont isolément positifs. 3.3 Profil virologique des asthmatiques Le diagnostic d’asthme a été retenu dans sept cas sur 30 (23 %). Afin de confronter la validité de nos données à celle de la littérature, nous avons comparé les résultats virologiques des échantillons selon le statut d’asthme [4], [5]. On retrouve bien une différence de portage de Rhinovirus entre les asthmatiques et les autres (respectivement : 85 % vs 25 % sur les ARP ; 71 % vs 40 % sur les LBA) (Fig. 4 ).Fig. 4 Comparaison de la positivité de la Polymerase chain reaction (PCR) à entéro-rhinovirus dans la population asthmatique vs non asthmatique. 4 Discussion Notre choix s’est porté vers l’étude de l’épidémiologie virale de nos patients par le biais d’une analyse moléculaire (PCR) virale multiplex. Le diagnostic virologique est dépendant de la qualité du prélèvement (caractère intracellulaire obligatoire), de sa rapidité de prise en charge et de la technique d’analyse utilisée. La PCR, très sensible, a supplanté les deux autres techniques utilisées auparavant pour le diagnostic viral : la culture et la recherche d’antigènes [6]. Elle est plus sensible notamment pour certains virus pneumotropes (Rhinovirus, Bocavirus, et certains CoV) qui peuvent mettre en défaut les autres techniques de diagnostic [7]. La PCR multiplex permet de rechercher dans le même temps un panel de virus. Son utilisation a permis d’accroître nos connaissances sur les causes des infections des voies respiratoires. La principale limite de cette technique est qu’elle ne peut témoigner du caractère actif de l’infection. La présence d’acides nucléiques appartenant au Rhinovirus peut se retrouver de façon prolongée, pouvant positiver la PCR plusieurs semaines après une infection [8]. Le développement de techniques quantitatives, malheureusement non encore disponibles en PCR multiplex, pourrait remédier à cet écueil. En cas de forte suspicion clinique et de négativité de cet examen, il reste donc préconisé d’effectuer une culture cellulaire qui reste la référence pour détecter un virus infectieux. Cette technique est particulièrement adaptée aux jeunes enfants, dont le taux d’infections virales est extrêmement élevé, non seulement à des fins épidémiologiques, mais également thérapeutiques, pronostiques et pour la mise en place de procédures d’isolement adéquates [2], [9], [10], [11], [12]. Un taux important de co-infection virale et bactérienne est retrouvé dans notre étude dévoilant le lien étroit, probablement potentialisateur, existant entre les deux types de pathogènes [13], [14]. Le recours à cette technique nous a permis de retrouver l’association classique entre asthme et présence d’entéro-rhinovirus dans les prélèvements rhinopharyngés (p = 0,009). Dans notre étude, le lien est moins fort au niveau du LBA (p = 0,16) dans cette population particulière, probablement lié à l’effectif réduit. Néanmoins, la même tendance se dessine. La technique de biologie moléculaire utilisée dans notre centre ne nous permet pas de distinguer les Rhinovirus des entérovirus. En cas de positivité de celle-ci, nous avons considéré qu’il s’agissait d’une infection à Rhinovirus compte-tenu du terrain, de la saisonnalité des examens et de l’épidémiologie des Rhinovirus. Dans de nombreux centres, la technique de choix concernant le site de prélèvement à visée virologique dans le cadre d’une infection respiratoire basse est la réalisation d’une ARP, l’indication d’endoscopie n’étant pas posée chez le tout venant. À l’instar de ce qui a été montré dans les dyskinésies ciliaires primitives [15], nous cherchons à déterminer si l’infection bronchopulmonaire virale peut être mise en évidence par un prélèvement peu invasif effectué dans un site facilement accessible en pratique courante. Notre étude montre une corrélation forte entre la positivité de la PCR virale multiplex au niveau des ARP et sa positivité au niveau du LBA (p = 0,00017). Ainsi, le risque d’avoir un LBA positif est 26 fois plus important si l’ARP est positive. L’association est clairement établie pour le Rhinovirus, microorganisme largement majoritaire sur notre set de prélèvements (p = 0,00001). Ces résultats confortent l’idée que l’infection virale touche l’appareil respiratoire haut et bas de façon diffuse. Néanmoins, ils ne montrent pas une concordance totale entre les deux sites de prélèvement, principalement liée à la faible représentativité de certains virus, ne permettant pas de conclure hormis pour l’entéro-rhinovirus. Nous continuons à ce jour les inclusions afin de pouvoir affiner les corrélations virus par virus. À la vue de ces résultats, la PCR virale multiplex sur l’ARP est un bon reflet du prélèvement dans le bas appareil. Elle devrait suffire au diagnostic de bronchopneumopathie virale chez l’enfant immunocompétent. L’accès au poumon profond par le LBA est un examen invasif, toutefois difficilement contournable chez l’enfant immunodéprimé ou en cas de pneumopathie grave sans germe identifié par d’autres techniques. 5 Conclusion La biologie moléculaire permet de préciser le spectre épidémiologique des infections respiratoires. La PCR virale multiplex, peu invasive au niveau rhinopharyngé, paraît bien corrélée aux résultats du LBA et plaide pour un continuum de l’infection virale tout au long de l’arbre respiratoire. L’ARP devrait suffire au diagnostic virologique d’une bronchopneumopathie chez l’enfant immunocompétent. Néanmoins, sa réalisation ne doit pas faire retarder la pratique du LBA en cas d’infection respiratoire basse traînante ou d’une pathologie sous-jacente associée (autre type de microorganisme, bactérie ou parasite). Prédominant dans notre étude, le Rhinovirus est connu pour produire de petites lésions tissulaires avec production de médiateurs pro-inflammatoires induisant un afflux de polynucléaires neutrophiles. Cette réponse immune, qui pourrait augmenter la réactivité bronchique chez l’asthmatique, est un facteur supposé d’exacerbation. Le sens de l’association Rhinovirus et asthme, bien démontrée par de larges échantillons de population [16], n’est toutefois pas clair. On sait que la fonction des cellules T régulatrices est perturbée chez l’atopique, et pas seulement au niveau de la réponse Th2. Le suivi de la cohorte COAST montre que le nombre d’épisodes de viroses sifflantes dans la première année de vie et le portage ultérieur de Rhinovirus dépendent de la qualité de la réponse Th1 mesurée dès la naissance [17]. Ces travaux semblent indiquer que l’asthme du jeune enfant prédispose au portage de microorganismes dans les voies aériennes et remettent en question le rôle déclenchant des virus, qui seraient plutôt des marqueurs : viroses asthmo-induites ? Déclaration d’intérêts Les auteurs déclarent ne pas avoir de conflits d’intérêts en relation avec cet article. 1 La technique utilisée dans notre centre est commercialisée sous le nom de « xTAG™ RVP ». 2 Statsoft Inc. 3 Olympus Medical Systems Corp, Tokyo ; Japon. ==== Refs Références 1 McIntosh K. Community-acquired pneumonia in children N Engl J Med 346 6 2002 429 437 11832532 2 Juven T. Mertsola J. Waris M. Leinonen M. Meurman O. Etiology of community-acquired pneumonia in 254 hospitalized children Pediatr Infect Dis J 19 4 2000 293 298 10783017 3 Heikkinen T. Marttila J. Salmi A.A. Ruuskanen O. Nasal swab versus nasopharyngeal aspirate for isolation of respiratory viruses J Clin Microbiol 40 11 2002 4337 4339 12409425 4 Lemanske R.F. Jr. Jackson D.J. Gangnon R.E. Evans M.D. Li Z. Rhinovirus illnesses during infancy predict subsequent childhood wheezing J Allergy Clin Immunol 116 3 2005 571 577 16159626 5 Gern J.E. Rhinovirus and the initiation of asthma Curr Opin Allergy Clin Immunol 9 1 2009 73 78 19532096 6 Leruez-Ville M. Diagnosis of viral respiratory infections Arch Péediatr 14 4 2007 404 409 7 Jennings L.C. Anderson T.P. Werno A.M. Beynon K.A. Murdoch D.R. Viral etiology of acute respiratory tract infections in children presenting to hospital: role of polymerase chain reaction and demonstration of multiple infections Pediatr Infect Dis J 23 11 2004 1003 1007 15545854 8 Jartti T. Lehtinen P. Vuorinen T. Koskenvuo M. Ruuskanen O. Persistence of rhinovirus and enterovirus RNA after acute respiratory illness in children J Med Virol 72 4 2004 695 699 14981776 9 Doan Q.H. Kissoon N. Dobson S. Whitehouse S. Cochrane D. A randomized, controlled trial of the impact of early and rapid diagnosis of viral infections in children brought to an emergency department with febrile respiratory tract illnesses J Pediatr 154 1 2009 91 95 18814887 10 Woo P.C. Chiu S.S. Seto W.H. Peiris M. Cost-effectiveness of rapid diagnosis of viral respiratory tract infections in pediatric patients J Clin Microbiol 35 6 1997 1579 1581 9163486 11 Marguet C. Lubrano M. Gueudin M. Le Roux P. Deschildre A. In very young infants severity of acute bronchiolitis depends on carried viruses PLoS One 4 2 2009 e4596 19240806 12 McIntosh K. Halonen P. Ruuskanen O. Report of a workshop on respiratory viral infections: epidemiology, diagnosis, treatment, and prevention Clin Infect Dis 16 1 1993 151 164 8383547 13 Brouard J. Vabret A. Freymuth F. Duhamel J.F. Virus bacteria interactions in acute viral pneumonia in infancy: clinical and therapeutic consequences Arch Pediatr 5 Suppl. 1 1998 22s 25s 10223157 14 Hament J.M. Kimpen J.L. Fleer A. Wolfs T.F. Respiratory viral infection predisposing for bacterial disease: a concise review FEMS Immunol Med Microbiol 26 3-4 1999 189 195 10575129 15 Verra F. Fleury-Feith J. Boucherat M. Pinchon M.C. Bignon J. Do nasal ciliary changes reflect bronchial changes? An ultrastructural study Am Rev Respir Dis 147 4 1993 908 913 8466127 16 Jackson D.J. Gangnon R.E. Evans M.D. Roberg K.A. Anderson E.L. Wheezing rhinovirus diseases in early life predict asthma development in high-risk children Am J Respir Crit Care Med 178 2008 667 672 18565953 17 Friedlander S.L. Jackson D.J. Gangnon R.E. Evans M.D. Li Z. Viral infection, cytokine dysregulation and the origins of childhood asthma and allergic diseases Pediatr Infect Dis J 24 2005 S170 S176 16378042
PMC007xxxxxx/PMC7185918.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)30313-4 10.1016/j.reval.2020.02.239 Mise Au Point Urticaire de l’enfant Urticaria in childrenBoralevi F. Léauté-Labrèze C. ⁎ Unité de dermatologie pédiatrique, hôpital Pellegrin-Enfants, place Amélie-Raba-Léon, 33076 Bordeaux, France ⁎ Auteur correspondant. 27 4 2020 October-November 2020 27 4 2020 60 6 476483 23 2 2020 24 2 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’incidence cumulée de l’urticaire chez l’enfant est proche de 10 %. On décrit la forme superficielle et la forme profonde, ou angioedème. Chez le jeune enfant de moins de 3 ans, l’urticaire est volontiers annulaire et ecchymotique et prise à tort pour un érythème polymorphe ou un œdème aigu hémorragique. La pseudo-maladie sérique est une forme particulière d’urticaire caractérisée par un angioedème des extrémités, une fièvre et des arthralgies, la principale cause est médicamenteuse (céphalosporines). Chez l’enfant, l’interrogatoire et l’examen clinique sont essentiels et permettent dans la plupart des cas de mettre en évidence une étiologie. Les principales causes d’urticaire aiguë ou récidivante sont les infections virales et/ou les médicaments (histaminolibération non spécifique), alors que les urticaires chroniques sont majoritairement de cause physique. Dans les pays développés, les infections parasitaires sont rarement en cause. Les arguments en faveur d’une allergie alimentaire sont : un contexte d’atopie, la survenue dans l’heure suivant la prise de l’aliment suspect, l’absence de fièvre ou de contexte infectieux, la durée inférieure à 24 heures, l’association éventuelle à d’autres manifestations d’anaphylaxie et la récidive à chaque nouvelle prise de l’aliment suspect. Le traitement de première intention d’une urticaire sans signe de gravité se limite à la prescription d’un antihistaminique non sédatif (associé à l’éviction de la cause lorsque celle-ci est déterminée). Près d’un tiers des cas d’urticaire de l’enfant évolue sur une durée prolongée de plus de 6 semaines, définissant l’urticaire chronique (le plus souvent à type d’urticaire récidivante bénigne lors des épisodes infectieux et/ou la prise de médicaments). Il est très rare qu’une urticaire, même chronique, révèle une maladie inflammatoire ou une maladie génétique comme une cryopyrinopathie, le bilan étiologique de première intention se limite habituellement aux examens suivants : NFS, VS et/ou CRP, transaminases. The cumulative incidence of urticaria in children is close to 10%. Two forms are described: the superficial form and the deep form, or angioedema. In young children aged under 3 years, urticaria is commonly annular and ecchymotic, and is mistaken for erythema multiforme or acute hemorrhagic edema. Serum sickness-like reaction is a particular form of urticaria characterized by angioedema of the extremities, fever and arthralgia, and it is chiefly drug-induced (cephalosporins). With children, questioning and clinical examination are essential and, in most cases, reveal an etiology. The main causes of acute or recurrent urticaria are viral infections and/or drugs (non-specific histamine release), whereas chronic urticaria is mostly due to physical causes. In developed countries, parasitic infections are rarely the cause. Arguments in favor of a food allergy are as follows: a setting of atopy, onset within one hour of taking the suspect food, absence of fever or infection, a duration of less than 24 hours, possible association with other signs of anaphylaxis, and further recurrence with each new intake of the suspect food. First-line treatment of urticaria without signs of severity consists solely of non-sedating antihistamine (associated with removal of the cause where the latter has been determined). Nearly one-third of cases of urticaria in children progress over a prolonged period of more than 6 weeks, thus constituting chronic urticaria (most often a form of mild recurrent urticaria during episodes of infection and/or medication). Chronic urticaria is very rarely due to an underlying inflammatory disease or a genetic disease such as cryopyrinopathy, and first-line etiological assessment is usually limited to the following tests: CBC, sedimentation speed and/or CRP, and transaminases. Mots clés Angioedème Virus Médicament Aliments Antihistaminiques Keywords Angioedema Viral infection Drug Food allergy Antihistamines ==== Body pmc1 Introduction L’urticaire de l’enfant se distingue de l’urticaire de l’adulte par sa présentation clinique, ses étiologies et son pronostic. Les données épidémiologiques disponibles indiquent qu’il s’agit d’une situation très fréquente en pédiatrie, avec une prévalence de 1 % par année de vie [1]. L’incidence cumulée chez le jeune enfant est évaluée entre 3,5 et 8 %, pour atteindre 16 à 24 % chez l’adolescent. Chez le nourrisson et le petit enfant, près de 60 % des cas associent des lésions d’urticaire superficielle et profonde (formes œdémateuses) et s’accompagnent également dans la moitié des cas de lésions purpuriques ecchymotiques. Alors que chez le grand enfant et l’adolescent, les formes œdémateuses sont plus rares (environ 15 %), rapportées isolément dans 6 % des cas ou associées à une forme superficielle dans 9 % des cas [2], [3]. Les formes graves, évoluant vers un choc anaphylactique, sont exceptionnelles chez le nourrisson mais leur incidence augmente avec l’âge [4], [5]. Les formes associées aux maladies systémiques (auto-immunité, maladies auto-inflammatoires.) sont rares, elles sont néanmoins importantes à connaître car leur prise en charge est spécifique [6]. Classiquement, dans les urticaires aiguës, le déclenchement implique un mécanisme IgE médié déclenché par des allergènes ingérés, appliqués, injectés, voire inhalés. La prévalence des formes allergiques d’urticaire est plus importante chez les sujets ayant des antécédents personnels ou familiaux atopiques. Chez l’enfant, l’urticaire est souvent déclenchée par une infection virale [3], [4], dans ce cas le mécanisme demeure incertain, il n’est pas clairement démontré qu’un mécanisme spécifique puisse être en cause (reconnaissance d’antigènes microbiens comme des allergènes), ce qui conduit à privilégier l’hypothèse d’une histaminolibération non spécifique. Comme chez l’adulte, dans les urticaires chroniques, le mécanisme est le plus souvent non allergique, lié à une histaminolibération non spécifique d’un allergène. Dans certaines formes d’urticaire chronique, un mécanisme auto-immun a pu être montré, médié par des auto-anticorps dirigés contre les récepteurs aux IgE [6], [7]. 2 Diagnostic Le diagnostic d’urticaire est avant tout clinique et il est habituellement facile (Fig. 1a). La principale difficulté diagnostique chez l’enfant vient de la présentation volontiers très annulaire, en médaillon, œdémateuse et ecchymotique (Fig. 1b et c) en particulier chez le jeune enfant (généralement avant 3 ans). Il est alors classique de voir des patients pour lesquels un diagnostic d’érythème polymorphe est évoqué, ou un œdème aigu hémorragique. Les principaux diagnostics différentiels sont listés dans le Tableau 1 .Fig. 1 a–c : urticaire : a : urticaire superficielle au cours d’une varicelle ; b : urticaire de présentation annulaire et ecchymotique souvent confondue avec un érythème polymorphe ; c : urticaire ecchymotique superficielle et profonde accompagnée d’œdème des pieds chez un nourrisson. Tableau 1 Diagnostic différentiel des urticaires et angioedèmes de l’enfant. Tableau 1Érythème polymorphe Œdème aigu hémorragique et purpura rhumatoïde Prurigos parasitaires Mastocytose Syndrome auriculotemporal Syndromes rares Œdèmes bradykiniques (œdème angioneurotique) Syndrome de Sweet Érythèmes annulaires de l’enfant : syndrome de Wells, érythème annulaire centrifuge… On oppose schématiquement les formes superficielles et profondes d’urticaire. 2.1 Urticaire superficielle Elle se manifeste par une éruption papuleuse (œdémateuse) érythémateuse, prurigineuse, classiquement migratrice, transitoire, disparaissant sans laisser de traces (Fig. 1a et b). La durée des poussées éruptives est extrêmement variable, allant de quelques minutes à quelques jours. 2.2 L’angioedème L’angioedème (ou urticaire profonde) est particulièrement fréquent chez l’enfant, il se manifeste par un œdème dermique et hypodermique, touchant volontiers les semi-muqueuses et les muqueuses ainsi que les extrémités (Fig. 1c). Il est souvent associé à des lésions d’urticaire superficielle, ce qui le distingue de l’angioedème des œdèmes bradykiniques (œdème angioneurotique héréditaire) qui est généralement isolé, unilatéral et sans atteinte superficielle concomitante. 2.3 Pseudo-maladies sériques Les pseudo-maladies sériques (serum sickness-like reactions en anglais) font partie du spectre des urticaires. Il s’agit d’éruptions urticariennes associant atteinte superficielle et profonde, touchant souvent les extrémités et les régions périarticulaires où l’urticaire revêt un caractère inhabituellement fixe, et s’accompagne d’importantes arthralgies et de fièvre. Les confusions se font le plus souvent avec :• certains prurigos parasitaires sont très aigus et peuvent avoir une présentation « urticarienne », c’est le cas des prurigos dus aux punaises de lit (Fig. 2a) ;Fig. 2 a–d : diagnostics différentiels de l’urticaire de l’enfant : a : prurigo par piqûres de punaises de lit ; b : mastocytose avec dermographisme et signe de Darier ; c : érythème polymorphe majeur ; d : œdème aigu hémorragique du nourrisson. • la mastocytose, les lésions jaunes ou brun chamois sont fixes et on peut déclencher un œdème, voire une bulle en les frottant (signe de Darier) (Fig. 2b) ; • l’érythème polymorphe se caractérise cliniquement par des lésions annulaires, avec de façon caractéristique une atteinte prédominant sur les extrémités mais affectant aussi les muqueuses (Fig. 2c). La lésion élémentaire en cocarde consiste en une lésion en cible avec 3 bandes concentriques, celle du centre évoluant vers une bulle ; • l’œdème aigu hémorragique du nourrisson se caractérise par des lésions arrondies érythémateuses et violacées, fixes, localisées essentiellement sur les membres (Fig. 2d), avec une atteinte fréquente des oreilles et un respect du tronc. Il s’agit d’une vascularite leucocytoclasique proche du purpura rhumatoïde de l’enfant ; • le purpura rhumatoïde, lors des poussées, est parfois précédé de lésions d’allure urticarienne qui prédominent sur les membres inférieurs et évoluent sur un mode ecchymotique, généralement sans prurit. 3 Étiologies Il est possible de suspecter voire de confirmer la cause d’une urticaire aiguë dans près de 40 % des cas (30 à 90 % selon les séries) [3], [4] et dans moins d’un tiers des cas dans les formes chroniques [8]. Les principales causes reconnues d’urticaires de l’enfant sont listées dans le Tableau 2 et détaillées ci-dessous, un interrogatoire et un examen clinique bien menés sont habituellement suffisants. Les causes d’urticaires aiguës de l’enfant diffèrent sensiblement de celles rencontrées chez l’adulte. Chez le nourrisson, les allergies alimentaires sont prédominantes, en particulier l’allergie IgE médiée aux protéines de lait de vache. Chez l’enfant, les infections virales et les causes médicamenteuses (majoritairement par histaminolibération non spécifique) sont les plus fréquentes. Il est classique de dire que la première cause est virale, la seconde médicamenteuse, et la troisième associe virus et médicament (phénomène d’histaminolibération non spécifique ou « fausse allergie »).Tableau 2 Principales causes d’urticaire aiguë chez l’enfant. Tableau 2Infections virales communes Virus influenza, adénovirus, entérovirus, EBV, coronavirus. Plus rarement virus des hépatites dont l’hépatite B Médicaments Principalement le groupe des bêtalactamines, autres antibiotiques, anti-inflammatoires non stéroïdiens (aspirine, ibuprofène), paracétamol. Produits libérateurs d’histamine : codéine, produits de contrastes de radiologie Aliments Protéines de lait de vache (prédominent avant 6 mois), œuf, arachide et fruits à coque, poissons et crustacés, fruits exotiques, additifs alimentaires Piqûres d’insectes Principalement hyménoptères Parasites Presque exclusivement dans les zones d’endémie Causes physiques Urticaire au froid, urticaire cholinergique, dermographisme Formes idiopathiques 3.1 Infections De nombreuses infections sont associées aux urticaires aiguës, et dans une moindre mesure chronique, chez l’enfant. Les causes virales dominent et sont bien documentées, tout comme les causes parasitaires. En revanche, le déclenchement d’urticaires lors d’infections bactériennes et fongiques reste controversé. 3.1.1 Virus Les infections virales représentent la cause la plus fréquente d’urticaire aiguë de l’enfant [3], [4], [7], [9]. Compte tenu de la fréquence des infections virales paucisymptomatiques, l’urticaire apparaît volontiers au premier plan et peut persister selon les cas d’une à 3 semaines. La présence d’une fébricule ou d’une fièvre transitoire, ou la présence de signes respiratoires, ORL ou digestifs au moins au début de l’éruption, constitue des arguments pour ce diagnostic étiologique. L’absence de toute symptomatologie infectieuse n’écarte pas pour autant cette hypothèse compte tenu de la survenue fréquente d’infections virales asymptomatiques. La majorité des virus impliqués dans des infections chez l’enfant a été associée à la survenue d’urticaires aiguës. Les virus les plus communs respiratoires ou digestifs dominent : influenza, adénovirus et entérovirus. Les Herpes viridae sont également bien représentés (herpes simplex, virus varicelle-zona, virus Epstein-Barr, cytomégalovirus…). Les virus responsables d’exanthèmes (rougeole, rubéole, oreillons, parvovirus B19…) peuvent également provoquer des lésions urticariennes généralement superficielles qui se mêlent à l’exanthème déjà présent, ou le précèdent. Les virus des hépatites A, B ou C sont également de fréquents pourvoyeurs d’urticaire, dans près d’un tiers des cas pour l’hépatite B, lors de la phase pré-ictérique. Parmi les infections virales plus exotiques, le chikungunya peut déclencher des lésions urticariennes. 3.1.2 Bactéries Quelques cas d’urticaires ont été rapportés dans des observations isolées concomitamment à des infections bactériennes. Un certain nombre de bactéries ont été incriminées, Mycoplasma pneumoniae en particulier, mais la responsabilité reste souvent douteuse, les enfants ayant par ailleurs été traités par antibiotiques (voir paragraphe médicaments). 3.1.3 Parasites La responsabilité d’une infection parasitaire dans la survenue d’une urticaire aiguë ou chronique a été clairement établie, mais compte tenu de la prévalence désormais faible des parasitoses dans les pays développés, cette étiologie n’est discutée qu’en seconde intention ou lorsqu’il existe une hyperéosinophilie et/ou une élévation des IgE totales, en particulier chez les enfants de retour de zones d’endémie. L’interrogatoire recherche des symptômes digestifs associés. Les parasites en cause sont les helminthiases surtout, plus rarement une trichinose, une distomatose ou dans les urticaires chroniques une infection à Toxocara canis. Enfin, il a été montré dans une étude cas-témoin égyptienne que Blastocystis hominis pourrait être fréquemment responsable d’urticaires aiguës ou chroniques [10], la prévalence de ce parasite étant supérieure à 50 % de la population dans les pays émergents et proche de 10 % dans les pays développés. 3.1.4 Infections fongiques Peu de données attestent de la responsabilité d’un agent fongique dans les urticaires, en particulier chez l’enfant. L’hypothèse d’un rôle possible de candidoses n’est pas confirmée. 3.2 Médicaments et vaccins La prise d’un médicament est souvent associée à la survenue d’une urticaire aiguë chez l’enfant, particulièrement dans le cas des bêtalactamines et de l’aspirine. Dans une majorité de cas, il s’agit de « fausses allergies » par histaminolibération non spécifique, mais la possibilité de vraies allergies nécessite de mener une enquête, d’abord anamnestique, puis allergologique si l’interrogatoire suspecte une allergie vraie. Les manifestations cliniques sont soit des urticaires superficielles, soit des urticaires associées à un angioedème d’autant plus important que l’enfant est jeune, soit plus rarement une présentation à type de pseudo-maladie sérique. 3.2.1 Bêtalactamines Les urticaires déclenchées lors de la prise de bêtalactamines sont les plus fréquentes et les plus étudiées. Dans une vaste étude française [11], 1431 enfants suspects d’être allergiques aux bêtalactamines ont été explorés (prick-tests et tests de provocation) : 15,9 % d’entre eux se sont révélés être de vrais allergiques au médicament qu’ils avaient pris, les 84,1 % restants correspondaient soit à des phénomènes d’histaminolibération non spécifiques, soit à des situations considérées à tort comme des suspicions d’allergie (exanthème infectieux par exemple). Une étude espagnole semblable et plus récente [12], menée auprès de 783 enfants suspects d’être allergiques aux bêtalactamines, n’a confirmé une allergie vraie que dans 8 % des cas. L’amoxicilline ou l’association amoxicilline–acide clavulanique sont les plus gros pourvoyeurs de réactions urticariennes médicamenteuses chez l’enfant (ce sont les antibiotiques les plus utilisés). La cause peut être une allergie au principe actif ou à un excipient tel que le benzoate de sodium. Les arguments cliniques en faveur d’une vraie allergie sont l’apparition rapide des signes d’urticaire après la prise médicamenteuse, l’existence de symptômes d’anaphylaxie, la survenue d’une pseudo-maladie sérique. Dans le cas d’allergies vraies, les réactions croisées avec d’autres antibiotiques de la même famille sont fréquentes, dans près de trois quarts des cas. Ainsi, chez un enfant ayant développé une urticaire lors de la prise d’un traitement antibiotique, la première étape est de bien préciser par l’interrogatoire le type d’éruption pour ne pas avoir à explorer une éruption liée à l’infection virale elle-même (exanthème subit, entérovirus…), puis secondairement de proposer une exploration allergologique (prick-test avec l’antibiotique suspecté) et enfin, d’envisager un test de provocation si le prick-test est négatif. En cas de positivité du test, il faut secondairement savoir évoquer la possibilité d’une allergie au principe actif lui-même ou une allergie à un conservateur ou un colorant présent dans le médicament en cause. Les céphalosporines sont les principales causes de pseudo-maladies sériques, principalement le cefaclor, mais également la ceftriaxone, le céfuroxime et la céfazoline. 3.2.2 Anti-inflammatoires non stéroïdiens et aspirine Ces médicaments affectent la synthèse des prostaglandines et sont de grands pourvoyeurs d’urticaire. Les manifestations surviennent généralement dans les minutes ou les heures qui suivent l’administration du produit et peuvent persister jusqu’à une semaine après la prise, même unique. Les principales molécules en cause sont l’ibuprofène, l’indométacine et l’aspirine. 3.2.3 Autres médicaments De nombreuses classes thérapeutiques peuvent être concernées [13]. Des antibiotiques autres que les bêtalactamines comme les cyclines, les anesthésiques locaux comme la lidocaïne, ou plus rarement les corticoïdes. Certaines molécules déclenchent des éruptions urticariennes isolées sans signes d’anaphylaxie, car ce sont des libérateurs d’histamine. Il s’agit de la codéine, des morphiniques, des produits de contraste de radiologie, voire des curares et de la quinine. 3.2.4 Vaccins La survenue d’éruptions urticariennes localisées ou diffuses après vaccination n’est pas exceptionnelle. Comme pour les éruptions survenant dans un contexte viral, elles doivent être distinguées des exanthèmes, généralement mineurs, post-vaccinaux, correspondant à une forme atténuée de l’infection contre laquelle le vaccin est dirigé (rougeole vaccinale par exemple). Les vraies urticaires post-vaccinales font évoquer une allergie à un conservateur ou un adjuvant. Dans le cas des vaccins viraux développés sur des cellules embryonnaires de poulet, il avait été longtemps considéré qu’ils devaient être évités chez l’enfant allergique à l’œuf, ce qui est maintenant remis en cause [14]. Le vaccin rougeole-oreillons-rubéole peut être administré sans risque et donc sans précautions particulières chez l’enfant allergique à l’œuf. Les réactions urticariennes post-vaccinales après le vaccin ROR sont liées à la présence de gélatine ou d’autres conservateurs selon les formulations. Les vaccins contre la grippe, la fièvre jaune et l’encéphalite à tiques sont également cultivés sur des cellules de poulet, et le risque qu’ils puissent contenir des traces d’ovalbumine les font éviter en cas d’allergie connue à l’œuf ; sauf lorsqu’ils sont jugés indispensables et alors après une procédure hospitalière (prick-test puis vaccination fractionnée sous surveillance en cas de prick-test négatif). D’autres vaccins peuvent déclencher une réaction urticarienne, ce sont avant tout les vaccins antitétanique, anti-hépatite B et anti-haemophilus. 3.3 Aliments L’urticaire aiguë est la manifestation clinique la plus fréquente d’une allergie alimentaire chez l’enfant, survenant dans 50 à 60 % des cas lorsque l’on consomme un aliment auquel on est allergique. Néanmoins, et à l’inverse, devant un épisode urticarien aigu survenant chez un enfant, la probabilité de découvrir une allergie alimentaire est assez limitée, n’excédant pas 10 % des cas, et même de l’ordre de 2 à 3 % des cas dans les séries publiées. De nombreux aliments sont de possibles pourvoyeurs d’allergie alimentaire et donc d’urticaire, chez l’enfant [15] on retrouve le plus souvent l’œuf, le lait de vache, l’arachide, la noisette et les autres fruits à coque, la moutarde, les poissons et crustacés, les fruits exotiques… Mais la liste est longue et inclut également les viandes (porc, bœuf…), les fruits (pomme, prune, pêche…), les légumes et apparentés (légumineuses comme petits pois et lentilles, céleri…), le blé et le sésame. Afin d’orienter le clinicien vers une allergie alimentaire, l’anamnèse :• précise le délai entre l’ingestion et les premières lésions urticariennes (le plus souvent moins de 30 minutes, sauf pour certains légumes et céréales) ; • recherche un syndrome oral lors de la mise de l’aliment en bouche : prurit buccal et pharyngé quasi immédiat, érythème péri-oral ; • recherche les autres signes d’anaphylaxie, en particulier digestifs (nausées, vomissements, douleurs abdominales, diarrhées) et respiratoires ; • précise le statut atopique, sachant que les patients atteints de dermatite atopique ont un risque multiplié par 10 de développer une allergie alimentaire, d’autant plus important que l’eczéma est sévère. Ensuite, l’étape suivante est la recherche d’une positivité des prick-tests et/ou des IgE spécifiques dirigés contre les aliments suspectés par l’anamnèse. Pour certains aliments comme l’arachide, l’étude des IgE spécifiques de protéines (rAraH1, rAraH2, rAraH8.) peut compléter l’enquête et apporter des éléments pronostiques. 3.4 Facteurs physiques Après l’étiologie virale, médicamenteuse et alimentaire, les urticaires physiques représentent une situation fréquente. Un peu moins de 5 % de la population générale présente un dermographisme, dont l’intensité est variable d’un sujet à l’autre. Il s’agit de la survenue d’une lésion urticarienne érythémateuse et œdémateuse lors du simple frottement de la peau. Il témoigne d’une dégranulation mécanique des mastocytes et de la libération localisée d’histamine sur les zones de frottement, suggérant chez ces patients un seuil abaissé de déclenchement des lésions urticariennes. L’urticaire au froid se caractérise par la survenue d’une éruption urticarienne sur la zone de contact avec un élément froid (liquide, air, objet), éventuellement généralisée en cas de contact diffus (air frais et surtout bain en eau fraîche). Les lésions disparaissent généralement rapidement après l’arrêt du contact avec le froid (quelques minutes jusqu’à moins d’une heure). Dans ces formes liées au froid, l’âge moyen est de 9 ans. Le risque majeur est la survenue concomitante de manifestations anaphylactiques, rapportées dans près d’un tiers des cas [16], avec la survenue possible de choc anaphylactique, et la description dans la littérature médicale d’évolution fatale après des bains en eau fraîche. Dans 90 % des cas, ces formes sont idiopathiques, avec quelques cas rapportés de déclenchement par des infections virales, en particulier le virus d’Epstein Barr, la rougeole et les virus des hépatites. Le diagnostic repose sur la réalisation d’un test au glaçon, qui consiste à appliquer durant quelques minutes un glaçon sur la face antérieure de l’avant-bras, ce qui entraîne le déclenchement d’une papule urticarienne dont la persistance varie de quelques minutes à une heure. L’éviction du facteur déclenchant est indispensable, avec contre-indication de la balnéation brutale en eau fraîche pour éviter les risques d’anaphylaxie sévère. L’urticaire aquagénique, à distinguer des urticaires au froid car surviennent au contact de l’eau quelle que soit la température, et l’urticaire solaire surviennent sur les zones d’exposition et disparaissent dès le retour à l’ombre, contrairement aux lucites. L’urticaire retardée à la pression survient généralement lors de pression mécanique verticale, comme la bretelle d’un sac à dos, ou sur la plante des pieds à la marche. Les lésions sont parfois retardées de quelques heures. Cliniquement, l’urticaire cholinergique se présente sous la forme de petites papules de quelques millimètres, survenant rapidement lors d’un exercice physique, lors d’un stress, voire lors de l’ingestion d’un aliment pimenté. Les lésions ne surviennent pas systématiquement lors de chaque effort physique et n’entraînent généralement qu’une gêne modérée, sans manifestations anaphylactiques associées. En revanche, l’urticaire induite par l’exercice, associant parfois une cause physique telle qu’un effort soutenu et une allergie alimentaire, le plus souvent à une céréale telle que le blé, peut induire des manifestations d’anaphylaxie, y compris sévères. 3.5 Allergènes de contact Elles constituent une entité clinique distincte car ici l’urticaire est en général localisée, limitée au point ou aux zones de contact avec l’allergène ou la substance en cause. Sont en cause, les phanères d’animaux, certains pollens de graminées ou d’arbres, le latex, certains insectes, les chenilles… L’interrogatoire est déterminant et peut s’appuyer sur la réalisation de tests cutanés, voire sur la mesure d’IgE spécifiques pour certaines suspicions (latex, piqûre d’hyménoptères). Le déclenchement par l’application de traitements locaux est également possible (bacitracine, céphalosporines, néomycine, rifadine, rarement le ketoprofène). 3.6 Urticaires syndromiques ou d’origine génétique Dans de très rares cas, les urticaires peuvent accompagner, et parfois révéler, une affection systémique, inflammatoire et/ou auto-immune [6], voire une maladie génétique. Dans les pathologies auto-immunes comme les thyroïdites, ou le lupus, on peut observer une vraie urticaire, mais dans les maladies génétiques l’éruption cutanée qualifiée d’urticaire est souvent « atypique », les lésions sont fixes et peu prurigineuses, en outre à la biopsie on retrouve un aspect inhabituel (vascularite à neutrophiles). C’est le cas des CAPS (pour cryopyrin-associated periodic syndromes) comprenant le syndrome de Muckle–Wells, le syndrome CINCA, et l’urticaire familiale au froid, liés à une mutation du gène NLRP3 intervenant sur l’inflammasome, mais c’est également le cas de l’arthrite chronique juvénile (maladie de Still de l’enfant) où l’éruption cutanée composée de petites papules rosées survient le soir lors des poussées de fièvre. Une éruption urticarienne est parfois décrite dans ces maladies :• lupus érythémateux disséminé et hypocomplémentémies ; • thyroïdites ; • maladie de Kawasaki ; • syndrome de Gleich (angioedème récurrent avec fièvre et hyperéosinophilie) ; • dermatite herpétiforme et pemphigoïde bulleuse de l’enfant ; • hémopathies : lymphomes hodgkiniens ou non. 4 La prise en charge thérapeutique et le pronostic 4.1 Urticaire aiguë L’urticaire aiguë, bien que spectaculaire, est le plus souvent non compliquée chez l’enfant et l’angioedème urticarien est relativement bénin, contrairement à l’angioedème bradykinique. Les signes de gravité sont à rechercher surtout en cas d’allergie IgE médiée :• signes d’anaphylaxie avec le risque de choc : rhinite, conjonctivite, prurit intense, troubles du comportement ; • un bronchospasme. Une anamnèse précise et un examen clinique complet sont bien souvent les seuls éléments indispensables de la recherche étiologique. Aucun examen biologique et/ou allergologique n’est systématiquement requis sauf si une allergie alimentaire ou une infection nécessitant un traitement sont suspectées (Fig. 3 ).Fig. 3 Démarche diagnostique devant une urticaire de l’enfant. La durée d’un épisode d’urticaire aiguë est très variable, fonction généralement de la cause. Ainsi, les formes allergiques sont de survenue brutale et d’évolution courte (résolution spontanée en quelques heures à 24 heures), alors que les urticaires associées aux infections peuvent persister plusieurs jours dans le cas des virus, voire plusieurs semaines dans les infections parasitaires. Le traitement consiste alors en l’administration per os en première intention d’un antihistaminique non sédatif, dans le but de couvrir la période d’activité de l’urticaire (en général une dizaine de jours) (Fig. 3). La desloratadine et la levocetirizine sont les plus utilisées chez l’enfant (nombreuses données d’efficacité et de tolérance). En cas d’angioedème important ou d’anaphylaxie (association de plusieurs signes d’anaphylaxie, choc hémodynamique), le traitement consiste en l’administration d’adrénaline par voie intramusculaire, en urgence, à la posologie de 0,01 mg/kg. En milieu hospitalier ou médicalisé, ce geste est associé à d’autres mesures de réanimation comme le remplissage vasculaire et éventuellement une corticothérapie générale (0,5 à 1 mg/kg durant quelques jours), malgré l’absence d’études contrôlées sur leur efficacité dans cette situation. Après un épisode anaphylactique, quelle qu’en soit la cause, un traitement préventif avec un dispositif permettant l’auto-injection par le patient lui-même ou par son entourage est systématiquement prescrit après une éducation thérapeutique ciblée (par exemple en cas d’allergie alimentaire à l’arachide, aux fruits à coque, aux poissons…). Après un épisode urticarien, deux tiers des enfants n’auront plus jamais d’autres épisodes. Le tiers restant se partage en formes récurrentes (parfois un ou quelques épisodes annuels) et formes chroniques avec une fréquence des poussées très variable, de quelques épisodes annuels à des cas où les lésions sont quotidiennes [3], [9]. 4.2 Urticaire chronique et/ou récidivante Associée à une anamnèse rigoureuse et à un examen clinique complet, une exploration biologique minimale est recommandée, comprenant la mesure de la vitesse de sédimentation et/ou le dosage de la protéine C-réactive, la réalisation d’un hémogramme et le dosage des transaminases (Fig. 3). En cas d’anomalie constatée à ce bilan de première intention, une exploration de l’auto-immunité peut être proposée, comprenant la recherche d’une thyroïdite biologique [8]. En cas d’hyperéosinophilie, la recherche d’une parasitose nécessite la réalisation d’un examen parasitologique des selles et éventuellement quelques sérologies parasitaires en fonction de la localisation géographique. Les urticaires chroniques peuvent s’éteindre spontanément dans la majorité des cas, après une durée moyenne d’évolution de 16 mois. Les facteurs associés à une résolution plus rapide dans les formes chroniques sont l’âge (< 8 ans) et le sexe féminin [8]. Outre rassurer la famille, le traitement repose sur les antihistaminiques. S’il s’agit d’une urticaire récidivante lors des épisodes d’infections virales, ou de prises médicamenteuses, on peut simplement prescrire l’antihistaminique lors des situations à risque (syndromes infectieux). En revanche, dans l’urticaire chronique spontanée quotidienne, on donne l’antihistaminique pour une période prolongée [8], [17] (plusieurs mois, reconduits en fonction des symptômes). Le but du traitement est avant tout de réduire voire de faire disparaître le prurit, même s’il persiste quelques poussées limitées de lésions urticariennes. En l’absence d’efficacité, une augmentation des doses est possible, avec une augmentation progressive d’un facteur 2, 3 ou 4 de la posologie. Cette augmentation de doses est aujourd’hui préférée à l’association de 2 anti-H1, même si cette dernière possibilité s’avère envisageable. En cas d’échec, les antileucotriènes ne sont plus recommandées, mais on peut avoir recours en seconde intention à l’omalizumab (anticorps monoclonal anti-IgE) [8], [17]. Déclaration de liens d’intérêts Les auteurs déclarent ne pas avoir de liens d’intérêts. ==== Refs Références 1 Brüske I. Standl M. Weidinger S. Epidemiology of urticaria in infants and young children in Germany—results from the German LISAplus and GINIplus Birth Cohort Studies Pediatr Allergy Immunol 25 2014 36 42 24236825 2 Zuberbier T. Asero R. Bindslev-Jensen C. EAACI/GA(2)LEN/EDF/WAO guideline: definition, classification and diagnosis of urticaria Allergy 64 2009 1417 1426 19772512 3 Mortureux P. Léauté-Labrèze C. Legrain-Lifermann V. Acute urticaria in infancy and early childhood Arch Dermatol 134 1998 319 323 9521030 4 Kudryavtseva A.V. Neskorodova K.A. Staubach P. Urticaria in children and adolescents: an updated review of the pathogenesis and management Pediatr Allergy Immunol 30 1 2019 17 24 30076637 5 Shrestha P. Dhital R. Poudel D. Donato A. Karmacharya P. Craig T. Trends in hospitalizations related to anaphylaxis, angioedema, and urticaria in the United States Ann Allergy Asthma Immunol 122 4 2019 401 406 30769181 6 Kosmeri C. Siomou E. Challa A. Tsabouri S. Investigation of autoimmune disease in children with chronic spontaneous urticaria Int Arch Allergy Immunol 180 4 2019 250 254 31522183 7 Léauté-Labrèze C. Boralevi F. Taïeb A. Urticaria Irvine A.D. Hoeger P.H. Yan A.C. Harper's textbook of pediatric dermatology 2011 Wiley-Blackwell editions 8 Caffarelli C. Paravati F. El Hachem M. Duse M. Bergamini M. Simeone G. Management of chronic urticaria in children: a clinical guideline Ital J Pediatr 45 1 2019 101 31416456 9 Cetinkaya P.G. Soyer O. Esenboga S. Sahiner U.M. Teksam O. Sekerel B.E. Predictive factors for progression to chronicity or recurrence after the first attack of acute urticaria in preschool-age children Allergol Immunopathol 47 5 2019 484 490 10 Zuel-Fakkar N.M. Abdel Hameed D.M. Hassanin O.M. Study of Blastocystis hominis isolates in urticaria: a case-control study Clin Exp Dermatol 36 2011 908 910 21790724 11 Ponvert C. Perrin Y. Bados-Albiero A. Allergy to betalactam antibiotics in children: results of a 20-year study based on clinical history, skin and challenge tests Pediatr Allergy Immunol 22 2011 411 418 21535179 12 Zambonino M.A. Corzo J.L. Muñoz C. Diagnostic evaluation of hypersensitivity reactions to beta-lactam antibiotics in a large population of children Pediatr Allergy Immunol 25 2014 80 87 24329898 13 Nettis E. Marcandrea M. Maggio G.D. Retrospective analysis of drug-induced urticaria and angioedema: a survey of 2287 patients Immunopharmacol Immunotoxicol 23 2001 585 595 11792017 14 Eigenmann P.A. Allergie à l’œuf : state of the art Rev Fr Aller Immunol Clin 43 2003 450 454 15 Rance F. Kanny G. Dutau G. Food hypersensitivity in children: clinical aspects and distribution of allergens Pediatr Allergy Immunol 10 1999 33 38 10410915 16 Alangari A.A. Twarog F.J. Shih M.C. Schneider L.C. Clinical features and anaphylaxis in children with cold urticaria Pediatrics 113 2004 313 317 14754943 17 Williams P.V. Pharmacologic management of chronic urticaria in pediatric patients: the gap between guidelines and practice Paediatr Drugs 22 1 2020 21 28 31858489
PMC007xxxxxx/PMC7194514.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)30715-5 10.1016/j.jaad.2020.04.099 JAAD Online Proposed approach for reusing surgical masks in COVID-19 pandemic Liu Yuangang PhD ∗ Leachman Sancy A. MD, PhD Bar Anna MD ∗ Department of Dermatology, Oregon Health & Science University, Portland, Oregon ∗ Correspondence to: Yuangang Liu, PhD, Department of Dermatology, L468R, Oregon Health & Science University, Portland, OR 97239. ∗ Correspondence to: Anna Bar, MD, Department of Dermatology, Oregon Health & Science University, Portland, OR 97239 26 4 2020 7 2020 26 4 2020 83 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. Graphical abstract ==== Body pmcTo the Editor: Coronavirus disease 2019 (COVID-19) is a novel human respiratory disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Washing hands and social distancing are measures recommended by the Centers for Disease Control and Prevention to prevent COVID-19 transmission. However, new evidence shows that the half-life of viable SARS-CoV-2 in aerosol is longer than 1 hour, indicating a high likelihood of airborne transmission.1 Furthermore, the existence of an asymptomatic carrier phase decreases the effectiveness of prevention strategies that rely on symptoms. There is a strong rationale for a universal mask policy. Wearing a face mask will not only prevent airborne viral transmission but also reduce the likelihood of one's hands touching the mouth and nose. It is particularly needed to prevent the transmission from asymptomatic medical professionals to patients and colleagues. Owing to the current shortage of masks, it is prudent to conserve masks whenever possible. More than 100 billion masks will be needed for 300 million Americans annually if 1 person uses 1 mask per day. This is far beyond the current capacity of United States face mask manufacturing. Although the United States Food and Drug Administration has approved mask decontamination by H2O2 vapor, it requires special equipment that limits its widespread application. A simple, effective decontamination method that does not disrupt filtration efficacy of the mask is needed. Decontamination of masks is challenging because the filtration capacity of polypropylene is vulnerable to most commonly used sterilization methods, including autoclaving, bleach, and alcohol.2 The filtration layer of masks is made of melt-blown polypropylene that determines the pore size of a face mask. An analysis of 5 different decontamination methods identified dry heat as a preferred method.2 Although the dry heat approach did not significantly change the filtration efficiency of melt-blown polypropylene, it forms crystals at higher temperatures.3 The accumulation of the crystals will ultimately compromise the filtration efficiency. On the basis of the low crystallinity of polypropylene at 70°C3 and data demonstrating that coronavirus can be effectively inactivated at 65°C for 30 minutes,4 dry heat at 65° to 70°C for 30 min should be an effective condition to decontaminate used masks. It has been demonstrated that the filtration efficiency of a face mask is not significantly changed after up to 20 cycles of decontamination with hot air (75°C) for 30 minutes in each cycle.5 Heating at 65° to 70°C can be achieved by baking in an oven, incubator, or even a blanket warmer. Although the efficiency of a mask treated under these conditions remains to be determined, this method provides a simple, straightforward, and effective strategy for decontamination of used masks. The general guideline for reuse of face masks includes:1. Masks contaminated with fluids should not be reused, due to the compromise of filtration efficiency. 2. When sanitizing with heat, place the mask in a brown paper bag, with your name on it, to avoid direct contact with the metal surface or other masks. 3. The 0.3- to 10-μm pore size of standard surgical face masks is much larger than the coronavirus (0.1 μm) and incompletely form-fits the face. Therefore, surgical masks should not be used when in contact with patients that are potentially positive for COVID-19. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 van Doremalen N. Morris D.H. Gamble A. Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1 N Engl J Med 382 2020 1564 1567 32182409 2 Lin T.H. Chen C.C. Huang S.H. Kuo C.W. Lai C.Y. Lin W.Y. Filter quality of electret masks in filtering 14.6-594 nm aerosol particles: effects of five decontamination methods PLoS One 12 2017 e0186217 29023492 3 Cheng S. Muhaiminul A.S.M. Yue Z. Effect of temperature on the structure and filtration performance of polypropylene melt-blown nonwovens AUTEX Res J 2020 10.2478/aut-2019-0067 4 Kariwa H. Fujii N. Takashima I. Inactivation of SARS coronavirus by means of povidone-iodine, physical conditions and chemical reagents Dermatology 212 Suppl 1 2006 119 123 16490989 5 Price A. Chu L.F. Addressing COVID-19 Face Mask Shortages. March 25, 2020. Learnly Anesthesia/Stanford AIM Lab COVID-19 Evidence Service Available at: https://stanfordmedicine.app.box.com/v/covid19-PPE-1-2
PMC007xxxxxx/PMC7194618.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)30710-6 10.1016/j.jaad.2020.04.094 JAAD Online Cutaneous manifestations in COVID-19: Lessons learned from current evidence Suchonwanit Poonkiat MD ∗ Leerunyakul Kanchana MD Kositkuljorn Chaninan MD Division of Dermatology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand ∗ Correspondence to: Poonkiat Suchonwanit, MD, Division of Dermatology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, 270 Rama VI Rd, Ratchathewi, Bangkok, Thailand 10400 24 4 2020 7 2020 24 4 2020 83 1 e57e60 © 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 ongoing pandemic of coronavirus disease 2019 (COVID-19) is a significant global concern. As of April 19, 2020, a total of 2,241,359 accumulated cases and 152,551 deaths have been reported worldwide.1 The clinical features of COVID-19 have been described in several articles. The disease typically presents with symptoms resembling other viral respiratory infections, most commonly with fever and dry cough. Patients with severe infection may later develop acute respiratory distress syndrome that could progress to multiple organ failure with a relatively high mortality rate.2 In addition, the disease is associated with leukopenia, thrombocytopenia, and elevated D-dimer levels that increase the risk of venous thromboembolism.3 Emerging evidence suggests that the uncontrolled release of proinflammatory cytokines resulting in cytokine storm syndrome plays an immunopathogenic role in disease progression and the development of severe disease.4 Cutaneous manifestations are considered an infrequent presentation of COVID-19, being rarely described in the literature. They are probably under-recognized due to a lack of dermatology consultations in this group of patients. The first evidence of skin manifestations was reported in 2 patients with severe respiratory disease in a study of 1099 cases in China. However, neither characteristics nor progression of the lesions were documented.2 Since then, subsequent case reports and case series have described COVID-19–associated skin lesions in patients with confirmed COVID-19, including clinical features that indicate viral exanthems (ie, morbilliform rash, petechial rash coexisting with thrombocytopenia, erythematous-to-purpuric coalescing macules, widespread urticaria, and varicella-like vesicles) and vasculopathy-related skin manifestations (ie, peripheral cyanosis with bullae and dry gangrene, transient unilateral livedo reticularis, and red papules on fingers resembling chilblains). Other patients with non-laboratory-confirmed COVID-19 showed urticaria and painful erythematous-to-violaceous patches evolving into tense vesicles or dark crusts. All cases reported so far are summarized in Table I .Table I Summary of reported COVID-19 cases with cutaneous manifestations between January 1, 2020, and April 19, 2020 Authors∗ No. Age, y and sex Cutaneous manifestations Extracutaneous manifestations Laboratory-confirmed COVID-19 case Associated with disease severity Skin biopsy Progression Article link Reported cases with skin manifestations that indicate viral exanthems Guan et al 2 of 1099 NA NA NA Yes Yes No NA https://doi.org/10.1056/NEJMoa2002032 Joob and Wiwanitkit 1 NA Skin rash with petechiae Fever, thrombocytopenia, respiratory symptoms Yes NA No NA https://doi.org/10.1016/j.jaad.2020.03.036 Recalcati 18 of 88 NA Erythematous rash (n = 14), widespread urticaria (n = 3), chickenpox-like vesicles (n = 1) NA Yes No No NA https://doi.org/10.1111/jdv.16387 Hunt and Koziatek 1 20, M Diffuse nonpruritic erythematous morbilliform rash on trunk and extremities Fever, multifocal pneumonia with decreased oxygen saturation Yes Yes No NA https://doi.org/10.5811/cpcem.2020.3.47349 Mahé et al 1 64, F Erythematous rash on both antecubital fossa, trunk, and axillary folds resembling symmetric drug-related intertriginous and flexural exanthem Fever, cough, asthenia, bilateral pneumonia Yes No No Improved within 5 days https://doi.org/10.1111/jdv.16471 Jimenez-Cauhe et al 1 84, F Mild pruriginous erythematous-purpuric, coalescing macules on the periaxillary area Bilateral pneumonia Yes NA No NA https://doi.org/10.1016/j.jaad.2020.04.016 Marzano et al 22 8-90; 16M and 6F Diffuse/scattered papulovesicular lesions on trunk (n = 22) and extremities (n = 4), mild itch (n = 9), pain (n = 2), burning (n = 3) Fever, cough, headache, weakness, coryza, dyspnea, hyposmia, hypogeusia, pharyngodynia, diarrhea, myalgia Yes No Yes (n = 7) 4-15 days https://doi.org/10.1016/j.jaad.2020.04.044 Lu et al 1 NA Urticaria Bilateral pneumonia with minimal symptom No No No NA https://doi.org/10.1002/jmv.25776 Henry et al 1 27, F Generalized urticaria on face and extremities Odynophagia, arthralgia, chills, fever, chest pain Yes No No NA https://doi.org/10.1111/jdv.16472 Fernandez-Nieto et al 1 32, F Urticaria NA Yes No Yes Improved within 5 days https://doi.org/10.1111/jdv.16470 Hoehl et al 1 of 2 NA Faint rash Minimal pharyngitis Yes No No NA https://doi.org/10.1056/NEJMc2001899 Reported cases with vasculopathy-related skin manifestations Zhang et al 7 49-71; 4 M and 3 F Finger/toe cyanosis, skin bullae, and dry gangrene Fever, cough, dyspnea, diarrhea Yes Yes No NA https://doi.org/10.3760/cma.j.issn.0253-2727.2020.0006 Mazzotta and Troccoli 1 13, M Erythematous-violaceous rounded lesions on toes with 1-cm diameter, tense blister, blackish crusts at 7 days later Low-grade fever, muscle pain, headache No No No Regressed in 2 weeks http://sectcv.es/wp-content/uploads/2020/04/acroischemia-ENG.pdf Manalo et al 2 67, M Transient nonpruritic blanching unilateral livedoid patch on right thigh Low-grade fever, nasal congestion, post-nasal drip, cough, hematuria Yes Yes No Resolved within 19 hours https://doi.org/10.1016/j.jaad.2020.04.018 47, F Unilateral transient asymptomatic rash on right leg resembling livedo reticularis Low-grade fever, mild headache, sinus pressure, anosmia Yes No No Resolved within 20 minutes Ma et al 1 of 3 69, M Dry gangrene on right index finger Fever, bilateral pneumonia, antiphospholipid syndrome with cerebral infarcts Yes Yes No NA https://doi.org/10.1016/j.clim.2020.108408 Zhang et al 1 of 3 69, M Ischemia on both lower limbs and digits of the left hand Fever, bilateral pneumonia, diarrhea, headache, multiple cerebral infarcts, positive antiphospholipid antibodies Yes Yes No NA https://doi.org/10.1056/NEJMc2007575 Alramthan and Aldaraji 2 27 and 35; 2 F Red-to-purple papules on the dorsal aspects of fingers (n = 2), diffused erythema in the subungual area of the right thumb (n = 1), clinical features resembling chilblains None Yes No No NA https://doi.org/10.1111/ced.14243 Estebanez et al 1 28, F Confluent erythematous-yellowish papules on both heels, later developed into pruritic erythematous plaques resembling urticarial vasculitis Dry cough, nasal congestion, fatigue, myalgia, arthralgia, diarrhea, ageusia, anosmia Yes No No NA https://doi.org/10.1111/jdv.16474 F, Female; M, male; NA, not available. ∗ References supporting this table are available from the corresponding author upon request. According to pre-existing data, we can speculate that cutaneous manifestations in COVID-19 may present in 2 major groups regarding their pathomechanisms: (1) clinical features similar to viral exanthems, an immune response to viral nucleotides; and (2) cutaneous eruptions secondary to systemic consequences caused by COVID-19, especially vasculitis and thrombotic vasculopathy. Apart from the above-mentioned, patients with COVID-19 are more likely to have an increased risk of adverse drug reactions and interactions of their treatment causing secondary cutaneous reactions at any point during the course of the disease. Therefore, identifying clues that support a viral cause or drug eruption is essential. Table II summarizes cutaneous reactions reported in proposed drugs for COVID-19 treatment.5 Table II Summary of possible mucocutaneous adverse effects reported for proposed COVID-19 treatments∗ Treatment Mucocutaneous adverse effects Chloroquine/hydroxychloroquine† • Common: itching, hair loss • Less common: morbilliform rash, erythroderma, exfoliative dermatitis, urticaria, eczematous eruption, erythema annulare centrifugum, photosensitivity • Rare: acute generalized exanthematous pustulosis Azithromycin† • Rare: morbilliform rash Lopinavir/ritonavir • Common: morbilliform rash • Rare: acute generalized exanthematous pustulosis, hair loss Corticosteroids • Common: skin atrophy, acneiform eruption, telangiectasia, petechiae, ecchymosis, striae, hirsutism Tocilizumab • Less common: anaphylaxis • Rare: morbilliform rash, erythroderma, leukocytoclastic vasculitis Convalescent plasma • Less common: morbilliform rash, itching, evanescent red spot ∗ References supporting this table are available from the corresponding author upon request. † Combination treatment increases the risk of QT prolongation. In summary, whether skin lesions in patients with COVID-19 are related with the virus remains unclear. Dermatologists should keep in mind that skin eruptions occurring in patients with COVID-19 could result from viral infections, systemic consequences, or prescribed drugs. Early recognition of cutaneous signs that are associated with severe complications and prompt management are essential to improve patient outcomes. Moreover, further clinical studies regarding skin manifestations in COVID-19 are required to comprehend the exact cutaneous features for more accurate diagnoses that may predict disease outcomes in particular patients. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not availabe from the authors. ==== Refs References 1 World Health Organization Coronavirus disease 2019 (COVID-19) Situation Report—90. April 19, 2020 Available at: https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200419-sitrep-90-covid-19.pdf?sfvrsn=551d47fd_2 2 Guan W.J. Ni Z.Y. Hu Y. Clinical characteristics of coronavirus disease 2019 in China N Engl J Med 2020 10.1056/NEJMoa2002032 3 Clerkin K.J. Fried J.A. Raikhelkar J. Coronavirus disease 2019 (COVID-19) and cardiovascular disease Circulation 2020 10.1161/CIRCULATIONAHA.120. 046941 4 Mehta P. McAuley D.F. Brown M. Sanchez E. Tattersall R.S. Manson J.J. COVID-19: consider cytokine storm syndromes and immunosuppression Lancet 2020 10.1016/s0140-6736(20)30628-0 5 Sanders J.M. Monogue M.L. Jodlowski T.Z. Cutrell J.B. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review JAMA 2020 10.1001/jama.2020.6019
PMC007xxxxxx/PMC7194708.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)30693-9 10.1016/j.jaad.2020.04.078 Commentary Applying the ethical principles of resource allocation to drugs in limited supply during a public health crisis Kong Ha Eun PhD a∗ Grant-Kels Jane M. MD bc Stoff Benjamin K. MD, MAB ad a Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia b Dermatology Department, University of Connecticut, Farmington, Connecticut c Dermatology Department, University of Florida, Gainesville, Florida d Emory Center for Ethics, Atlanta, Georgia ∗ Reprint requests: Ha Eun Kong, PhD, Department of Dermatology, Emory University School of Medicine, 1525 Clifton Rd NE, Atlanta, GA 30322. 21 4 2020 7 2020 21 4 2020 83 1 170171 © 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 pmcDrug shortages occur for many reasons, including production delays, material shortages, surging demand, and hoarding. During shortages, health care systems must determine how to fairly distribute these scarce resources to patients. Unfortunately, no single distribution framework applies to all shortages. However, general allocation principles for scarce health care resources, grounded in distributive justice and utility, can be applied, although particular rules will differ depending on the circumstances. For example, chloroquine and hydroxychloroquine, familiar drugs to dermatologists commonly used against malaria and autoimmune diseases, have shown promise against COVID-19 in clinical trials.1 Consequently, demand for these drugs has surged, portending critical shortages for all indications, including dermatologic diseases.2 How should dermatologists prescribe these drugs during the pandemic? A recent, timely article outlines recommendations for ethical health care resource allocation during a pandemic (Table I ).3 During a pandemic, priority should be given to those whose survival would benefit most from treatment to maximize benefit to society. Applying this principle to antimalarials, patients with severe COVID-19, as well as patients with malaria or severe rheumatologic disease, for whom other effective treatments are unavailable, should be favored. If dermatology patients eligible for antimalarials have other, comparably effective treatment options, dermatologists should recommend alternatives, particularly for mild-to-moderate disease. Finally, providers should not prescribe these drugs to the “worried well,” who may be hoarding medication in case of illness.Table I Application of ethical principles of resource allocation in the COVID-19 pandemic∗ Ethical principle Application to COVID-19 Maximize benefits Saving the most lives/life-years is the highest priority. Treat people equally Random selection can be used for selecting among patients with comparable prognoses. Promote and reward social value Health care workers should be prioritized. With other factors equal, give priority to COVID-19 research participants. Give priority to worst off Give priority to sickest and youngest of population if it aligns with maximizing benefits (eg, saving most years of life or preventing further spread of virus). ∗ Adapted from Emanuel et al.3 Clinicians must reassess allocation strategies as new data emerge. The efficacy of antimalarials for COVID-19 should be assessed via randomized clinical trials, which are ongoing. For example, a small open-label French study demonstrated a reduction in viral load but did not assess mortality or morbidity.1 In contrast, for patients with systemic lupus erythematosus, a randomized controlled trial showed that discontinuing hydroxychloroquine leads to a 2.5-times increased relative risk of clinically relevant flares and a 6-times increased relative risk of severe exacerbation compared with controls.4 While the benefit of antimalarials to patients with COVID-19 remains uncertain, high-quality evidence supports continuing treatment in patients with severe systemic lupus erythematosus. What is the role of patient autonomy in public health emergencies? Under normal circumstances, if a reasonable patient prefers antimalarials for skin disease, and the treatment is indicated, then the drugs should be prescribed. However, patient autonomy is diminished in public health emergencies as health care ethics shifts priority to populations over individuals.5 Currently, many states in the United States have limited prescribing of hydroxychloroquine, but these limitations generally do not apply to patients receiving the drug for approved indications.6 In applying the ethical principles of resource allocation (Table I), we argue that dermatologists should continue to prescribe antimalarials to patients with severe skin disease, but only in the minimum reasonable allotment in accordance with state prescribing regulations during the pandemic, rather than higher volumes. If new data demonstrate efficacy and safety of antimalarials against COVID-19, antimalarials should be generally reallocated to patients with COVID-19, with the exception of a select few patients with very severe dermatologic disease, until supplies meet demand. Furthermore, allocation should prioritize front-line health care workers because of their instrumental value to society. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. ==== Refs References 1 Gautret P. Lagier J.-C. Parola P. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial Int J Antimicrob Agents 2020 105949 32205204 2 Mehta B. Salmon J. Ibrahim S. Potential shortages of hydroxychloroquine for patients with lupus during the coronavirus disease 2019 pandemic JAMA Health Forum 1 4 2020 e200438 36218613 3 Emanuel E.J. Persad G. Upshur R. Fair allocation of scarce medical resources in the time of Covid-19 N Engl J Med 2020 NEJMsb2005114 4 Bykerk V. Sampalis J. Esdaile J.M. A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus N Engl J Med 324 3 1991 150 154 1984192 5 Berlinger N. Wynia M. Powell T. Ethical Framework for Health Care Institutions & Guidelines for Institutional Ethics Services Responding to the Coronavirus Pandemic. The Hastings Center, March 16, 2020 Available at: https://www.thehastingscenter.org/ethicalframeworkcovid19/ 6 Idaho State Board of Pharmacy FAQ for COVID-19 Declaration of Emergency. March 27, 2020 https://bop.idaho.gov/wp-content/uploads/sites/99/2020/03/FAQ-COVID_03212020.pdf
PMC007xxxxxx/PMC7194926.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)30701-5 10.1016/j.jaad.2020.04.085 Research Letter 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 Gisondi Paolo MD a∗ Zaza Gianluigi MD b Del Giglio Micol MD a Rossi Mattia MD b Iacono Valentina MD b Girolomoni Giampiero MD a a Section of Dermatology and Venereology, Department of Medicine, University of Verona, Verona, Italy b Section of Nephrology, Department of Medicine, University of Verona, Verona, Italy ∗ Correspondence to: Paolo Gisondi, MD, Department of Medicine, Section of Dermatology and Venereology, University of Verona, Piazzale A. Stefani 1, 37126 Verona 21 4 2020 7 2020 21 4 2020 83 1 285287 © 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: There is uncertainty concerning the outcome of COVID-19 infection in patients receiving systemic therapies such as biologics and immunosuppressive drugs.1 Whether biologics for psoriasis should be interrupted for preventing severe complications of COVID-19 infection is debated.2 , 3 We performed a retrospective observational study to determine whether patients with chronic plaque psoriasis on biologic or other immunosuppressive therapy and patients who had received a renal transplant had a higher risk of hospitalization or death from COVID-19 infection compared with the general population of Verona during the observation period from February 20 to April 10, 2020. Inclusion criteria for patients with psoriasis and transplant were being regularly monitored at the Division of Dermatology and Nephrology of the Azienda Ospedaliera Universitaria Integrata Verona, respectively, being treated with a biologic or immunosuppressive medication, and being a resident in Verona. Data were obtained by consulting the electronic medical records of the hospital and compared with the Verona population (n = 257,353) (Table I ). The overall study population resides in Verona, so that the reference hospital is the same. Data of Verona residents were derived from the national public database4 and are expressed as means ± SD or percentages. Statistical analyses for comparison between patients and the general population included the unpaired t test and the χ2 test.Table I Study population including patients with psoriasis on biologic therapy, renal transplant recipients, and general population∗ Parameter† Patients with PsO on biologic therapy (n = 980) Renal transplant recipients (n = 247) General population (n = 257,353) P Individuals positive for COVID-19 …‡ …‡ 3199 (1.2) Hospitalized for COVID-19–related disease 0 1 (0.4) 589 (0.2) Died of COVID-19–related disease 0 0 227 (0.08) Male sex 568 (58) 157 (63.5) 133,823 (52) <.05 Age, y 56.4 ± 12.4 57.7 ± 13.1 44 <.05 Obesity 294 (30) 25 (10) 25,220 (9.8) <.05 Cardiovascular disease 137 (12) 164 (66) 20,588 (8) <.05 Hypertension 333 (34) 200 (81) 48,897 (19) <.05 Diabetes 117 (12) 32 (13) 9779 (3.8) <.05 Psoriatic arthritis 303 (31) - - Biologic or immunosuppressive therapy Anti TNF-α inhibitors: 490 (50) CNI monotherapy: 18 (7) IL-17 inhibitors: 274 (28) CNI plus antimetabolite: 195 (79) - IL-12/23 inhibitor: 166 (17) mTORi monotherapy: 4 (1.6) - IL-23 inhibitors: 49 (5) mTORi + CNI: 12 (4.8) - Antimetabolite monotherapy: 6 (2.4) - Antimetabolite + mTORi: 11 (4.4) - CNI, Calcineurin inhibitors; IL, interleukin; mTORi, mammalian target of rapamycin inhibitor; TNF, tumor necrosis factor; PsO, psoriasis. ∗ Data of patients with psoriasis and transplant recipients are derived from the hospital's electronic medical record. Data of the general population are derived from https://www.azero.veneto.it/-/emergenza-coronavirus, https://www.epicentro.iss.it, and http://demo.istat.it, accessed on April 10, 2020. † Data are presented as number (%) or as mean ± SD. ‡ Asymptomatic individuals were not tested, so the true number of patients positive for COVID-19 is unknown. As of April 10, 2020, 3199 patients (1.2% of population) in Verona were positive for COVID 19 (including those who did not require hospitalization or die).5 Among 980 patients with chronic plaque psoriasis on biologics, no hospitalization or death was documented. Among 243 patients who had received a renal transplant, 1 required hospitalization for fever and pneumonia but fully recovered. The prevalence of obesity, hypertension, diabetes, and positive history of cardiovascular diseases was higher in patients with psoriasis and those who had received a transplant than the general population. The mean age and prevalence of male sex was higher in patients than in controls. We acknowledge the limitations of this preliminary study, including the absence of molecular or serologic testing for COVID-19 infection in our study population, because current criteria for performing diagnostic tests for COVID-19 exclude general asymptomatic individuals. The large difference in sample size between patients and the general population and the very low number of hospitalizations and deaths in the patients group do not permit us to draw any inferential statistics. However, the objective of the study was not investigating the prevalence of COVID-19 infection in our patients, but rather reporting the occurrence of the severe outcomes, such as hospitalization and death, related to the COVID-19 infection. The strength of the study is that we have access to the full medical records of the patients, so that if there had been a case of hospitalization or death from COVID-19, it would have been detected. Although patients with psoriasis and transplant recipients are older, burdened by metabolic and cardiovascular comorbidities, and above all, immunosuppressed, there is no early signal of an increased hospitalization or death from COVID-19. We acknowledge that patients on biologics or immunosuppressive drugs may have self-isolated more effectively and focused on improved hygiene, thus limiting their own infection risk. Funding sources: None. Conflicts of interest: Dr Gisondi served as consultant for AbbVie, Almirall, Amgen, Celgene, Eli Lilly, Janssen, LEO Pharma, MSD, Novartis, Pfizer, Pierre Fabre, Sanofi, and UCB. Dr Girolomoni served as consultant for AbbVie, Abiogen, Almirall, Amgen, Bayer, Biogen, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, Hospira, LEO Pharma, Merck, MSD, Mundipharma, Novartis, Pfizer, Pierre Fabre, Regeneron, Sandoz, Sanofi, and Sun Pharma. Drs Del Giglio, Rossi, Zaza, and Iacono have no conflicts of interest to declare. IRB approval status: The IRB was notified of the observational study. Reprints not available from the authors. ==== Refs References 1 American Academy of Dermatology \| Association Coronavirus Resource Center. Guidance on the use of biologic agents during COVID-19 outbreak Available at: https://www.aad.org/member/practice/coronavirus/clinical-guidance 2 Bashyam A.M. Feldman S.R. Should patients stop their biologic treatment during the COVID-19 pandemic J Dermatolog Treat 2020 1 2 3 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 5 2020 1217 1218 32199889 4 EpiCentro: L'epidemiologia per la sanità pubblica Istituto Superiore di Sanità. SARS-CoV-2. Consulta i dati Available at: https://www.epicentro.iss.it 5 Azienda Zero Emergenza Coronavirus SARS-CoV-2/COVID-19 Available at: https://www.azero.veneto.it/-/emergenza-coronavirus
PMC007xxxxxx/PMC7194984.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)30711-8 10.1016/j.jaad.2020.04.095 Review Role of phototherapy in the era of biologics Torres Angeli Eloise MD ab Lyons Alexis B. MD b Hamzavi Iltefat H. MD b Lim Henry W. MD b∗ a Manila, Philippines b Photomedicine and Photobiology Unit, Department of Dermatology, Henry Ford Health System, Detroit, Michigan ∗ Correspondence to: Henry W. Lim, MD, Department of Dermatology, Henry Ford Medical Center, 3031 West Grand Blvd, Suite 800, Detroit, MI 48202. 24 4 2020 2 2021 24 4 2020 84 2 479485 21 4 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. Phototherapy is a safe and effective treatment for many dermatologic conditions. With the advent of novel biologics and small molecule inhibitors, it is important to critically evaluate the role of phototherapy in dermatology. Surveys have shown that many dermatology residency programs do not dedicate time to teaching residents how to prescribe or administer phototherapy. Limitations of phototherapy include access to a center, time required for treatments, and insurance approval. Home phototherapy, a viable option, is also underused. However, it should be emphasized that modern phototherapy has been in use for over 40 years, has an excellent safety profile, and does not require laboratory monitoring. It can be safely combined with many other treatment modalities, including biologics and small molecule inhibitors. In addition, phototherapy costs significantly less than these novel agents. Dermatologists are the only group of physicians who have the expertise and proper training to deliver this treatment modality to our patients. Therefore, to continue to deliver high-quality, cost-effective care, it is imperative that phototherapy be maintained as an integral part of the dermatology treatment armamentarium. Key words biologics broadband ultraviolet B excimer narrowband ultraviolet B phototherapy psoralen plus UVA psoriasis ultraviolet A1 Abbreviations used BB-UVB broadband ultraviolet B CR clearance rate IL interleukin NB-UVB narrowband ultraviolet B PASI Psoriasis Area and Severity Index PUVA psoralen and ultraviolet A UV ultraviolet UVB ultraviolet B ==== Body pmc Capsule Summary • Novel and effective targeted therapies for dermatologic diseases raise questions regarding the role of phototherapy. • Despite therapeutic advancements, phototherapy still has a role as a safe, well-established, cost-effective treatment option; only dermatologists have the expertise and training to make this treatment available to our patients. Ever since Goeckerman introduced the use of ultraviolet (UV) B (UVB) and tar in 1925,1 phototherapy has been an integral part of dermatology training and expertise. Modern phototherapy has been in use for over 40 years.2 This started with broadband UVB (BB-UVB) phototherapy and, in 1988, was replaced with the more effective narrowband UVB (NB-UVB) phototherapy. Psoralen and UVA (PUVA)—more accurately termed photochemotherapy—began in 1974.3 Targeted phototherapy with an excimer laser or excimer lamp began in 1997.4 Exciting advances in the understanding of the molecular pathway and pathophysiology of dermatologic diseases have led to the development of many highly effective targeted therapies in psoriasis, atopic dermatitis, vitiligo, alopecia areata, and other dermatoses. These biologics and small molecule inhibitors have become an important part of dermatology practice, which raises the question on the role of phototherapy. Use of phototherapy A 5-year report in 2002 showed that phototherapy use in the United States is declining. From 1993 to 1998, patient visits decreased by 85% for PUVA and by over 90% for phototherapy in general. Among the reasons cited for this decrease were the development of newer systemic agents, reluctance of patients to adhere to multiple weekly treatments, fear of UV-induced skin malignancies, and modifications in insurance coverage.5 However, a 2018 study found that billing for phototherapy increased by 5% annually over a 15-year period (2000-2015). This study included Medicare beneficiaries only and did not account for patients with private insurance or those paying out of pocket; hence, it is likely that the actual number of patients receiving phototherapy is much higher. It should be noted that this increase was driven primarily by the use of excimer laser (25%-30% increase). In the same period, the use of UVB phototherapy and PUVA decreased by 3% to 6% and 9%, respectively.6 In other parts of the world, phototherapy use was higher than in the United States. In Australia, a nationwide survey of practicing dermatologists published in 2002 showed that 71% of respondents provided phototherapy, and among them, almost 90% had their own treatment facilities.7 In France, the number of UV treatments administered annually increased by 12% from 2007 to 2010—nearly a decade after biologics were first introduced; however, follow-up data (2013-2016) saw a decline of the same by 15%, which was attributed to delays in initiation of biologic therapy.8 Although clinical inertia was suggested as a reason for this delay,8 , 9 it is also worthwhile to consider the fact that many guidelines do not endorse biologics as first-line agents, and a stepwise approach is still advocated.10 Phototherapy training among dermatology residents A 2017 study by Goyal et al11 showed that there was a disparity between the demand for phototherapy and the time devoted to learning it during residency. Responses obtained from dermatology program directors across the United States showed that a majority (67%) regarded their phototherapy training as inadequate, which was primarily attributed to time deficiency.11 A cross-sectional survey12 among US dermatology residents, published in 2015, showed that approximately 59% did not obtain any hands-on phototherapy training and that 42% had never observed phototherapy at all. Fewer than half of the residents felt that they could comfortably administer NB-UVB unsupervised, and fewer than 20% were comfortable with administering other modalities (excimer laser, PUVA, and BB-UVB). Similarly, in 2015, Anderson et al13 found that, among US dermatology residents, 29% and 76% were not comfortable with prescribing outpatient and home phototherapy, respectively. This discomfort stemmed from a lack of exposure and is significant because dermatology trainees who do not develop enough confidence to prescribe phototherapy during residency are less likely to do so in practice. Phototherapy and biologics Efficacy data Phototherapy primarily uses UV radiation. Depending on the pathogenesis of the disease being treated and the specific modality prescribed, phototherapy counteracts the pathologic changes that characterize inflammatory skin diseases through several key mechanisms: (1) induction of apoptosis, (2) modification of the cytokine milieu, and (3) immunosuppression.14, 15, 16 Phototherapy has been used successfully to treat many skin diseases. A partial list is shown in Table I . Among these, phototherapy for psoriasis has the most data. The different modalities that can be used for psoriasis are BB-UVB, NB-UVB, excimer light or laser, and PUVA (oral, topical, hand-foot soak, and bath/full-body soak).17 BB-UVB is rarely used today and has largely been replaced by NB-UVB because of the latter's better efficacy.18 Table I Common indications for phototherapy Psoriasis Vitiligo Cutaneous T-cell lymphoma/mycosis fungoides Polymorphous light eruption Atopic dermatitis Pruritus Oral PUVA has superior efficacy to NB-UVB for psoriasis. Treatment with NB-UVB can produce substantial improvement of moderate to severe psoriasis after approximately 20 to 36 treatments, whereas oral PUVA can generate equal or better results after a median of 16 to 17 sessions.18 In a systematic review by Almutawa et al,17 oral PUVA achieved the highest clearance rate (CR) (79%) but caused symptomatic erythema and blistering in 17% of patients. NB-UVB attained a 68% CR and was better tolerated (adverse effects in 7.8%), and bath PUVA was the least effective (58% CR) and least tolerated (adverse effects in 21%). Hence, although oral PUVA is more efficacious, better tolerability makes NB-UVB a preferred first-line phototherapy modality.17 In practice, the high cost and intermittent availability of 8-methoxypsoralen in the United States, together with well-known, long-term adverse effects of photoaging and photocarcinogenesis, have further limited the use of PUVA. Excimer laser or excimer light is a form of targeted UVB. It limits UV exposure to the involved areas only, making it ideal for localized disease (less than 10% body surface area) as well as difficult-to-treat areas such as the scalp, palms, and soles.4 It can produce results with as few as 8 treatment sessions compared to conventional NB-UVB, thereby reducing the cumulative UV dose.4 , 18 Outside the realm of psoriasis, NB-UVB is a first-line UV-based treatment option for many conditions including vitiligo, early mycosis fungoides, and atopic dermatitis. UVA1 penetrates deeper into the dermis and has shown benefit for sclerosing skin disorders such as morphea and scleroderma.19 NB-UVB and UVA1 are also useful for therapeutic hardening of patients with polymorphous light eruption and solar urticaria, respectively.20 For treatment-resistant dermatitis of the hands and feet, topical PUVA is frequently used. Oral PUVA is helpful for plaque stage mycosis fungoides, other forms of cutaneous lymphoma, and as a second-line UV-based treatment option for recalcitrant skin conditions that have failed or responded inadequately to NB-UVB.21 The list of photoresponsive dermatoses is long, which underscores the versatility of this treatment modality. Biologics are injected or infused monoclonal antibodies that block specific proinflammatory cytokines or receptors implicated in the pathophysiology of psoriasis and other inflammatory diseases.16 , 22 These agents are grouped according to their cytokine target(s) as follows: tumor necrosis factor inhibitors (etanercept, infliximab, adalimumab, certolizumab), interleukin (IL) 12/IL-23 inhibitor (ustekinumab), IL-17 inhibitors (secukinumab, ixekizumab, brodalumab), and IL-23 inhibitors (guselkumab, tildrakizumab, risankizumab-rzaa).22 A 2019 meta-analysis found risankizumab-rzaa to be the most efficacious biologic for psoriasis, followed by ixekizumab, guselkumab, and brodalumab.23 Kim et al24 noted that IL-17 inhibitors have the earliest onset of efficacy. The fastest, brodalumab, attained a 50% reduction in Psoriasis Area and Severity Index score (PASI) in less than 2 weeks and a 75% reduction in PASI in 4 weeks. The IL-17 inhibitors were also among the biologic agents that had the most sustained activity together with the IL-23 inhibitors and IL-12/23 inhibitor. A comparative study by Inzinger et al25 showed that the efficacy rates of oral PUVA were comparable to those of infliximab and exceeded those of etanercept, efalizumab, alefacept, adalimumab, and ustekinumab. Additionally, a recent trial comparing patient-reported outcomes of NB-UVB versus adalimumab versus placebo showed that improvements in overall health-related quality of life scores were equivalent for both active interventions after 12 weeks.26 Safety and adverse effect profile The acute adverse effects of phototherapy are relatively minor and include pruritus, tenderness, erythema, tanning, and blister formation.18 For PUVA, the application or ingestion of a photosensitizer can incite skin phototoxicity, nausea, and/or vomiting.18 The true risk of UV-induced skin cancer has long been a subject of debate and is a cause of hesitation for patients and providers alike. PUVA has been found to significantly increase the risk of squamous cell carcinoma in a dose-dependent manner, whereas the incidences of PUVA-induced melanoma and basal cell carcinoma are much lower.14 , 27 NB-UVB and UVA1 have had no evidence of increased risk of photocarcinogenesis and are considered safe with proper supervision by most practitioners.14 , 27 , 28 These risks can be mitigated via thoughtful patient and modality selection, proper dosing and dose adjustment, protection of uninvolved areas, monitoring of cumulative UV dose, and periodic full-body skin examinations.14 With the exception of PUVA, phototherapy does not require any pretreatment laboratory workup and can be safely administered to pediatric, elderly, and pregnant patients. The adverse effects and safety of biologic medications should also be considered. With proper patient screening, biologics have shown good safety, particularly when compared to traditional systemic agents24; however, long-term data are scarce. Patients taking biologics have an increased risk of infection because of the immunomodulatory effects of the medication. Tumor necrosis factor inhibitors have specifically been associated with an elevated risk of tuberculosis, hepatitis B, lymphoma, and other malignancies, whereas IL-17 inhibitors have been shown to induce and exacerbate inflammatory bowel disease and increase the risk for mucocutaneous candidiasis.24 , 29 Depression and suicidality have been reported among patients taking brodalumab, although evidence on causation remains controversial.24 , 29 Furthermore, parenteral administration of biologics makes injection site and infusion reactions a possibility.24 , 29 To minimize these risks, patients who are candidates for biologic therapy require workup before initiation and at regular intervals throughout treatment. Laboratory tests consisting of a complete blood count, liver function test, hepatitis panel, and tuberculosis screening are regularly performed.22 , 30 Additional tests may be warranted depending on patient-specific or medication-specific risk factors. Recent guidelines suggest that certain biologic agents may be safely administered to pregnant, lactating, and pediatric patients; however, information regarding this is still limited.22 , 31 The COVID-19 pandemic raised numerous questions regarding biologics' safety that lack clear, evidence-based answers. Based on experience with HIV-positive patients, and in keeping with the practice of social distancing, home phototherapy is a reasonable option during this pandemic. Cost The price of treatment is a reality that must be considered when formulating a management plan; and for chronic skin conditions, this may entail lifelong expenditures. According to a study in Scotland, the average price for a course of NB-UVB is £257, whereas topical medications cost £128 annually per patient. Implementing NB-UVB resulted in a 40% reduction in cost (£50.74 per patient annually) due to less need for medications.32 A 2010 analysis estimated that biologics cost at least twice as much as NB-UVB and PUVA combined. The least expensive biologic included in the study, adalimumab, was quoted at $23,538 for the first year of therapy alone, compared to $3148 and $7582 for a year of NB-UVB and PUVA, respectively.33 Six years later, the price of adalimumab increased by more than 2-fold ($58,045) for the first year of therapy alone.34 Home phototherapy units cost anywhere between $2500 and $5000.35 , 36 They can offset the indirect expenses incurred from office-based treatment (transportation, lost income from work absences, inconvenience), but a disadvantage is that patients must pay for the device up front because few insurance policies offer coverage. A comparative study showed that although in-office phototherapy was less costly at the beginning of treatment, it became 5 times more expensive than home phototherapy after 3 months.36 Additionally, when compared to biologics, home phototherapy cost up to 36 times less over a 3-year period.37 Biologics have remarkable efficacy and a good safety record to date, and they are convenient to administer. This may provide rationale for physicians and patients to justify the high cost, especially when factoring in the intangible phototherapy expenses. However, some patients may respond inadequately to biologic therapy and require dose escalation or more frequent administration, thereby further increasing the cost of treatment.34 Combination therapies In practice, treatments are often combined to enhance efficacy when rapid suppression of disease activity is desired or when monotherapy is insufficient to achieve and maintain control. Several reviews and guidelines on psoriasis treatment have reported on the combination of phototherapy with various topical drugs, traditional systemic agents, and biologics.14 , 16 , 38 , 39 With each medication having its own adverse effects, enhanced toxicity from combining 2 or more modalities is a possibility. Contrarily, some combinations of medications may lower the chances of long-term adverse effects by reducing the cumulative dose of either modality alone or have minimal to no additive toxicity because of the relatively short duration of adjunctive treatment.38 The concomitant administration of acitretin with NB-UVB has been found to hasten clinical response, reduce the required acitretin dose, and decrease the number of phototherapy sessions by approximately 20%, thereby lowering the cumulative UV dose and theoretical risk for photocarcinogenesis.14 , 38 , 40 Similar effects have been observed with acitretin plus PUVA, and given the established skin cancer risk with this modality, the coadministration of an oral retinoid is particularly valuable.40, 41, 42, 43 Because retinoids have a keratolytic effect, phototherapy dose escalations must be proceeded with cautiously when using this combination.14 Most protocols recommend UV dose reduction by 33%. Several studies have shown that NB-UVB in conjunction with biologics is safe, synergistic, and well tolerated, although long-term data on these combinations have not been explored. Patients with moderate to severe psoriasis who complied with thrice-weekly NB-UVB in addition to etanercept showed biopsy-proven improvement without additional adverse effects compared to etanercept alone.38 , 44 Moreover, a half-body comparison of adalimumab plus NB-UVB versus adalimumab alone yielded a 33% greater PASI reduction on the irradiated body half compared to the nonirradiated half.45 Analogous results were obtained in a similar trial on ustekinumab.46 Erythema was the most common adverse effect.45 , 46 To date, there are no studies on the combination of PUVA with any biologic.41 Limitations of phototherapy One major challenge concerning adherence to phototherapy is limited access. In the United States, phototherapy facilities are concentrated in urban areas of the East and West Coasts and the Midwest region east of Mississippi, leaving 89% of counties without a treatment center.6 This misdistribution appears to reflect the geographic location of dermatology providers in general and not the underuse of phototherapy per se. Nonetheless, the indirect costs of travel and lost income from missing work can discourage patients from complying with repeated phototherapy treatments.6 Other limiting factors are the resources needed to establish a phototherapy center (equipment, space, trained staff) and the need for prior authorization. Home phototherapy devices can potentially address these hurdles. Several randomized trials have shown that home-based and office-based phototherapy are equally safe and effective, with higher satisfaction and adherence in favor of home phototherapy; however, this also entails higher up-front costs for the patient and the need for a provider who is sufficiently familiar with home phototherapy.47 In addition, phototherapy has possible long-term risks. Therefore, in practice, it is usually administered intermittently, and patients may experience disease relapses within weeks to months of discontinuation. Combining phototherapy with other modalities can not only decrease the likelihood or severity of a relapse but also lower the risk of adverse effects from either modality alone. With proper patient education, home-based phototherapy is another option. The advantages and limitations of phototherapy and biologics are summarized in Table II .Table II Summary of advantages and limitations of phototherapy and biologics Phototherapy Biologics Advantages Effective Rapid acting (targeted phototherapy) Known long-term safety record No laboratory monitoring needed Safe for children and pregnant and nursing mothers (NB-UVB) Lower cost Highly effective (takes 8-12 weeks) Immune modulators Good short-term safety record Convenient to administer Limitations Availability and access Necessitates equipment, staff, and space Requires patient's time and effort Involves thorough patient education (for home phototherapy) Expensive cost Requires laboratory testing and monitoring Lacking long-term safety data Conclusion Phototherapy remains an indispensable treatment option for many cutaneous diseases. Its versatility, cost effectiveness, and unparalleled safety makes it a viable first-line treatment or adjunct when other treatment regimens fall short. Just as there are numerous indications for phototherapy alone, there are a wide variety of modalities with which it can be combined. As dermatologic management becomes more individualized and costly, improved access to this treatment modality through expanding residency training curricula and prescribing of home devices will prove that even in the era of biologics, phototherapy will stand the test of time. Dermatologists are the only group of physicians who have the knowledge and expertise to supervise the delivery of phototherapy. Therefore, it is essential that we as a specialty continue to make sure this treatment option is available to our patients. Funding sources: None. Disclosure: Dr Lyons is a subinvestigator for Incyte, Beiersdorf, Unigen Inc, General Electric, Lenicura, Estée Lauder, miRagen, Biofrontera, Pfizer, and L'Oréal. Dr Hamzavi is an investigator for Patient-Centered Outcomes Research Institute, Incyte Corporation, Beiersdorf, Estée Lauder, Unigen Inc, Ferndale Healthcare Inc, Pfizer, Allergan, and Johnson & Johnson. Dr Lim is an investigator for Incyte, Beiersdorf, L'Oréal, Pfizer, and PCORI; has served as consultant for Pierre Fabre, ISDIN, Ferndale, and Galderma; and has participated as a speaker in general educational session for Pierre Fabre, Eli Lilly, Johnson & Johnson, and Ra Medical System. Dr Torres has no conflicts of interest to declare. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Honigsmann H. History of phototherapy in dermatology Photochem Photobiol Sci 12 2013 16 21 22739720 2 Roelandts R. History of human photobiology Lim H.W. Honigsmann H. Hawk J.L.M. Photodermatology 2007 Informa Healthcare USA New York 1 14 3 Parrish J.A. Fitzpatrick T.B. Tanenbaum L. Pathak M.A. Photochemotherapy of psoriasis with oral methoxsalen and longwave ultraviolet light N Engl J Med 291 1974 1207 1211 4422691 4 Ly K. Smith M.P. Thibodeaux Q.G. Beck K.M. Liao W. Bhutani T. Beyond the booth: excimer laser for cutaneous conditions Dermatol Clin 38 2020 157 163 31753188 5 Housman T.S. Rohrback J.M. Fleischer A.B. Jr. Feldman S.R. Phototherapy utilization for psoriasis is declining in the United States J Am Acad Dermatol 46 2002 557 559 11907508 6 Tan S.Y. Buzney E. Mostaghimi A. Trends in phototherapy utilization among Medicare beneficiaries in the United States, 2000 to 2015 J Am Acad Dermatol 79 2018 672 679 29574089 7 Huynh N.T. Sullivan J.R. Commens C.A. Survey of phototherapy practice by dermatologists in Australia Australas J Dermatol 43 2002 179 185 12121394 8 Aubin F. Courtois J. Puzenat E. Phototherapy in France: quantitative data (2007-2016) from the National Health Insurance Register J Eur Acad Dermatol Venereol 32 2018 e224 e225 29224240 9 Lavoie K.L. Rash J.A. Campbell T.S. Changing provider behavior in the context of chronic disease management: focus on clinical inertia Annu Rev Pharmacol Toxicol 57 2017 263 283 27618738 10 Ighani A. Partridge A.C.R. Shear N.H. Comparison of management guidelines for moderate-to-severe plaque psoriasis: a review of phototherapy, systemic therapies, and biologic agents J Cutan Med Surg 23 2019 204 221 30463416 11 Goyal K. Nguyen M.O. Reynolds R.V. Perceptions of U.S. dermatology residency program directors regarding the adequacy of phototherapy training during residency Photodermatol Photoimmunol Photomed 33 2017 321 325 28857313 12 Danesh M.J. Butler D.C. Beroukhim K. A cross-sectional survey study to evaluate phototherapy training in dermatology residency Photodermatol Photoimmunol Photomed 31 2015 269 270 26018552 13 Anderson K.L. Huang K.E. Huang W.W. Feldman S.R. Training for prescribing in-office and home phototherapy Photodermatol Photoimmunol Photomed 31 2015 325 332 26285141 14 Benakova N. Phototherapy of psoriasis in the era of biologics: still in Acta Dermatovenerol Croat 19 2011 195 205 21933648 15 Racz E. Prens E.P. Phototherapy of psoriasis, a chronic inflammatory skin disease Adv Exp Med Biol 996 2017 287 294 29124709 16 Richard E.G. Honigsmann H. Phototherapy, psoriasis, and the age of biologics Photodermatol Photoimmunol Photomed 30 2014 3 7 24313462 17 Almutawa F. Alnomair N. Wang Y. Hamzavi I. Lim H.W. Systematic review of UV-based therapy for psoriasis Am J Clin Dermatol 14 2013 87 109 23572293 18 Totonchy M.B. Chiu M.W. UV-based therapy Dermatol Clin 32 2014 399 413 24891061 19 Walker D. Jacobe H. Phototherapy in the age of biologics Semin Cutan Med Surg 30 2011 190 198 22123416 20 Lyons A.B. Peacock A. Zubair R. Hamzavi I.H. Lim H.W. Successful treatment of solar urticaria with UVA1 hardening in three patients Photodermatol Photoimmunol Photomed 35 2019 193 195 30576021 21 Lim H.W. Silpa-archa N. Amadi U. Menter A. Van Voorhees A.S. Lebwohl M. Phototherapy in dermatology: a call for action J Am Acad Dermatol 72 2015 1078 1080 25981004 22 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 23 Armstrong A.W. Puig L. Joshi A. Comparison of biologics and oral treatments for plaque psoriasis: a meta-analysis JAMA Dermatol 156 2020 258 269 32022825 24 Kim H.J. Lebwohl M.G. Biologics and psoriasis: the beat goes on Dermatol Clin 37 2019 29 36 30466686 25 Inzinger M. Heschl B. Weger W. Efficacy of psoralen plus ultraviolet A therapy vs. biologics in moderate to severe chronic plaque psoriasis: retrospective data analysis of a patient registry Br J Dermatol 165 2011 640 645 21564068 26 Noe M.H. Wan M.T. Shin D.B. Patient-reported outcomes of adalimumab, phototherapy, and placebo in the Vascular Inflammation in Psoriasis Trial: a randomized controlled study J Am Acad Dermatol 81 2019 923 930 31163241 27 Thompson K.G. Kim N. Distinguishing myth from fact: photocarcinogenesis and phototherapy Dermatol Clin 38 2020 25 35 31753190 28 Hearn R.M. Kerr A.C. Rahim K.F. Ferguson J. Dawe R.S. Incidence of skin cancers in 3867 patients treated with narrow-band ultraviolet B phototherapy Br J Dermatol 159 2008 931 935 18834483 29 Kaushik S.B. Lebwohl M.G. Review of safety and efficacy of approved systemic psoriasis therapies Int J Dermatol 58 2019 649 658 30246393 30 Menter A. Gottlieb A. Feldman S.R. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics J Am Acad Dermatol 58 2008 826 850 18423260 31 Cline A. Bartos G.J. Strowd L.C. Feldman S.R. Biologic treatment options for pediatric psoriasis and atopic dermatitis Children (Basel) 6 9 2019 103 31514420 32 Boswell K. Cameron H. West J. Narrowband ultraviolet B treatment for psoriasis is highly economical and causes significant savings in cost for topical treatments Br J Dermatol 179 2018 1148 1156 29901862 33 Beyer V. Wolverton S.E. Recent trends in systemic psoriasis treatment costs Arch Dermatol 146 2010 46 54 20083692 34 Shahwan K.T. Kimball A.B. Managing the dose escalation of biologics in an era of cost containment: the need for a rational strategy Int J Womens Dermatol 2 2016 151 153 28492030 35 Anderson K.L. Feldman S.R. A guide to prescribing home phototherapy for patients with psoriasis: the appropriate patient, the type of unit, the treatment regimen, and the potential obstacles J Am Acad Dermatol 72 2015 868 878 25748310 36 Dillon J.P. Ford C. Hynan L.S. Pandya A.G. A cross-sectional, comparative study of home vs in-office NB-UVB phototherapy for vitiligo Photodermatol Photoimmunol Photomed 33 2017 282 283 28660721 37 Hyde K. Cardwell L.A. Stotts R. Feldman S.R. Psoriasis treatment cost comparison: biologics versus home phototherapy Am J Pharm Benefits 10 2018 18 21 38 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 39 Farahnik B. Patel V. Beroukhim K. Combining biologic and phototherapy treatments for psoriasis: safety, efficacy, and patient acceptability Psoriasis (Auckl) 6 2016 105 111 29387597 40 Lebwohl M. Acitretin in combination with UVB or PUVA J Am Acad Dermatol 41 1999 S22 S24 10459143 41 Menter A. Korman N.J. Elmets C.A. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 5. Guidelines of care for the treatment of psoriasis with phototherapy and photochemotherapy J Am Acad Dermatol 62 2010 114 135 19811850 42 Tanew A. Guggenbichler A. Honigsmann H. Geiger J.M. Fritsch P. Photochemotherapy for severe psoriasis without or in combination with acitretin: a randomized, double-blind comparison study J Am Acad Dermatol 25 1991 682 684 1838750 43 Nijsten T. Stern R. Oral retinoid use reduces cutaneous squamous cell carcinoma risk in patients with psoriasis treated with psoralen-UVA: a nested cohort study J Am Acad Dermatol 49 2003 644 650 14512910 44 Gambichler T. Tigges C. Scola N. Etanercept plus narrowband ultraviolet B phototherapy of psoriasis is more effective than etanercept monotherapy at 6 weeks Br J Dermatol 164 2011 1383 1386 21466532 45 Wolf P. Hofer A. Weger W. Posch-Fabian T. Gruber-Wackernagel A. Legat F.J. 311 nm ultraviolet B-accelerated response of psoriatic lesions in adalimumab-treated patients Photodermatol Photoimmunol Photomed 27 2011 186 189 21729166 46 Wolf P. Weger W. Legat F.J. Treatment with 311-nm ultraviolet B enhanced response of psoriatic lesions in ustekinumab-treated patients: a randomized intraindividual trial Br J Dermatol 166 2012 147 153 21910714 47 Jacob J. Pona A. Cline A. Feldman S. Home UV phototherapy Dermatol Clin 38 2020 109 126 31753183
PMC007xxxxxx/PMC7195037.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)30714-3 10.1016/j.jaad.2020.04.098 JAAD Online Reply: Potential role of Janus kinase inhibitors in COVID-19 Napolitano Maddalena MD a∗ Fabbrocini Gabriella MD b Patruno Cataldo MD, PhD c a Department of Health Sciences Vincenzo Tiberio, University of Molise, Campobasso, Italy b Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy c Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy ∗ Correspondence to: Dr Maddalena Napolitano, Via Pansini 5, Naples 80131, Italy 24 4 2020 7 2020 24 4 2020 83 1 e65e65 © 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 letter of Peterson et al1 about the use of Janus kinase (JAK) inhibitors in the time of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The authors reported that discontinuation of JAK inhibitors in the setting of the initial infection, such as with SARS-CoV-2, may be beneficial given the role of JAK-signal transducer and activator of transcription (STAT)–dependent type I (α/β) and type II (γ) interferons in antiviral immunity. However, data in the literature regarding the possible use of JAK inhibitors in COVID 19 patients is growing. Recently, Richardson et al2 proposed baricitinib as potential treatment for pneumonia during COVID-19, because it would be able to reduce the ability of the virus to infect lung cells.2 The lung is particularly prone to SARS-CoV-2 infection probably because of the presence of the alveolar type II cell. This cell expresses on its surface the protein angiotensin-converting enzyme 2, a receptor used by the virus to invade the host.2 One of the known regulators of endocytosis is the AP2-associated protein kinase 1 (AAK1).2 Disruption of AAK1 might, in turn, interrupt the passage of the virus into cells and also the intracellular assembly of virus particles.3 Baricitinib on therapeutic dosing is reported to be able to inhibit AAK1 functions and to bind the cyclin G-associated kinase, another regulator of endocytosis of virus.3 In both phase II and phase III trials on atopic dermatitis, baricitinib had a good safety profile. Headache, nasopharyngitis, and an increase in creatine phosphokinase levels were the most common adverse events.4 The increased incidence of infective diseases, such as reactivation of varicella zoster, herpes simplex, and Epstein-Barr virus strains, reported in trials for rheumatoid arthritis was not observed in patients with atopic dermatitis.4 Upadacitinib is a selective JAK1 inhibitor and is currently being investigated for atopic dermatitis treatment.5 Preclinical research showed that disruption of JAK1 signaling induced by upatacitinib reduced not only the expression of T-helper 2 and 22 cytokines but also the levels of interleukin (IL) 6, through inhibition phosphorylation of STAT3.6 IL-6 also plays a central role in the “cytokine storm” damaging lung in COVID-19 patients.1 Recently, tocilizumab, a monoclonal antibody that competitively inhibits the binding of IL-6 to its receptor, has been used to treat complications of COVID-19–induced pneumonia. In addition, China's National Health Commission and the Italian Medicines Agency approved the tocilizumab use in patients with severe infection with extensive lung disease and with elevated IL-6 levels detected by the laboratory. All of these preclinical data seem to suggest that treatment with both baricitinib and upatacitinib should not be stopped during the COVID-19 pandemic. Obviously, a careful assessment is mandatory for each individual patient reporting any adverse effect. Funding sources: None. Conflicts of interest: Dr Napolitano has acted as a speaker for Sanofi. Dr Fabbrocini has acted as a speaker and consultant for AbbVie and LEO Pharma. Dr Patruno has acted as a speaker and consultant for AbbVie, Novartis, Pfizer, and Sanofi. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Peterson D. Damsky W. King B. The use of Janus kinase inhibitors in the time of SARS-CoV-2 J Am Acad Dermatol 82 6 2020 e223 e226 32278797 2 Richardson P. Griffin I. Tucker C. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease Lancet 395 10223 2020 e30 e31 32032529 3 Pu S.Y. Xiao F. Schor S. Feasibility and biological rationale of repurposing sunitinib and erlotinib for dengue treatment Antiviral Res 155 2018 67 75 29753658 4 Napolitano M. Fabbrocini G. Cinelli E. Stingeni L. Patruno C. Profile of baricitinib and its potential in the treatment of moderate to severe atopic dermatitis: a short review on the emerging clinical evidence J Asthma Allergy 13 2020 89 94 32099414 5 Guttman-Yassky E. Thaçi D. Pangan A.L. Upadacitinib in adults with moderate to severe atopic dermatitis: 16-week results from a randomized, placebo-controlled trial J Allergy Clin Immunol 145 3 2020 877 884 31786154 6 Parmentier J.M. Voss J. Graff C. In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494) BMC Rheumatol 2 2018 23 30886973
PMC007xxxxxx/PMC7195051.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)30709-X 10.1016/j.jaad.2020.04.093 JAAD Online Characterization of acute acral skin lesions in nonhospitalized 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, Irycis, Madrid, Spain ∗ Reprint requests: Diego Fernandez-Nieto, MD, Dermatology Department, Ramon y Cajal University Hospital, Carretera Colmenar Viejo km 9.100, 28034 Madrid, Spain 24 4 2020 7 2020 24 4 2020 83 1 e61e63 © 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) has been associated with several skin manifestations, including widespread urticaria, erythematous rash, and varicella-like exanthem.1 , 2 Ischemic and ecchymotic acral lesions have also been described in patients with severe forms of COVID-19 as a manifestation of clotting disorders.3 Coincident with the COVID-19 pandemic, similar acral lesions have being described in healthy young patients.4 However, the clinical implication and relation to COVID-19 remains unclear. We designed a retrospective study of general consultations from March 5 to April 15, 2020, in Spain. Inclusion criteria were the presence of skin lesions as the reason for the consultation, collection of clinical photographs, and informed consent. Exclusion criteria included nonacral skin lesions and lack of clinical data. From 346 initial patients, 132 fulfilled selected criteria. Patients' data are summarized in Table I . Mean age was 19.9 years (range, 1-56 years). Of the 132 patients, 54 (40.9%) had close contact with a patient with confirmed COVID-19, 28 (21.2%) had close contact with a health worker, and 19 (14.4%) were clinically diagnosed with COVID-19. None of the patients had COVID-19 pneumonia or specific medication. COVID-19 symptoms began in 16 patients before the skin lesions, with a mean latency time of 9.2 days (range, 3-30 days), and skin lesions in 3 patients started at the same time. Mean duration of the skin lesions was 8.7 days (range, 2-24 days).Table I Clinical characteristics of patients with acroischemic lesions Characteristic∗ Clinical pattern of acral lesions Total (N = 132) P value† Chilblain-like (n = 95 [72.0]) Erythema multiforme-like (n = 37 [28.0]) Age, y 23.4 (2-56) 12.2 (1-29) 19.9 (1-56) <.001 Sex .415 Male 49 (51.6) 22 (59.4) 71 (53.8) Female 46 (48.4) 15 (40.6) 61 (46.2) COVID-19 symptoms 19 (25.0) 6 (16.2) 18 (13.6) .618 Location of skin lesions Hands 33 (34.7) 8 (21.6) 41 (31.1) .144 Feet 73 (76.8) 35 (94.6) 108 (81.8) .018 Distribution of skin lesions Digital 87 (91.6) 33 (89.2) 120 (90.9) .738‡ Dorsal 23 (24.2) 12 (32.4) 35 (26.5) .336 Ventral 3 (3.2) 15 (40.6) 18 (13.6) <.001 Heels/wrists 12 (12.6) 10 (27.0) 22 (16.7) .046 Other 0 2 (5.4) 2 (1.5) .077‡ Duration of skin lesions, d 9.2 (3-24) 7.4 (2-15) 8.7 (2-24) .019 ∗ Data are presented as the mean (range) or number (%). † To compare a qualitative variable with a quantitative one, the Student t parametric test was used after assenting normality. To compare two qualitative variables, the χ2 test or Fisher exact test were used. ‡ Fischer's exact test was used. In 11 patients, a real-time reverse-transcription polymerase chain reaction test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was performed from a nasopharyngeal swab, after the onset of skin lesions. The test result was positive in 2 patients (18.1%). Serologic assays were not performed. After the clinical images were evaluated, we could describe 2 different patterns of acute acral lesions, which can overlap (Table I). The chilblain-like pattern, which was present in 95 patients (72.0%), is characterized by red-to-violet macules, plaques, and nodules, usually at the distal aspects of toes and fingers (Fig 1, A-C). The erythema multiforme-like pattern was present in 37 patients (28.0%) and is characterized by rounded erythematous macules and vesicles that tend to coalesce. Compared with classical erythema multiforme, individual lesions are smaller (<1 cm diameter). It does not usually present typical targetoid lesions and tends to be less widespread (Fig 2 , A-C). Only 2 of 37 patients (5.4%) also presented lesions at other sites of the body, including elbows, knees, and ears.Fig 1 Chilblain-like acral lesions. A, Ecchymotic plaques and nodules with a bruising appearance over the distal aspects of toes. B, Confluent erythematous-violaceous diffuse plaques sparing some toes and the dorsal feet. C, Close-up view of the lateral and plantar aspects of toes. Fig 2 Erythema multiforme-like acral lesions. A, Erosion and crust formation over dusky plaques in the dorsal aspects of digits. A Koebner phenomenon is present over the hallux valgus. B, Circular lesions, some of them with a targetoid appearance, over the plantar surface. C, Confluent vesicles over a dusky area. Blood coagulation is altered in COVID-19 patients. Elevated levels of D-dimer and prothrombin time are associated with a poor prognosis.5 True ischemic acral lesions have been described in severely ill patients with COVID-19, manifesting a disseminated intravascular coagulation. There is an increasing concern about the clinical implications of acute acral lesions in asymptomatic or mildly symptomatic patients. The patients in this study did not develop COVID-19 pneumonia or any other complication. The latency time between COVID-19 symptoms and skin manifestations and the low positive rate for nasopharyngeal swabs suggest that it represents a late manifestation of SARS-CoV-2 infection. Whether the lesions represent a coagulation disorder or a hypersensitivity reaction is yet to be known. The authors would like to thank all the health workers that have been relentlessly fighting against COVID-19 in Spain. Special thanks for their help in data collection to Dr Leticia Alonso-Castro, Adrian Alegre-Sanchez, Adrian Diago-Irache, Cristina Garcia-Millan, Bibiana Perez-Garcia, Montserrat Fernandez-Guarino, Elena de las Heras-Alonso, Sandra Chamorro-Tojeiro, Johannes Haemmerle, Carlos Alberto Yépez-Tovar, Paula Alonso-Barreiros, Asuncion Ballester, Jose Jesus Larreina, Cristina Pindado-Ortega, Gonzalo Segurado-Miravalles, and Pablo Miguel Fonda-Pascual. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: The Institutional Review Board approved this study. ==== Refs References 1 Recalcati S. Cutaneous manifestations in COVID-19: a first perspective J Eur Acad Dermatol Venereol 2020 10.1111/jdv.16387 2 Marzano A.V. Genovese G. Fabbrocini G. Varicella-like exanthem as a specific COVID-19-associated skin manifestation: multicenter case series of 22 patients J Am Acad Dermatol 83 1 2020 280 285 32305439 3 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 2020 E006 [in Chinese] 32220276 4 Mazzotta F. Trocoli T. Acute acro-ischemia in the child at the time of COVID-19 Eur J Pediatr Dermatol 2020 [Online ahead of print] 5 Xiong M. Liang X. Wei Y.-D. Changes in blood coagulation in patients with severe coronavirus disease 2019 (COVID-19): a meta-analysis Br J Haematol 2020 10.1111/bjh.16725
PMC007xxxxxx/PMC7195318.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)30719-2 10.1016/j.jaad.2020.04.103 JAAD Online What matters most: Why the COVID-19 pandemic should prompt us to revisit the dermatology resident selection process Karasik Daniel BA a O'Connor Daniel M. MD ab Nathan Neera R. MD, MSHS ab∗ a Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts b Harvard Combined Dermatology Residency Training Program, Harvard Medical School, Boston, Massachusetts ∗ Correspondence to: Neera R. Nathan, MD, MSHS, Department of Dermatology, Massachusetts General Hospital, 55 Fruit St, BH616, Boston, MA 02114 26 4 2020 7 2020 26 4 2020 83 1 e55e55 © 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 the analysis by Stoj and Grant-Kels1 regarding the ethical obligation of dermatology trainees to provide essential patient care. Expanding on this concept, we propose that the COVID-19 pandemic should serve as a call to action for our specialty to revisit the dermatology resident selection process, with the goal of emphasizing ideals highlighted as being fundamentally important in this time of global crisis. The upcoming shift of the United States Medical Licensing Examination Step 1 score reporting to pass/fail will leave a vacuum that may be filled by relevant selection criteria to meet the current and future needs of our specialty and medicine. The COVID-19 pandemic has placed unprecedented demands on the dermatology community, including having to adapt to rapidly changing paradigms of patient care and personal safety. Dermatologists have been presented with difficult ethical and professional dilemmas, including halting most clinical operations to conserve personal protective equipment and support social distancing, and in some cases, practicing medicine well beyond the purview of skin disease. Despite these challenges, members of our field have chosen to prioritize the lives of others over their own personal health or revenue. Similar demands have trickled down to trainees, who have been presented with unplanned changes to clinical duties, unconventional methods to fulfill educational requirements remotely, and uncertainty for the foreseeable future. The COVID-19 pandemic has underscored the importance of qualities such as self-sacrifice, resilience, teamwork, and adaptability in all clinicians, which should be appropriately mirrored in the dermatology resident selection process in addition to traditional measures of excellence.2 The residency applicant screening and selection processes should stress each applicant's personal and professional journey (“distance traveled”).3 Special attention should be given to applicants who have demonstrated sustained volunteerism, a commitment to address health care disparities, ability to overcome difficult personal circumstances, Gold Humanism Honor Society membership, or prior military service. Several of these attributes have been proposed by prior authors as a means to increase diversity in dermatology, another critical need in the specialty.3, 4, 5 This type of information may be extracted from already available components of the residency application, including the personal statement, letters of recommendation, curriculum vitae, the Medical Student Performance Evaluation, and the interview. Moreover, experience garnered from using virtual communication platforms during COVID-19 may be used to establish virtual interviews of prospective candidates, which may help to reduce financial barriers to applying to dermatology3, 4, 5 for applicants who are otherwise qualified. Assessment of a broader range of personal and professional accomplishments may identify prospective residents who exhibit selflessness or grit and will enhance the robustness and diversity of our workforce and our potential to contribute to the house of medicine. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Stoj V.J. Grant-Kels J.M. Dermatology residents and the care of COVID-19 patients J Am Acad Dermatol 82 6 2020 1572 1573 32259536 2 National Resident Matching Program (NRMP) Results of the 2018 NRMP Program Director Survey. June 2018 Available at: https://www.nrmp.org/wp-content/uploads/2018/07/NRMP-2018-Program-Director-Survey-for-WWW.pdf 3 Pritchett E.N. Pandya A.G. Ferguson N.N. Hu S. Ortega-Loayza A.G. Lim H.W. Diversity in dermatology: roadmap for improvement J Am Acad Dermatol 79 2018 337 341 29653209 4 Pandya A.G. Alexis A.F. Berger T.G. Wintroub B.U. Increasing racial and ethnic diversity in dermatology: a call to action J Am Acad Dermatol 74 2016 584 587 26774427 5 Chen A. Shinkai K. Rethinking how we select dermatology applicants–turning the tide JAMA Dermatol 153 2017 259 260 28030657
PMC007xxxxxx/PMC7195352.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)30532-6 10.1016/j.jaad.2020.04.001 JAAD Online Surgical Pearl Wearing the N95 mask with a plastic handle reduces pressure injury Jiang Wanting BSN Cao Wenwen MSN Liu Qian BSN ∗ Department of Plastic Surgery, Hospital of Skin Diseases and Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, Jiangsu, China ∗ Correspondence to: Qian Liu, BSN, Department of Plastic Surgery, Hospital of Skin Diseases and Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing 210042, Jiangsu, China. 10 4 2020 6 2020 10 4 2020 82 6 e191e192 © 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 N95 mask plastic handle pressure injury ==== Body pmcSurgical challenge An outbreak of the 2019 novel coronavirus diseases (COVID-19) in Wuhan, China, has spread quickly worldwide and was recently declared a pandemic by the World Health Organization. Among the infection prevention measures for health care workers, wearing a medical N95 face mask properly is important. However, using an ear loop-style N95 face mask for a long time can cause pressure injury on the skin of the ear (Fig 1 , A) that may cause people to adjust the mask constantly, putting them at higher risk of infection.Fig 1 (A) Pressure injury on skin of the auricle. (B) A sample of a plastic handle. (C) The handle with bilateral ear bands fixed on the occipital bone. (D) Side view of the mask held in place with the plastic handle. The solution A plastic handle (Fig 1, B) can be used in conjunction with the ear loop-style N95 mask to solve this problem. First wear the mask according to its instruction. And then hook elastic bands of the mask to each side of the handle from behind, respectively. Next, fix the plastic handle in the middle of the occipital bone (Fig 1, C) and adjust both sides of the ear band to avoid pressing the skin. In our experience, it does not compromise the fit of the mask. This method has 2 advantages. First it is simple and easy to operate, making the mask comfortable to wear (Fig 1, D), avoiding uncomfortable and injury, and moreover, making the mask space more airtight. Second, the plastic handle is relatively easy to obtain and can be reused after being disinfected by 75% alcohol or chlorine-containing disinfectant. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Exempt. Reprints not available from the authors.
PMC007xxxxxx/PMC7198135.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)30778-7 10.1016/j.jaad.2020.04.156 JAAD Online Reply to “Varicella-like exanthem as a specific COVID-19–associated skin manifestation: multicenter case series of 22 patients”: Discussing specificity Ortega-Quijano Daniel MD ∗ Jimenez-Cauhe Juan MD Burgos-Blasco Patricia MD Jimenez-Gomez Natalia MD Fernandez-Nieto Diego MD Servicio de Dermatología, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain ∗ Correspondence to: Daniel Ortega-Quijano, MD, Dermatology Department, Ramon y Cajal University Hospital, Carretera Colmenar Viejo km 9.100, 28034 Madrid, Spain 4 5 2020 7 2020 4 5 2020 83 1 e87e87 © 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 article by Marzano et al1 addressing the specificity of varicella-like exanthem to diagnose coronavirus disease (COVID-19). Although this type of COVID-19–associated rash is rare, the authors claim that it is more specific than others without having performed a diagnostic accuracy study.2 This type of study would calculate the association of COVID-19 status (yes/no) with the type of exanthem (varicella-like/non–varicella-like) in a predetermined number of patients (to ensure sufficient statistical power) and in a defined population with a known prevalence of COVID-19 disease. Starting from the assumption that the data are not sufficient to draw such a robust conclusion, we would like to contribute our vision of such an important issue. Firstly, for clinicians, specificity is of little value. The positive predictive value, that is, the probability that a person with a varicella-like rash has COVID-19, is much more relevant, because a high value would justify severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing. The positive predictive value is affected by the prevalence of the disease. Consequently, as we are going through the peak of the COVID-19 pandemic, it is evident by applying the Bayes theorem that the conditional probability of COVID-19 given a varicella-like rash is enormous. However, this probability is as high given a dengue-like, erythematous, or urticarial rash. Therefore, the positive predictive value for COVID-19 of skin rashes, regardless of which, is high. For us, the main contribution of the study by Marzano et al1 is that with all exanthems currently having a high positive predictive value for COVID-19, that of varicella-like rash is probably the highest because vesicular rash is more specific for viral disease than others.3 In addition, at the current stage of the pandemic, COVID-19 is more frequent in adults, where varicella is not. This gives varicella-like rash additional COVID-19 positive predictive value compared with the rest of the rashes. The main factor that at this moment reduces the positive predictive value of rashes for COVID-19 is adverse drug reactions. Unfortunately, this topic is being less discussed in the literature. To conclude, because things will change fast as the pandemic progresses, as the adult population becomes infected, the age at diagnosis of COVID-19 is expected to decrease.4 At that time, this rash will be an important differential diagnosis of varicella itself. In this context, the Tzanck test and varicella-zoster polymerase chain reaction should be subjected to new diagnostic accuracy studies. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Marzano A.V. Genovese G. Fabbrocini G. Varicella-like exanthem as a specific COVID-19-associated skin manifestation: multicenter case series of 22 patients J Am Acad Dermatol 83 1 2020 280 285 32305439 2 Recalcati S. Cutaneous manifestations in COVID-19: a first perspective [e-pub ahead of print] J Eur Acad Dermatol Venereol 2020 10.1111/jdv.16387 3 Drago F. Paolino S. Rebora A. The challenge of diagnosing atypical exanthems: a clinico-laboratory study J Am Acad Dermatol 67 6 2012 1282 1288 22627037 4 Keeling M.J. Rohani P. Modeling Infectious Diseases in Humans and Animals 1st ed. 2007 Princeton University Press Princeton, NJ
PMC007xxxxxx/PMC7198162.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)30789-1 10.1016/j.jaad.2020.04.161 Research Letter Chilblains is a common cutaneous finding during the COVID-19 pandemic: A retrospective nationwide study from France de Masson Adèle MD, PhD ab Bouaziz Jean-David MD, PhD ab Sulimovic Luc MD ac Cassius Charles MD ab Jachiet Marie MD a Ionescu Marius-Anton MD, PhD a Rybojad Michel MD a Bagot Martine MD, PhD ab∗ Duong Tu-Anh MD, PhD d on behalf of the SNDV (French National Union of Dermatologists-Venereologists)Denjean Dominique Labarthe Marie-Pierre Bézier Maud Risbourg Marie Payan Geneviève Alain Sabrina Mathivon Frédéric Cohen-Letessier Anny Kerob Delphine Hellier Jean-Philippe Comte Christelle Keller Fabielle Brue Caroline Lestang Paul Allanore Laurence Pierkarski-Carp Eliane Amoric Anne Serpier Hervé Pruvost Philippe Guibal Fabien Giacchero Damien Funck-Brentano Elisa Fortuny Sandrine Sierra Gallay Isabelle Zavarro Agnès Bider-Valle Caroline Lagrange Sylvie Grynberg Etty Weill Florence Penso Dominique Gomel Marie Schneider Jean Larabelle Anne Bonhomme Philippe Gautier Marie-Sophie Hatchuel Jean Mourtada Imane Fite Charlotte Oliveres-Ghouti Catherine Domergue Elisabeth Fourcade-Roch Sabrina Lecanu Sylvie Sebban Nathalie Halioua Bruno Bellut Anne Keller Fabienne Baratte Isabelle Lejoyeux Françoise Ollivaud Laurence Abirached Georges Burnouf Marielle Reynayd-Mendel Beatrix Dauendorffer Jean-Noël Sebaoun Joëlle Larabelle Anne Garrat Hervé Pomper Marie-Martine Heudes Anne-Marie Beaulieu Isabelle Cartier Hugues Arsouze Amélie Lons-Danic Dominique Pelletier Michèle Payan Geneviève Gallais Valérie Piantade Valérie Risbourg Marlène Reuter Georges Dahan Serge Creusot Murielle Kolli Abdallah Egasse-Broca Isabelle Rigon Jean-Luc Sabban Pascale Flacher Hélène Jaillard Benoît André Pierre Debjoux Dominique Poirier Elodie Solyga Bénédicte Perrussel Marc Makhloufi Sabrina Margnier Bertrand Huzar Clotilde Vandame Laetitia Thelu Hortense Chollet Anne-Claire Marchal Frédérique Naouri Michael Nadaud Marion Boissy Elodie Lameche Abdelhamid Berdougo Charles Rolland Audrey Fléchet Marie-Laure Colonna Gabriel Jouannet Delphine Berdah Isabelle Truchot Françoise Lavallée Isabelle a Department of Dermatology, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris b Human Immunology, Pathophysiology and Immunotherapy, Institut National de la Santé et de la Recherche Médicale U976, Université de Paris, Paris c French National Union of Dermatologists-Venereologists (SNDV) d Department of Dermatology, Mondor Hospital, Assistance Publique-Hôpitaux de Paris, Chaire Avenir Santé numérique, Equipe 8 Institut Mondor de Recherche Biomédicale, Human Immunology, Pathophysiology and Immunotherapy, Université Paris Est Créteil, Créteil, France ∗ Correspondence to: Martine Bagot, MD, PhD, Department of Dermatology, Research Unit INSERM U976, Saint-Louis Hospital, Université de Paris, 1 avenue Claude Vellefaux, 75010 Paris, France 4 5 2020 8 2020 4 5 2020 83 2 667670 © 2020 by the American Academy of Dermatology, Inc. Published by Elsevier 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 19 (COVID-19), a pneumonia associated with severe acute respiratory syndrome coronavirus 2 (SARS-Cov2), was first identified in Wuhan, China, in December 2019, and was characterized as a pandemic by the World Health Organization on March 11, 2020. Fever, dry cough, dyspnea, fatigue, anorexia, ageusia, and anosmia are common symptoms of COVID-19. Reported skin manifestations of COVID-19 include erythematous lesions, sometimes with dengue-like petechiae,1 and urticaria and chickenpox-like vesicles.2 We performed a retrospective observational nationwide study of skin lesions encountered during the COVID-19 pandemic in France from March 18 to April 9, 2020, in an outpatient setting of French private practices. Patients gave informed consent for the publication of their photographs. The study enrolled 277 patients, half were male, and the median age was 27 years (range, 2-98 years). The lesions were classified into 6 categories: urticarial in 26 (9%; Fig 1 , A), vesicular in 41 (15%; Fig 1, B), acral in 142 (51%; Fig 1, C), morbilliform in 25 (9%; Fig 1, D and E), petechial in 7 (3%), livedo reticularis in 4 (1%), and other types in 41 (15%). Some patients presented with cutaneous signs fitting in multiple categories (detailed in Table I ). Acral lesions were unexpectedly common (n = 142). Chilblain-like lesions were the most frequent of the acral lesions (106 of 142 [75%]; Fig 1, C; Supplemental Fig 1, available via Mendeley at https://doi.org/10.17632/2f9rpvh9vd.1). Vesicular acral (dyshidrosis-like) lesions were reported in 20 patients (14%). Acrodynia was present in 18 patients (6%), sometimes isolated.Fig 1 Different types of skin rashes observed during the COVID-19 pandemic: (A) urticaria-like; (B) vesicular or chickenpox-like; (C) chilblains; (D) maculopapular; and (E) pityriasis rosea-like. Table I Characteristics of the patients Characteristic∗ No. (%) or median (range) All patients 277 Male sex 129/259 (50) Age, y 27 (2-98) SARS-Cov2 PCR test 34/277 (12) Positive PCR test 25/34 (74) Contact with a patient with COVID-19 31/277 (11) Suggestive extracutaneous symptoms† 103/277 (37) Fever 48/277 (17) Respiratory symptoms 44/277 (16) Anosmia/ageusia 18/277 (6) Digestive symptoms 16/277 (6) Acrodynia 18/277 (6) Morbilliform lesions 25/277 (9) Male sex 10/21 (48) Age, y 29 (2-70) Location of lesions Trunk or limbs 25/25 (100) Face 2/25 (8) Acral lesions 142/277 (51) Male sex 67/132 (51) Age, y 27 (6-73) Type of lesions Chilblains 106 (75) Dyshidrosis-like lesions 20 (14) Other 16 (11) Location of lesions Hands 23/34 (68) Feet 18/34 (53) Vesicular lesion 41 (15) Male sex 22/38 (58) Age, y 43 (8-74) Type and location of lesions Vesicles/varicella-like lesions of the trunk and limbs 21 (51) Acral dyshidrosis-like lesions 20 (49) Livedo reticularis 4 (1) Male sex 1/2 (50) Age, y 15 Urticarial lesions 26 (9) Male sex 13/23 (57) Median age (range) 3 (2-23) Location of lesions Trunk and limbs 24 (92) Face 2 (8) Petechial lesions 7 (3) Male sex 5/7 (71) Age, y 21 (5-70) Location of lesions Diffuse 3/7 (43) Acral 2/7 (29) Limbs 2/7 (29) Other types of lesions‡ 41 (15) Male sex 11/36 (31) Median age (range) 40 (1-98) Location of lesions, n (%) Trunk and limbs 33/41 (80) Face 8/41 (20) PCR, Polymerase chain reaction; SARS-Cov2, severe acute respiratory syndrome coronavirus 2. ∗ Some patients presented with cutaneous signs fitting in multiple categories. † There were 19 patients who reported suggestive extracutaneous symptoms and contact with a patient with COVID-19. ‡ Including eczema-like, angiomatous, and annular lesions. Among the 277 patients, 34 had a SARS-Cov2 polymerase chain reaction (PCR) test, of which 25 (74%) were positive, and 7 of these 25 (28%) had acral lesions. Among the patients without a positive PCR test, 115 patients had suggestive extracutaneous symptoms (detailed in Table I) or reported a close contact with a patient with COVID-19, or both. In addition, 59 patients had isolated chilblains (without any past history of chilblains and in the absence of cold exposure), without associated extracutaneous symptoms; this may suggest cutaneous symptoms of COVID-19, because this finding has been documented in some patients with a positive SARS-Cov2 PCR test in our case series and in 2 recently published case reports.3 , 4 Histologic examination of 3 chilblain-like lesions showed a lichenoid dermatitis with a perivascular and eccrine mononuclear infiltrate and vascular microthrombi in 2 cases. Owing to the retrospective, outpatient setting and the limited number of available SARS-Cov2 PCR tests in France to date, most patients were not tested. However, the number of observed chilblain-like lesions in patients without significant past medical history is extremely unusual during the spring season in France, especially because people are staying inside, and may suggest a link with COVID-19. Finally, the presence of microthrombi in patients with chilblains is consistent with the altered coagulation status observed in patients with severe COVID-19.5 Although the number of tested patients does not allow us to draw firm conclusions regarding a direct link between SARS-Cov2 and these skin lesions, the unexpected outbreak of acral skin lesions in this epidemic context requires further investigation. The authors thank all of the dermatologists of the French National Union of Dermatologists-Venereologists (SNDV), general practitioners, and pediatricians, who provided data and pictures, and the patients involved in this study. Drs Bagot and Duong share last authorship. Collaborators: Dominique Denjean, Marie-Pierre Labarthe, Maud Bézier, Marie Risbourg, Geneviève Payan, Sabrina Alain, Frédéric Mathivon, Anny Cohen-Letessier, Delphine Kerob, Jean-Philippe Hellier, Christelle Comte, Fabielle Keller, Caroline Brue, Paul Lestang, Laurence Allanore, Eliane Pierkarski-Carp, Anne Amoric, Hervé Serpier, Philippe Pruvost, Fabien Guibal, Damien Giacchero, Elisa Funck-Brentano, Sandrine Sierra Fortuny, Isabelle Gallay, Agnès Zavarro, Caroline Bider-Valle, Sylvie Lagrange, Etty Grynberg, Florence Weill, Dominique Penso, Marie Gomel, Jean Schneider, Anne Larabelle, Philippe Bonhomme, Marie-Sophie Gautier, Jean Hatchuel, Imane Mourtada, Charlotte Fite, Catherine Oliveres-Ghouti, Elisabeth Domergue, Sabrina Fourcade-Roch, Sylvie Lecanu, Nathalie Sebban, Bruno Halioua, Anne Bellut, Fabienne Keller, Isabelle Baratte, Françoise Lejoyeux, Laurence Ollivaud, Georges Abirached, Marielle Burnouf, Beatrix Reynayd-Mendel, Jean-Noël Dauendorffer, Joëlle Sebaoun, Anne Larabelle, Hervé Garrat, Marie-Martine Pomper, Anne-Marie Heudes, Isabelle Beaulieu, Hugues Cartier, Amélie Arsouze, Dominique Lons-Danic, Michèle Pelletier, Geneviève Payan, Valérie Gallais, Valérie Piantade, Marlène Risbourg, Georges Reuter, Serge Dahan, Murielle Creusot, Abdallah Kolli, Isabelle Egasse-Broca, Jean-Luc Rigon, Pascale Sabban, Hélène Flacher, Benoît Jaillard, Pierre André, Dominique Debjoux, Elodie Poirier, Bénédicte Solyga, Marc Perrussel, Sabrina Makhloufi, Bertrand Margnier, Clotilde Huzar, Laetitia Vandame, Hortense Thelu, Anne-Claire Chollet, Frédérique Marchal, Michael Naouri, Marion Nadaud, Elodie Boissy, Abdelhamid Lameche, Charles Berdougo, Olivo, Rosado, Berdougo, Hamelin, Audrey Rolland, Marie-Laure Fléchet, Gabriel Colonna, Boglio, Rafii, Lefevre, Delphine Jouannet, Isabelle Berdah, Trouche, Santos, Françoise Truchot, and Isabelle Lavallée. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Approved. Reprints not available from the authors. ==== Refs References 1 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 2 Recalcati S. Cutaneous manifestations in COVID-19: a first perspective J Eur Acad Dermatol Venereol 2020 10.1111/jdv.16387 [e-pub ahead of print] 3 Alramthan A. Aldaraji W. A case of COVID-19 presenting in clinical picture resembling chilblains disease. First report from the Middle East Clin Exp Dermatol 2020 10.1111/ced.14243 [e-pub ahead of print] 4 Kolivras A. Dehavay F. Delplace D. Coronavirus (COVID-19) infection-induced chilblains: a case report with histopathological findings JAAD Case Rep 2020 10.1016/j.jdcr.2020.04.011 [e-pub ahead of print] 5 Tang N. Bai H. Chen X. Gong J. Li D. Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy J Thromb Haemost 18 5 2020 1094 1099 32220112
PMC007xxxxxx/PMC7198184.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)30777-5 10.1016/j.jaad.2020.04.155 JAAD Online Invited commentary on the letter “The COVID-19 crisis: A unique opportunity to expand dermatology to underserved populations” Kovarik Carrie MD a∗ Lee Ivy MD b Tejasvi Trilokraj MD c Lipoff Jules B. MD a a Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania b Pasadena Premier Dermatology, Pasadena, California c Department of Dermatology, University of Michigan, Ann Arbor, Michigan ∗ Correspondence to: Carrie L. Kovarik, MD, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce St, 2 Maloney Bldg, Philadelphia, PA 19104 4 5 2020 7 2020 4 5 2020 83 1 e85e86 © 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 authors Ashrafzadeh and Nambudiri1 for their response to our article, “Telehealth: Helping your patients and practice survive and thrive during the COVID-19 crisis.” Their letter emphasized opportunities and challenges associated with using teledermatology to expand access to underserved populations. Recent collapse of community hospitals and local clinics has left millions of Americans at risk of losing health care access.2 Access is particularly limited for patients with skin disease who have Medicaid or other public insurance, because many dermatologists are not accepting these patients.3 In addition, some states with substantial Medicaid expansion programs, such as New Mexico, were recently reporting member care organizations below access standards in dermatology for both rural and urban areas.4 Virtual care has been identified as a strategy to ensure access to essential health care services in vulnerable communities.2 Among states with a large Medicaid population and store-and-forward reimbursement before COVID-19 (eg, California), teledermatology has been shown to improve access to dermatology care among Medicaid enrollees.3 In many states with limited teledermatology reimbursement, volunteer programs have attempted to bridge the gap in care. For example, AccessDerm began in 2010 as an American Academy of Dermatology Presidential Initiative and has provided free teledermatology care to >2400 underserved patients throughout the United States. These programs∗ allow for partnerships to be created between local clinics and dermatologists who understand the cultural needs of the patient population, community resources, and insurance (or lack of) restrictions that may make necessary in-person referrals challenging.5 Although the recent 1135 Waiver lifted many restrictions on telemedicine, at-risk populations still face obstacles. Medicaid patients may seek primary care via telemedicine in some cases, but subspecialist referrals, such as dermatology, remain difficult. Many dermatologists may neither take Medicaid nor accept new patients through telemedicine. Many vulnerable patients have severe acute and chronic dermatologic diseases, and Medicaid and residence in low-income communities have been associated with skin disease-related readmissions.6 Teledermatology has improved access to dermatology services for many vulnerable populations; yet, building sustainable, long-term programs is difficult given the lack of widespread reimbursement. We hope that new temporary changes will bring significant attention to the importance of establishing telemedicine as a cornerstone of excellent medical care for all patients. Practice may finally catch up to what research has proven: teledermatology improves access to care. What will telemedicine look like post-COVID-19? A quote attributed to Mahatma Gandhi says, “The true measure of any society can be found in how it treats its most vulnerable members.” Likewise, whatever shape telemedicine takes in the future, we must leverage its power to expand access to care to help those who need it most. Indeed, teledermatology is more than technology and infrastructure—it is workflow, collaboration, and partnership. We hope that lessons learned, partnerships built, workflows implemented, and new reimbursement models created during COVID-19 will align all stakeholders in caring for the underserved. Teledermatology must be created based on relationships with other local providers to provide patients with the most relevant, culturally competent, and community-based care. Funding sources: None. Conflicts of interest: Dr Lipoff is the current chair, Dr Tejasvi is vice chair, and Drs Lee and Kovarik are past chairs/advisors of the American Academy of Dermatology Teledermatology. IRB approval status: Not applicable. Reprints not available from the authors. ∗ Before COVID-19, programs such as AccessDerm and AZOVA Volunteer Peer to Peer Network allowed for free use to volunteer programs. During COVID-19, many vendors have an option available for no fees: https://www.aad.org/member/practice/telederm/vendors. ==== Refs References 1 Ashrafzadeh S. Nambudiri V.E. The COVID-19 crisis: a unique opportunity to expand dermatology to underserved populations J Am Acad Dermatol 83 1 2020 e83 e84 32380217 2 Bhatt J. Bathija P. Ensuring access to quality health care in vulnerable communities Acad Med 93 9 2018 1271 1275 29697433 3 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 4 New Mexico Human Services Department Centennial Care Waiver Demonstration Section 1115 Quarterly Report. Demonstration Year: 5(1/1/2018–12/31/2018) Waiver Quarter: 1/2018. June 11, 2018 Available at: https://www.medicaid.gov/Medicaid-CHIP-Program-Information/By-Topics/Waivers/1115/downloads/nm/Centennial-Care/nm-centennial-care-qtrly-rpt-jan-mar-2018.pdf 5 Chansky P.B. Simpson C.L. Lipoff J.B. Implementation of a dermatology teletriage system to improve access in an underserved clinic: a retrospective study J Am Acad Dermatol 77 5 2017 975 977 29029909 6 Arnold J.D. Crockett R.M. Kirkorian A.Y. Hospital readmissions among patients with skin disease: a retrospective cohort study J Am Acad Dermatol 79 4 2018 696 701 30143368
PMC007xxxxxx/PMC7202818.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)30821-5 10.1016/j.jaad.2020.05.002 Current Issues and Opinion Perspectives on the recommendations for skin cancer management during the COVID-19 pandemic Geskin Larisa J. MD a∗ Trager Megan H. BA a Aasi Sumaira Z. MD b Bickers David R. MD a Carvajal Richard D. MD c Nghiem Paul MD d Taback Bret MD e Zeitouni Nathalie C. MD f Samie Faramarz H. MD, PhD a∗ a Department of Dermatology, Columbia University Irving Medical Center, New York, New York b Department of Dermatology, Stanford Medicine, Stanford, California c Division of Hematology, Department of Medicine, Columbia University Irving Medical Center, New York, New York d Department of Dermatology, University of Washington Medical Center, Seattle, Washington e Department of Surgery, Columbia University Irving Medical Center, New York, New York f Department of Dermatology, University of Arizona College of Medicine, Phoenix, Arizona ∗ Reprint requests: Larisa Geskin and Faramarz Samie, 161 Fort Washington Ave, 12th Floor, New York, NY, 10032. 6 5 2020 7 2020 6 5 2020 83 1 295296 © 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. Abbreviations used cSCC cutaneous squamous cell carcinoma SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 ==== Body pmcThe National Comprehensive Cancer Network and American College of Mohs Surgery have released guidelines for managing cancer during the human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. The detailed National Comprehensive Cancer Network and American College of Mohs Surgery recommendations are available online (https://www.nccn.org/covid-19/default.aspx and https://www.mohscollege.org/), and here we provide our perspective.1 Clinical judgment should be exercised on a case-by-case basis while interpreting the general guidelines. All efforts should be directed toward minimizing unnecessary exposures to patients and staff. Excisional biopsies with narrow margins to completely remove all suspicious lesions, including melanoma, Merkel cell carcinoma, and others, should be attempted to minimize travel and to allow for delays in definitive treatment, if necessary. We divide skin cancers into low-, intermediate-, and high-risk categories to guide treatment decisions. The low-risk category includes basal cell carcinoma, cutaneous squamous cell carcinoma (cSCC) in situ, and cSCC without high-risk factors (≥2 cm in diameter, poorly differentiated histologically, perineural invasion ≥0.1 mm, or invasion beyond subcutaneous fat),2 melanoma in situ, and indolent cutaneous lymphomas. For this category, elective therapies, operations, and radiation may be postponed for at least 3 months. Again, clinical judgment on a case-by-case basis weighing individual risks for the patient, including risks of serious complications and death from COVID-19, should be exercised. For the intermediate-risk category (T1 melanomas with clear margins after biopsy, T1 melanomas without a clear margin, assuming most of the tumor was removed, and T1b melanomas), wide local excisions should be performed, and sentinel lymph node biopsies should be reviewed on a case-by-case basis and may be postponed. Therapy-related travel for the high-risk category (high-risk cSCC, invasive, thick and ulcerated melanoma, Merkel cell carcinoma, tumors with aggressive histology or in sensitive areas) must be weighed against each patient's risks. For rapidly growing cSCC, particularly of the head and neck (eyes, ears, lips, mouth) and symptomatic lesions, more immediate treatment may be considered. Mohs micrographic surgery may be used for high-risk squamous cell carcinoma and rare cancers, including undifferentiated pleomorphic sarcoma and adnexal tumors with concern for rapidly developing metastasis. To minimize surgical team exposure, the least complex reconstruction to preserve function should be considered. Operating room use should be avoided to conserve resources and minimize potential SARS-CoV-2 exposures. For basal cell carcinoma in sites where delay may compromise preservation of function, neoadjuvant therapy with hedgehog inhibitors may be considered until definitive management can be safely achieved. Infusion therapies, including in the adjuvant setting for melanoma, pose serious risks due to necessity of infusion center visits. Immunotherapy conceivably confers additional risk due to deleterious immune activation resulting from SARS-CoV-2. The National Comprehensive Cancer Network resources propose alternative immunotherapy regimens (see complete guidelines for reference). Telemedicine visits should be prioritized, limiting in-person visits for biopsies of highly suspicious lesions and for in-office therapies for the highest-risk cancers. This pandemic presents evolving challenges, and we must continue to provide optimal treatment for our patients while preventing global spread of the disease and preserving resources. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. ==== Refs References 1 Ueda M. Martins R. Hendrie P.C. Managing cancer care during the COVID-19 pandemic: agility and collaboration toward a common goal J Natl Compr Canc Netw 18 4 2020 366 369 2 Baum C.L. Wright A.C. Martinez J.-C. A new evidence-based risk stratification system for cutaneous squamous cell carcinoma into low, intermediate, and high risk groups with implications for management J Am Acad Dermatol 78 2018 141 147 28917382
PMC007xxxxxx/PMC7204667.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)30818-5 10.1016/j.jaad.2020.04.164 JAAD Online Reply to: “A dermatologic manifestation of COVID-19: Transient livedo reticularis” Thomas Cristina MD ab∗ a Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts b Department of Internal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts ∗ Correspondence to: Cristina Thomas, MD, Brigham and Women's Hospital, Department of Dermatology, 221 Longwood Ave, Boston, MA 02115 7 5 2020 8 2020 7 5 2020 83 2 e155e156 © 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: I enthusiastically read the article by Manalo et al, “A dermatologic manifestation of COVID-19: Transient livedo reticularis.”1 The authors should be commended for quickly recognizing and reporting possible cutaneous findings of COVID-19. With any emerging disease, we must integrate a rapidly evolving evidence base into our understanding of the illness. Although Manalo et al1 postulate a potential etiology of livedo reticularis in COVID-19 involving low-grade disseminated intravascular coagulation, recent data suggest other mechanisms for vaso-occlusive findings in nonsevere infection. Disseminated intravascular coagulation is much less common in those with mild COVID-19 infection, affecting only 0.6% of survivors as opposed to 71.4% of nonsurvivors in one study.2 Similarly, most reports of large-vessel thromboses and microemboli in COVID-19 are in those with severe illness. Supporting this observation is a retrospective study demonstrating that thromboprophylaxis has a mortality benefit in only patients severely ill with COVID-19 with a high sepsis-induced coagulopathy score.3 Although studies in mild disease are limited, these combined data suggest that disseminated intravascular coagulation and macrothromboses may be restricted to severe COVID-19 infections. This is not unexpected, given that severe infection is accompanied by features of the Virchow triad, including venous stasis in the setting of immobility, hypercoagulability as a result of cytokine storm, and endothelial cell dysfunction due to sepsis and inflammation. With this in mind, what then accounts for the vaso-occlusive phenomena that preferentially affect cutaneous small vessels in mild cases of COVID-19? Emerging data show several other potential factors may play a role in microthrombi formation in less severe disease. Inflammation commonly predisposes patients to thrombosis. As demonstrated in a retrospective study, patients with severe COVID-19 have high levels of inflammatory cytokines, including interleukin 1β, 8, and 9, interferon-γ, and tumor necrosis factor-α, among others. Although less profoundly elevated than in severe illness, levels remain moderately elevated in nonsevere disease.4 Many of these involved cytokines are thought to promote thrombogenesis, and even mild cytokine elevations in nonsevere disease could theoretically contribute to thrombosis. Another potential reason for microthrombosis in nonsevere COVID-19 infection is due to the mechanism of viral entry into cells. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to bind angiotensin-converting enzyme 2 (ACE2), a transmembrane enzyme, allowing entry into the cell.5 ACE2 binding results in decreased expression of ACE2, activation of the renin-angiotensin system, promotion of platelet aggregation, and thrombus formation. Because endothelial cells also express ACE2, SARS-CoV-2 may additionally cause direct endothelial dysfunction after binding to ACE2, leading to subsequent thrombosis. In the setting of mild disease where profound coagulopathy is unlikely, mild elevations in prothrombotic cytokines and direct endothelial cell damage by SARS-COV-2 may theoretically contribute to the small-vessel occlusive phenomena noted in the skin. Other potential mechanisms include complement activation, antiphospholipid antibody production, and tissue factor expression on endothelial cells. The balance between coagulation cascade activation and fibrinolysis in patients with COVID-19 is complex, and further studies may elucidate this delicate tug-of-war. Until further data are available, the skin appears to represent an innocent bystander in the prothrombotic milieu of SARS-CoV-2 infection. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Manalo I.F. Smith M.K. Cheeley J. A dermatologic manifestation of COVID-19: transient livedo reticularis J Am Acad Dermatol 83 2 2020 700 32283229 2 Tang N. Li D. Wang X. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia J Thromb Haemost 18 4 2020 844 847 32073213 3 Tang N. Bai H. Chen X. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy [e-pub ahead of print]. J Thromb Haemost https://doi.org/10.1111/jth.14817 4 Huang C. Wang Y. Li X. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Lancet 395 10223 2020 497 506 31986264 5 Hoffmann M. Kleine-Weber H. Schroeder S. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor Cell 181 2 2020 271 280.e8 32142651
PMC007xxxxxx/PMC7204694.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)30817-3 10.1016/j.jaad.2020.05.001 JAAD Online Reply to: “Reply: A dermatologic manifestation of COVID-19: Transient livedo reticularis” Manalo Iviensan F. MD a∗ Smith Molly K. MD b Cheeley Justin MD ac Jacobs Randy MD de a Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia b Pariser Dermatology Specialists, Norfolk, Virginia c Depatment of Medicine, Emory University School of Medicine, Atlanta, Georgia d Riverside School of Medicine, University of California, Riverside, California e Internal Medicine Residency Program, Hemet Valley Medical Center, Hemet, California ∗ Correspondence to: Iviensan Manalo, MD, Department of Dermatology, Emory University School of Medicine, 1525 Clifton Rd, Ste 100, Atlanta, GA 30329 7 5 2020 8 2020 7 5 2020 83 2 e157e157 © 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 appreciate the additional information from Dr Christina Thomas1 on our report2 of transient livedo reticularis occurring in patients with COVID-19. Dr Thomas astutely notes that disseminated intravascular coagulation and macrothromboses appear to be more prominent in severely ill COVID-19 populations and that other potential factors, such as inflammatory cytokines or the viral mechanism of binding to angiotensin-converting enzyme 2, may play a role in microthrombi formation in less severe disease. Our overall knowledge of the emerging COVID-19 infection and grasp of its mechanism causing coagulopathy in nonsevere cases is constantly evolving. Several mechanisms have been proposed, but in the largest analysis of cases published to date of 1099 patients with laboratory-confirmed COVID-19 in China, a D-dimer ≥0.5 mg/L was noted in 46.4% of nonsevere cases and in 59.6% of severe cases.3 Moreover, the International Society of Thrombosis and Haemostasis has issued recommendations of measuring D-dimer, prothrombin time, and platelet count in all patients with COVID-19, acknowledging that guidelines may change as our knowledge evolves.4 Interestingly, antiphospholipid antibodies (specifically anticardiolipin IgA and anti–β2-glycoprotein I, IgA, and IgG) have also been reported in severe COVID-19 infection.5 As cited in our original paper with findings of 62 publications indexed on PubMed when “COVID” and “thrombosis” are concurrently searched at the time of this writing, patients with COVID-19 have certainly been shown to exhibit a thrombophilic state.2 In addition, transient livedo reticularis can mimic erythema ab igne, but neither of our patients had histories placing them at risk for erythema ab igne. We originally proposed that the 2 patients who exhibited transient livedo reticularis perhaps had low-grade disseminated intravascular coagulation. Although it is still a possibility, we propose expanding that hypothesis to them having had a low-grade thrombophilic or hyperviscosity state, with possible etiologies including the formation of intravascular thrombosis, cold agglutinins, lupus anticoagulant, cryofibrinogens, or cryoglobulins. The concurrent hematuria in patient 1 could be explained by renal microinfarctions or intravascular hemolysis. We continue to support our original statement that at this time, while the etiology for a hypercoagulable state is unknown, complete blood count, coagulation studies, fibrin degradation products, urinalysis, and tissue histopathology in patients with livedo reticularis related to COVID-19 may further clarify the pathomechanisms of this vasculopathy. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. ==== Refs References 1 Thomas C. Reply to: “A dermatologic manifestation of COVID-19: transient livedo reticularis.” J Am Acad Dermatol 83 2 2020 e155 e156 32387666 2 Manalo I. Smith M. Cheeley J. Jacobs R. A dermatologic manifestation of COVID-19: transient livedo reticularis J Am Acad Dermatol 83 2 2020 700 32283229 3 Guan W. Ni Z. Hu Y. Clinical characteristics of coronavirus disease 2019 in China N Engl J Med 382 18 2020 1708 1720 32109013 4 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 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/PMC7205672.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)30839-2 10.1016/j.jaad.2020.05.012 JAAD Online Exploring the risk of severe COVID-19 infection in patients with hidradenitis suppurativa Seltzer Janyla A. BS a Okeke Chidubem A.V. BS a Perry Jessica D. BA a Shipman William D. PhD b∗ Okoye Ginette A. MD c Byrd Angel S. MD, PhD c a Howard University College of Medicine, Washington, DC b Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, New York c Department of Dermatology, Howard University College of Medicine, Washington, DC ∗ Correspondence to: William D. Shipman, PhD, Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, 1300 York Ave, C-103, New York, NY 10065 8 5 2020 8 2020 8 5 2020 83 2 e153e154 © 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 recent letter by Shah et al1 highlighting the epidemiology of COVID-19 infection and the impact on African American populations captivated our attention. As the world continues to battle this global pandemic, it is important that we acknowledge vulnerable populations and address the needs in these populations to minimize mortality and morbidity. As Shah et al1 noted, ethnic minority groups may have a greater risk of infection due to comorbidities. In this letter, we want to emphasize the need to assess racial and ethnic disparities in the COVID-19 pandemic and also bring attention to the potential risk of COVID-19 infection in patients with hidradenitis suppurativa (HS). HS is a chronic inflammatory skin condition that disproportionately affects African Americans2 and has several comorbidities that are also risk factors for severe COVID-19 infection. Recent studies have shown that comorbidities associated with HS include smoking history, metabolic syndrome (including hypertension), obesity, cardiovascular complications, hypertriglyceridemia, dyslipidemia, and inflammatory bowel disease.3 Some of these comorbidities, such as smoking and obesity, have even been implicated as risk factors or pathogenic triggers. In addition to COVID-19 infection disproportionately affecting racial and ethnic minorities, emerging data demonstrate that risk factors for severe COVID-19 infection are strikingly similar to HS comorbidities3 , 4 (Fig 1 ). Obesity, cardiovascular conditions, diabetes, hypertension (or metabolic syndrome in HS), and smoking history are all comorbidities or risk factors, or both, in both diseases.3 , 4 In addition, many patients with HS are treated with various immunomodulators or immunosuppressants, and whether immunomodulator or immunosuppressant use increases the risk of severe COVID-19 infection is still unclear.Fig 1 Overlap of comorbidities associated with hidradenitis suppurativa and risk factors of severe COVID-19 infection. Price et al5 recently commented on how immunosuppressant and immunomodulator use in dermatology patients may increase susceptibility, persistence, and possible reactivation of viral infections, especially when broad immunosuppressants across multiple cytokine axes are used. Currently, there is no clear recommendation on withdrawing or modifying immunomodulator or immunosuppressant therapies in patients with HS, but it should be considered when determining the risk of severe COVID-19 infection in patients with both HS and COVID-19 infection. Our depiction of the comorbidities of HS and the risk factors for severe COVID-19 infection shows a striking overlap. Multiple comorbidities could result in greater challenges in the treatment of patients with HS with COVID-19 infection and may also impact decisions on whether to withdraw or modify current therapy for patients with HS. The overlapping comorbidities of HS and risk factors for severe COVID-19 infection should highlight the need for patients with HS to exercise caution during this pandemic. Patients with HS should follow guidelines from the Centers for Disease Control and Prevention and should discuss with their dermatologist or general practitioner whether more rigid guidelines for precautions, such as social distancing, are warranted. Whether patients with HS are at a greater risk of contracting COVID-19 or are more likely to develop more severe disease is still unknown, but the substantial overlap in risk factors or comorbidities, or both, is certainly worth further consideration and may warrant counseling of these patients. Authors Seltzer and Okeke contributed equally. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Shah M. Sachdeva M. Dodiuk-Gad R.P. COVID-19 and racial disparities J Am Acad Dermatol 83 1 2020 e35 32305444 2 Vlassova N. Kuhn D. Okoye G.A. Hidradenitis suppurativa disproportionately affects African Americans: a single-center retrospective analysis Acta Derm Venereol 95 8 2015 990 991 26073615 3 Tzellos T. Zouboulis C.C. Review of comorbidities of hidradenitis suppurativa: implications for daily clinical practice Dermatol Ther (Heidelb) 10 1 2020 63 71 31955366 4 Zheng Z. Peng F. Xu B. Risk factors of critical & mortal COVID-19 cases: a systematic literature review and meta-analysis [e-pub ahead of print] J Infect 2020 10.1016/j.jinf.2020.04.021 5 Price K.N. Frew J.W. Hsiao J.L. Shi V.Y. COVID-19 and immunomodulator/immunosuppressant use in dermatology J Am Acad Dermatol 82 5 2020 e173 e175 32224277
PMC007xxxxxx/PMC7205728.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)30835-5 10.1016/j.jaad.2020.05.008 Research Letter The importance of fit testing in decontamination of N95 respirators: A cautionary note Ozog David MD a∗ Parks-Miller Angela CCRP, CWCA a Kohli Indermeet PhD ab Lyons Alexis B. MD a Narla Shanthi MD a Torres Angeli E. MD, DPDS a Levesque Martin MPH a Lim Henry W. MD a Hamzavi Iltefat H. MD a a Photomedicine and Photobiology Unit, Department of Dermatology, Henry Ford Hospital, Detroit, Michigan b Department of Physics & Astronomy, Wayne State University, Detroit, Michigan ∗ Correspondence to: David Ozog, MD, Department of Dermatology, Henry Ford Medical Center New Center One, 3031 W Grand Blvd, Ste 800, Detroit, MI 48202 8 5 2020 8 2020 8 5 2020 83 2 672674 © 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 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) COVID-19 pandemic resulted in a critical shortage of personal protective equipment (PPE), particularly N95 filtering facepiece respirators (FFRs). Decontamination methods and reuse of FFRs, including ultraviolet germicidal irradiation (UVGI), hydrogen peroxide vaporization, microwave-generated steaming, and dry heating, have been rushed into implementation. However, if the treatment affects filtration or fit, decontamination is achieved but loss of integrity could be catastrophic to the wearer. Our recent JAAD publication discusses research with a repurposed dermatology phototherapy desktop device to administer UVGI for N95 decontamination.1 This letter highlights critical differences in fit testing performance collected for different respirator models treated with UVGI administered with this repurposed unit. The effects on respirators of using the suggested UVGI dose of 1 to 2 J/cm2 were variable.2 The respirator fit testing was conducted by the Henry Ford Health System Department of Infection Prevention and Control according to the saccharin solution aerosol protocol laid out by the United States Occupational Safety and Health Administration (OSHA).3 Irradiation of respirators with UVGI was conducted by the Henry Ford Health System Department of Dermatology Photomedicine Unit. A new, unused respirator served as the test respirator, and irradiation was performed after establishing that an unused respirator passed a baseline fit test. The outside-facing and wearer-facing surfaces of the respirators were irradiated by the Daavlin Desktop UVC Germicidal Lamp (Daavlin, Bryan, OH) with a dose of 1.5 J/cm2 to each side. If the respirator passed this test, it was considered to have successfully completed 1 cycle. This process was then repeated to establish the number of irradiation cycles that the respirator would pass the fit test. Testing was ceased if a respirator did not pass the fit test. The results are reported in Table I .Table I Results of Henry Ford Health System respirator fit testing FFR model∗ Saccharin solution aerosol fit test performed UVC cycles attempted/fit test cycles passed Passing cumulative UVC dose (3 J/cm2 = 1 cycle) 3M N95 Respirator—1860 NIOSH TC-84A-0006 Baseline, cycles 1-6, 15, 20 & 25 25/20 60 J/cm2 3M N95 Respirator—9210 NIOSH TC-84A-2669 Baseline, cycles 1-2 2/2† 6 J/cm2 3M N95 Respirator—8210 NIOSH TC-84A-0007 Baseline, cycles 1-2 2/1 3 J/cm2 Cardinal Health USA N95 R/S Respirator—NIOSH TC-84A-5529 & 5527 (small/regular) Baseline, cycles 1-2 2/1 3 J/cm2 Moldex N95 Respirator #2300N95—NIOSH TC-84A-0328 This N95 respirator passed the baseline fit test on 1 individual. Owing to immediate breakage of straps upon user removal on 2 respirators, testing ceased. 0 N/A Moldex N95 Respirator 1511 (small)—NIOSH TC-84A-0013 This N95 respirator failed the baseline fit test on 3 individuals. 0 N/A Moldex N95 Respirator 1512 (medium)—NIOSH TC-84A-0013 Baseline, cycles 1-3 3/2 6 J/cm2 3M N95 Respirator—9010 NIOSH TC-84A-4243 This N95 respirator failed the baseline fit test on 2 individuals. 0 N/A Cardinal Health USA N95A-S Respirator—NIOSH TC-84A-5463 This N95 respirator failed the baseline fit test on 2 individuals. 0 N/A GB2626-2206 KN95 Respirator—KN95-01-01 This N95 respirator failed the baseline fit test on 2 individuals. 0 N/A FFR, Filtering facepiece respirator; N/A, not available; NIOSH, National Institute for Occupational Safety and Health; UVC, ultraviolet C. ∗ 3M, St Paul, Minnesota; Cardinal Health, Dublin, Ohio; Moldex-Metric, Culver City, California. † Limited resources prevented testing of additional UVC cycles. The UVGI treatment may degrade polymers in the respirators themselves and impact the elasticity of the bands.4 The myriad respirators available in this crisis react differently to a given UVGI dose and survive different numbers of decontamination cycles. This may hold true for other respirator treatment methods as well. Our data strongly indicate that to protect the safety of the N95 respirator user, fit testing after decontamination must be done each time a new model is introduced to a health care system. This has significant safety implications, because varied decontamination methods are being used by different institutions.5 In addition, N95 respirators should be physically examined before and after decontamination cycles to check for signs of degradation that may have occurred while removing and handling. Funding sources: None. Conflicts of interest: Drs Lyons and Narla are subinvestigators for Biofrontera. Dr Ozog is an investigator for Biofrontera. Dr Lim has participated as a speaker in general educational session for Ra Medical System. Drs Lim and Hamzavi are investigators for the Light Treatment Effectiveness (LITE) study, which is funded by 10.13039/100006093 Patient-Centered Outcomes Research Institute , and home phototherapy machines are provided by Daavlin. Authors Park-Miller, Ohli, Levesque, and Torres and have no conflicts of interest to declare. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Hamzavi I. Lyons A.B. Kohli I. Ultraviolet germicidal irradiation: possible method for respirator disinfection to facilitate reuse during COVID-19 pandemic J Am Acad Dermatol 82 6 2020 1511 1512 32246972 2 Heimbuch B.K. Harnish D. Research to Mitigate a Shortage of Respiratory Protection Devices During Public Health Emergencies 2020 Applied Research Associates, Inc. Available at: https://www.ara.com/sites/default/files/MitigateShortageofRespiratoryProtectionDevices_3.pdf 3 Occupational Safety and Health Administration Appendix A to §1910.134—Fit Testing Procedures (Mandatory) Available at: https://www.osha.gov/laws-regs/regulations/standardnumber/1910/1910.134AppA 4 Lindsley W.G. Martin S.B. Jr. Thewlis R.E. Effects of ultraviolet germicidal irradiation (UVGI) on N95 respirator filtration performance and structural integrity J Occup Environ Hyg 12 2015 509 517 25806411 5 Torres A, Lyons AB, Narla S et al. Ultraviolet-C and other methods of decontamination of filtering facepiece N-95 respirators during the COVID-19 pandemic [e-pub ahead of print]. Photochem Photobiol Sci. 10.1039/D0PP00131G. Accessed April 10, 2020.
PMC007xxxxxx/PMC7212997.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)30846-X 10.1016/j.jaad.2020.05.018 Research Letter Association of outdoor activity restriction and income loss with patient-reported outcomes of psoriasis during the COVID-19 pandemic: A web-based survey Kuang Yehong MD abc Shen Minxue PhD abcd Wang Qiaolin BS a Xiao Yi MD abc Lv Chengzhi MD e Luo Yan BS ac Zhu Wu MD abc∗ Chen Xiang MD abc∗ a Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China b National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, China c Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis (Xiangya Hospital), Changsha, China d Department of Social Medicine and Health Management, Xiangya School of Public Health, Central South University, Changsha, China e Department of Psoriasis, Dalian Dermatosis Hospital, Dalian, Liaoning, China ∗ Correspondence to: Wu Zhu, MD, and Xiang Chen, MD, Xiangya Hospital, Central South University, Dermatology, No 87 Xiangya Rd, Changsha 410000, China 11 5 2020 8 2020 11 5 2020 83 2 670672 © 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: Under the circumstances of the COVID-19 epidemic, patients with psoriasis or other chronic diseases have been confronted with limited accessibility to health care and medicine. Some underwent income loss or unemployment, which placed them at additional risks of adverse health outcomes.1 The impacts of COVID-19 varied across subgroups of people, and we used outdoor activity restriction and loss of income as the proxy measures of the impacts. We investigated the associations of these impacts with the patient-reported outcomes of psoriasis through a web-based survey in China between February 25, 2020, and March 6, 2020. Outdoor activity restriction was categorized as unaffected, restricted, and quarantined. Loss of income was categorized as complete loss, reduced, and unaffected. The primary outcome was the exacerbation of disease, determined by the Global Rating of Change. Secondary outcomes included perceived stress (visual analog scale),2 symptoms of anxiety (2-item Generalized Anxiety Disorder) and depression (2-item Patient Health Questionnaire), adherence to treatment, and health care use. Covariates included sex, age, educational level, annual income, marital status, type of psoriasis, course of disease, body surface area of lesions, and comorbidities. Details of the measures are provided in the supplemental materials (available via Mendeley at http://doi.org/10.17632/gtmhpx4g2f.1). The data were analyzed with R, version 3.5.2 (R Core Team, Vienna, Austria). Multivariable logistic regression was used to estimate the associations with adjustments. The effect size is presented as adjusted odds ratio (aOR) and 95% confidence interval (CI). P values of less than .05 were considered statistically significant. A total of 926 valid questionnaires was collected. One reported confirmed infection with COVID-19. The mean age of the patients was 33.1 ± 12.2 years, and 36.9% were female. The characteristics of participants are shown in the supplemental materials. A total of 405 (43.7%) reported moderate to much exacerbation of psoriasis. After adjustments, outdoor activity restriction was positively associated with the exacerbation of psoriasis, stress, and symptoms of anxiety and depression in a dose-response manner but was not associated with nonadherence (Table I ). Similarly, income loss was associated with the exacerbation of psoriasis, stress, and symptoms of anxiety and depression (Table II ). Differently, income loss was significantly associated with nonadherence to treatment but was not associated with health care utilization. To further determine the independent factors, stepwise regression was conducted, and we found that nonadherence to treatment (aOR, 3.69; 95% CI, 2.67-5.18), stress (aOR, 1.17; 95% CI, 1.11-1.23), quarantine (aOR, 2.05; 95% CI, 1.33-3.18), and income loss (aOR, 1.51; 95% CI, 1.06-2.15) were independently associated with the exacerbation of psoriasis.Table I Associations of outdoor activity restriction with patient-reported outcomes of psoriasis Patient-reported outcomes Unaffected (n = 512) Restricted (n = 291) Quarantined at home or in hospital (n = 123) n (%) OR n (%) OR (95% CI) aOR (95%CI)∗ P n (%) OR (95% CI) aOR (95%CI)∗ P Deteriorated psoriasis 194 (37.9) 1 139 (47.8) 1.50 (1.12-2.01) 1.39 (1.03-1.88) .034 72 (58.5) 2.31 (1.55-3.46) 2.08 (1.38- 3.15) .001 Perceived stress (VAS, ≥7) 76 (14.8) 1 64 (22.0) 1.62 (1.12-2.34) 1.48 (1.01-2.18) .044 30 (24.4) 1.85 (1.15-2.99) 1.51 (0.92-2.71) .107 Anxiety (GAD-2, ≥3) 321 (62.7) 1 199 (68.4) 1.29 (0.95-1.75) 1.16 (0.85-1.60) .346 94 (76.4) 1.93 (1.23-3.04) 1.66 (1.04-2.64) .033 Depression (PHQ-2, ≥3) 327 (63.9) 1 209 (71.8) 1.44 (1.06-1.97) 1.23 (0.89-1.71) .219 95 (77.2) 1.92 (1.21-3.04) 1.60 (1.00-2.59) .053 Nonadherence to treatment 344 (67.2) 1 204 (70.1) 1.15 (0.84-1.56) 1.04 (0.76-1.45) .793 86 (69.9) 1.14 (0.74-1.74) 1.06 (0.68-1.65) .804 No health care use 339 (66.2) 1 198 (68.0) 1.09 (0.80-1.48) 1.09 (0.80-1.50) .580 68 (55.3) 0.63 (0.42-0.94) 0.66 (0.44-1.00) .049 aOR, Adjusted odds ratio; CI, confidence interval; GAD-2, 2-item Generalized Anxiety Disorder; OR, unadjusted odds ratio; PHQ-2, 2-item Patient Health Questionnaire; VAS, visual analog scale. ∗ Adjusted for age, educational level, annual income, marital status, history of hypertension, type of psoriasis, and income loss. Table II Associations of income loss with patient-reported outcomes of psoriasis Patient-reported outcomes Unaffected (n = 263) Reduced (n = 265) Complete loss (n = 398) n (%) OR n (%) OR (95% CI) aOR (95% CI)∗ P n (%) OR (95% CI) aOR (95% CI)∗ P Deteriorated psoriasis 89 (33.8) 1 100 (37.7) 1.19 (0.83-1.69) 1.12 (0.77-1.62) .561 216 (54.3) 2.32 (1.68-3.20) 2.15 (1.46-3.15) <.001 Perceived stress (VAS, ≥7) 26 (9.9) 1 39 (14.7) 1.57 (0.93-2.67) 1.57 (0.91-2.71) .103 105 (26.4) 3.27 (2.06-5.19) 3.26 (1.91-5.57) <.001 Anxiety (GAD-2, ≥3) 146 (55.5) 1 174 (65.7) 1.53 (1.08-2.18) 1.39 (0.96-2.00) .080 294 (73.9) 2.27 (1.63-3.15) 1.73 (1.17-2.56) .006 Depression (PHQ-2, ≥3) 146 (55.5) 1 177 (66.8) 1.61 (1.13-2.29) 1.48 (1.02-2.15) .038 308 (77.4) 2.74 (1.96-3.85) 2.37 (1.58-3.57) <.001 Nonadherence to treatment 156 (59.3) 1 173 (65.3) 1.29 (0.91-1.84) 1.22 (0.84-1.76) .292 305 (76.6) 2.25 (1.60-3.16) 2.18 (1.45-3.26) <.001 No health care use 181 (68.8) 1 179 (67.5) 0.94 (0.65-1.36) 0.92 (0.62-1.35) .656 245 (65.3) 0.73 (0.52-1.01) 0.78 (0.52-1.16) .216 aOR, Adjusted odds ratio; CI, confidence interval; GAD-2, 2-item Generalized Anxiety Disorder; OR, unadjusted odds ratio; PHQ-2, 2-item Patient Health Questionnaire; VAS, visual analog scale. ∗ Adjusted for age, educational level, annual income, marital status, history of hypertension, type of psoriasis, and outdoor activity restriction. Loss of income and work-related benefits experienced by the unemployed consequently lead to impaired health outcomes3 through mechanisms involving unhealthy coping behaviors and increased psychological distress.4 This hypothesis is supported by our finding that nonadherence behavior (68.5%) and perceived stress were independently associated with both income loss and exacerbation of psoriasis. Isolation and temporarily closed outpatient services further limited patients' abilities to access to health care, especially for those who were not familiar with or able to access teledermatology, resulting in discontinued treatment and deteriorated condition.5 In conclusion, telemedicine and a supply of medications in addition to mental health intervention are needed for patients with psoriasis to improve their health outcomes. The authors would like to thank the Psoriatic Patient Blog (https://www.yxb365.com/portal.php) and the Psoriasis Blog New Media (WeChat Official Account: yxbnpx8) for their assistance in the online survey. Drs Kuang and Shen are cofirst authors. Funding sources: Supported by the 10.13039/501100001809 National Natural Science Foundation of China (62041208, 81974479, 81573049, 81830096), the 10.13039/100007225 Ministry of Science and Technology of the People's Republic of China (2016YFC0900802, 2018YFC0117004, 2016YFC0901705), the Emergency Project of Prevention and Control for COVID-19 of 10.13039/501100002822 Central South University (502701002), and the 10.13039/501100002767 Department of Science and Technology of Hunan Province (2018SK2082, 2018SK2086). The funders did not participate in this study. Conflicts of interest: None disclosed. IRB approval status: Reviewed and approved by the institutional research ethics boards of Xiangya Hospital, Central South University, Changsha, China (approval 202002024). Reprints not available from the authors. ==== Refs References 1 Dooley D. Fielding J. Levi L. Health and unemployment Annu Rev Public Health 17 1996 449 465 8724235 2 Lesage F.X. Berjot S. Validity of occupational stress assessment using a visual analogue scale Occup Med (Lond) 61 6 2011 434 436 21505089 3 Renahy E. Mitchell C. Molnar A. Connections between unemployment insurance, poverty and health: a systematic review Eur J Public Health 28 2 2018 269 275 29360958 4 Bijlsma M.J. Tarkiainen L. Myrskyla M. Martikainen P. Unemployment and subsequent depression: a mediation analysis using the parametric G-formula Soc Sci Med 194 2017 142 150 29100139 5 Dommasch E.D. Lee M.P. Joyce C.J. Garry E.M. Gagne J.J. Drug utilization patterns and adherence in patients on systemic medications for the treatment of psoriasis: a retrospective, comparative cohort study J Am Acad Dermatol 79 6 2018 1061 1068 29981385
PMC007xxxxxx/PMC7214862.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)30508-9 10.1016/j.jaad.2020.03.085 Research Letter Ultraviolet germicidal irradiation: Possible method for respirator disinfection to facilitate reuse during the COVID-19 pandemic Hamzavi Iltefat H. MD a∗ Lyons Alexis B. MD a Kohli Indermeet PhD ab Narla Shanthi MD a Parks-Miller Angela CCRP, CWCA a Gelfand Joel M. MD, MSCE c Lim Henry W. MD a Ozog David M. MD a a Department of Dermatology, Henry Ford Hospital, Detroit, Michigan b Department of Physics & Astronomy, Wayne State University, Detroit, Michigan c Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania ∗ Correspondence to: Iltefat H. Hamzavi, MD, Department of Dermatology, Henry Ford Medical Center New Center One, 3031 W Grand Blvd, Ste 800, Detroit, MI 48202 1 4 2020 6 2020 1 4 2020 82 6 15111512 © 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 ability to disinfect and reuse disposable N95 filtering facepiece respirators is urgently needed during the current COVID-19 pandemic because supplies are running low in hospitals throughout the United States and abroad. Ultraviolet (UV) germicidal irradiation (UVGI) is one possible method for respirator disinfection to facilitate the reuse of dwindling supplies. Dermatology offices often use narrow-band UVB to treat skin diseases. If necessary, we propose a possible repurposing of phototherapy devices, including these UVB units, to serve as a platform for UVC germicidal disinfection. UVGI is a disinfection method that uses UVC radiation to inactivate microorganisms by causing DNA damage and preventing replication. Previous studies have shown that UVC can inactivate coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV).1 One study of respirators contaminated with H1N1 influenza A found significant reductions (≥3-log reduction) in viable influenza virus under substantial artificial soiling conditions after being treated for 60 to 70 seconds at an irradiance of 17 mW/cm2, resulting in a UVGI dose of ∼1 J/cm2 measured at 254 nm.2 The efficacy of this dose has been verified in additional studies, and higher doses (up to 2 J/cm2) have been shown to provide diminished benefit after 1 J/cm2.3 , 4 It is recommended to treat used masks, but not visibly soiled, to allow the 3-log reduction reported in the literature to be sufficient to achieve safe reuse levels.5 It is important to note that the time to deliver 1 J/cm2 depends on the irradiance; hence, it can be longer or shorter depending on the delivery device's capabilities. In a prototype model that has been developed (Fig 1 ), this dose can be delivered in 1 minute and 40 seconds at an irradiance of 10 mW/cm2. The distance from the lamp to the top of the table in Fig 1 is approximately 14 cm.Fig 1 Image of prototype being developed by Daavlin. The field of irradiation is approximately 15 inches × 45 inches, and depending on the manufacturer of the mask, this would allow for the treatment of ∼18 to 27 masks (2 minutes per side). (A) With ultraviolet light on and (B) ultraviolet light off. (Photographs used with permission of Bob Golding, Daavlin, Byron, Ohio.) However, UV radiation does degrade polymers, which presents the possibility that UVGI exposure, while decontaminating, may also reduce the efficacy of the respirator and decrease protection to workers. Lindsley et al6 exposed 4 different models of N95 filtering facepiece respirators to UVGI doses of 120 to 950 J/cm2. Results of the study showed that UVGI exposure led to a small increase in particle penetration (up to 1.25%) and had little effect on the flow resistance. However, at higher UVGI doses, the strength of the layers of the respirator material was substantially reduced (in some cases, >90%), but this significantly varied among the different models. UVGI had less of an effect on the respirator straps: a dose of 2360 J/cm2 reduced the breaking strength of the straps by 20% to 51%.6 It should be noted that the dosages used in the study above are 100- to 1000-times higher than those shown to disinfect H1N1 influenza A–contaminated respirators. Therefore, considering that many of our health care providers are using substitutes for N95 filtering facepiece respirators that offer very limited degree of protection, using UVGI and repurposing phototherapy devices could be the best practical solution at this time. We would like to thank Bob Golding and his team at Daavlin (Byron, OH) for leading the reengineering of a phototherapy device that can be used to disinfect N95 masks. Funding sources: None. Conflicts of interest: Drs Lyons and Narla are subinvestigators and Dr Ozog is an investigator for Biofrontera. Dr Lim has participated as a speaker in general educational sessions for Ra Medical System. Drs Hamzavi and Lim are investigators and Dr Gelfand is principal investigator for the Light Treatment Effectiveness (LITE) study, which is funded by the 10.13039/100006093 Patient-Centered Outcomes Research Institute and for which the home phototherapy machines are provided by Daavlin. Dr Kohli and Ms Parks-Miller have no relevant conflicts of interest to report. IRB approval status: Not applicable. Additional supplemental material will be available on Mendeley after publication. Reprints not available from the authors. ==== Refs References 1 Bedell K. Buchaklian A.H. Perlman S. Efficacy of an automated multiple emitter whole-room ultraviolet-C disinfection system against coronaviruses MHV and MERS-CoV Infect Control Hosp Epidemiol 37 2016 598 599 26818469 2 Mills D. Harnish D.A. Lawrence C. Sandoval-Powers M. Heimbuch B.K. Ultraviolet germicidal irradiation of influenza-contaminated N95 filtering facepiece respirators Am J Infect Control 46 2018 e49 e55 29678452 3 Fisher E.M. Shaffer R.E. A method to determine the available UV-C dose for the decontamination of filtering facepiece respirators J Appl Microbiol 110 2011 287 295 21054699 4 Mills D.S. Lawrence C. Heimbuch B. Harnish D.A. Ultraviolet Germicidal Irradiation of Influenza-Contaminated N95 Filtering Facepiece Respirators. Poster presentation at: American Society for Microbiology. Poster Presentation Available at: https://www.fda.gov/downloads/EmergencyPreparedness/Counterterrorism/MedicalCountermeasures/MCMRegulatoryScience/UCM505730.pdf 2016 5 Eickmann M. Gravemann U. Handke W. Inactivation of three emerging viruses - severe acute respiratory syndrome coronavirus, Crimean-Congo haemorrhagic fever virus and Nipah virus - in platelet concentrates by ultraviolet C light and in plasma by methylene blue plus visible light Vox Sang 2020 10.1111/vox.12888 6 Lindsley W.G. Martin S.B. Jr. Thewlis R.E. Effects of ultraviolet germicidal irradiation (UVGI) on N95 respirator filtration performance and structural integrity J Occup Environ Hyg 12 2015 509 517 25806411
PMC007xxxxxx/PMC7228687.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)30863-X 10.1016/j.jaad.2020.05.032 Research Letter COVID-19 and personal protective equipment: Treatment and prevention of skin conditions related to the occupational use of personal protective equipment Desai Seemal R. MD ab∗ Kovarik Carrie MD c Brod Bruce MD c James William MD c Fitzgerald Matthew E. DrPh d Preston Ave MSN, RN, CWOCN e Hruza George J. MD, MBA f a Department of Dermatology, The University of Texas Southwestern Medical Center, Dallas, Texas b Innovative Dermatology, Plano, Texas c Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania d American Academy of Dermatology, Rosemont, Illinois e Department of Nursing, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania f Department of Dermatology, Saint Louis University, St Louis, Missouri ∗ Correspondence and reprint requests to: Seemal R. Desai, MD, 5425 W Spring Creek Pkwy, Ste 265, Plano, TX 75024 15 5 2020 8 2020 15 5 2020 83 2 675677 © 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: There have been an increasing number of reports of occupationally induced skin conditions in health care workers related to the use of personal protective equipment (PPE) during the coronavirus disease 2019 (COVID-19) pandemic.1 , 2 The breadth and variety of different types of PPE, such as facemasks, gloves, and respiratory equipment, as well as the extended use beyond previous standards, have led to a spectrum of common dermatologic conditions, including contact/irritant dermatitis, pressure-related skin injury, acneiform eruptions, and moisture-associated skin irritation (Table I ).Table I Skin condition related to masks—treatment and prevention strategies Skin condition Surgical mask N95 mask Contact/irritant dermatitis Use alcohol-free barrier film wipe behind the ears before wearing, or Apply thin foam dressing behind the ear beneath ear loop of surgical mask. N95 mask straps should be worn on the crown of the head, so should not be sitting on top of the ears. Pressure-related skin injury Apply thin foam dressing behind the ears beneath ear loop of surgical mask. Prophylactic dressings can be used under surgical masks for treatment/prevention. Proposed materials include a thin hydrocolloid dressing or thin foam dressing. Cut/adjust material to application site and apply dressing to skin without tension. Once PPE is removed at end of shift, wash hands, don clean gloves, gently remove dressings, and wash hands again. When removing prophylactic dressings, close eyes and avoid inhaling any aerosolized virus or particles. Apply alcohol-free barrier film wipe (not spray) on areas of direct PPE contact (eg, nose, cheeks, forehead, behind the ears) to protect skin from moisture and friction. Before applying, ensure the area is free of make-up, etc. Do not apply to eyes or eyelids. Allow to dry for 90 seconds before donning PPE. Wear facial PPE correctly and make sure size is correct. If skin damage is present, consider applying petrolatum to open areas 3-4 times a day when away from work. If an open area of skin is present, a hydrocolloid dressing may be used to help it heal; however, using these dressings under N95 masks requires refit testing to ensure adequate seal. Acne Wash your face with gentle, mild fragrance free, noncomedogenic cleanser in the morning and at the end of the day. Take appropriate breaks from the mask: 15 minutes off every 2 hours. Wash your face with gentle, mild fragrance-free, noncomedogenic cleanser in the morning and at the end of the day. Take appropriate breaks from the mask: 15 minutes off every 2 hours. Moisture- associated skin irritation Wash your face with gentle, mild fragrance-free, noncomedogenic cleanser in the morning and at the end of the day. Take appropriate breaks from the mask: 15 minutes off every 2 hours. Wash your face with gentle, mild fragrance-free, noncomedogenic cleanser in the morning and at the end of the day. Take appropriate breaks from the mask: 15 minutes off every 2 hours—if safe and practical to do so. PPE, Personal protective equipment. Surgical and N95 masks, as well as goggles and face shields, have been reported to cause contact dermatitis, typically behind the ears (from elastic straps), on the bridge of the nose, or rarely on the entire face. Mask-induced contact dermatitis and contact urticaria can occur due to adhesives, rubber in straps, free formaldehyde released from the nonwoven polypropylene, and from metals in clips.3 , 4 The tighter and more secure N95 masks can cause significant skin damage due to pressure on anatomic points such as the bridge of the nose and across the zygoma. Moisture can accumulate under either type of facemask and predispose to skin breakdown and, potentially, superinfection. Facial PPE should be adjusted to fit correctly and should not lead to excess pressure or discomfort on any one particular area of the face. Skin should be routinely cleaned and moisturized using noncomedogenic emollients at least 1 hour before using facial PPE. Petrolatum-based products are not recommended as a skin sealing or repair agent because they may interfere with the integrity of the mask itself, in particular, the N95.5 According to the Centers for Diseases Control and Prevention, contact dermatitis accounts for 10% to 15% of all health care occupational illnesses. Glove-related allergic contact dermatitis is relatively common in health care workers. The most common causes are rubber accelerators used in the manufacturing of gloves. Skin manifestations include pruritus, erythema, scale, vesicles, and in prolonged cases, hyperpigmentation and lichenification. Health care workers should be encouraged to use moisturizers frequently, especially when not in direct patient care, and ensure hands are clean and dry before the use of gloves and other PPE during patient contact time. For more severe cases of contact dermatitis, topical corticosteroids and other prescription therapies may be warranted. In addition to masks, gloves, and respirators, the repetitive and prolonged use of sterilizing agents, including hand soaps, detergents, and repeated exposure to water, can lead to irritated skin and an increased risk for contact sensitization. To reduce this risk, especially after handwashing, emollients with ceramides or petrolatum, or both, may be beneficial.6 As health care workers, we are ultimately responsible for protecting our patients, ourselves, and the broader community. Wearing PPE for extended periods, as has occurred in the era of COVID-19, can have potentially serious consequences for health care workers. Recognizing occupationally induced skin conditions from PPE, and which of these can be prevented or minimized with proper measures, is critical to help mitigate long-term skin sequelae and maintain compliance. We would like to thank staff at the American Academy of Dermatology for their logistical and administrative support. We would also like to thank, in particular, Theresa Carbone, BSN, RN, CWOCN, William Falone, MSN, RN, CWON, and Shawn Parsons, MSN, CRNP, CWON, along with the Penn Medicine Wound Care Nursing Collaborative, for their ongoing efforts to educate health care workers and the public on the occupational risks in the era of COVID-19. Funding sources: None. Conflicts of interest: Drs Desai, Kovarik, Brod, and Hruza are part of the American Academy of Dermatology Ad Hoc Task Force on COVID-19. Authors James, Fitzgerald, and Preston have no conflicts of interest to declare. IRB approval status: Not applicable. Supplemental material available via Mendeley at https://doi.org/10.17632/y5f78b42s5.1. ==== Refs References 1 Gheisari M, Araghi F, Moravvej H, et al. Skin reactions to non-glove personal protective equipment: an emerging issue in the COVID-19 pandemic [e-pub ahead of print]. J Eur Acad Dermatol Venereol. 10.1111/jdv.16492. Accessed May 7, 2020. 2 Lan J. Song Z. Miao X. Skin damage among health care workers managing coronavirus disease-2019 J Am Acad Dermatol 82 2020 1215 1216 32171808 3 Foo C. Goon A.T. Leow Y.H. Adverse skin reactions to personal protective equipment against severe acute severe acute respiratory syndrome-a descriptive study in Singapore Contact Dermatitis 55 2006 291 294 17026695 4 Donovan J. Kudla I. Holness L. Skin reactions following use of N95 facial masks Dermatitis 18 2007 104 5 National Pressure Injury Advisory Panel (NPIAP) NPIAP position statements on preventing injury with N95 masks Available at: https://cdn.ymaws.com/npiap.com/resource/resmgr/position_statements/Mask_Position_Paper_FINAL_fo.pdf 2020 6 Beiu C. Mihai M. Popa L. Frequent hand washing for COVID-19 prevention can cause hand dermatitis: management tips Cureus 12 2020 e7506 32373409
PMC007xxxxxx/PMC7231491.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)30922-1 10.1016/j.jaad.2020.05.057 Research Letter Retrospective analysis of smell and taste disturbances associated with dermatologic medications reported to the United States Food and Drug Administration and relevance to COVID-19 infections Wang Yu BA a Lipner Shari R. MD, PhD b∗ a State University of New York Stonybrook Medical School, Stonybrook, New York b Department of Dermatology, Weill Cornell Medicine, New York, New York ∗ Correspondence to: Shari R. Lipner, MD, PhD, 1305 York Ave, New York, NY 10021 17 5 2020 8 2020 17 5 2020 83 2 682684 © 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: Smell and taste disturbances are more recently reported symptoms of the novel coronavirus disease 2019 (COVID-19).1 Many commonly used dermatologic medications can also cause smell/taste changes. With COVID-19 testing shortages in the United States, these medication adverse events warrant careful consideration. In this study, we analyzed the United States Food and Drug Administration Adverse Event Reporting Database (FAERS) for the most common dermatologic medications associated with smell/taste disturbances and their relevance to COVID-19 infections. The FAERS database was searched for the most common medications causing smell/taste disturbances and then filtered for dermatologic drugs. The data were substantiated using 2 other databases and recorded. The National Institute of Health Clinical Studies Database was queried for clinical trial data, and PubMed was examined for case reports/series on smell/taste disturbances associated with these medications. Taste disturbances were 6.11-times more common than smell disturbances, with 10,232 and 62,524, respectively, reported to FAERS during the study period (Tables I and II ). Adalimumab was the most common dermatologic medication associated with anosmia in FAERS (84 cases), which was not corroborated in clinical trials or in a PubMed search (Table I).Table I Top 10 dermatologic medications in the United States Food and Drug Administration Adverse Event Reporting Database (FAERS) associated with smell disturbances, with the corresponding clinical trial data and the number of cases reports or case series in PuMmed∗ Medication Cases in FAERS (% of all anosmia/hyposmia/smell disturbance cases) Rank of all medications associated with anosmia/hyposmia/smell disturbance Clinical trial data Case reports/cases series in PubMed, No. Adalimumab (injection) 84 (0.82) 7 of 956 No anosmia/hyposmia reported in phase III clinical trials, no anosmia/hyposmia reported in phase IV trials 0 Etanercept (injection) 75 (0.73) 22 of 956 No anosmia/hyposmia reported in phase III clinical trials, no anosmia/hyposmia reported in phase IV trials 1 Terbinafine hydrochloride (oral) 68 (0.66) 24 of 956 No anosmia/hyposmia reported in phase III clinical trials, no anosmia/hyposmia reported in phase IV trials 0 Cetirizine hydrochloride (oral) 27 (0.26) 45 of 956 No anosmia/hyposmia reported in phase III clinical trials, anosmia/hyposmia were reported in phase IV trials 0 Vismodegib (oral) 16 (0.14) 96 of 956 No anosmia/hyposmia reported in phase III clinical trials, anosmia/hyposmia were reported in phase IV trials 0 Secukinumab (injection) 14 (0.14) 109 of 956 No anosmia/hyposmia reported in phase III clinical trials, no anosmia/hyposmia reported in phase IV Trials 0 Prednisolone (oral) 13 (0.13) 113 of 956 No anosmia/hyposmia reported in phase III clinical trials, anosmia/hyposmia were reported in phase IV trials 0 Spironolactone (oral) 12 (0.13) 125 of 956 No anosmia/hyposmia reported in phase III clinical trials, no anosmia/hyposmia reported in phase IV trials 0 Isotretinoin (oral) 11 (0.12) 145 of 956 No anosmia/hyposmia reported in phase III clinical trials, no anosmia/hyposmia reported in phase IV trials 1 Fluconazole (oral) 9 (0.09) 153 of 956 No anosmia/hyposmia reported in phase III clinical trials, No anosmia/hyposmia reported in phase IV trials 0 ∗ There were 10,232 cases of smell disturbances reported to FAERS, from January 1, 1997, to December 31, 2019, using the key words anosmia, hyposmia, and smell disturbance. Table II Top 10 dermatologic medications in the United States Food and Drug Administration Adverse Event Reporting Database (FAERS) associated with taste disturbances, with the corresponding clinical trial data and the number of cases reports or case series in PubMed∗ Medication Cases in FAERS (% of all ageusia/dysgeusia/taste disturbance cases Rank of all medications associated with ageusia/dysgeusia/taste disturbance Clinical trial data Case reports/cases series in PubMed, No. Vismodegib (oral) 1054 (1.69) 11 of 2591 67% ageusia/dysgeusia reported in phase III clinical trials, ageusia/dysgeusia were reported in phase IV trials 2 Etanercept (injection) 937 (1.50) 14 of 2591 No ageusia/dysgeusia reported in phase III clinical trials, no ageusia/dysgeusia reported in phase IV trials 1 Terbinafine hydrochloride (oral) 920 (1.47) 15 of 2591 2.8% ageusia/dysgeusia reported in phase III clinical trials, ageusia/dysgeusia were reported in phase IV trials 9 Apremilast (oral) 223 (0.36) 71 of 2591 No ageusia/dysgeusia reported in phase III clinical trials, no ageusia/dysgeusia reported in phase IV trials 1 Methotrexate (oral) 176 (0.28) 105 of 2591 No ageusia/dysgeusia reported in phase III clinical trials, no ageusia/dysgeusia reported in phase IV trials 1 Secukinumab (injection) 151 (0.24) 296 of 2591 No ageusia/dysgeusia reported in phase III clinical trials, no ageusia/dysgeusia reported in phase IV trials 0 Spironolactone (oral) 68 (0.11) 376 of 2591 No ageusia/dysgeusia reported in phase III clinical trials, no ageusia/dysgeusia reported in phase IV trials 0 Isotretinoin (oral) 57 (0.09) 430 of 2591 No ageusia/dysgeusia reported in phase III clinical trials, no ageusia/dysgeusia reported in phase IV trials 2 Tacrolimus (23 topical, 20 oral) 43 (0.07) 689 of 2591 No ageusia/dysgeusia reported in phase III clinical trials, no ageusia/dysgeusia reported in phase IV trials 0 Mycophenolate sodium (oral) 42 (0.07) 691 of 2591 No ageusia/dysgeusia reported in phase III clinical trials, no ageusia/dysgeusia reported in phase IV trials 0 ∗ There were 62,524 cases of taste disturbances reported to FAERS from January 1, 1969, to December 31, 2019, using the key words ageusia, dysgeusia, and taste disturbance. Apremilast and methotrexate were associated with 223 and 176 cases of taste disturbances, respectively (Table II). An 83-year-old woman reported bitter taste after 4 weeks of apremilast treatment, which resolved 3 months after discontinuation.2 A 22-year-old woman presented with reproducible dysgeusia 5 to 6 hours after methotrexate ingestion, with resolution 24 to 36 hours after folic acid administration.3 We found that 60% of the listed dermatologic medications caused both smell and taste disturbances (Tables I and II). Vismodegib is well known for causing taste disturbances, reported in 67% of patients in phase III clinical trials, and smell disturbances were reported in a phase IV trial. For terbinafine, taste disturbances were reported in 2.8% of phase III clinical trial patients, and taste/smell changes were described in 17 patients from an Italian adverse event reporting database.4 There are 2 case reports of smell/taste changes with isotretinoin treatment for acne, in a 23-year-old woman after 4 weeks of therapy and in a 36-year-old woman after 20 weeks of treatment, with resolution 6 months after discontinuation.5 , 6 Although there are no clinical trial data describing smell/taste disturbances with etanercept, these changes were reported in a 31-year-old woman after several months of etanercept therapy for ankylosing spondylitis.7 This study is subject to several limitations. FAERS data are collected from patients, physicians, and pharmaceutical companies, without confirmation of adverse events or dosage information. Although many of these dermatologic medications are associated with smell/taste disturbances, there is no proof of causation. In conclusion, smell and taste disturbances are reported in approximately one-third of patients with COVID-19 and also with medications frequently used in dermatology. Taste disturbances are about 6 times more common than smell disturbances, and most dermatologic medications listed cause both changes. Therefore, dermatologists should be familiar with these lists and review both current medication lists in patients presenting with anosmia or dysgeusia and counsel patients of the possibility of smell/taste disturbances when initiating new treatments. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Xydakis M.S. Dehgani-Mobaraki P. Holbrook E.H. Smell and taste dysfunction in patients with COVID-19. [e-pub ahead of print] Lancet Infect Dis. 10.1016/S1473-3099(20)30293-0 2020 2 Damiani G. Bragazzi N.L. Grossi E. Severe bitter taste associated with apremilast Dermatol Ther 32 3 2019 e12876 30882959 3 Duhra P. Foulds I.S. Methotrexate-induced impairment of taste acuity Clin Exp Dermatol 13 2 1988 126 127 3214955 4 Tuccori M. Lapi F. Testi A. Drug-induced taste and smell alterations: a case/non-case evaluation of an Italian database of spontaneous adverse drug reaction reporting Drug Saf 34 10 2011 849 859 21879779 5 Halpern S.M. Todd P.M. Kirby J.D. Loss of taste associated with isotretinoin Br J Dermatol 134 2 1996 378 6 Heise E. Schnuch A. Taste and olfactory disturbances after treatment for acne with isotretinoin, a 13-cis-isomer of retinoic acid Eur Arch Otorhinolaryngol 247 6 1990 382 383 2149010 7 Suri R. Ronish B. Anklesaria Z. Woo H. Spelunking Meckel Cave: a 31-year-old with diplopia and loss of taste and smell Chest 154 2 2018 e45 e48 30080523
PMC007xxxxxx/PMC7235557.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)30941-5 10.1016/j.jaad.2020.05.073 Research Letter Cutaneous manifestations related to coronavirus disease 2019 (COVID-19): A prospective study from China and Italy De Giorgi Vincenzo MD a∗ Recalcati Sebastiano MD b Jia Ziyi MD c Chong Wei MD c Ding Renyu MD d Deng Yunhua MD e Scarfi Federica MD f Venturi Federico MD a Trane Luciana MD a Gori Alessia MD a Silvestri Flavia MD a Gao Xing-Hua MD g Lotti Torello MD h a Department of Dermatology, University of Florence, Florence, Italy b Department of Dermatology, Azienda Socio Sanitaria Territoriale Lecco, Alessandro Manzoni Hospital, Lecco, Italy c Department of Emergency, The First Hospital of China Medical University, Shenyang, China d Intensive Care Unit, The First Hospital of China Medical University, Shenyang, China e Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Tecnology, Wuhan, China f Dermatology Unit, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy g Department of Dermatology, The First Hospital of China Medical University, Shenyang, China h Dermatology, University of Studies Guglielmo Marconi, Rome, Italy ∗ Reprint requests: Vincenzo de Giorgi, MD, Department of Dermatology, University of Florence, Via Michelangelo 41, 50124 Florence, Italy 19 5 2020 8 2020 19 5 2020 83 2 674675 © 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 report the results of a binational, multicenter, prospective study to assess cutaneous involvement during the course of coronavirus disease 2019 (COVID-19). Between January 1 and March 15, 2020, we investigated the epidemiologic and clinical features of cutaneous manifestations in adult patients with COVID-19. The data were collected prospectively by experienced dermatologists in Wuhan, Hubei province, China, and Lecco, Lombardia region, Italy. Institutional Review Boards approved the study. Four participating hospitals (3 in China, 1 in Italy) enrolled patients diagnosed with COVID-19, according to World Health Organization interim guidance.1 Whenever possible, all new cutaneous findings and pre-existing dermatologic diagnoses were recorded at admission to assess the possible influence of hospital-based treatment and external factors. History and physical examinations were used to categorize all dermatologic conditions as pre-existing vs newly arising. This observational cross-sectional study enrolled 678 patients with polymerase chain reaction-confirmed COVID-19. Patients were classified by disease severity based on Chinese Diagnosis and Treatment Scheme for SARS-CoV-2: 6.0% (41 patients) were considered “critically-ill,” 17.5% (118 patients) “severe,” 18.7% (127 patients) “common,” and 57.8% (392 patients) “mild.” In this cohort, 53 patients (7.8%) had new dermatologic conditions that were detected at admission or during hospitalization. This subgroup was a mean age of 55.9 years (range, 28-69 years), and 60% were men (Table I ). Of the dermatologic conditions, 44% were present on the day of the COVID-19 diagnosis, roughly at the onset of the typical flu-like symptoms. The remaining 56% of dermatoses were observed at a mean of 11.7 days (range, 2-23 days after hospitalization).Table I Main epidemiologic and clinical characteristics of the study population Variables Patients∗ Total Patients with COVID-19 (pharyngeal swab-positive) 678 Italian patients 92 Chinese patients 586 Degree of disease severity† Critical types 41 (6) Severe types 118 (17.5) Common types 127 (18.7) Mild types 392 (57.8) Patients with COVID19 with skin manifestations 53 (7.8) Male 32 (60) Female 21 (40) Age, y 55.9 (28-69) Chinese patients 53.2 (28-65) Italian patients 58.6 (35-69) Inflammatory skin manifestations related to COVID-19 53 Erythematous rash 37 (70) Diffuse urticaria 14 (26) Varicelliform rash with vesiculation 2 (4) Vascular skin manifestations in intensive care patients Diffuse petechiae, purpura, and acroischemia 13 Onset of inflammatory skin manifestations related to COVID-19 53 Before hospitalization 23 (44) After hospitalization 30 (56) Duration of inflammatory skin manifestations, d 3 (2-5) COVID-19, Coronavirus disease 2019. ∗ Patient data are presented as number (%) or mean (range). † Degree of disease severity: For the mild type: slight clinical symptoms with no pneumonia presentation in imaging. For the common type: manifestations such as fever or respiratory presentation with pneumonia by radiography, or both. For the severe type (meeting any of the following conditions): (1) dyspnea, respiration rate 30 times/min; (2) finger oxygen saturation under resting 93%; (3) arterial partial pressure of arterial oxygen/fraction of inspired oxygen 300 mm Hg (1 mm Hg = 0.133 kPa). For the critical type (meeting any of the following conditions): (1) respiratory failure requiring mechanical ventilation; (2) shock; (3) combined with other organ failures requiring an intensive care unit. Of the 53 patients with new inflammatory skin findings, the most common finding was erythematous rash (70%), seen over a wide spectrum of clinical appearances (macular, papular, maculopapular, and erythema multiforme-like eruptions), followed by diffuse urticaria (26%). Two patients (4%) had scattered vesicular, varicelliform eruptions2; in both, we ruled out herpes simplex virus and varicella zoster virus clinically and by performing polymerase chain reaction. Most patients who presented with an erythematous rash had mild itch. There was no correlation between the presence of rash and fever. Involved sites were primarily the trunk and upper limbs, but the head and face were largely spared. In this group, younger patients seem to display more intense and disseminated cutaneous manifestations, including darker red, larger wheal-like and purpuric lesions. All exanthems were short-lived and resolved spontaneously without specific dermatologic treatment after mean of 3 days (range, 2-5 days). The dermatologic manifestations could not be correlated to COVID-19 severity. Diffuse petechiae, gravity-dependent, and multiple, generalized palpable purpura, and acroischemia (primarily finger/toe cyanosis, but neither skin bulla nor dry gangrene) were seen in more severe cases. These manifestations were associated with clotting disorders, reflected in increased prothrombin time and fibrinogen and D-dimer levels, which are seen in intensive care patients.3, 4, 5 In conclusion, some patients with COVID-19 present with inflammatory cutaneous findings: 7.8% in our cohort of hospitalized adults. These skin findings are generally mild and self-limiting and do not correlate with overall prognosis. They generally resolve promptly without specific therapy. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Institutional Review Boards approved this study. ==== Refs References 1 World Health Organization Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected: interim guidance Available at: https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected 2020 2 Marzano A.V. Genovese G. Fabbrocini G. Varicella-like exanthem as a specific COVID-19-associated skin manifestation: multicenter case series of 22 patients J Am Acad Dermatol 83 1 2020 280 285 32305439 3 Huang C. Wang Y. Li X. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Lancet 6736 2020 1 10 4 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 10223 2020 507 513 32007143 5 Fernandez-Nieto D. Jimenez-Cauhe J. Suarez-Valle A. 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
PMC007xxxxxx/PMC7235574.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)30942-7 10.1016/j.jaad.2020.05.074 Review Hydroxychloroquine effects on psoriasis: A systematic review and a cautionary note for COVID-19 treatment Sachdeva Muskaan BHSc a Mufti Asfandyar MD b Maliyar Khalad BA a Lytvyn Yuliya PhD a Yeung Jensen MD, FRCPC b∗ a Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada b Department of Dermatology, University of Toronto, Toronto, Ontario, Canada ∗ Correspondence to: Jensen Yeung, MD, FRCPC, Derm, Women's College Hospital, Division of Dermatology, 76 Greenville St, 5th Floor, Toronto, ON M5S 1B2, Canada. 19 5 2020 8 2020 19 5 2020 83 2 579586 14 5 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 While evidence suggests that hydroxychloroquine (HCQ) may decrease the viral load in patients with a COVID-19 infection, a number of case reports indicate adverse dermatologic effects of this potential treatment. Objective To conduct a systematic review of previously reported cases of psoriasis onset, exacerbation, or relapse after HCQ treatment. Methods Embase and MEDLINE were comprehensively searched for original studies examining adverse effects of HCQ treatment related to psoriasis. Participant demographics and details of HCQ administration and psoriasis diagnosis were extracted from 15 articles representing 18 patients. Results Women accounted for a significantly larger number of cases of psoriasis compared with men and unreported sex (14 [77.8%] vs 2 [11.1%] vs 2 [11.1%], respectively). In addition, 50% (n = 9) of the patients did not have a history of psoriasis before taking HCQ. Of the 18 patients, 9 (50.0%) experienced de novo psoriasis, 5 (27.8%) experienced exacerbation of psoriatic symptoms, and 4 (22.2%) had a relapse of psoriasis after HCQ administration. Conclusion HCQ treatment may result in induction, exacerbation, or relapse of psoriasis. Monitoring for adverse effects of HCQ treatment is necessary, and clinical trials are essential in characterizing the safety profile of HCQ use in patients with a COVID-19 infection. Key words COVID-19 exacerbation hydroxychloroquine induction Plaquenil psoriasis relapse Abbreviations used HCQ hydroxychloroquine IL interleukin ==== Body pmc Capsule Summary • Dermatologic effects of hydroxychloroquine are poorly understood. • Cases of new onset, relapse, or exacerbations of psoriasis have been reported with the use of hydroxychloroquine. It is especially important to monitor for such adverse effects during the potential use of hydroxychloroquine for treatment or prophylaxis in patients with a COVID-19 infection. Hydroxychloroquine (HCQ) has been approved since 1955 for the prevention and treatment of malaria.1 Since then, its use has been extended to effectively treat a number of autoimmune disorders,2 such as systemic lupus erythematosus3 , 4 and rheumatoid arthritis.5 Evidence suggests that HCQ may also have potent antiviral properties. This discovery prompted recent investigations for the potential use of this drug to treat patients with COVID-19, a novel infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) initially reported in Wuhan, China, in December 20196 and resulting in more than 200,000 deaths worldwide by April 2020.7 Recent open-labeled, nonrandomized clinical trials showed that HCQ may decrease viral load and may improve outcomes in a small number of patients with COVID-19.8, 9, 10, 11 Despite the lack of strong evidence, the rapid spread of COVID-19 led the United States Food and Drug Administration to approve emergency use of HCQ in hospitalized patients who do not have alternative treatment options.12 However, the efficacy and safety profile of this drug are yet to be reported in ongoing randomized controlled trials.13 A number of case reports indicate adverse dermatologic effects of HCQ treatment, including new onset or exacerbation of psoriasis. Most recently, a 71-year-old patient with COVID-19 was reported to have an exacerbation of pre-existing psoriasis with silvery-scaled psoriatic plaques after 4 days of HCQ treatment.14 As the incidence of COVID-19 infections increase, it is important for health care providers to recognize and manage the relevant adverse effects associated with potential HCQ treatment. Therefore, this systematic review was conducted to comprehensively summarize existing literature on the new onset, exacerbations, or relapse of psoriasis after HCQ use. This will be an important step in assessing the potential dermatologic impact of HCQ. Methods This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Search strategy The search was conducted using the Embase and MEDLINE databases in OVID on April 21, 2020. No language or date restrictions were applied. Variations of the following keywords were used for the search: “hydroxychloroquine,” “Plaquenil,” “chloroquine,” or “anti-malarial” in combination with “psoriasis,” “plaque,” “guttate,” “pustular,” “erythrodermic psoriasis,” or “psoriatic.” Study eligibility criteria Original articles that explored the effects of HCQ on psoriasis were included in this systematic review if they (1) involved human participants, (2) were observational (ie, case reports, case series, cross-sectional, or cohort studies) or experimental (ie, randomized controlled trials) studies, (3) involved HCQ as an intervention, (4) included patients with psoriasis, and (5) were written in the English language. Study selection Two reviewers (M.S and K.M.) independently screened titles, abstracts, and full texts of retrieved articles and determined study eligibility. Discrepancies or conflicts were resolved through discussion with a third reviewer (A.M.). Reference lists from all relevant articles were checked to identify additional studies not identified in the initial database search. Data collection Two reviewers (M.S and K.M.) independently reviewed and extracted data from each study using a structured form. Conflicts were reviewed collectively, and if consensus was not reached, a third reviewer was consulted (A.M.). Study design, patient demographic data, dose and frequency of HCQ, and details of psoriasis diagnosis and lesions were extracted and are summarized in Table I .14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 Because there are no standardized response criteria for psoriatic lesions from HCQ use, we defined response as follows:1. “Exacerbation” was defined as worsening of existing psoriasis, in terms of severity or lesion count, after administration of HCQ. 2. “Relapse” was defined as eruption of psoriatic lesions after administration of HCQ in individuals with a past medical history of psoriasis. 3. “Induction” was defined as de novo eruption of psoriatic lesions after administration of HCQ, without a current or past medical history of psoriasis. Table I The effect of hydroxychloroquine (HCQ) on psoriasis Study information Demographic information Information about HCQ Information about psoriatic lesions after HCQ administration Evidence level15 Study type, year Sample size Age, sex Comorbidities Psoriasis history Dose and frequency Concurrent treatment (dose and frequency) Latency period Type of psoriasis Outcome Lesion description Location BSA/PASI score CR,16 2019 1 65, F Rheumatoid arthritis No NR Methylprednisolone (NR) 1 week Inverse psoriasis Induction Maculopapular, erythematous rash with silver hue and irregular borders Scalp, face, neck, armpits, breasts, back, groin, buttocks, mouth NR 5 CR,17 2018 1 41, F Systemic lupus erythematosus No 200 mg twice daily Prednisone (30-60 mg daily) 2 months Erythrodermic psoriasis Induction Erythroderma Toenails were yellow and showed hyperkeratosis Full body BSA: 100% PASI: 61.2 5 CR,18 2019 1 34, F Systemic lupus erythematosus No 200 mg daily Prednisolone (20 mg daily), tacrolimus (3 mg daily) 3 weeks Generalized pustular psoriasis Induction Pustular rash Auricle, scalp, forearm 21 days after HCQ initiation NR 5 CR,14 2020 1 71, F COVID-19 infection Yes 2 × 400 mg first day, 2 × 200 mg daily Oseltamivir (2 × 75 mg) 4 days NR Relapse Silver-scaled psoriatic plaques separated from the surrounding tissue with sharp borders Full body NR 5 CS,19 2014 2 40, F Lichen planopilaris No 2 × 200 mg daily None 1 month Pustular psoriasis of erythema centrifugum type Induction Erythematous papules and erythema migrans centrifugum-like skin lesions, with peripheral collarette of tiny superficial pustules Lumbar and presternal areas, scalp NR 4 37, F None Yes 100 mg daily Methylprednisolone (NR) 3 weeks Pustular transformation of pregnancy-triggered psoriasis Relapse Suberythroderma with areas of extensive exfoliation and islands of healthy-looking skin partially covered by confluent superficial pustules NR NR CR,20 2018 1 56, F Crohn's disease, rheumatoid arthritis Yes 200 mg daily Ustekinumab (90 mg every 2 months) 1 year Inverse psoriasis Relapse Large, well-demarcated pink plaques with minimal scale and a few satellite lesions with a collarette of scale Vagina extending into the perineum, buttocks, and perianal area NR 5 CR,21 1985 1 31, F Psoriatic arthritis Yes 200 mg daily None 11 days NR Relapse Generalized erythroderma with macular and popular lesions coalescing in a reticular pattern. Desquamation and bullae (0.5 cm-1cm) Face, arms, trunk and forearms NR 5 CR,22 2015 1 50, F Lichen planus pigmentosus No NR NR 4 weeks NR Induction Multiple, thick, erythematous, scaly papules confluent into plaques Blue-gray ill-defined patches Scalp, ears, neck, back, chest, abdomen, bilateral upper and lower extremities, dorsal surfaces of hands and feet Face, neck, upper portion of chest, lower part of back, upper aspect of abdomen BSA: 80% 5 CR,23 1987 1 60, M Rheumatoid arthritis No 200 mg twice daily Prednisone (10 mg twice daily), naproxen (500 mg twice daily) 3 weeks NR Induction Generalized erythematous 1- to 2-mm popular and pustular eruption Trunk, arms, hands, penis NR 5 CR,24 1990 1 69, M Pemphigus erythematous No 200 mg daily Quinidine bisulfate (500 mg daily), isosorbide dinitrate (10 mg daily) 2 weeks Pustular psoriasis Induction Erythematous patches and multiple small pustules Trunk and flexures NR 5 CR,25 2015 1 57, F Primary Sjogren syndrome (however, lack of sicca symptoms or mucosal dryness makes this diagnosis unlikely) Polyarthralgia No NR NR 1 week NR Induction Diffuse targetoid erythematous papules and plaques 15-20 hyperkeratotic 1-2 cm plaques Back BSA: 80% 5 P,26 2015 2/114 NR Psoriatic arthritis Yes NR NR 3.5 years (mean) NR Exacerbation Increase in psoriatic lesions NR NR 4 Psoriatic arthritis Yes NR NR 3.5 years (mean) NR Exacerbation Increase in psoriatic lesions NR NR CS,27 1989 2 40, F Systematic lupus erythematosus Yes 200 mg daily Methotrexate (10 mg once/week) 2 weeks NR Exacerbation Plaque-like psoriatic lesions Bilateral malar patches Face and full body 50% BSA 4 25, F Systematic lupus erythematosus Yes NR NR NR NR Exacerbation Pustular lesions Scalp, trunk, limbs NR CR,28 2016 1 70, F Mixed connective tissue disorder Yes NR NR 2 weeks Generalized pustular psoriasis Exacerbation Extensive erythematous patches Full body NR 5 CR,29 2010 1 55 F None No NR Prednisolone (0.5 mg/kg) 3 weeks NR Induction Thick, scaly psoriasiform plaques Around eyes, upper neck, upper back NR 5 BSA, Body surface area; CR, case report; CS, case series; F, female; M, male; NR, not reported; PASI, Psoriasis Area and Severity Index; P, prospective. Level of evidence evaluation and statistical analysis The level of evidence for all included articles was assessed independently by 2 reviewers (M.S. and K.M.) using the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence.15 Owing to the considerable heterogeneity of the included studies, a descriptive analysis was undertaken. Results The search strategy yielded 354 records once duplicates were removed. After screening the titles and abstracts for relevance, 55 records were selected for a full-text review. In total, 15 studies met eligibility criteria and were used for data collection and analysis of 18 patients (Fig 1 , Table I).14 , 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 The analysis of the level of evidence showed that 3 studies (20.0%) had a level of evidence of 4,19 , 26 , 27 and 12 studies (80.0%) had a level of evidence of 5.14 , 16, 17, 18 , 20, 21, 22, 23, 24, 25 , 28 , 29 Overall, patients were aged between 25 and 71 years. There were 2 men (11.1%) and 14 women (77.8%), and the sex of 2 patients (11.1%) was not reported.Fig 1 Selection process for study inclusion in the systematic review. Of 18 patients who reported psoriasis-related complications due to HCQ, 9 (50%) did not have a history of psoriasis before taking HCQ, and 9 (50.0%) did have a psoriasis diagnosis before HCQ treatment. Psoriasis history was not reported for 1 patient (5.6%). Comorbidities were present in 88.9% (n = 16) of patients: 22.2% (n = 4) had systemic lupus erythematosus, 16.7% (n = 3) had rheumatoid arthritis, 16.7% (n = 3) had psoriatic arthritis, 11.1% (n = 2) had lichen planus, 5.6% (n = 1) had Crohn's disease, and 1 patient each had COVID-19, pemphigus erythematosus, mixed connective tissue disorder, polyarthralgia, and primary Sjogren syndrome. Of the 18 patients, 50.0% (n = 9) experienced de novo psoriasis, 27.8% (n = 5) experienced exacerbation of psoriatic symptoms, and 22.2% (n = 4) had a relapse of psoriasis after HCQ administration. From the 9 de novo psoriasis cases, 33.3% (n = 3) had pustular psoriasis, 11.1% (n = 1) had inverse, 11.1% (n = 1) had erythrodermic, and the type of psoriasis was not recorded in 44.4% (n = 4). The type of psoriasis in the 9 patients experiencing exacerbation or relapse of psoriasis after HCQ treatment included 22.2% (n = 2) pustular, 11.1% (n = 1) inverse, and was not recorded in 66.7% (n = 6). No pattern was noted in the location of the psoriatic lesions after HCQ use. Specifically, the distribution of lesions was 38.9% (n = 7), on the chest/abdomen, 33.3% (n = 6) on the limbs and digits, 27.8% (n = 5) on the scalp, 22.2% (n = 4) on the face, and 16.77% (n = 3) on the back groin/buttocks and neck, respectively. Four patients (22.2%) reported lesions covering the entire body. Discussion Psoriasis is an autoimmune, chronic inflammatory skin disease that may be induced or exacerbated by HCQ, a synthetic antimalarial drug commonly used for the treatment of autoimmune disorders such as systemic lupus erythematosus and rheumatoid arthritis.1 , 12 , 25 In the 15 studies identified in the literature, which included 18 patients, the data demonstrated that 50.0% of patients experienced a new diagnosis of psoriasis and that 50.0% of these patients experienced a relapse or an exacerbation of previously diagnosed psoriasis. In light of the potential for HCQ use to treat COVID-19 infections,6 , 30 it is important for health care providers to recognize the impact of HCQ on psoriasis onset, relapse, or exacerbation. Although the exact mechanisms by which antimalarial drugs are able to induce psoriatic flares are not completely understood,19 several potential mechanisms have been implicated. An in vitro study conducted by Wolf et al31 noted hyperproliferation and irregular keratinization on skin cultures induced by HCQ. This may be due to the inhibiting effect HCQ has on epidermal transglutaminase activity, which leads to an initial break in the epidermal barrier. The resulting epidermal proliferation aimed at barrier restoration may lead to the induction or worsening of psoriasis.31 In addition, HCQ may promote the production of interleukin (IL)-17 via p38-dependant IL-23 release, resulting in increased keratinocyte growth.32 Furthermore, HCQ may interfere with the cholesterol metabolism process, which is crucial for the structural and functional integrity of the stratum corneum.33 Lastly, among the patients identified in this study, women predominated (77.8% [n = 14]). Given that autoimmune diseases are more prevalent in women, the role of sex hormones may be suggested.34 Our systematic review has several limitations that must be considered. Firstly, all summarized studies are case reports and case series. As a result, the lack of larger trials and the observational nature of the studies limit the scope of analysis and generalizability of our findings to all patients using HCQ treatment. Additionally, attributing the development of psoriasis to HCQ use alone is difficult, because autoimmune comorbidities, such as rheumatoid arthritis and systemic lupus erythematosus, may predispose individuals to psoriasis due to dysregulation of common cytokines.17 , 18 It is important to note that 92.3% of the studied patients had comorbid conditions, with the autoimmune disorders rheumatoid arthritis (33.3%) and systemic lupus erythematosus (25.0%) being the 2 most significant. As a result, attributing causality between psoriatic development or exacerbation and HCQ use alone may be difficult, because these autoimmune comorbidities may predispose individuals to psoriasis due to dysregulation of common cytokines such as Il-17 and IL-23.35 , 36 Furthermore, 6 patients (33.3%) reported in this systematic review were also taking oral steroids. Of these 6 patients, 2 developed de novo erythrodermic psoriasis and pustular psoriasis respectively, and 1 experienced a relapse of pustular psoriasis. Given that oral steroids have been reported to induce or precipitate erythrodermic and pustular psoriasis, HCQ may not have been solely responsible for the induction or relapse of psoriasis in these cases.37 , 38 In addition to the known adverse effects of HCQ, such as QT prolongation, conduction abnormalities, and restrictive or dilated cardiomyopathy,39 , 40 it is also essential to understand the impact of HCQ on exacerbation, relapse, or new onset of psoriatic lesions. Although no robust peer-reviewed evidence exists at this time, a recent news article reported a higher mortality rate (27.8%) among patients with COVID-19 who were administered HCQ compared with those who were not (11.4%).41 This article brought attention to the significance of waiting for further evidence before extensive promotion and acceptance of this drug. Additional studies examining the safety profile of HCQ, especially in patients with psoriasis, are desperately needed before its potential use for COVID-19 infection. Given the lack of rigorous evidence available, further studies with larger sample sizes are required to confirm the findings reported in this systematic review. Many randomized trials are actively recruiting participants to determine the safety profile of HCQ treatment in patients with COVID-19.42, 43, 44, 45, 46 The results from these studies will be key to determining whether HCQ treatment is significantly associated with exacerbation, relapse or new onset of psoriasis. Funding sources: None. Conflicts of interest: Dr Yeung has been a speaker, consultant, and investigator for AbbVie, Allergan, Amgen, Astellas, Boehringer Ingelheim, Celgene, Centocor, Coherus, Dermira, Eli Lilly, Forward, Galderma, GSK, Janssen, Leo, MedImmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Takeda, UCB, Valeant, and Xenon. Ms Sachdeva, Mr Maliyar, and Drs Mufti and Lytvyn have no conflicts of interest to declare. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Balak D. Hajdarbegovic E. Drug-induced psoriasis: clinical perspectives Psoriasis (Auckl) 7 2017 87 94 29387611 2 Rainsford K.D. Parke A.L. Clifford-Rashotte M. Kean W.F. Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases Inflammopharmacology 23 5 2015 231 269 26246395 3 Ponticelli C. Moroni G. Hydroxychloroquine in systemic lupus erythematosus (SLE) Expert Opin Drug Saf 16 3 2017 411 419 27927040 4 Costedoat-Chalumeau N. Dunogué B. Morel N. Le Guern V. Guettrot-Imbert G. Hydroxychloroquine: a multifaceted treatment in lupus Presse Med 43 6 Pt 2 2014 e167 e180 24855048 5 Olsen N.J. Schleich M.A. Karp D.R. Multifaceted effects of hydroxychloroquine in human disease Semin Arthritis Rheum 43 2 2013 264 272 23481418 6 Guo Y.-R. Cao Q.-D. Hong Z.-S. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status Mil Med Res 7 1 2020 11 32169119 7 Han Y, Yang H. The transmission and diagnosis of 2019 novel coronavirus infection disease (COVID-19): a Chinese perspective [e-pub ahead of print]. J Med Virol. doi:10.1002/jmv.25749, Accessed May 7, 2020. 8 Gautret P, Lagier J-C, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial [e-pub ahead of print]. Int J Antimicrob Agents. doi:10.1016/j.ijantimicag.2020.105949, Accessed May 7, 2020. 9 Gao J. Tian Z. Yang X. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies Biosci Trends 14 2020 72 73 32074550 10 Chen Z. Hu J. Zhang Z. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial [preprint]. Version 2 medRxiv 2020 https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v3 11 Yan D. Zhang Z. Therapeutic effect of hydroxychloroquine on novel coronavirus pneumonia (COVID-19). Chinese Clinical Trials Registry Available at: http://www.chictr.org.cn/showproj.aspx? proj=48880 12 U.S. Food and Drug Administration Letter: Request for Emergency Use Authorization For Use of Chloroquine Phosphate or Hydroxychloroquine Sulfate Supplied From the Strategic National Stockpile for Treatment of 2019 Coronavirus Disease Available at: https://www.fda.gov/media/136534/download 2020 13 Sahraei Z. Shabani M. Shokouhi S. Saffaei A. Aminoquinolines against coronavirus disease 2019 (COVID-19): chloroquine or hydroxychloroquine Int J Antimicrob Agents 55 4 2020 105945 32194152 14 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 10.1111/dth.13383 32259878 15 Centre for Evidence Based Medicine (CEBM) Oxford Centre for Evidence-based Medicine - Levels of Evidence (March 2009) Available at: https://www.cebm.net/2009/06/oxford-centre-evidence-based-medicine-levels-evidence-march-2009 2016 16 Ullah A. Zeb H. Khakwani Z. Murphy F.T. Hydroxychloroquine-induced inverse psoriasis BMJ Case Rep 12 2 2019 bcr-2018 17 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 Med J (Engl) 131 15 2018 1887 1888 30058593 18 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 19 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 20 Darwin E. Deshpande A. Lev-Tov H. Development of drug-induced inverse psoriasis in a patient with Crohn's disease ACG Case Rep J 5 2018 e47 29951562 21 Slagel G.A. James W.D. Plaquenil-induced erythroderma J Am Acad Dermatol 12 5 1985 857 862 3159760 22 Seminario-Vidal L. Hughey L.S. Hydroxychloroquine de novo-induced psoriasis in a patient with lichen planus pigmentosus Skinmed 13 6 2015 492 26861533 23 Friedman S.J. Pustular psoriasis associated with hydroxychloroquine J Am Acad Dermatol 16 6 1987 1256 1257 3597864 24 Lotem M. Ingber A. Segal R. Sandbank M. Generalized pustular drug rash induced by hydroxychloroquine Acta Derm Venerol 70 3 1990 250 251 1972842 25 McCoy S. Nagaraja V. Paviol S. Gudjonsson J.E. Kahlenberg J.M. Exacerbation of psoriasis due to hydroxychloroquine Arch Med 7 2015 1 3 26 Aydın S. Yılmazer B. Bayındır Ö. AB0827 Hydroxychloroquine does not increase psoriasis in psoriatic arthritis: time on drug analysis based on real life data Ann Rheum Dis 74 2015 1177 27 Green L.S. Saperia D. Lowe N.J. David M. Coexistent psoriasis and lupus erythematosus: successful therapy with etretinate J Dermatolog Treat 1 1 1989 19 22 28 Maglie R. Dini V. Romanelli M. Pustular psoriasis induced by hydroxychloroquine: a case report to confirm a rare association: 3734 J Am Acad Dermatol 74 5 2016 29 Ahmad K. Ramsay B. Evolution of signs… rethink… rebiopsy: P2208 J Am Acad Dermatol 62 3 2010 AB79 30 Zhai P. Ding Y. Wu X. Long J. Zhong Y. Li Y. The epidemiology, diagnosis and treatment of COVID-19 Int J Antimicrob Agents 2020 105955 32234468 31 Wolf R. Schiavo A.L. Lombardi M.L. Angelis F.D. Ruocco V. The in vitro effect of hydroxychloroquine on skin morphology in psoriasis J Dermatol 38 2 2001 154 157 32 Said A. Bock S. Lajqi T. Müller G. Weindl G. Chloroquine promotes IL-17 production by CD4+ T cells via p38-dependent IL-23 release by monocyte-derived Langerhans-like cells J Immunol 193 12 2014 6135 6143 25385822 33 Ruiz-Irastorza G. Ramos-Casals M. Brito-Zeron P. Khamashta M.A. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review Ann Rheum Dis 69 01 2010 20 28 19103632 34 Moroni L. Bianchi I. Lleo A. Geoepidemiology, gender and autoimmune disease Autoimmun Rev 11 6-7 2012 A386 A392 22142547 35 Ayala-Fontánez N. Soler D.C. McCormick T.S. Current knowledge on psoriasis and autoimmune diseases Psoriasis (Auckl) 6 2016 7 29387591 36 Furue K. Ito T. Tsuji G. Kadono T. Nakahara T. Furue M. Autoimmunity and autoimmune co-morbidities in psoriasis Immunology 154 1 2018 21 27 29315555 37 Elston G.E. Charles-Holmes R. Carr R.A. Precipitation of generalized pustular psoriasis by prednisolone Clin Exp Dermatol 31 1 2006 133 134 16309508 38 Rendo M. Boster J. Dalton S.R. Yun H. An uncommon presentation of erythrodermic psoriasis in a patient without a history of psoriasis Cureus 11 7 2019 e5099 31523531 39 Shapiro M. Levy Y. The association between hydroxychloroquine treatment and cardiovascular morbidity among rheumatoid arthritis patients Oncotarget 9 5 2017 6615 6622 29464097 40 Jallouli M. Hydroxychloroquine-induced pigmentation in patients with systemic lupus erythematosus JAMA Dermatol 149 8 2013 935 23824340 41 Cohen E. Nigam M. Study finds no benefit, higher death rate in patients taking hydroxychloroquine for Covid-19. April 21, 2020. CNN Health Available at: https://www.cnn.com/2020/04/21/health/hydroxychloroquine-veterans-study/index.html 42 ClinicalTrials.gov Hydroxychloroquine Treatment for Severe COVID-19 Pulmonary Infection (HYDRA Trial) (HYDRA). Identifier NCT04315896. March 20, 2020. Bethesda (MD): National Library of Medicine (US) Available at: https://clinicaltrials.gov/ct2/show/NCT04315896?id= NCT04315896 43 ClinicalTrials.gov The PATCH Trial (Prevention And Treatment of COVID-19 With Hydroxychloroquine) (PATCH). Identifier NCT04329923. April 9 2020. Bethesda (MD): National Library of Medicine (US) Available at: https://clinicaltrials.gov/ct2/show/NCT04329923?id=NCT04329923 44 ClinicalTrials.gov. Hydroxychloroquine for COVID-19 (COV-HCQ). Identifier NCT04342221. April 10, 2020. Bethesda (MD): National Library of Medicine (US) Available at: https://clinicaltrials.gov/ct2/show/NCT04342221?id=NCT04342221 45 ClinicalTrials.gov A Randomized Controlled Clinical Trial: Hydroxychloroquine for the Treatment of COVID-19 in Hospitalized Patients (OAHU-COVID19). Identifier NCT04345692. April 10, 2020. Bethesda (MD): National Library of Medicine (US) Available at: https://clinicaltrials.gov/ct2/show/NCT04345692?id= NCT04345692 46 ClinicalTrials.gov Hydroxychloroquine in Outpatient Adults With COVID-19). Identifier NCT04333654. April 10, 2020. Bethesda (MD): National Library of Medicine (US) Available from: https://clinicaltrials.gov/ct2/show/NCT04333654?id=NCT04333654 2000
PMC007xxxxxx/PMC7237944.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)30943-9 10.1016/j.jaad.2020.04.180 JAAD Online 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 Llamas-Velasco Mar MD, PhD a∗ Rodríguez-Jiménez Pedro MD a Chicharro Pablo MD a De Argila Diego MD a Muñoz-Hernández Patricia MD b Daudén Esteban MD, PhD a a Department of Dermatology, Instituto de Investigación Sanitaria la Princesa (IIS-IP), Hospital Universitario de La Princesa, Madrid, Spain b Department of Pathology, Hospital Universitario de La Princesa, Madrid, Spain ∗ Correspondence to: Mar Llamas-Velasco, Dermatology Department, Diego de León St 62, CP 28006, Madrid, Spain 20 5 2020 9 2020 20 5 2020 83 3 e253e254 © 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 have read with great interest the article by Marzano et al1 considering varicella-like papulovesicular exanthem as a rare but specific coronavirus disease 2019 (COVID-19)–associated skin manifestation. They included patients with a COVID-19–positive nasopharyngeal swab and no medications in the previous 15 days with varicella-like lesions.1 A previous case report of COVID19-related varicella-like vesicles had also been published by Recalcati2 for the very first time. However, only the Marzano et al1 article included scarce clinical images due to safety or logistic concerns. In these past few weeks we have been living in an epidemic situation in Spain, considered by the World Health Organization as an area of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) of community transmission, especially in Madrid.3 Since then, we began to observe different skin manifestations in patients with COVID-19 infection. We encountered 3 in-ward patients during the last few weeks, all with microbiologically proven COVID-19 by nasopharyngeal swab, and all of them presenting with vesicles (Table I, Figs 1 and 2 ).Table I Summary of patients with coronavirus disease 2019 (COVID-19) positivity and cutaneous scattered vesicles Patient Sex Age, y Past relevant medical history COVID symptoms Chest x-ray Total number of days since onset of symptoms Medications Lymphocyte count∗ 1 Female 59 None Fever Dry cough Dyspnea Bilateral interstitial pneumonia 25 Hydroxychloroquine Lopinavir/ritonavir Ceftriaxone 620/mm3 2 Male 69 None Fever Dry cough Dyspnea Myalgias Bilateral interstitial pneumonia 43 Hydroxychloroquine Lopinavir/ritonavir Amoxicillin/clavulanic acid 820/mm3 3 Male 79 Parkinson disease Melanoma Fever Skin rash Normal 21 None 710/mm3 ∗ Lower count of lymphocytes of the patient during the follow-up of COVID-19 infection. Fig 1 Patient 1: Vesicles and punched out perioral erosions. Because the COVID-19 infection mechanism to produce vesicles is not known, we performed a herpesvirus family microarray polymerase chain reaction of the vesicle fluid, and we demonstrated a combination of herpes simplex-1 virus, herpes simplex-6 virus, and Epstein-Barr virus in patient 1, herpes simplex-1 virus and herpes simplex-7 in patient 2, and varicella zoster virus in patient 3. We could not simultaneously perform SARS-COV-2 polymerase chain reaction in the vesicle fluid, so we cannot completely rule out its additional involvement. Marzano and colleagues did not mention in their article whether they ruled out a herpes virus infection in every case; one might assume they did, and therefore used the term varicella-like exanthem.Fig 2 Patient 3: Hemorrhagic blisters on the (A) anterior trunk and (B) posterior trunk. COVID-19 infection characteristically produces lymphopenia, and we have previous evidence of lymphopenia, which is a known factor favoring herpesvirus recurrences, in our 3 patients. We would like to know whether the patients in the Marzano et al1 report also had this characteristic sign in their blood tests. Finally, we agree with the idea of further studying this recently described varicella-like exanthem to clarify how we can distinguish it from other dermatosis and use it to identify otherwise asymptomatic patients to test them earlier. But even today, when it seems that all of our patients are affected by COVID-19 and all the skin diseases may be related to COVID-19, we must keep in mind that other dermatologic diseases still exist. That is why we think that when we face a patient presenting with a varicella-like rash, we should perform Tzanck smear, virus culture, polymerase chain reaction on the vesicle fluid, or skin biopsy, or a combination of these, to rule out disseminated forms of other common viral infections. Drs Llamas-Velasco and Rodríguez-Jiménez contributed equally to the manuscript. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Marzano A.V. Genovese G. Fabbrocini G. Varicella-like exanthem as a specific COVID-19-associated skin manifestation: multicenter case series of 22 patients J Am Acad Dermatol 83 1 2020 280 285 32305439 2 Recalcati S. Cutaneous manifestations in COVID-19: a first perspective [e-pub ahead of print]. J Eur Acad Dermatol Venereol. 10.1111/jdv.16387 3 World Health Organization Novel coronavirus situation reports https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports
PMC007xxxxxx/PMC7241383.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)30947-6 10.1016/j.jaad.2020.05.078 JAAD Online Comment on: “Acral findings during the COVID-19 outbreak: Chilblain-like lesions should be preferred to acroischemic lesions” 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, Ramón y Cajal Health Research Institute, Madrid, Spain ∗ Correspondence to: Diego Fernandez-Nieto, Dermatology Department, Ramon y Cajal University Hospital, Carretera Colmenar Viejo km 9.100, 28034 Madrid, Spain 21 5 2020 9 2020 21 5 2020 83 3 e233e234 © 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 appreciate the interest in our article and the comment by Drs Piccolo and Bassi1 in which they propose to use the term “chilblain-like lesions” instead of “acroischemic lesions” to denominate the acral lesions in patients with coronavirus disease 2019 (COVID-19). At the time we were analyzing our study, only 2 papers reporting “acroischemia” in COVID-19 patients had been published, and thus, we acquired the same name. In the next days, numerous articles were published reporting these acral lesions with different terms, including chilblain-like lesions, chilblains, pseudochilblain, erythema pernio-like, perniosis-like, vascular skin symptoms, vascular acrosyndromes, COVID-19–induced chilblains, or chilblains of lockdown, among others. Dermatology has been traditionally a morphologic and descriptive specialty, and we still use a plethora of ancient names based on morphology of skin lesions. We are prone to create new terms by adding the prefix pseudo-, or the suffix-like to original entities' names. This is usually due to clinical or histologic resemblance to the original entities or to an incomplete understanding of their pathophysiology.2 It is true that many of the reported cases are morphologically similar to classical chilblains or pernio. However, several articles from different countries reported acral lesions with little or no resemblance to chilblains, also affecting other areas than just the fingers, including yellowish-erythematous plaques on the heels, targetoid pink plaques on the dorsum of feet, hands or elbows, swollen and violaceous toes, or acral non-necrotic purpura. We also found in our study a pattern with coalescing macules and vesicles, some of them with targetoid appearance, which did not fit in the classical chilblain description.3 As Piccolo and Bassi stated, etymology of the word “chilblains” includes chill-(cold). However, most of the reported cases in COVID-19 times have not been related to cold exposure. Given the suggested alterations in coagulation, endothelial dysfunction, and thrombotic response associated with COVID-19,4 it is not unreasonable to think that similar stimuli (with different intensity) may play a role in these acral lesions both in asymptomatic and hospitalized patients. In fact, a recent French study did find “vascular microthrombi” in 2 biopsy specimens from nonhospitalized patients with chilblain-like lesions.5 We believe that acral skin lesions in COVID-19 patients are a continuum ranging from subtle erythematous macules, chilblain-like lesions, to gangrene or digital ischemia. It is possible that multiple etiologic factors are involved in the development of COVID-19 acral and nonacral skin lesions, including both coagulation disorders and immune responses. We agree that an international etymologic consensus should be created to group these skin manifestations, at least until the exact pathogenesis is elucidated. Chilblain-like lesions is the term used most often nowadays. It is a morphologic term that is better than the etiologic term acroischemic lesions. However, it is not a perfect term, because it would cover most of the skin manifestations, but not all of them. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Piccolo V. Bassi A. Acral findings during the COVID-19 outbreak: chilblain-like lesions should be preferred to acro-ischemic lesions J Am Acad Dermatol 83 3 2020 e231 32446827 2 Ghosh S. Jain V.K. “Pseudo” nomenclature in dermatology: what's in a name? Indian J Dermatol 58 5 2013 369 376 24082182 3 Fernandez-Nieto D. Jimenez-Cauhe J. Suarez-Valle A. Characterization of acute acroischemic 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 4 Levi M. Thachil J. Iba T. Levy J.H. Coagulation abnormalities and thrombosis in patients with COVID-19 Lancet Haematol 7 6 2020 e438 e440 32407672 5 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
PMC007xxxxxx/PMC7242179.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)30946-4 10.1016/j.jaad.2020.05.077 JAAD Online Acral findings during the COVID-19 outbreak: Chilblain-like lesions should be preferred to acroischemic lesions Piccolo Vincenzo MD a∗ Bassi Andrea MD bc a Dermatology Unit, University of Campania Luigi Vanvitelli, Naples, Italy b Unità Operativa di Dermatologia Lucca-Azienda USL Toscana Nordovest, Italy c Department of Health Science, University of Florence, Florence, Italy ∗ Correspondence to: Vincenzo Piccolo, MD, c/o II Policlinico, Edificio 9, Primo piano Via Pansini 5-80131, Naples, Italy 22 5 2020 9 2020 22 5 2020 83 3 e231e231 © 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 the recent paper by Fernandez-Nieto et al1 published in JAAD. The authors report a case series of acute acroischemic lesions affecting 132 nonhospitalized patients during the coronavirus disease 2019 (COVID-19) outbreak. The same cutaneous findings have been described all over the world, including a preliminary study that we conducted.2 In their article, Fernandez-Nieto et al1 repeatedly use the appellative “acroischemic” for this cutaneous manifestation. Moreover, they hypothesize a relationship between a COVID-19–related altered coagulation profile and these acral lesions. As the authors state, true ischemic lesions have been reported in severely ill patients with proven coronavirus infection.3 Although the comparison between acral lesions in asymptomatic patients and ischemic lesions in severe cases is important, we find the term “acute acroischemic lesions” not accurate. Patients present with painful or itchy erythematous-edematous lesions of the extremities, sometimes evolving to blistering. This presentation is similar to what it is commonly seen in chilblains. The word “chilblains” itself etymologically refers to cold exposure (chill = cold, blain = sore). The term chilblain-like lesions, in our opinion, therefore would be preferable for the lesions that present in these patients rather than acroischemic lesions. In addition, histopathology of these lesions is quite similar to chilblains, with an absence of true necrosis; this is different to what is typically found in hospitalized patients.4 Although the exact pathogenesis of this cutaneous sign is not known yet, a worldwide common nomenclature would in our opinion be a good starting point to avoid confusion among clinicians. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the author. ==== Refs References 1 Fernandez-Nieto D, Jimenez-Cauhe J, Suarez-Valle A, et al. Characterization of acute acroischemic lesions in nonhospitalized patients: a case series of 132 patients during the COVID-19 outbreak. J Am Acad Dermatol. 83(1):e61-e63. 2 Piccolo V. Neri I. Filippeschi C. Chilblain-like lesions during COVID-19 epidemic: a preliminary study on 63 patients [e-pub ahead of print] J Eur Acad Dermatol Venereol. 10.1111/jdv.16526 2020 3 Zhang Y. Cao W. Xiao M. Clinical and coagulation characteristics in 7 patients with critical COVID-2019 pneumonia and acro-ischemia [in Chinese] Zhonghua Xue Ye Xue Za Zhi 41 4 2020 302 307 32447934 4 Kolivras A. Dehavay F. Delplace D. Coronavirus (COVID-19) infection-induced chilblains: a case report with histopathological findings JAAD Case Rep 6 6 2020 489 492 32363225
PMC007xxxxxx/PMC7243762.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)30965-8 10.1016/j.jaad.2020.05.093 JAAD Online Recommendations for medical student preparedness and equity for dermatology residency applications during the COVID-19 pandemic Stewart Claire R. BA a Chernoff Karen A. MD b Wildman Horatio F. MD b Lipner Shari R. MD, PhD b∗ a Weill Cornell Medical College, New York, New York b Department of Dermatology, Weill Cornell Medicine, New York, New York ∗ Correspondence to: Shari R. Lipner, MD, PhD, Department of Dermatology, Weill Cornell Medicine, 1305 York Ave, 9th Floor, New York, NY 10021 22 5 2020 9 2020 22 5 2020 83 3 e225e226 © 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 affected medical education dramatically, and medical students are anxious for guidance on the upcoming residency application process. Students interested in dermatology are in an unprecedented position. Most have limited exposure to dermatology during the first years of medical school, and many will not be able to complete dermatology subinternships until right before the application deadlines.1 Traditionally, away rotations were critical for developing connections with faculty and obtaining letters of recommendation. With these clinical experiences delayed or cancelled, many students are concerned that they will be at a disadvantage for matching into a residency program. In response to the COVID-19 pandemic, dermatology residency program directors released a consensus statement recommending a more holistic review process [p 1], highlighting that away rotations should not be “perceived as required” [p 2], the absence of a step 2 score should not prevent students from applying [p 3], and “lack of opportunity for students with smaller home programs or in areas more affected by the crisis” would be taken into consideration [p 4].2 Although dermatology was 1 of the first 2 specialties to release a statement, 6 other specialty consensus statements have been released as of May 15, 2020, all recommending no or limited away rotations with letters of recommendation written by home program faculty.3 Many specialties have recommended that students without home programs complete rotations at the nearest institution. Although the recommendations put forth thus far are a welcome first step, additional measures are necessary to ensure a safe and equitable experience for medical students applying for dermatology residencies. We strongly urge academic departments to restrict away rotations. Such a recommendation will help equilibrate the application process, such that applicants from areas most affected by COVID-19 are not unduly disadvantaged compared to peers who participate in away electives. Exceptions should be made only for students without home programs who could rotate at the closest Accreditation Council for Graduate Medical Education (ACGME)-accredited department. Furthermore, opportunities should be made available for students to participate in virtual didactics and grand rounds. Student participation would be encouraged using the chat feature in online video platforms for questions. Dermatology faculty and/or residents could lead virtual small group sessions with medical students to discuss material and provide opportunities for questions and feedback for students who are not comfortable raising questions in a larger group. The American Academy of Dermatology's standardized online curriculum should also be used to provide basic dermatology education, coupled with resident-led teaching sessions to answer questions and provide insight into dermatology residency.4 Offering these experiences to students will offer opportunities to interact with a diverse group of dermatology faculty. Our specialty is in a unique position to rethink the professional experiences we deem necessary for prospective residents. By being creative in our responses to the changes necessitated by the COVID-19 pandemic, students will have opportunities to be safely and adequately prepared to begin dermatology residency while also gaining a resilience and flexibility developed by weathering this uncertain time. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 McCleskey P.E. Gilson R.T. DeVillez R.L. Medical student core curriculum in dermatology survey J Am Acad Dermatol 61 2009 30 35 19410336 2 AAMC. Dermatology Residency Program Director Consensus Statement on 2020-21 Application Cycle. Available at: 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. Accessed June 29, 2020. 3 Association of American Medical Colleges AAMC. Specialty Responses to COVID-19. Available at: https://students-residents.aamc.org/applying-residency/article/specialty-response-covid-19/. Accessed June 29, 2020. 4 Cipriano S.D. Dybbro E. Boscardin C.K. Shinkai K. Berger T.G. Online learning in a dermatology clerkship: piloting the new American Academy of Dermatology Medical Student Core Curriculum J Am Acad Dermatol 69 2013 267 272 23683728
PMC007xxxxxx/PMC7243770.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)30964-6 10.1016/j.jaad.2020.05.092 Research Letter Prescription restrictions on hydroxychloroquine among the largest Florida pharmacy chains during the COVID-19 pandemic: An observational study Hadeler Edward BA Bray Fleta MD ∗ University of Miami Miller School of Medicine, Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, Miami, Florida ∗ Correspondence to: Fleta Bray, MD, University of Miami Miller School of Medicine, Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, 1600 NW 10th Ave, RMSB, Room 2023-A, Miami, FL 33136 22 5 2020 9 2020 22 5 2020 83 3 959961 © 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: Hydroxychloroquine has long been used by dermatologists in the treatment of chronic disease, with use across such broad conditions as connective tissue disease, sarcoidosis, to lichen planopilaris. The medication has generally enjoyed wide availability at a more affordable cost. Earlier this year, hydroxychloroquine became a household name after political leaders touted the drug's efficacy in the treatment and postexposure prophylaxis of COVID-19. As demand for hydroxychloroquine grew, pharmacies reported shortfalls in supply and began implementing restrictions on dispensation.1 Our study seeks to characterize these restrictions in Florida-based locations of the nation's most profitable retail pharmacies. The 6 largest pharmacies with locations in Florida (CVS, Walgreens, Walmart, Humana, Publix, and Costco) and 2 mail-order pharmacy companies (Cigna-Express Scripts and Optum Rx by UnitedHealth) were identified based on total prescription dispensing revenue in 2019.2 April 2020 policies regarding dispensation limits for new prescriptions of hydroxychloroquine and prescription refills were obtained from online data, where available. Otherwise, dispensation limits were obtained by phone from corporate offices and, when redirected, confirmed with at least 3 local pharmacists at different locations. Restriction limitations, when applicable, for new hydroxychloroquine prescriptions and prescription refills are summarized in Table I . All pharmacies had strict limitations that prohibited new prescriptions in excess of a 14- or 30-day supply. Three pharmacies also reduced prescriptions for refills to 30-day supplies at a time (Fig 1 ). Our study identifies impacts to hydroxychloroquine prescribing practices in Florida's largest markets. It is a limitation of this study that only the largest pharmacy chains in the United States by revenue with locations serving Florida were evaluated.Table I Pharmacy prescription restrictions for hydroxychloroquine Pharmacy Total prescription dispensing revenue in 2019 across all drugs3 Restrictions—patients requiring new prescriptions Restrictions—refills for patients with established prescriptions CVS Health $109 billion 14-day supply∗ 90-day supply† Walgreens $84.3 billion 14-day supply‡ 30-day supply† Cigna/Express Scripts $45.8 billion 30-day supply†,§ 90-day supply†,§ UnitedHealth Group OptumRx $25.8 billion 30-day supply†,§,¶ 90-day supply†,§ Walmart $21.2 billion 30-day supply† 90-day supply† Humana Pharmacy Solutions $6.9 billion 30-day supply† 30-day supply† Publix $4 billion 30-day supply† 30-day supply† Costco Wholesale Corp. $2.7 billion 14-day supply‡ 90-day supply† ∗ Subsequent refills up to 90-day supply for US Food and Drug Administration–approved indications. † Prescriptions filled only for US Food and Drug Administration–approved indications. ‡ Subsequent refills limited to a 14-day supply. § Additional preauthorization required. ¶ Subsequent refills limited to a 30-day supply, up to 90 days with prior authorization. Fig 1 Prescription restrictions for hydroxychloroquine. The increased demand for hydroxychloroquine during the COVID-19 pandemic has resulted in heightened scrutiny of prescriptions. Amid the increasing demand and restrictions, patients with chronic dermatologic and rheumatologic conditions may be at harm; Michaud et al3 suggest that rheumatology patients have already begun rationing their medication regimens against professional advice because of shortages.3 A major concern lies in patients with new diagnoses of inflammatory and autoimmune conditions who require new prescriptions of hydroxychloroquine, now subject to more stringent quantity limits. Currently available data regarding the efficacy of hydroxychloroquine in the treatment of COVID-19 are conflicting,4 , 5 and the durability of this new indication for hydroxychloroquine remains to be seen. If current market demand for hydroxychloroquine continues to exceed supply, and large national shortages for hydroxychloroquine continue to persist, subsequent prescription limitations may put dermatology patients at risk. Continued efforts should be made to ensure that medication is available for patients with chronic rheumatologic and dermatologic conditions that require hydroxychloroquine, including upholding proper prescribing practices by doctors. Dermatologists are called to self-police and limit prescriptions for hydroxychloroquine to those for dermatologic purposes. Dermatologists should also anticipate increased clarification queries on International Classification of Diseases codes and imposed quantity limits and will face local variance in supply. Compounding and nonchain pharmacies may serve as supplementary sources to meet increased demand. Dermatologists must be aware of, and adapt to, identifiable changes in the market for hydroxychloroquine for the benefit of their patients. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: N/A. Reprints not available from the authors. ==== Refs References 1 American Medical Association Boards of pharmacy and other actions relating to COVID-19 prescribing Available from: https://www.ama-assn.org/system/files/2020-04/board-of-pharmacy-covid-19-prescribing.pdf 2 Paavola A. 15 largest pharmacies in the US Available from: https://www.beckershospitalreview.com/pharmacy/15-largest-pharmacies-in-the-us.html 3 Michaud K. Wipfler K. Shaw Y. Experiences of patients with rheumatic diseases in the US during early days of the COVID-19 pandemic ACR Open Rheumatol 2020 acr2.11148 4 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 24 2020 2493 2502 32392282 5 Carlucci P. Ahuja T. Petrilli C.M. Rajagopalan H. Jones S. Rahimian J. Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and azithromycin alone: outcomes in hospitalized COVID-19 patients medRχiv 2020 10.1101/2020.05.02.20080036
PMC007xxxxxx/PMC7252068.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)30857-4 10.1016/j.jaad.2020.05.026 JAAD Online COVID-19 and its effect on medical student education in dermatology Loh Tiffany Y. MD a Hsiao Jennifer L. MD b Shi Vivian Y. MD a∗ a University of Arizona, Division of Dermatology, Tucson, Arizona b University of California–Los Angeles, Division of Dermatology, Los Angeles, California ∗ Correspondence to: Vivian Y. Shi, MD, Dermatology Division, University of Arizona, 7165 N Pima Canyon Dr, Tucson, AZ 85718 12 5 2020 8 2020 12 5 2020 83 2 e163e164 © 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 the article by Oldenburg and Marsch1 that highlighted the significant effect on the delivery of dermatology resident education by the coronavirus disease 2019 (COVID-19) pandemic. Because many medical schools have suspended clinical rotations since March 2020,2 telemedicine has become vital to medical education. As Oldenburg and Marsch1 pointed out, resident education is essential and “should not be sidelined during the COVID-19 pandemic.” We are in agreement and would also like to underscore the importance of including medical students in our educational pursuits. The majority of US medical students receive minimal exposure to dermatology. Only 0.24% to 0.3% of medical schools' curricula are spent on dermatology,3 which often translates to decreased comfort with managing basic dermatologic conditions. Ulman et al4 found that in a quiz on basic dermatologic problems, fourth-year medical students received average scores of 49.9% and 32.2% on diagnostic and treatment items (70% was considered proficient). These trends are concerning, given that 35.5% of patients treated in primary care have dermatologic complaints.5 Unfortunately, the deficiency in dermatologic education may only be exacerbated during the COVID-19 pandemic. Dermatology is a visual field, and repetitive patient encounters are required for clinicians to develop the skills necessary for diagnosing and managing dermatologic conditions. Teledermatology offers a potential solution to medical student education during the COVID-19 pandemic. Herein, we discuss methods of implementing teledermatology to optimize medical student learning. Although many dermatology appointments have been transitioned to virtual visits, medical students can still participate in these encounters. They may join video conferencing patient care encounters at the patient's and attending physician's discretion (Table I ). This allows medical students to learn fundamental dermatologic concepts while participating in patient care, which can help optimize their learning in the absence of in-person visits.Table I Guidelines for encouraging medical student participation in virtual patient encounters The resident and attending physician initiate the video call with the patient. If permitted by the patient, the medical student then joins the video call. Resident interviews the patient while attending physician is present during the call and listening. If permitted by the attending physician, the medical student may also help with the patient interview. Resident explains the assessment and plan to the patient. Attending physician may then give additional input or suggestions. If further discussion about a case is needed after the patient encounter, the resident, medical student, and attending physician can discuss the case after the patient leaves the virtual video conference. Other online resources can also be helpful for supplementing medical education (Table II ). Many dermatology residency programs hold online lectures, Kodachrome sessions, and journal clubs, and residents nationwide are often invited to join. Virtual dermatology society conferences, webinars, and podcasts are also available to most residencies. Although it is commendable that these resources are often available free to residents, it may also be beneficial to extend the invitation to medical students.Table II Online resources for learning dermatology American Academy of Dermatology basic dermatology curriculum: https://www.aad.org/member/education/residents/bdc Visual Dx: https://www.visualdx.com/professionals/student-resident NEJM photo challenge: https://www.nejm.org/multimedia/images-in-clinical-medicine Figure 1: https://www.figure1.com/ Although telemedicine is useful, it is also important to recognize that there are elements of dermatology education that cannot be replaced virtually, such as the ability to assess texture, perform biopsies, or use tools such as dermoscopy, Wood's lamp, and potassium hydroxide scraping. Ultimately, in-person visits are still needed. For the time being, however, it is important to optimize tele-education and to involve medical students as much as possible. Medical education has changed significantly during the COVID-19 pandemic, and teledermatology has become essential for educational continuity. Dermatology education is important for all medical students because the majority will likely continue to encounter dermatologic problems throughout their careers, and it is our responsibility to include them in our educational endeavors to the best of our ability. Funding sources: None. Conflicts of interest: None disclosed. Reprints not available from the authors. ==== Refs References 1 Oldenburg R. Marsch A. Optimizing teledermatology visits for dermatology resident education during the COVID-19 pandemic J Am Acad Dermatol 82 6 2020 e229 32283238 2 Important guidance for medical students on clinical rotations during the coronavirus (COVID-19) outbreak https://www.aamc.org/news-insights/press-releases/important-guidance-medical-students-clinical-rotations-during-coronavirus-covid-19-outbreak 3 McCleskey P.E. Gilson R.T. DeVillez R.L. Medical Student Core Curriculum in Dermatology survey J Am Acad Dermatol 61 2009 30 35 19410336 4 Ulman C.A. Binder S.B. Borges N.J. Assessment of medical students' proficiency in dermatology: are medical students adequately prepared to diagnose and treat common dermatologic conditions in the United States? J Educ Eval Health Prof 12 2015 18 25989840 5 Lowell B.A. Froehlich C.W. Federman D.G. Kirsner R.S. Dermatology in primary care: prevalence and patient disposition J Am Acad Dermatol 45 2001 250 255 11464187
PMC007xxxxxx/PMC7252077.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)30757-X 10.1016/j.jaad.2020.04.136 JAAD Online Can hydroxychloroquine be useful in the prevention of COVID-19? An Italian survey in dermatologic and rheumatologic patients already under treatment Vastarella Maria MD a Patrì Angela MD a∗ Annunziata Maria Carmela MD a Cantelli Mariateresa MD a Nappa Paola MD a Tasso Marco MD b Costa Luisa PhD b Caso Francesco PhD b Fabbrocini Gabriella MD a a Sections of Dermatology and Venereology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Napoli, Italy b Section of Rheumatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Napoli, Italy ∗ Correspondence to: Angela Patrì, MD, Department of Clinical Medicine and Surgery, Section of Dermatology and Venereology, University of Naples Federico II, Via Pansini 5, 80131 Naples, Italy 1 5 2020 7 2020 1 5 2020 83 1 e77e79 © 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 World Health Organization declared the coronavirus disease 2019 (COVID-19) a pandemic on March 11, 2020. To date, there is an urgent need for effective drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Chloroquine and hydroxychloroquine (HCQ) have been shown to inhibit SARS-CoV-2 in vitro, and HCQ seems more effective than chloroquine.1 , 2 The aim of our research was the evaluation of HCQ preventive effects on the acquisition of SARS-CoV-2 infection. We conducted an observational retrospective study through a telephone survey among patients in treatment with HCQ for chronic dermatologic or rheumatologic diseases referring to the Dermatologic and Rheumatologic Clinics of the University of Naples Federico II, Italy. The survey and its results are summarized in Table I, Table II, Table III .Table I Questions asked in the telephone survey and dermatologic patients' answers Patient Age, y Dermatologic diagnosis HCQ dose, mg/d Duration (ongoing?) History of respiratory symptoms or fever∗ Exposure to people with respiratory symptoms or fever∗ Exposure to established COVID-19 cases HCQ-related toxicity 1 58 LPP 200 18 mo (yes) No No No None 2 57 LPP+FFA 200 30 mo (yes) No No No None 3 17 LPP 200 7 mo (yes) No No No None 4 60 LPP 200 12 mo (yes) No No No None 5 59 LPP 200 24 mo (yes) No No No None 6 58 LLP 200 12 mo (yes) No No No None 7 31 LLP 600 18 mo (yes) No No No None 8 64 LLP 200 12 mo (yes) No No No None 9 65 LLP 200 12 mo (yes) No No No None 10 47 LLP 200 15 mo (yes) No No No None 11 62 LLP 200 7 mo (yes) No No No Visual decline 12 66 LLP 200 3 mo (yes) No No No Visual fogging 13 58 LLP 200 12 mo (yes) No No No None 14 74 LLP 200 12 mo (yes) No No No None 15 56 LLP 200 12 mo (yes) No No No None 16 61 LLP+AGA 200 15 mo (yes) No No No None 17 85 FFA 200 12 mo (yes) No No No None 18 62 LLP 200 6 mo (yes) No No No None 19 48 LLP 200 5 mo (yes) No Yes, a son with fever No None 20 55 LLP 200 5 mo (yes) No No No None 21 68 LLP 200 12 mo (yes) No No No None 22 60 LLP 200 11 mo (yes) No No No None 23 70 LLP 200 14 mo (yes) No No No None 24 72 LLP 200 14 mo (yes) No No No None 25 29 LLP 200 15 mo (yes) No No No None 26 56 LLP 200 12 mo (yes) No No No None 27 40 LLP 200 15 mo (yes) Yes, fever ≤37.2°C No No None 28 38 LLP 200 32 mo (yes) No No No None 29 18 DLE 200 10 mo (yes) No No No None 30 67 LLP and RA 200 36 mo (yes) No No No None AGA, Androgenetic alopecia; DLE, discoid lupus erythematosus; FFA, frontal fibrosing alopecia; HCQ, hydroxychloroquine; LPP, lichen planopilaris; RA, rheumatoid arthritis. ∗ In the last 2 months. Table II Questions asked in the telephone survey and rheumatologic patients' answers Patient, No. Age, y Rheumatologic diagnosis HCQ dose, (mg/d) Duration (ongoing?) History of respiratory symptoms or fever∗ Exposure to people with respiratory symptoms or fever∗ Exposure to established COVID-19 cases HCQ-related toxicity 1 37 SLE 200 × 2 18 mo (yes) No No No None 2 55 SA 200 × 2 24 mo (yes) No No No None 3 54 SA 200 × 2 24 mo (yes) No No No None 4 59 SA 200 × 2 20 mo (yes) No No No None 5 31 UCTD 200 × 2 36 mo (yes) No No No None 6 61 SLE 200 × 2 36 mo (yes) No No No None 7 31 SLE 200 × 2 30 mo (yes) No No No None 8 43 Myositis 200 × 2 8 mo (yes) No No No None 9 53 SLE 200 × 2 36 No No No None 10 51 SLE 200 × 2 8 mo (yes) No No No None 11 64 Sjögren 200 × 2 170 mo (yes) No No No None 12 59 Sjögren 200 × 2 60 mo (yes) No No No None 13 34 UCTD 200 × 2 4 mo (yes) No No No None 14 33 UCTD 200 × 2 29 mo (yes) No No No None 15 47 SLE 200 × 2 12 mo (yes) No No No None 16 51 UCTD 200 × 2 60 mo (yes) No No No None 17 32 UCTD 200 × 2 24 mo (yes) No No No None 18 67 UCTD 200 × 2 16mo (yes) No No No None 19 36 SLE 200 × 2 19 mo (yes) No No No None 20 53 SLE 200 × 2 48 mo (yes) No No No None 21 52 SLE 200 × 2 240 mo (yes) No No No None 22 40 SA 200 × 2 34 mo (yes) No No No None 23 49 SS 200 × 2 144 mo (yes) No No No None 24 69 Sjögren 200 × 2 21 mo (yes) No No No None 25 45 SLE 200 × 2 36 No No No None 26 42 SLE 200 × 2 78 mo (yes) No No No None 27 32 UCTD 200 × 2 38 mo (yes) No No No None 28 37 Sjögren 200 × 2 80 mo (yes) No No No None 29 42 UCTD 200 × 2 84 mo (yes) No No No None 30 48 UCTD 200 × 2 180 mo (yes) No No No None 31 33 UCTD 200 × 2 10 mo (yes) No No No None 32 53 SLE 200 × 2 140 mo (yes) No No No None 33 39 UCTD 200 × 2 2 mo (yes) No No No None 34 55 SLE 200 × 2 9 mo (yes) No No No None 35 37 UCTS 200 × 2 8 mo (yes) No No No None 36 38 SLE 200 × 2 18 mo (yes) No No No None HCQ, Hydroxychloroquine; SA, seronegative arthritis; SLE, systemic lupus erythematosus; SS, systemic sclerosis; UCTD, undifferentiated connective tissue disease. ∗ In the last 2 months. Table III Survey's main results Patients No. Mean age, y Dose of HCQ Mean duration, mo History of respiratory symptoms or fever,∗ No. (%) Exposure to people with respiratory symptoms or fever,∗ No. (%) Exposure to established COVID-19 cases, No. (%) Dermatologic 30 55.5 200 mg/d 14.2 1 (3.44) 1 (3.44) 0 (0) Rheumatologic 36 46.16 200 mg 2× 50.1 0 (0) 0 (0) 0 (0) HCQ, Hydroxychloroquine. ∗ In the last 2 months. We reviewed 66 patients, 30 dermatologic patients (8 men and 22 women; median age, 55.5 years; medium duration of HCQ treatment, 14.2 months; range, 3-36 months) and 35 rheumatologic patients (5 men and 30 women; median age, 46.1 years; medium duration of HCQ treatment, 50.1 months; range 2-240 months). Overall, 65 of the 66 patients (98.4%) in treatment with HCQ had not developed fever, sore throat, fatigue, cough, or dyspnea in the previous 2 months. One patient had reported a temperature of 37.2° C for only 1 day, without any other associated symptoms. Mostly, the treatment was well tolerated, without related adverse events; only 2 patients described a brief episode of visual impairment. These patients were suggested to have an examination of the ocular fundus, beyond the regular 6-month ophthalmic follow-up already performed. HCQ has immunomodulatory properties and an attractive adverse effect profile.2 It could contribute to the suppression of the cytokine release syndrome responsible for the progression of COVID-19 to severe clinical forms through several mechanisms, including (1) reduction of T-cell activation and differentiation, (2) decreased production of cytokines by T cells and B cells (eg, interleukin 1 and 6 and tumor necrosis factor), and (3) attenuation of proinflammatory signaling pathways activation. Interestingly, HCQ and chloroquine inhibit receptor binding and membrane fusion, 2 critical steps required for cell entry by coronaviruses.3 However, HCQ offers advantages compared with chloroquine, including a better clinical safety profile, possible higher daily dose, and fewer pharmacologic interactions.1 , 2 , 4 In our study, no patient already in treatment with HCQ developed symptoms suggestive for SARS-CoV-2 infection, although Italy is currently the third-most infected country in the world. Limitations of our study are the low sample size and the absence of exposure to established cases of COVID-19 in the interviewed patients. Further studies on larger samples are needed to assess the possible protective effect of HCQ on SARS-CoV-2 infection. We recommend extending this kind of survey to all patients actually in treatment with HCQ, possibly stratifying them according to residency, posology, other ongoing systemic treatments, comorbidities, and starting prospective observational study for a more extended period (4-6 months). The in vivo demonstration of prophylactic efficacy of HCQ could be a revolutionary result to prevent the transmission of the virus, until the development of a vaccine. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Liu J. Cao R. Xu M. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro Cell Discov 6 2020 16 32194981 2 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) [e-pub ahead of print] Clin Infect Dis https://doi.org/10.1093/cid/ciaa237 3 Zhou D. Dai S.M. Tong Q. COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression [e-pub ahead of print] J Antimicrob Chemother 10.1093/jac/dkaa114 4 Patrì A. Fabbrocini G. Hydroxychloroquine and ivermectin: a synergistic combination for COVID-19 chemoprophylaxis and/or treatment? J Am Acad Dermatol 82 6 2020 e221 32283237
PMC007xxxxxx/PMC7260504.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)31002-1 10.1016/j.jaad.2020.05.126 Commentary Advances in skin science enable the development of a COVID-19 vaccine Falo Louis D. Jr MD, PhD ∗ Department of Dermatology, Departments of Dermatology and Bioengineering, and the University of Pittsburgh Clinical and Translational Science Institute, Hillman Cancer Institute, and McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania ∗ Correspondence to: Louis D. Falo, Jr, MD, PhD, University of Pittsburgh, Dermatology, Medical Arts Bldg, Ste 500, Pittsburgh, PA 15213. 30 5 2020 10 2020 30 5 2020 83 4 12261227 © 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 pmcJenner's skin inoculation preventing smallpox exemplifies the capacity of a skin-targeted vaccine to successfully combat a pandemic. Skin biologists have elucidated the intricate cutaneous immunoregulatory networks that are highly responsive to environmental conditions and capable of inducing potent immune responses that can be local and systemic.1 , 2 Skin is rich in antigen-presenting cells and in accessory cells with innate immune function such as resident T cells, innate lymphoid cells, mast cells, neutrophils, neurons, and keratinocytes. Our group and others have focused efforts on developing skin-targeted immunization strategies including skin-targeted delivery of protein, plasmid DNA, and viral vectored vaccines. These efforts are enabled by advances in bioengineering that are resulting in more effective and controlled delivery of vaccine components to skin microenvironments such as microneedle arrays. Microneedle arrays span a broad range of technologies, including several being explored for the development of vaccines against influenza, malaria, diphtheria, and other infectious diseases.3 Our efforts have focused on microneedle arrays made of a dissolvable matrix. Deliverables, including antigens and immunomodulators, can be integrated into the matrix so that the needles are actually the vaccine. When applied to the skin, the dry sharp needles penetrate the stratum corneum and then absorb moisture and dissolve, releasing vaccine components into the epidermis and upper dermis. Therefore, the delivery of very small amounts of cargo results in high local concentrations within the skin microenvironment that improves effectiveness while minimizing systemic exposure to improve safety. An important benefit is that vaccine components embedded in these microneedle arrays are stable at room temperature, obviating the “cold chain” that has been a major barrier to global immunization campaigns. We used this technology platform to construct and test a skin-targeted coronavirus disease 2019 vaccine consisting of a recombinant S1 subunit protein from severe acute respiratory syndrome coronavirus 2 embedded in a microneedle array. The efficiencies of this process enabled us to rapidly design and fabricate a prototype vaccine, and to begin animal testing within a few weeks of the release of the viral sequence. This resulted in the first peer-reviewed description of a coronavirus disease 2019 vaccine generating potent severe acute respiratory syndrome coronavirus 2 antibody responses.4 This “PittCoVacc” vaccine is now being developed for a phase 1 clinical trial and would join our ongoing clinical trial evaluating microneedle array delivery of an immunogenic cell death–inducing chemotherapeutic for the treatment of skin cancer. Most recently, we showed that adenoviral vectors could also be embedded in microneedle arrays and maintain their infectivity.5 The multicomponent microneedle array fabrication strategy enabled the delivery of both antigen-expressing adenovectors and adjuvant in the same microneedle arrays, resulting in a vaccine that induced both antibody responses and enhanced cytotoxic cellular immunity that is likely important for “universal” vaccines and cancer immunotherapies. Taken together, these and studies by others demonstrate the potential for the development of cutaneous immune engineering strategies to control systemic immune responses, including the potential for developing novel vaccine strategies and immunotherapies, and even negative immunization strategies to treat systemic allergy and autoimmune diseases. Advances in skin biology are making important contributions to the fight against the coronavirus disease 2019 pandemic, demonstrating once again that dermatology is more than skin deep. Funding sources: None. Conflicts of interest: Dr Falo is an inventor of related intellectual property and founder and scientific advisor of SkinJect. Reprints not available from the author. ==== Refs References 1 Kabashima K. Honda T. Ginhoux F. Egawa G. The immunological anatomy of the skin Nat Rev Immunol 19 1 2019 19 30 30429578 2 Kashem S.W. Haniffa M. Kaplan D.H. Antigen-presenting cells in the skin Annu Rev Immunol 35 2017 469 499 28226228 3 Kim Y.C. Park J.-H. Prausnitz M.R. Microneedles for drug and vaccine delivery Adv Drug Deliv Rev 64 14 2012 1547 1568 22575858 4 Kim E. Erdos G. Huang S. Microneedle array delivered recombinant coronavirus vaccines: immunogenicity and rapid translational development EBioMedicine 55 2020 102743 32249203 5 Erdos G. Balmert S.C. Carey C.D. Improved cutaneous genetic immunization by microneedle array delivery of an adjuvanted adenovirus vaccine J Invest Dermatol 2020 10.1016/j.jid.2020.03.966 Published online April 21, 2020
PMC007xxxxxx/PMC7262530.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)30998-1 10.1016/j.jaad.2020.05.122 JAAD Online Reply to: “Characterization of acute acro-ischemic lesions in non-hospitalized patients: A case series of 132 patients during the COVID-19 outbreak” Ruggiero Giuseppe MD a Arcangeli Fabio MD b Lotti Torello MD b Ametrano Orsola MD c Ruggiero Cosimo MD d Cucchiara Salvatore MD, PhD d Oliva Salvatore MD, PhD d∗ a National Head of the Dermatology Study Group of the Italian Federation of General Pediatricians, Rome, Italy b University of Rome “Guglielmo Marconi,” Rome, Italy c Dermatology Unit, AORN Santobono-Pausilipon, Naples, Italy d Pediatric Gastroenterology and Liver Unit, Maternal and Child Health Department, Sapienza University of Rome, Rome, Italy ∗ Correspondence to: Salvatore Oliva, MD, PhD, Pediatric Gastroenterology and Liver Unit, Maternal and Child Health Department, Sapienza University of Rome, Viale Regina Elena 324-00161, Rome, Italy 1 6 2020 9 2020 1 6 2020 83 3 e237e239 © 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 article by Fernandez-Nieto et al.1 Cutaneous manifestations of coronavirus disease 2019 (COVID-19) are rarely reported. In their letter, Fernandez-Nieto et al1 described an increased number of acroischemic lesions in young patients from Spain. Most patients were asymptomatic or mildly symptomatic, and none of them developed COVID-19 pneumonia or any other complication. It is intriguing that in Italy we are observing the same uncommon increase. Italy and Spain are the 2 European countries with the highest incidence of COVID-19.2 In Italy, after the outbreak onset, many general pediatricians reported on our pediatric dermatology network unusual foot injuries similar to chilblains and without any other symptoms. These lesions have never been described with this frequency before, being usually rare. Thus, we circulated a specific online form among members of the Italian Federation of General Pediatricians to verify the possible association between chilblainlike lesions and COVID-19. Fernandez-Nieto et al1 applied a different approach by analyzing dermatology consultations for cutaneous lesions. We reached the same results and conclusions for 100 children (Table I ). The Spanish authors found 132 cases in 41 days, whereas ours were collected in 10 days. Even in our cohort, lesions were mostly located in the extremities of the limbs, with only 2 cases involving the face. We found a lower rate of systemic symptoms (16% vs 25%), but our population was slightly younger (mean age 12.5 vs 23.4 years), being likely less symptomatic.3 Almost the same number of positive SARS-CoV-2 test results (1 vs 2 patients) was described in both cohorts. Our patient with a positive result also had extracutaneous symptoms (fever and pharyngodynia). He was exposed to subjects with COVID-19 (family members), as were the COVID-19–infected Spanish patients. This confirms that the chance of finding infected children increases if all cohabiting family members are tested after an index case. Indeed, only 11% of patients in our cohort were tested for severe acute respiratory syndrome Coronavirus 2 (Sars-CoV-2) because of the rigid testing policy in Italy. The Spanish group tested only 8%, thus confirming the difficulty in having testing in overwhelmed public health systems.Table I Characteristic of Spanish and Italian cohorts Characteristics Spain, n = 132 Italy, n = 100 Age, mean (range) 19.9 (1-56 y) 12.9 (3 mo-17 y) Male sex (%) 71 (53.8) 64 (64) Cutaneous symptoms (pain, itching, burning, swelling, erythema) (%) NA 61 (61) COVID-19 symptoms (%) 18 (13.6) 16 (16) COVID-19–positive cases (%) 2 (1.5) 1 (1) Location of skin lesions (%) Hands: 41 (31) Feet: 108 (81.8) Hands: 25 (25) Feet: 75 (75) Duration of skin lesions, mean (range), d 8.7 (2-24) Improvement at day 12 = 76% Therapy (%) 74 (74) Topical steroids 40 Topical antibiotics 8 Topical heparin 9 Topical antifungal 4 Systemic antibiotics NA 2 Systemic steroids 4 Antihistamines 4 Paracetamol 6 Gentamicin + betamethasone 11 No therapy 26 (26) Improvement by day 4 (%) Therapy 31 (41.9) No therapy 13 (49.9) Improvement by day 8 (%) Therapy 43 (58.1) No therapy 19 (73.1) Improvement by day 12 (%) Therapy 55 (74.3) No therapy 21 (80.7) COVID-19, Coronavirus disease 2019; NA, not applicable. We did not differentiate between chilblainlike and erythema multiforme–like lesions. We observed and collected only lesions appearing as circumscribed erythematous edematous elements with a purplish-red color, which were thus defined as erythema perniolike lesions (Fig 1 ). A local or systemic therapy was considered in only 74 of 100 cases (74%) (Table I). Up to 80% of patients by day 12 had a favorable outcome regardless of the therapy used. This observation is additional evidence for a COVID-19 etiology. Indeed, it is known that chilblains can be secondary to viral infections. The likelihood of other seasonal non–COVID-19 infections was extremely low because children were having contact only with their family members because of the national lockdown.4 Fig 1 Photographs from 2 enrolled patients. A, Left foot lesions at day 0 in a 13-year-old patient with swelling, erythema, and itching. B, Right foot lesions at day 12 in a 13-year-old patient with pain, burning, swelling, erythema, and itching. We definitively agree with Fernandez-Nieto et al1 about the relationship between erythema perniolike acrolocated lesion onset and COVID-19. General pediatricians worldwide should pay attention to skin lesions during the COVID-19 pandemic. We would like to thank the following persons for contributing to data collection: Biasci Paolo (Italian Federation of General Pediatricians President), Doria Mattia (National Secretary for Scientific and Ethical Activities of Italian Federation of General Pediatricians), Alfinito Mario, Amadori Annalisa, Annibali Amedeo, Battistini Alberto, Bellino Antonino, Berti Marina, Bonadies Lucia, Buffone Maria Raffaela, Buono Giovanni Carlo, Campagna Angela, Candio Francesco, Careddu Domenico, Cartiglia Maria Laura, Caruso Vincenzo, Caternolo Maria, Ciampolini Massimo, Cocchiara Cristoforo, Contiguglia Nino, Cortesia Paolo, Costamagna Martina, Cristofanelli Palmina, De Bona Lidia, De Santis Rosamaria, Di Carlo Maria Teresa, Di Stasio Alessandra, Dolceamore Teresa Rita, Ferri Francesca Donatella, Foderi Stefania, Galioto Roberta, Galli Antonella, Gamboni Cosetta, Giacomin Annamaria, Grasso Silvana, Grasso Maria Carmela, Guaraldi Nicola, Gulino Antonino, Hensen Joanne, La Boria Maria Agata, Licordari Amalia, Longhini Federico, Lualdi Rosa, Mariani Danila, Mazzola Maria Pia, Mura Antonella, Napoli Mario, Paolini Paoletti Fabrizia, Piccione Concetta, Quinci Maria, Ravera Brunella, Romano Maria Rosaria, Sacchetti Roberto, Senesi Paolo, Simonelli Anna Rita, Sonaglia Franca, Squazzini Giuseppe, Stanzione Maria, Stramondo Prospero Sergio, Vallati Marina, Zinna Maria Concetta, Zucchi Graziano. Funding sources: None. Conflicts of interest: None disclosed. Reprints not available from the authors. ==== Refs References 1 Fernandez-Nieto D. Jimenez-Cauhe J. Suarez-Valle A. 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 World Health Organization Coronavirus disease 2019 (COVID-19) situation report– 78 Available from: https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200421-sitrep-92-covid-19.pdf?sfvrsn=38e6b06d_6 3 Dong Y. Mo X. Hu Y. Epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in China Pediatrics 145 2020 e20200702 32179660 4 Lazzerini M. Barbi E. Apicella A. Delayed access or provision of care in Italy resulting from fear of COVID-19 Lancet Child Adolesc Health 4 2020 e10 e11 32278365
PMC007xxxxxx/PMC7265862.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)31022-7 10.1016/j.jaad.2020.05.145 Dermatopathology Chilblain-like acral lesions during the COVID-19 pandemic (“COVID toes”): Histologic, immunofluorescence, and immunohistochemical study of 17 cases Kanitakis Jean MD, PhD ab∗ Lesort Cécile MD a Danset Marie MD a Jullien Denis MD, PhD a a Department of Dermatology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France b Department of Anatomic Pathology, Lyon Sud Hospital Center, Pierre Bénite, France ∗ Correspondence to: Jean Kanitakis, MD, PhD, Edouard Herriot Hospital, Dermatology, 5 place d'Arsonval, Lyon 69003, France. 2 6 2020 9 2020 2 6 2020 83 3 870875 23 5 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 During the coronavirus disease 2019 pandemic, several acral chilblain-like lesions were observed in young patients with suspected, but mostly unconfirmed, infection with severe acute respiratory syndrome coronavirus 2. The histopathologic aspect of these lesions is as yet poorly known. Objective To investigate the pathologic features of chilblain-like lesions. Methods Biopsies were obtained from 17 cases of chilblain-like lesions during the coronavirus disease 2019 pandemic in France and were studied by routine histologic examination, immunohistochemistry, and direct immunofluorescence. The patients had suspected but unconfirmed infection with severe acute respiratory syndrome coronavirus 2 (negative nasopharyngeal polymerase chain reaction and serologic test results). Results Chilblain-like lesions showed many features in common with those reported in idiopathic and autoimmune-related chilblains, including epidermal necrotic keratinocytes, dermal edema, perivascular and perieccrine sweat gland lymphocytic (predominantly CD3/CD4+) inflammation, and frequent vascular changes (endothelialitis, microthromboses, fibrin deposition, and immunoreactant deposits on vessels). Conclusions Chilblain-like lesions show histopathologic features similar to those of idiopathic and autoimmune-related chilblains, with a high rate of vascular changes and direct immunofluorescence positivity. The role of severe acute respiratory syndrome coronavirus 2 in the development of these puzzling lesions remains to be elucidated. Key words chilblains COVID-19 dermatopathology direct immunofluorescence eosinophils immunohistochemistry SARS-CoV-2 ==== Body pmc Capsule Summary • Several acral chilblain-like lesions have been observed during the coronavirus disease 2019 pandemic. Their histopathologic features are poorly known. • Chilblain-like lesions show findings comparable to those of idiopathic and autoimmune-related chilblains, and frequently contain vascular changes and immune deposits (immunoglobulins, complement, or both) on dermal vessels by direct immunofluorescence. Introduction Coronavirus disease 2019 (COVID-19) is a multisystemic infection manifesting mainly with fever, cough, and pneumonia that may be severe and lethal. The disease is due to a new zoonotic-transmitted coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This was initially isolated in Wuhan, China, in December 2019 but has since spread worldwide, causing a pandemic disease with hundreds of thousands of fatalities.1 , 2 COVID-19 is a multisystemic disease affecting several systems in addition to the respiratory one, such as the gastrointestinal tract3 and the central nervous system.4 Several skin manifestations have been reported in patients with confirmed or suspected COVID-19, including morbilliform rashes, a papulovesicular varicella-like eruption, urticaria, livedoid rashes, and petechial and purpuric lesions.5, 6, 7, 8, 9 In addition, several puzzling cases of chilblain-like lesions of the extremities (mainly the toes) have been recorded in several countries in Europe and the Middle East contemporarily with the COVID-19 spread.10, 11, 12, 13, 14, 15 These lesions accounted for 19% to 38% of all cutaneous lesions associated with known or strongly suspected COVID-19 in 2 recent studies from France10 and Spain13; they were observed in young patients with no systemic symptoms or only mild ones, and appeared rather late in the course of the (suspected) infection. These lesions have been termed COVID-toes,16 even though their causal relationship with SARS-CoV-2 has not been convincingly proven. Among 63 such Italian cases, a swab test result was positive in merely 3.2% of patients.11 Another report on chilblain-like lesions included 2 patients with COVID-19–positive test results, but another patient had negative results by polymerase chain reaction and rapid antibody test.15 The pathologic features of chilblain-like lesions in this setting have not been extensively studied. Until now, a histopathologic study of chilblain-like lesions had been published in only 1 COVID-19–confirmed case17 and in 4 possible but unconfirmed COVID-19–positive cases.10 , 16 We performed a histopathologic, immunohistochemical, and immunofluorescence study of a series of 17 chilblain-like lesions to obtain further insight into their pathogenesis, and especially to assess whether these lesions have diagnostic microscopic features allowing their differentiation from clinically similar lesions, such as idiopathic chilblains and those associated with autoimmune disorders (namely, lupus erythematosus). Patients and methods This case series study included 17 patients (11 men and 6 women; mean age 32 years; range 15-63 years) who were referred to our dermatology department in April 2020 for cutaneous, red-violaceous, edematous, rarely necrotic, chilblain-like lesions localized on the toes (n = 9), the feet (heel and sole; n = 6), and fingers (n = 2). Among these patients, 5 mentioned recent nonspecific general symptoms preceding the onset of cutaneous lesions (cough, fever, or weakness) and 6 suspected a possible contamination from a family member (although only 2 of them had had positive test results for SARS-CoV-2). No clinical or biological evidence in favor of an underlying autoimmune disease was present (basic evaluation included routine blood tests and levels of inflammatory markers, D-dimers, antinuclear antibodies, complement, cryoglobulins, and antiphospholipid antibodies). A nasopharyngeal polymerase chain reaction test for SARS-CoV-2 and serologic testing for antibodies to this virus were performed concomitantly with the skin biopsies; all these tests had negative results. Two skin biopsies were obtained from chilblain-like lesions from each of these patients. Formalin-fixed, paraffin-embedded skin specimens were studied microscopically for various epidermal and dermal changes associated with idiopathic and autoimmune-related chilblains. To characterize cells participating in the inflammation, the sections were immunolabeled for CD3, CD4, CD8 (T, T-helper, and T-suppressor/cytotoxic cells), CD20 (B cells), CD79a (plasma cells), CD30 (activated T cells), CD68 (histiomonocytic cells), and CD303/BDCA-2 (plasmacytoid dendritic cells) with an immunoperoxidase technique and diaminobenzidine as chromogen. Snap-frozen biopsies were studied by direct immunofluorescence for the presence of immunoreactants (IgA, IgG, IgM, and C3). Results Hematoxylin-eosin–stained tissue sections showed several common features between most chilblain-like lesion cases, with some quantitative variations. The detailed findings are shown in Supplemental Table I (available via Mendeley at https://data.mendeley.com/datasets/8k44cy638x/1). Briefly, the most common epidermal changes included deep horizontal zones of parakeratosis within the horny layer (71%), possibly because of preceding bullae, and scattered or confluent necrotic or apoptotic keratinocytes (41%), which in 3 cases resulted in areas of epidermal necrosis (Fig 1 ). The dermis invariably contained a perivascular inflammatory cell infiltrate, which was made predominantly of lymphocytes; it was also localized around eccrine sweat glands, producing an aspect of lymphocytic eccrine hidradenitis, in 47% of cases (Fig 2 ), and extended occasionally to the subcutaneous adipose tissue as perivascular cuffs. Rare eosinophils were admixed in 4 cases (23.5%) (Fig 3 ). Additional frequent findings included erythrocyte extravasation (82%) (Fig 3); papillary dermis edema (76%), which was massive in 4 cases, resulting in the formation of subepidermal pseudobullae (Fig 1); endothelial cell swelling (65%) (Fig 3 ); and moderately increased interstitial mucin deposition (41%). Less frequent, although remarkable, findings included the presence of vascular microthrombi within superficial dermal capillaries and more rarely in dermal venules (Fig 4) and fibrinoid deposits in the upper dermis and in the wall of dermal venules (Fig 5 ).Fig 1 Chilblain-like lesion. Scanning magnification shows diffuse upper dermal edema and a dense dermal (perivascular and perieccrine sweat gland) inflammatory infiltrate. (Hematoxylin-eosin-saffron stain; original magnification: ×40.) esg, Eccrine sweat gland. Fig 2 Chilblain-like lesion. Dense lymphocytic infiltrate around an eccrine sweat gland. Inset: perieccrine clusters of CD303+/BDCA-2 plasmacytoid dendritic cells. (Hematoxylin-eosin-saffron stain; original magnification: ×250; inset [immunoperoxidase revealed with diaminobenzidine]; original magnification: ×250.) Fig 3 Chilblain-like lesion. Dense lymphocytic dermal perivascular infiltrate admixed with occasional eosinophils (arrowheads). Endothelial cell swelling and extravasated red blood cells (asterisks). Fig 4 Chilblain-like lesion. Eosinophilic thrombi within the lumen of a dermal venule. (Hematoxylin-eosin-saffron stain; original magnification: ×400.) Fig 5 Chilblain-like lesion. Eosinophilic fibrin deposits on the wall of a dermal venule. Inset shows vascular deposits of immunoglobulin M. (Hematoxylin-eosin-saffron stain; original magnification: ×400; inset [direct immunofluorescence]; original magnification: ×400.) The immunohistochemical study, performed in 5 representative cases, revealed that the majority (>75%) of dermal infiltrating cells were CD3+ T cells, with a CD4:CD8 ratio of approximately 3:2. Few B or plasma cells (CD20+/CD79a+) were found (<10% of all lymphocytes). Scattered CD30+-activated T cells (accounting for <15% of all lymphocytes) were found in the upper dermis. All biopsies contained CD303/BDCA-2+ plasmacytoid dendritic cells, usually in small perivascular or perieccrine clusters in the mid dermis (Fig 2, inset) and occasionally also in the papillary dermis. Several CD68+ histiomonocytic cells were scattered throughout the dermis. Direct immunofluorescence examination result was positive in 14 of 17 frozen biopsy specimens (82%). The examination showed vascular deposits of IgM, IgA, and C3 in 9, 5, and 5 cases, respectively (Fig 5, inset). In the 3 remaining cases, direct immunofluorescence result was either negative or showed nonspecific findings (such as C3 microgranular deposits at the dermal-epidermal junction or IgM deposits on colloid bodies of the papillary dermis). Discussion Although the clinical appearance of the chilblain-like lesions we investigated in this study is similar, if not identical, to that of both idiopathic and autoimmune-related chilblains, these lesions are distinct from an etiologic point of view. Indeed, the chilblain-like lesions appeared during March 2020 (which was in France one of the warmest months ever recorded), a fact that is against the role of cold and humid weather, as is the case for idiopathic chilblains. Furthermore, the autoimmunity evaluation performed for our patients (namely, for antinuclear antibodies) ruled out an underlying autoimmune disease, such as lupus erythematosus, which may be associated with pernio-like lesions (lupus pernio). The term COVID toes reflects the particular circumstances under which the outbreak of chilblain-like lesions was recorded, although the term COVID chilblains (by analogy to idiopathic or autoimmune chilblains) would be more correct. Our study, which to our knowledge includes the largest series of pathologically studied chilblain-like lesions to date, showed that these lesions share several pathologic features with both idiopathic and autoimmune-associated chilblains. Indeed, despite some claimed differences, idiopathic and autoimmune-related chilblains are difficult to separate pathologically. Papillary edema and perieccrine sweat gland localization of the dermal infiltrate have been claimed to favor the diagnosis of idiopathic chilblains over autoimmune-related chilblains,18, 19, 20 although an earlier study did not find such differences.21 Conversely, basal cell layer vacuolization and interface changes were claimed to be more common in autoimmune-related chilblains versus idiopathic chilblains,18 , 19 but the differences are not discriminating from a statistical point of view. More recently, it was reported that the presence of abundant dermal mucin and interstitial fibrin was associated with lupus erythematosus, but that the number and distribution of CD123+ plasmacytoid dendritic cells and CD30+ lymphocytes had no discriminatory role.20 Our results show that the chilblain-like lesions exhibit, to various degrees, the most common pathologic features of idiopathic chilblains and autoimmune-related chilblains, including necrotic epidermal keratinocytes, papillary edema, dense perivascular and perieccrine sweat gland inflammation, predominance of CD3+/CD4+ T cells, and presence of CD303+ plasmacytoid dendritic cells and CD30+-activated cells in the dermal infiltrate. Rarer but remarkable findings include the presence of vascular microthromboses and fibrin deposition in the wall of dermal venules. The presence of eosinophils in the dermal infiltrate has not been, as far as we know, reported in idiopathic chilblains or autoimmune-related chilblains18, 19, 20, 21, 22 and is remarkable, even though eosinophils were found in small numbers and in a minority of our cases. Similarly, the high rate of positive-result direct immunofluorescence showing vascular deposits of IgM, IgA, or C3 is an original finding. Indeed, direct immunofluorescence result was negative in a case of COVID-19–associated chilblain,17 showed a lupus band test in 21% of cases of autoimmune-related chilblains,22 and showed nonspecific findings in cases of idiopathic chilblains associated with myelomonocytic leukemia23; these studies did not mention specific vascular deposits. The pathogenesis of these chilblain-like lesions remains unclear. Our findings—namely, the deposits of immunoglobulins and C3 on dermal vessels and the presence of vascular microthrombi, swollen endothelial cells (endothelialitis), and fibrin deposits within the wall of dermal venules—suggest a vascular involvement in the genesis of chilblain-like lesions. So far, the presence of capillary microthrombi has been highlighted in 3 cases with probable COVID-1910 , 16 and could be related to the altered coagulation status observed in patients with (severe) COVID-19.24 Nevertheless, the precise role of SARS-CoV-2 in the development of chilblain-like lesions, although possible from an epidemiologic point of view, remains unclear. The presence of endothelialitis in chilblain-like lesions is consistent with a role of the SARS-CoV-2 because endothelialitis in several organs has been reported in the course of COVID-1925; however, few patients with chilblain-like lesions had confirmed infection with SARS-CoV-2,11 , 15 , 17 and most of them (including the patients in this study) had negative test results.11 Furthermore, a search for SARS-Cov-2 performed with polymerase chain reaction in 3 of the skin biopsies included in our study had negative results (data not shown). It can be speculated that chilblain-like lesions develop as an indirect consequence of viral infection, via an exaggerated immune response that can contain the infectious potential of the virus, but induces vascular injury that is the pathologic substratum of chilblain-like lesions. If this hypothesis is confirmed, chilblain-like lesions could be regarded as a paraviral manifestation, as recently suggested for an erythematous-scaly eruption in a patient with COVID-19, in which skin polymerase chain reaction did not detect SARS-CoV-2 in the skin lesions.26 In conclusion, our findings suggest that the pathologic features of chilblain-like lesions (COVID toes) are similar to those of idiopathic and autoimmune-related chilblains. Novel findings may include the presence of eosinophils in the dermal infiltrate and the high positivity rate of direct immunofluorescence examination, which highlights the involvement of vascular injury in the genesis of these lesions. If confirmed by a larger number of observations, these findings could shed more light on the pathogenesis of chilblain-like lesions. However, the precise role of SARS-CoV-2 in the development of these lesions remains to be elucidated. We thank our colleagues who referred patients to us, and Dr Georgia Karayannopoulou (AHEPA Hospital, Thessaloniki, Greece) for fruitful discussions. Drs Kanitakis and Lesort contributed equally to the article. Funding sources: None. Conflicts of interest: None disclosed. 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 8 2020 727 733 31978945 2 Novel Coronavirus Pneumonia Emergency Response Epidemiology Team The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China Zhonghua Liu Xing Bing Xue Za Zhi 41 2 2020 145 151 32064853 3 Hajifathalian K. Mahadev S. Schwartz R.E. SARS-COV-2 infection (coronavirus disease 2019) for the gastrointestinal consultant World J Gastroenterol 26 14 2020 1546 1553 32327904 4 Helms J. Kremer S. Merdji H. Neurologic features in severe SARS-CoV-2 infection N Engl J Med 382 23 2020 2268 2270 32294339 5 Sachdeva M. Gianotti R. Shah M. Cutaneous manifestations of COVID-19: report of three cases and a review of literature J Dermatol Sci 98 2 2020 75 81 32381430 6 Marzano A.V. Genovese G. Fabbrocini G. Varicella-like exanthem as a specific COVID-19-associated skin manifestation: multicenter case series of 22 patients J Am Acad Dermatol 83 1 2020 280 285 32305439 7 Diaz-Guimaraens B. Diaz-Guimaraens B. Dominguez-Santas M. Petechial skin rash associated with severe acute respiratory syndrome coronavirus 2 infection JAMA Dermatol 2020 10.1001/jamadermatol.2020.1741 8 Manalo I.F. Smith M.K. Cheeley J. Jacobs R.A. Dermatologic manifestation of COVID-19: transient livedo reticularis J Am Acad Dermatol 83 2 2020 700 32283229 9 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 10 de Masson A. Bouaziz J.-D. Sulimovic L. on behalf of the SNDV (French Union of Dermatologists-Venereologists) 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 11 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 12 Recalcati S. Barbagallo T. Frasin L.A. Acral cutaneous lesions in the time of COVID-19 J Eur Acad Dermatol Venereol 2020 10.1111/jdv.16533 13 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 2020 10.1111/bjd.19163 14 Alramthan A. Aldaraji W. A case of COVID-19 presenting in clinical picture resembling chilblains disease. First report from the Middle East Clin Exp Dermatol 2020 10.1111/ced.14243 15 Landa N. Mendieta-Eckert M. Fonda-Pascual P. Aguirre T. Chilblain-like lesions on feet and hands during the COVID-19 pandemic Int J Dermatol 59 6 2020 739 743 32329897 16 Sigal A. Zirn J. Lipper G. Shapiro P. A case of pernio-like lesions (“COVID toes”) with histologic confirmation of microthrombi https://docs.google.com/document/d/1QrCmMYX1eXRfhDewC-Y6lugEfGPwOq-U4ppUAnhlibg/mobilebasic Accessed June 26, 2020 17 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 18 Boada A. Bielsa I. Fernández-Figueras M.T. Ferrándiz C. Perniosis: clinical and histopathological analysis Am J Dermatopathol 32 1 2010 19 23 20098080 19 Crowson A.N. Magro C.M. Idiopathic perniosis and its mimics: a clinical and histological study of 38 cases Hum Pathol 28 4 1997 478 484 9104949 20 Wang L. Chan P. Comparative analysis of chilblain lupus erythematosus and idiopathic perniosis: histopathologic features and immunohistochemistry for CD123 and CD30 Am J Dermatopathol 40 4 2018 265 271 28719438 21 Cribier B. Djeridi N. Peltre B. Grosshans E. A histologic and immunohistochemical study of chilblains J Am Acad Dermatol 45 6 2001 924 929 11712041 22 Viguier M. Pinquier L. Cavelier-Balloy B. Clinical and histopathologic features and immunologic variables in patients with severe chilblains. A study of the relationship to lupus erythematosus Medicine (Baltimore) 80 3 2001 180 188 11388094 23 Nazzaro G. Genovese G. Marzano A.V. Idiopathic chilblains in myelomonocytic leukemia: not a simple association Int J Dermatol 57 5 2018 596 598 29318596 24 Tang N. Bai H. Chen X. Gong J. Li D. Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy J Thromb Haemost 18 5 2020 1094 1099 32220112 25 Varga Z. Flammer A.J. Steiger P. Endothelial cell infection and endotheliitis in COVID-19 Lancet 395 10234 2020 1417 1418 32325026 26 Sanchez A. Sohier P. Benghanem S. Digitate papulosquamous eruption associated with severe acute respiratory syndrome coronavirus 2 infection JAMA Dermatol 2020 10.1001/jamadermatol.2020.1704
PMC007xxxxxx/PMC7271853.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)31028-8 10.1016/j.jaad.2020.06.003 JAAD Online Could antiphospholipid antibodies contribute to coagulopathy in COVID-19? Parodi Aurora MD ab Gasparini Giulia MD ac∗ Cozzani Emanuele MD, PhD ab a Section of Dermatology, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy b Ospedale Policlinico San Martino IRCCS, Genoa, Italy c Department of Experimental Medicine, University of Genoa, Genoa, Italy ∗ Correspondence to: Giulia Gasparini, MD, Section of Dermatology, Department of Health Sciences (DISSAL), University of Genoa, Via Pastore 1, 16132 Genoa, Italy 4 6 2020 9 2020 4 6 2020 83 3 e249e249 © 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 the article by Manalo et al.1 Coronavirus disease 2019 (COVID-19) patients may develop a thrombophilic state, and extensive microthrombosis has been found at autoptic examination in numerous organs.2 We agree with Manalo et al1 that it is likely that this phenomenon does not spare the skin, where it plausibly expresses itself through livedo reticularis and acral ischemia.1 , 2 Hypercoagulability in COVID-19 patients should not be underestimated because in the worst-case scenario it may lead to death by causing pulmonary embolism or disseminated intravascular coagulation.2 The pathogenesis underlying thrombophilia in COVID-19 patients is not clear yet. A recent report described 3 cases of Chinese patients affected by COVID-19 who had coagulopathy and antiphospholipid antibodies.3 Indeed, livedo reticularis and acral ischemia can be observed in antiphospholipid syndrome. Disseminated intravascular coagulation also may be substantially indistinguishable from the most severe form of antiphospholipid syndrome; namely, catastrophic antiphospholipid syndrome, in which a “thrombotic storm” affects 3 or more organs or systems simultaneously, leading to multiorgan failure.4 Zhang et al3 cautioned that this might be a fortuitous coincidence because antiphospholipid antibodies may arise transiently in patients with critical illness and various infections. Moreover, the presence of these antibodies may rarely lead to thrombotic events that are difficult to differentiate from other causes of multifocal thrombosis in critically patients, such as disseminated intravascular coagulation, heparin-induced thrombocytopenia, and thrombotic microangiopathy.3 Nonetheless, antiphospholipid syndrome often arises after infectious triggers.4 Viral induction of autoimmunity can be explained by various phenomena, including epitope spreading, molecular mimicry, cryptic antigen, and bystander activation.5 Remarkably, greater than one-third of the immunogenic proteins in severe acute respiratory syndrome corona virus 2 have potentially problematic homology to proteins that are key to the human adaptive immune system.5 Moreover, severe acute respiratory syndrome corona virus 2 seems to induce organ injury through alternative mechanisms beyond direct viral infection, including immunologic injury.2 Could antiphospholipid antibodies play a role in inducing coagulopathy in COVID-19 patients? Is coagulopathy in COVID-19 patients a manifestation of mild to very severe forms of antiphospholipid syndrome? This is could be a far-fetched hypothesis but perhaps worth perusing to better understand the pathologic mechanisms underlying the very dangerous coagulopathy observed in COVID-19 patients. Moreover, antiphospholipid antibody testing is simple, rapid, and easily accessible. Further studies are needed to investigate the validity of this hypothesis and its possible clinical implications on anticoagulant therapy management in COVID-19 patients. Funding sources: None. Conflicts of interest: None disclosed. Reprints not available from the authors. ==== Refs References 1 Manalo I.F. Smith M.K. Cheeley J. Jacobs R. A dermatologic manifestation of COVID-19: transient livedo reticularis J Am Acad Dermatol 83 2 2020 700 32283229 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 Zhang Y. Xiao M. Zhang S. Coagulopathy and antiphospholipid antibodies in patients with COVID-19 N Engl J Med 382 17 2020 e38 32268022 4 Linnemann B. Antiphospholipid syndrome - an update Vasa 47 6 2018 451 464 30205764 5 Lyons-Weiler J. Pathogenic priming likely contributes to serious and critical illness and mortality in COVID-19 via autoimmunity J Transl Autoimmun 3 2020 100051 32292901
PMC007xxxxxx/PMC7286262.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)31075-6 10.1016/j.jaad.2020.06.015 JAAD Online Assessing the risk of dupilumab use for atopic dermatitis during the COVID-19 pandemic Kearns Donovan G. BA a Uppal Shelley PhD b Chat Vipawee S. BS c Wu Jashin J. MD d∗ a Loma Linda University School of Medicine, Loma Linda, California b Albany Medical College School of Medicine, Albany, New York c Medical College of Georgia at Augusta University, Augusta, Georgia d Dermatology Research and Education Foundation, Irvine, California ∗ Correspondence and reprint requests to: Jashin J. Wu, MD 10 6 2020 9 2020 10 6 2020 83 3 e251e252 © 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 midst of the COVID-19 pandemic, physicians are using what is known of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus to establish practice guidelines for dermatologic conditions, particularly in regard to the use of immunosuppressive medications.1 The effect of immunosuppressive medications on the clinical course of coronavirus disease 2019 (COVID-19) infection is currently unclear. There is some evidence to support the use of targeted immunosuppressive medications against cytokine storm; however, there is concern that patients treated with biologic medications may have worse outcomes.1 Although knowledge regarding the risk of biologic use during the COVID-19 pandemic is extremely limited, we can use data from previous trials to extrapolate a medication's potential risk based on its infection rate when compared with placebo. Dupilumab, an interleukin (IL) 4-α receptor antagonist that inhibits IL-4 and IL-13 signaling, is a treatment for patients aged ≥12 years with moderate to severe atopic dermatitis (AD). IL-4 is critical in mediating type 2 T-helper cell polarization and regulating humoral immunity.2 Given that IL-4 and IL-13 are significant in orchestrating and maintaining adaptive immunity, we sought to identify and address the risks associated with dupilumab use during the COVID-19 pandemic. Infection rates with dupilumab were investigated in 3 randomized, placebo-controlled phase III clinical trials : In three randomiazed, placebo-controlled phase III clinical trials (Study of Dupilumab Monotherapy Administered to Adult Patients With Moderate-to-Severe Atopic Dermatitis [SOLO] 1, SOLO 2, and Study to Assess the Efficacy and Long-term Safety of Dupilumab (REGN668/SAR231893) in Adult Participants With Moderate-to-Severe Atopic Dermatitis [CHRONOS]). Adults with moderate to severe AD received dupilumab (300 mg) weekly (QW), dupilumab 300 mg every 2 weeks (Q2W), or placebo. By week 16, “infection or infestations,” as classified by Medical Dictionary for Regulatory Activities, developed in 35% of the patients receiving dupilumab Q2W and in 34% of those receiving dupilumab QW compared with 28% of patients receiving placebo in SOLO 1 and in 28%, 29%, and 32% of patients, respectively, in SOLO 2. In CHRONOS, where all 3 groups were allowed the use of concomitant topical corticosteroids, with or without topical calcineurin inhibitors, infection or infestations developed in 57% of the patients receiving dupilumab Q2W and in 53% of those receiving dupilumab QW, compared with 58% of patients receiving placebo. Nasopharyngitis was the most commonly reported infection among all treatment groups (Table I ).3 Furthermore, the conclusion in all 3 trials was that the rate of infection was not increased in dupilumab-treated patients compared with placebo.4 Table I Rate of infections in dupilumab for atopic dermatitis compared with placebo∗ Infections, overall, No. (%) URTI, No. (%) Nasopharyngitis, No. (%) Dupilumab Placebo Dupilumab Placebo Dupilumab Placebo 516 (41) 321 (41) 87 (6) 42 (5) 172 (13) 100 (13) URTI, Upper respiratory tract infection. ∗ These data are a combined average of three phase III trials. The dupilumab group is a combined average of two treatment schedules (once per week or once per two weeks). This study's analysis was limited to the data from the original dupilumab trials, because the authors did not specify whether infections were bacterial or viral. However, these findings support the notion that healthy patients with AD, without risk factors, using dupilumab during the COVID-19 pandemic should not be predisposed to infection, upper respiratory tract infection, or nasopharyngitis (Table I). Clinicians considering discontinuing dupilumab in high-risk patients should be aware that discontinuation of biologic medications has been shown to result in decreased response to treatment and the development of antidrug antibodies.5 The American Academy of Dermatology currently recommends that patients with active COVID-19 infection should discontinue any systemic treatment under the guidance of a dermatologist. Furthermore, patients without high-risk comorbidities or signs/symptoms of active COVID-19 infection can continue or initiate dupilumab treatment based on the safety data from phase III clinical trials. 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. Authors Kearns, Uppal, and Chat have no conflicts of interest to disclose. IRB approval status: Not applicable. ==== Refs References 1 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 5 2020 1217 1218 32199889 2 Heeb L.E.M. Egholm C. Boyman O. Evolution and function of interleukin-4 receptor signaling in adaptive immunity and neutrophils Genes Immun 21 3 2020 143 149 32139893 3 Simpson E.L. Bieber T. Guttman-Yassky E. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis N Engl J Med 375 24 2016 2335 2348 27690741 4 Blauvelt A. de Bruin-Weller M. Gooderham M. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial Lancet 389 10086 2017 2287 2303 28478972 5 Worm M. Simpson E.L. Thaci D. Efficacy and safety of multiple dupilumab dose regimens after initial successful treatment in patients with atopic dermatitis: a randomized clinical trial JAMA Dermatol 156 2 2019 131 143
PMC007xxxxxx/PMC7293835.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)31094-X 10.1016/j.jaad.2020.06.033 JAAD Online Asynchronous teledermatology in medical education: Lessons from the COVID-19 pandemic Su Mack Y. PhD Lilly Evelyn MD Yu JiaDe MD Das Shinjita MD ∗ Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts ∗ Correspondence and reprint requests to: Shinjita Das, MD, Department of Dermatology, Massachusetts General Hospital, 50 Staniford St, Room 292, Boston, MA 02114 14 6 2020 9 2020 14 6 2020 83 3 e267e268 © 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 spurred an unprecedented response from governments and health care systems to curb its spread. As part of this response, dermatology practices have dramatically reduced in-person visits.1 These changes pose a significant challenge to maintaining dermatology education for residents and medical students. Furthermore, consistent with interim guidance from the Association of American Medical Colleges,2 many medical schools have also restricted medical student participation from direct patient contact. Dermatology practices have converted to telemedicine (reimbursed on a limited scale before COVID-19) to care for patients. This shift in care delivery has created opportunities for engaging trainees in virtual visits for continued education.3 We propose participation in asynchronous teledermatology as a complementary educational experience for medical students that will remain valuable when direct patient contact resumes. Whereas “virtual visits” occur synchronously and require patient and provider coavailability, eConsults (provider-to-provider) and eVisits (provider-to-patient) use “store-and-forward” technology to allow specialist review at a separate time with greater efficiency (Table I ). Asynchronous teledermatology holds promise to expand access to dermatologic care,4 is a viable adjunct to in-person dermatology,5 and in our experience, augments trainee education.Table I Types of telemedicine categorized by participants and timing Category Synchronous Asynchronous Provider-to-patient Virtual visit eVisit Provider-to-provider Virtual consult eConsult We designed a teledermatology rotation in which medical students participate in both synchronous and asynchronous patient care. Students have autonomy to preview eConsult cases in a self-directed manner to formulate a differential diagnosis and document a preliminary note within the electronic medical record (Epic Systems, Verona, WI). Staffing of the eConsults in conference format with an attending provides short-interval feedback and solidifies initial learning. After making any necessary revisions, the attending attests and finalizes the note. Unlike patients in the dermatology clinic who will continue with the specialist, eConsult patients most often follow-up with the referring provider, not dermatology.4 Consequently, students learn to develop a prescriptive treatment plan understandable to the nonspecialist. Students focus on a broad differential to educate referring providers about stepwise management and different referral decisions based on a range of possible clinical responses. Furthermore, eConsults are particularly well suited for medical students—even those not pursuing dermatology—because they feature dermatologic conditions commonly encountered by ambulatory providers (eg, eczema, seborrheic keratoses, and during the pandemic, “COVID toes”). Our institution's pilot dermatology eVisit program currently focuses on patients with chronic stable disease (eg, acne and psoriasis). Through eVisits, medical students learn the importance of longitudinal monitoring and thoughtful adjustment of therapies for chronic dermatologic conditions based on both clinical response and adverse effects. Students also quickly gain perspective on the broad spectrum of disease severity and response to therapy. As direct care asynchronous teledermatology gains traction, we anticipate expanding eVisits to more patients and dermatologic conditions. The COVID-19 pandemic has required dermatologists to adopt innovative methods to provide patient care and continue trainee education. Our experience highlights the value of asynchronous teledermatology in medical student education. Although a return to in-person visits will be a welcome return to our routine, telemedicine will remain an important component of future dermatologic care. We believe that engaging medical students in asynchronous teledermatology provides complementary learning experiences that will enhance medical student education in dermatology. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. ==== 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 Association of American Medical Colleges Guidance on Medical Students' Participation in Direct Patient Contact Activities Available at: https://www.aamc.org/system/files/2020-04/meded-April-14-Guidance-on-Medical-Students-Participation-in-Direct-Patient-Contact-Activities.pdf 2020 3 Oldenburg R. Marsch A. Optimizing teledermatology visits for dermatology resident education during the COVID-19 pandemic J Am Acad Dermatol 82 6 2020 e229 32283238 4 Seiger K. Hawryluk E. Kroshinsky D. Kvedar J.C. Das S. Pediatric dermatology eConsults: reduced wait times and dermatology office visits [e-pub ahead of print] Pediatr Dermatol 2020 10.1111/pde.14187 5 Keller J.J. Johnson J.P. Latour E. Inpatient teledermatology: diagnostic and therapeutic concordance among a hospitalist, dermatologist, and teledermatologist using store-and-forward teledermatology J Am Acad Dermatol 82 5 2020 1262 1267 31972258
PMC007xxxxxx/PMC7294268.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)31095-1 10.1016/j.jaad.2020.06.034 Health Policy & Practice Redeployment of dermatologists during COVID-19: Implementation of a large-scale, centralized results management infrastructure Ran Nina A. MD, MTR a Samimi Sara S. MD a Zhang Junqian MD a Chaiyachati Krisda H. MD, MPH, MSHP b Mallozzi Colleen P. MBA, BSN, RN, BSIS c Hanson C. William III MD c Howell John T. III MD c Day Susan C. MD, MPH b Mollanazar Nicholas K. MD, MBA ac∗ a Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania b Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania c Office of the Chief Medical Information Officer, University of Pennsylvania Health System, Philadelphia, Pennsylvania ∗ Correspondence to: Nicholas K. Mollanazar, MD, MBA, Department of Dermatology, University of Pennsylvania, 3600 Spruce St, 2 Maloney, Philadelphia, PA 19104. 15 6 2020 9 2020 15 6 2020 83 3 974976 9 6 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. Key words coronavirus COVID-19 dermatologists dermatology EpicCare redeployment result SmartData SmartPhrases surge staffing Abbreviations used COVID-19 coronavirus disease 2019 ==== Body pmcOn March 13, 2020, the White House declared a State of Emergency in response to the growing coronavirus disease 2019 (COVID-19) pandemic.1 As health systems across the country fortified themselves to treat and limit infection, they shared a common goal: to test large numbers of patients and swiftly disseminate test results. Discussions of COVID-19 results have added complexity, because they must address patient questions on symptom management, test interpretation, self-isolation, and our evolving understanding of the disease.2 , 3 The scale, infectivity, and public health implications of COVID-19 have required health systems to rapidly develop new workflows and to redeploy physicians to support these operations. Dermatologists are well-suited to manage test results, because patient evaluation and counseling are integral to our practice, and we can redirect these skills to guide patients on COVID-19. At Penn Medicine, we have rapidly redeployed our dermatology department to create a COVID-19 Results Management team. An Applied Informatics Specialist/Physician Builder within our faculty spearheaded this effort in collaboration with Penn's Information Technology leadership. On March 25, our department began covering all ambulatory COVID-19 results, and in our first week of operation, we processed 2222 results. On March 30, we expanded our efforts to include all COVID-19, respiratory virus panel, and influenza results for all discharged patients seen in our 5 emergency departments and our urgent care center. In our first month, we managed a total of 14,296 results (Fig 1 ).Fig 1 Reported positive results, reported negative results, and proportion of total reported results that are positive, by day. Numbers above bars indicate total results reported that day. Critical to our performance has been the rapid reconfiguration of our electronic health record, EpicCare, to identify all patients with new COVID-19 results from all ambulatory practices across the health system. This report of patients is run 3 times every day. Patients who are positive and negative populate electronic patient lists that are shared within our team of 85 providers, who volunteer for half-day shifts. An early, critical discovery was the need to manually confirm the laboratory result within each patient's medical record, because the EpicCare sorting strategy is not 100% accurate. Furthermore, we created department-level documentation tools (SmartPhrases) that allow for standardization of the language and resources provided to patients. The content of these SmartPhrases was developed in collaboration with our internal medicine and infectious disease colleagues and vetted for accuracy and consistency. This standardization allows us to collectively update our recommendations as new COVID-19 guidelines emerge while also enabling providers to give patient-specific advice for positive, negative, and indeterminate results (Fig 2 ). The SmartPhrases also contain background SmartData elements that allow us to track patient severity, outreach, and enrollment in internal COVID-19 monitoring initiatives. All providers use these documentation tools without exception, which ensures fidelity to our tracking system.Fig 2 Communication of positive, negative, and indeterminate results. Top row, Results for patients who are positive are directly discussed through phone communication, which serves 4 main purposes. Subsequent rows, Patients are provided additional resources if needed. Patients who are negative are contacted by phone or by direct messaging via Penn Medicine's patient portal. Patients with indeterminate results, typically due to test sample degradation, are called and asked to self-isolate until their symptoms resolve. ED, Emergency department; eval, evaluation; HCP, health care provider; PCP, primary care provider. We have rapidly redeployed our dermatology workforce to handle all COVID-19, influenza, and respiratory virus panel results from all emergency department and ambulatory test sites within our health care system. We have developed a sustainable, scalable strategy that can incorporate other departments as we resume normal dermatology clinical operations. Through this model, our department has continued to address urgent dermatologic needs while also supporting Penn Medicine's response to the COVID-19 pandemic. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Proclamation No. 9994, 85 F.R. 15337 (March 18, 2020). 2 Ai T, Yang Z, Hou H, et al. Correlation of chest CT and RT-PCR testing in coronavirus disease 2019 (COVID-19) in China: a report of 1014 cases [e-pub ahead of print]. Radiology. https://doi.org/10.1148/radiol.202020064, Accessed May 30, 2020. 3 Yang Y, Yang M, Shen C, et al. Evaluating the accuracy of different respiratory specimens in the laboratory diagnosis and monitoring the viral shedding of 2019-nCoV infections [preprint]. medRxiv. 10.1101/2020.02.11.20021493.
PMC007xxxxxx/PMC7297678.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)31140-3 10.1016/j.jaad.2020.06.043 Original Article Acute pancreatic injuries: A complication of Stevens-Johnson syndrome/toxic epidermal necrolysis associated with cytotoxic immunocell activation Gao Xuemei MD a Tang Xuhua MD, PhD a Ai Lu BS b Gao Qian MD a Liao Qiman MD a Chen Mukai MD a Chen Xiaohong MD a Zhou Hui MD a Ye Yanting MD a Li Minyi RN a Han Jiande MD a∗ Wang Fang MD, PhD a∗ a Department of Dermatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong b Department of Laboratory Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong ∗ Correspondence to: Fang Wang, MD, PhD, or Jiande Han, MD, Department of Dermatology, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Er Rd, Guangzhou, Guangdong 510080, China. 17 6 2020 3 2021 17 6 2020 84 3 644653 10 6 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 Complications involving internal organs are usually present in Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, pancreatic complications are rarely reported and studied. Objective To summarize clinical characteristics of SJS/TEN-associated acute pancreatic injuries and to investigate underlying inflammatory mechanisms. Methods Clinical records of 124 inpatients with SJS/TEN were reviewed. Serum levels of tumor necrosis factor α, interleukin (IL) 6, IL-18, IL-15, IL-12p70, and soluble CD56 were determined in 18 healthy donors and 17 patients with SJS/TEN, including 3 with acute pancreatic injuries. Results Acute pancreatic injury was diagnosed in 7.3% of patients (9/124) in the SJS/TEN cohort. Elevation of serum transaminase level and hypoalbuminemia occurred more frequently in patients with acute pancreatic injuries compared with those without pancreatic symptoms (P = .004 and <.001, respectively). Although acute pancreatic injury did not alter mortality rate of SJS/TEN, it was associated with longer hospitalization stays (P = .008). Within the serum cytokines whose levels were elevated in SJS/TEN, only IL-18 was found to be selectively increased in patients with acute pancreatic injuries compared with those without them (P = .03). Limitations Cohort was small. Conclusion Acute pancreatic injury is a gastrointestinal complication of SJS/TEN in which hepatotoxicity is more likely to occur. Overexpression of IL-18 might be involved in this unique entity. Graphical abstract Key words complication cytokine storm interleukin 18 liver dysfunction pancreatitis Stevens-Johnson syndrome toxic epidermal necrolysis Abbreviations used IL interleukin SJS Stevens-Johnson syndrome TEN toxic epidermal necrolysis ==== Body pmc Capsule Summary • Stevens-Johnson syndrome and toxic epidermal necrolysis are well known to cause visceral complications. Pancreatic injuries are rarely reported. • Acute pancreatic injures are identified as gastrointestinal complications associated with Stevens-Johnson syndrome and toxic epidermal necrolysis. This entity needs specific screening and monitoring during clinical practice. Introduction Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening skin diseases that are often triggered by a drug and are characterized by erythema, blisters, epidermal detachment, and mucosal erosions. These 2 diseases are considered to be the same condition that vary in the extent of epidermal detachment.1 Although the diseases are rare, the mortality rate is less than 10% for SJS but is as high as 45% for TEN.2 SJS/TEN is fatal not only because of its devastating skin barrier dysfunction but also because of frequent and broad visceral complications. The Toxic Epidermal Necrolysis–Specific Severity-of-Illness Score has listed visceral complications such as kidney dysfunction as risk factors to determine disease mortality.3 So far, documented SJS/TEN-associated complications within internal organs include lungs (pneumonia), heart (myocarditis), kidneys (nephritis), liver (hepatitis), and the esophagus (esophageal stricture).4 Among them, gastrointestinal involvement has the highest incidence rate and generally presents with transient liver enzyme increases and gastrointestinal tract epithelial necrosis.5, 6, 7, 8 However, pancreatic injuries related to SJS/TEN have been rarely reported.9 , 10 Accumulating evidence has shown that SJS/TEN is mediated by cytotoxic T lymphocytes and, to a lesser extent, natural killer cells.11 Activation of cytotoxic T lymphocytes and natural killer cells results in release of cytotoxic molecules such as perforin, granzymes, and granulysin, which ultimately lead to widespread epithelial keratinocyte apoptosis and necrosis.12 Despite advances in understanding skin pathology and immunology, the pathogenesis of damage to internal organs remains unclear. Our previous study has shown that tumor necrosis factor α and interleukin (IL) 6 may promote SJS/TEN-associated interstitial pneumonia13; however, the role cytokines play in other visceral involvements has not been fully studied. Given that the pancreas is histologically composed of epithelial cells, which can become targets of cytotoxic T lymphocytes and natural killer cells, we hypothesized that pancreatic injuries would occur in the context of SJS/TEN and cytokines related to cytotoxic T lymphocytes, and natural killer cells may contribute to its development. In this study, we systemically reviewed records of 124 inpatients with SJS/TEN from January 2000 to June 2019 and found 9 patients with a diagnosis of acute pancreatic injuries. Herein, we present characteristics of this unique entity by analyzing data with respect to demography, clinical manifestations, laboratory features, and outcomes. Furthermore, we compared serum levels of multiple cytokines between patients with acute pancreatic injuries and nonpancreatitis patients. We found that the cytotoxic T lymphocyte–activating and natural killer cell–activating cytokine IL-18 underwent a significant increase in the setting of acute pancreatic injuries and thus might be a biomarker for this entity. Materials and methods Patients and diagnosis criteria A total of 124 patients with SJS/TEN who were admitted to the First Affiliated Hospital, Sun Yat-sen University from January 2000 to June 2019 were identified according to the diagnostic criteria described by Bastuji-Garin et al,14 in which SJS/TEN subtypes were mainly classified by the extent of epidermal detachment in addition to skin lesions (widespread erythematous or purpuric macules and flat atypical targets) and involvement of mucous membranes. SJS and SJS/TEN overlap were respectively defined as detachment of the body surface area below 10% and between 10% and 30%, whereas TEN was defined as detachment greater than 30% of body surface area.14 All enrolled patients had clear medical records of drug administration before skin symptoms. We retrospectively documented their disease history, clinical manifestations, laboratory test results (including complete blood cell count), compressive metabolic panel, serum lipase and amylase activity, autoantibody levels, and imaging examination results, including transabdominal ultrasonography and abdominal computed tomographic scan. For diagnosis of acute pancreatic injuries, the Atlanta classification standard was used.15 The diagnosis of acute pancreatitis was made when at least 2 of the following 3 features were met: typical abdominal pain, biochemical evidence consistent with pancreatitis (serum level of lipase activity or amylase activity 3-fold greater than the upper limit of normal), and characteristic findings of acute pancreatitis suggested by imaging tomography. Pancreatic hyperenzymemia was defined as an increase in pancreatic enzyme levels more than 3 times the upper limit of normal in the absence of symptoms and abdominal computed tomographic imaging of pancreatic diseases.16 Cytokine evaluation In January 2017, we started a series of SJS/TEN-related scientific studies, which were approved by the ethics committee of the hospital. For cytokine tests, 17 patients with SJS/TEN, 3 with acute pancreatic injuries, were enrolled from December 2017 to June 2019 after consent was obtained from each individual. Simultaneously, 18 sex- and age-matched healthy controls were recruited (Supplemental Table I; available at https://data.mendeley.com/datasets/6vycp9yvnp/draft?a=00db49dc-1212-47e3-9596-dd5ac2e136d4). Peripheral blood (5 mL) was obtained from each of 17 patients during the acute stage before treatment, as well as from 18 controls. Serum specimens were suspended from clotted blood centrifuged at 4°C and 2,500 rpm for 10 minutes and then stored at –80°C until tested. Serum samples were tested for 6 cytokines; namely, tumor necrosis factor α, IL-6, IL-18, IL-15, IL-12p70, and soluble CD56. Multiplex cytokine analysis kits were obtained from R&D Systems, and data were collected with Luminex 100 (Luminex, Austin, TX). Data analysis was performed with MILLIPLEX Analyst (version 5.1, EMD Millipore Corporation, Billerica, MA). Statistical analysis Data with normal distributions were described as mean ± standard deviation. For data not following a normal distribution, median (interquartile range) was used. Differences of incidence rate between every 2 groups were compared by Fisher's exact test. Differences of cytokine levels were assessed with the 2-tailed unpaired Student t test when they were normally distributed. For data that were not normally distributed, the Mann-Whitney-Wilcoxon nonparametric test was performed to detect significant differences. All tests were performed with GraphPad Prism (version 8.0, GraphPad Software, Inc). P < .05 was considered to indicate a statistically significant difference. Results Description of patients In the entire cohort, SJS, SJS/TEN overlap, and TEN were diagnosed in 91, 4, and 29 patients, respectively. Acute pancreatic injury was documented in 9 of these patients. Among them, 8 patients met the diagnosis of acute pancreatitis, whereas the other patient received a diagnosis of hyperamylasemia. Therefore, the morbidity rate of acute pancreatic injuries was 7.3%. Among the patients with acute pancreatic injuries, there were 3 with SJS, 1 with SJS/TEN overlap, and 5 with TEN (Fig 1, A ). Accordingly, the acute pancreatic injury incidence rate was 3.3% (3/91) in SJS, 25.0% (1/4) in SJS/TEN overlap, and 17.2% (5/29) in TEN. The acute pancreatic injury morbidity rate in TEN was much higher compared with that in SJS (P = .02) (Fig 1, B).Fig 1 Incidence rate and distribution of acute pancreatic injuries in patients with Stevens-Johnson syndrome/toxic epidermal necrolysis. A, Acute pancreatic injuries and nonpancreatitis in the subtypes of Stevens-Johnson syndrome. Patient numbers are shown at the top of the bar. B, Incidence of acute pancreatic injuries in Stevens-Johnson syndrome patients, patients with Stevens-Johnson syndrome/toxic epidermal necrolysis overlap, and in the toxic epidermal necrolysis cohort. P values are determined by Fisher's exact test. API, Acute pancreatic injury; NP, nonpancreatitis; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis. Demography The acute pancreatic injuries cohort consisted of 5 female patients and 4 male patients aged 12 to 69 years (median 31 years [interquartile range 19-56 years]). In the other 115 patients without pancreatic symptoms, the sex ratio of female:male was 1:1.05, and the ages ranged from 5 to 93 years (median 46 years [interquartile range 26-60 years]). The statistical analyses of sex distribution and age revealed no significant difference between the 2 groups (P = .74 and .15, respectively). Clinical manifestations Similar to classic acute pancreatitis, abdominal pain occurred in 7 patients (7/9; 77.8%) in the initial stage (from day 0 to 8) of SJS/TEN (Table I ). However, common triggers in classic acute pancreatitis appear dispensable for SJS/TEN-associated acute pancreatic injuries because gallstone history and alcohol abuse were found in only 1 patient each (Table I). Neither of the incidence rates showed significant difference between acute pancreatic injuries and nonpancreatitis groups (P = .20 and .26, respectively) (Fig 2, A and B ).Table I Demographic and clinical details of patients with acute pancreatic injuries in the context of Stevens-Johnson syndrome/toxic epidermal necrolysis Case Diagnosis Sex/age, years Culprit drug Biliary history Alcohol abuse Abdominal pain/interval∗ (days) API Hospitalization stay (days) Treatment Outcome 1† SJS/TEN overlap F/33 Nimesulide/sulfonamides No No No/NA AP 17 Low-fat liquid diet, octreotide acetate, steroids and etanercept Cured 2† TEN F/22 TCM No No No/NA Hyperamylasemia 40 Low-fat liquid diet, octreotide acetate, steroids, IVIG Cured 3† TEN F/17 Uncertain No No Yes/0 AP 53 Fasting, octreotide acetate, steroids, IVIG Cured 4 TEN M/52 Aminopyrine/Cefoperazone No No Yes/0 AP 18 Fasting, somatostatin, steroids Cured 5 TEN M/69 Allopurinol Yes No Yes/8 AP 25 Fasting, somatostatin, steroids Cured 6 TEN F/59 Carbamazepine No No Yes/7 AP 14 Fasting, octreotide acetate, steroids, IVIG Cured 7 SJS F/20 Cephalosporin No No Yes/6 AP 31 Fasting, somatostatin, steroids Cured 8 SJS M/12 Acetaminophen/kitasamycin No No Yes/1 AP 30 Fasting, somatostatin, antibiotics, steroids Chronic hyperamylasemia 9 SJS M/31 Acetaminophen/sulfonamides No Yes Yes/1 AP 9 Fasting, octreotide acetate, steroids, IVIG Cured AP, Acute pancreatitis; API, acute pancreatic injuries; F, female patient; IVIG, intravenous immunoglobulin; M, male patient; NA, not available; SJS, Stevens-Johnson syndrome; TCM, traditional Chinese medicine; TEN, toxic epidermal necrolysis. ∗ Interval from rash to abdominal pain. † Subjects underwent serum cytokine examination. Fig 2 Comparison of disease triggers, laboratory test results, and prognosis between the acute pancreatic injuries group and nonpancreatitis group in the context of Stevens-Johnson syndrome/toxic epidermal necrolysis. No significant difference was revealed in biliary history (A), alcohol abuse (B), kidney dysfunction (D), positive autoantibody results (E), and mortality rate (F) between the 2 groups. C, A higher incidence rate of liver dysfunction was shown in patients with acute pancreatic injuries than in the nonpancreatitis cohort. G, The average hospitalization stay was much greater when patients developed acute pancreatic injuries. Fisher's exact test was applied for comparison (A-F); the P value was determined by Student t test (G).API, Acute pancreatic injury; NP, nonpancreatitis. Accessory examinations Liver dysfunction is reflected by increased serum transaminase levels and decreased albumin levels.17 Transaminase level elevation and hypoalbuminemia were found in 77.8% (7/9) and 100% (9/9) of patients, respectively, with acute pancreatic injuries. Both were significantly higher than those in nonpancreatitis patients (31/115, 27.0%, P = .004 for comparison of transaminase elevation; 42/115, 36.5%, P < .001 for hypoalbuminemia) (Fig 2, C). In contrast to liver dysfunction, no difference in the incidence of kidney dysfunction was observed (P = .65) (Fig 2, D). Results of autoantibody tests were available for 7 patients with acute pancreatic injuries and 56 in the nonpancreatitis cohort. The percentage of positive autoantibody results was 3 of 9 (33.3%) in patients with acute pancreatic injuries, whereas 15 patients (15/115; 13.0%) without pancreatic injuries exhibited positive serum autoantibody levels. The difference between the 2 groups was not statistically significant (P = .12) (Fig 2, E). According to the imaging examinations, pancreas abnormality presenting as diffuse enlargement of the pancreas was found in 4 patients (4/9; 44.4%). Detailed auxiliary test results are listed in Table II .Table II Auxiliary examination results of patients with Stevens-Johnson syndrome/toxic epidermal necrolysis accompanied by acute pancreatic injuries Case Pancreas function Liver function Kidney function Autoantibody Abdominal CT or ultrasonographic scan Lipase (N = 23–300 U/L) Amylase (N = 30–110 U/L) ALT (N = 1–40 U/L) AST (N = 1–37 U/L) ALP (N = 0–110 U/L) ALB (N = 35–50 g/L) Cr (N = 56–115 μmol/L) ANA Anti-Ro/SSA antibodies 1 1429↑ 503↑ 725↑ 730↑ 403↑ 31↓ 58 (+) (+) Diffuse enlargement of the pancreas 2 2684↑ 1386↑ 148↑ 73↑ 191↑ 27↓ 40↓ (–) (–) NA 3 1930↑ 400↑ 1042↑ 2503↑ 503↑ 24.2↓ 56 (+) (–) NA 4 397↑ 436↑ 140↑ 108↑ 84 28↓ 56 NA NA Unclear border of the pancreas, pancreatic duct dilatation 5 958↑ 1028↑ 58↑ 38↑ 65 23↓ 446↑ NA NA Gallstones in the gallbladder 6 1294↑ 235↑ 94↑ 83↑ 503↑ 29.6↓ 53↓ (+) (–) No evidence of pancreatic disease 7 525↑ 814↑ 13 20 42 34↓ 56 (–) (–) Diffuse enlargement of the pancreas, haziness in the peripancreatic fat 8 2098↑ 533↑ 87↑ 52 182↑ 23↓ 112 (–) NA Diffuse enlargement of the pancreas 9 4603↑ 630↑ 89↑ 140↑ 120↑ 31↓ 973↑ (–) (–) No evidence of pancreatic disease ALB, Albumin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; ANA, antinuclear antibodies; AST, aspartate aminotransferase; Cr, creatinine; CT, computed tomography; N, normal range; NA, not available; +, positive; –, negative. Treatment and prognosis To control SJS/TEN, a combination of systemic corticosteroids and intravenous immunoglobulin therapy was administered. To treat pancreatic injuries, 7 patients with abdominal pain were given a short period of fasting, whereas the other 2 patients received a low-fat solid diet. Simultaneously, all 9 patients were given intravenous injection of proton-pump inhibitors and antisecretory agents. The therapeutics were effective and the survival rate for acute pancreatic injuries cohort was 100%. Although 3 of the 115 patients without pancreatic symptoms died because of SJS/TEN, no significant difference in mortality rate was found between the 2 groups (P > .99) (Fig 2, F). However, the hospitalization stay of patients with acute pancreatic injuries ranged from 9 to 53 days (average 26.3 ± 13.9 days), which was significantly longer than that of nonpancreatitis patients (average 14.9 ± 4.9 days) (P = .008) (Fig 2, G). Cytokine profile In patients who had serum cytokine tests, the SJS/TEN group exhibited elevated serum levels of tumor necrosis factor α, IL-6, IL-18, IL-15, and IL-12p70 compared with healthy controls (Supplemental Table II; available at https://data.mendeley.com/datasets/4jwjfc5gzv/draft?a=d83ff42c-96b1-45d1-ba85-cb801da61fda). Conversely, soluble CD56 levels were significantly lower in SJS/TEN group than those in heathy controls (Supplemental Table II). In the SJS/TEN cohort, we compared cytokine results between groups classified by the existence of pancreatic injuries (Supplemental Table I). IL-18 levels were significantly increased in the acute pancreatic injuries group (average 1.35 ± 0.12 × 103 pg/mL) compared with the nonpancreatitis individuals (median 0.86 × 103 pg/mL [interquartile range 0.63-1.15 × 103 pg/mL], P = .03) (Fig 3, C ). None of the other cytokines was significantly different between the 2 groups (Fig 3, A, B, D, and F).Fig 3 Comparison of serum cytokine levels. None of cytokines, including tumor necrosis factor α (A), IL-6 (B), IL-15 (D), IL-12p70 (E), and soluble CD56 (F), has significantly different levels between the nonpancreatitis group (n = 14) and acute pancreatic injuries group (n = 3). IL-18 levels were significantly increased in the acute pancreatic injuries group compared with those in nonpancreatitis patients (C). Symbols represent individuals. P values were determined by Mann-Whitney-Wilcoxon test. API, Acute pancreatic injury; IL, interleukin; NP, nonpancreatitis; TNF, tumor necrosis factor. Discussion To date, there are only a few publications that have reported SJS/TEN-associated acute pancreatic injuries. Dylewski et al9 reported 4 pediatric patients with TEN who developed asymptomatic hyperamylasemia and hyperlipasemia among a cohort of 10 patients. A study conducted by Chatproedprai et al18 disclosed 1 pancreatitis patient with SJS/TEN overlap in a reviewed database of 36 patients. Two other reports each described a single patient with pancreatic damage in the process of SJS/TEN.19 , 20 In the current study, we found 9 patients with acute pancreatic injuries in a cohort of 124 individuals. These epidemiologic data indicate that acute pancreatic injuries should be identified as a complication of SJS/TEN, although the incidence rate may be variable among studies. In the present acute pancreatic injuries cohort, we found that more patients developed liver dysfunction compared with those without pancreatic symptoms. Thus, we suspect that acute pancreatic injury is a gastrointestinal complication analogous to injuries in other gastrointestinal organs. Patients with acute pancreatic injuries did not show more evidence of kidney toxicity or positive autoantibody results, suggesting that SJS/TEN may have preference and subtypes regarding toxicity in diverse internal organs. Moreover, we found that patients with acute pancreatic injuries on average had longer hospitalization stays, implying increased financial and medical burdens. Therefore, screening and early monitoring for acute pancreatic injuries are required via abdominal symptom inquiry, physical examination of the abdomen, and routine laboratory tests for lipase and amylase activity. It has been well recognized that classic acute pancreatitis is usually triggered by gallstones or alcohol abuse.21 Occasionally, drugs such as acetaminophen and valproic acid also contribute to the etiology.22 In the present cohort, neither biliary disorders nor alcohol abuse was present as a trigger for SJS/TEN-associated acute pancreatic injuries. Additionally, the culprit drug spectrum is broader than the one that is regularly related to acute pancreatitis. Thus, we hypothesize that acute pancreatic injury in the context of SJS/TEN is more likely to be mediated by systemic inflammation than by common mechanical obstruction or dysfunction in pancreatic ducts. Among the cytokines that we examined, IL-6 is commonly used in classic acute pancreatitis as an early marker to predict disease severity.23 Some studies have shown that the assessment of serum IL-6 increases the accuracy of systemic inflammatory response syndrome in severe acute pancreatitis.24, 25, 26 In an acute pancreatitis rat model, an increase of serum IL-6 precedes severe pancreatic edema and necrosis.27 However, in our present study, the level of IL-6 did not show significant elevation in SJS/TEN patients with acute pancreatic injuries. This negative finding indicates that acute pancreatic injuries related to SJS/TEN may have a cytokine profile distinct from those in classic acute pancreatitis. Previously, only 1 study reported that serum IL-18 levels were elevated in patients with classic acute pancreatitis and might aggravate liver injuries.28 In an obese murine model, injection of IL-18 combined with IL-12 was sufficient to cause pancreatic necrolysis.29 In another pancreatitis murine model, tumor necrosis factor α directly mediated protease activation and subsequent necrosis of pancreatic acinar cells.30 In the present acute pancreatic injuries cohort, in addition to the significant elevation of serum IL-18 level, that of IL-12p70 and tumor necrosis factor α also exhibited an increasing trend. These results indicate that cytotoxic cytokine dysregulation might be a cause for acute pancreatic injuries in the setting of SJS/TEN. However, because of the small cohort size and the lack of pancreas histopathology, the precise role cytokines play in acute pancreatic injury mechanisms and whether they have distinct function in mediating other internal organ toxicities associated with SJS/TEN will be an interesting area of further inquiry. Consistent with previous studies,12 , 13 , 31 , 32 we found a universal elevation of levels of multiple cytokines in SJS/TEN. In addition to tumor necrosis factor α, IL-6, IL-15, IL-18, and IL-12, other cytokines we previously found had elevated levels in SJS/TEN included IL-10, interferon gamma, and interferon gamma–inducible chemokines CXCL9 and CXCL10.33 , 34 Such phenomena led us to speculate that drug-induced SJS/TEN could be another form of “cytokine storm” syndrome,35 the condition that is triggered by a wide variety of infections such as COVID-1936 , 37 or noninfectious diseases such as graft-versus-host disease.38 In contrast to the broad cytokine-level elevation, we found a significant decrease of serum-soluble CD56 in SJS/TEN. CD56 (also called neural cell adhesion molecule 1) is expressed on the surface of natural killer cells and some innate lymphoid cells and is a well-known phenotypic marker for natural killer cells.39 , 40 Soluble CD56 can be released from membrane-bound CD56 by enzymatic cleavage of the extracellular domain.41 A decreased expression of soluble CD56 in SJS/TEN serum may indicate more peripheral natural killer cells have migrated to skin lesions, which is consistent with the histopathologic findings from skin bulla.11 Notwithstanding this, future studies will be required to clearly define cytokine diversity and their specific function in promoting the SJS/TEN process. Conclusions In conclusion, acute pancreatic injury is identified as a visceral complication associated with SJS/TEN. The specific monitoring may help reduce medical burdens. Given that more symptoms in internal organs are identified in SJS/TEN, specific subclassification will be needed. The precise role cytokines play in internal organ injuries related to SJS/TEN is an outstanding question for further studies. We thank all patients participating in this study and physicians from the Department of Dermatology in the First Affiliated Hospital of Sun Yat-sen University for their clinical practice. We also would like to express our deepest appreciation to Dr. Madison R. Mack for editing. Drs Gao and Tang contributed equally to this article. Funding sources: Supported by the 10.13039/501100001809 National Natural Science Foundation of China (grant 81703111) and the 10.13039/501100003453 Natural Science Foundation of Guangdong Province (grant 2016A030313246). Conflicts of interest: None disclosed. ==== Refs References 1 Duong T.A. Valeyrie-Allanore L. Wolkenstein P. Severe cutaneous adverse reactions to drugs Lancet 390 2017 1996 2011 28476287 2 Struck M.F. Hilbert P. Mockenhaupt M. Severe cutaneous adverse reactions: emergency approach to non-burn epidermolytic syndromes Intensive Care Med 36 2010 22 32 19787334 3 Bastuji-Garin S. Fouchard N. Bertocchi M. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis J Invest Dermatol 115 2000 149 153 10951229 4 Lee H.Y. Walsh S.A. Creamer D. Long-term complications of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN): the spectrum of chronic problems in patients who survive an episode of SJS/TEN necessitates multidisciplinary follow-up Br J Dermatol 177 2017 924 935 28144971 5 Yamane Y. Matsukura S. Watanabe Y. Retrospective analysis of Stevens-Johnson syndrome and toxic epidermal necrolysis in 87 Japanese patients—treatment and outcome Allergol Int 65 2016 74 81 26666483 6 Lerch M. Mainetti C. Terziroli Beretta-Piccoli B. Current perspectives on Stevens-Johnson syndrome and toxic epidermal necrolysis Clin Rev Allergy Immunol 54 2018 147 176 29188475 7 Jha A.K. Suchismita A. Jha R.K. Spectrum of gastrointestinal involvement in Stevens - Johnson syndrome World J Gastrointest Endosc 11 2019 115 123 30788030 8 Brown C.S. Defazio J.R. An G. Toxic epidermal necrolysis with gastrointestinal involvement: a case report and review of the literature J Burn Care Res 38 2017 e450 e455 27058583 9 Dylewski M.L. Prelack K. Keaney T. Asymptomatic hyperamylasemia and hyperlipasemia in pediatric patients with toxic epidermal necrolysis J Burn Care Res 31 2010 292 296 20182382 10 Chosidow O. el Wady Z. Devanlay M. Hyperamylasemia in toxic epidermal necrolysis Arch Dermatol 129 1993 792 793 7685157 11 Stern R.S. Divito S.J. Stevens-Johnson syndrome and toxic epidermal necrolysis: associations, outcomes, and pathobiology-thirty years of progress but still much to be done J Invest Dermatol 137 2017 1004 1008 28411832 12 Su S.C. Chung W.H. Cytotoxic proteins and therapeutic targets in severe cutaneous adverse reactions Toxins (Basel) 6 2014 194 210 24394640 13 Wang F. Gao X. Chen X. Successful treatment of interstitial lung disease related to Stevens-Johnson syndrome/toxic epidermal necrolysis overlap with etanercept: a case report and published work review J Dermatol 46 2019 1035 1038 31436331 14 Bastuji-Garin S. Rzany B. Stern R.S. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme Arch Dermatol 129 1993 92 96 8420497 15 Banks P.A. Bollen T.L. Dervenis C. Classification of acute pancreatitis—2012: revision of the Atlanta classification and definitions by international consensus Gut 62 2013 102 111 23100216 16 Choung B.S. Kim S.H. Seo S.Y. Pancreatic hyperenzymemia is associated with bacterial culture positivity, more severe and right-sided colitis Dig Dis Sci 59 2014 2272 2279 24728985 17 Hall P. Cash J. What is the real function of the liver ‘function’ tests? Ulster Med J 81 2012 30 36 23536736 18 Chatproedprai S. Wutticharoenwong V. Tempark T. Clinical features and treatment outcomes among children with Stevens-Johnson syndrome and toxic epidermal necrolysis: a 20-year study in a tertiary referral hospital Dermatol Res Pract 2018 2018 3061084 29853855 19 Tatnall F.M. Dodd H.J. Sarkany I. Elevated serum amylase in a case of toxic epidermal necrolysis Br J Dermatol 113 1985 629 630 20 Tagami H. Iwatsuki K. Elevated serum amylase in toxic epidermal necrolysis Br J Dermatol 115 1986 250 251 2427102 21 Thomasset S.C. Carter C.R. Acute pancreatitis Surgery (Oxford) 34 2016 292 300 22 Simons-Linares C.R. Elkhouly M.A. Salazar M.J. Drug-induced acute pancreatitis in adults Pancreas 48 2019 1263 1273 31688589 23 Rau B.M. Kruger C.M. Schilling M.K. Anti-cytokine strategies in acute pancreatitis: pathophysiological insights and clinical implications Rocz Akad Med Bialymst 50 2005 106 115 16358948 24 Czako L. Takacs T. Varga I.S. The pathogenesis of L-arginine-induced acute necrotizing pancreatitis: inflammatory mediators and endogenous cholecystokinin J Physiol Paris 94 2000 43 50 10761688 25 Watanabe T. Kudo M. Strober W. Immunopathogenesis of pancreatitis Mucosal Immunol 10 2017 283 298 27848953 26 Mayer J. Rau B. Gansauge F. Inflammatory mediators in human acute pancreatitis: clinical and pathophysiological implications Gut 47 2000 546 552 10986216 27 Jain S. Midha S. Mahapatra S.J. Interleukin-6 significantly improves predictive value of systemic inflammatory response syndrome for predicting severe acute pancreatitis Pancreatology 18 2018 500 506 29779831 28 Ueda T. Takeyama Y. Yasuda T. Significant elevation of serum interleukin-18 levels in patients with acute pancreatitis J Gastroenterol 41 2006 158 165 16568375 29 Sennello J.A. Fayad R. Pini M. Interleukin-18, together with interleukin-12, induces severe acute pancreatitis in obese but not in nonobese leptin-deficient mice Proc Natl Acad Sci U S A 105 2008 8085 8090 18515422 30 Sendler M. Dummer A. Weiss F.U. Tumour necrosis factor alpha secretion induces protease activation and acinar cell necrosis in acute experimental pancreatitis in mice Gut 62 2013 430 439 22490516 31 Su S.C. Mockenhaupt M. Wolkenstein P. Interleukin-15 is associated with severity and mortality in Stevens-Johnson syndrome/toxic epidermal necrolysis J Invest Dermatol 137 2017 1065 1073 28011147 32 Wang F. Ye Y. Luo Z.Y. Diverse expression of TNF-alpha and CCL27 in serum and blister of Stevens-Johnson syndrome/toxic epidermal necrolysis Clin Transl Allergy 8 2018 12 29713456 33 Wang F. He D. Tang X. Chemokine expression in diverse nonimmediate drug hypersensitivity reactions: focus on thymus activation-regulated chemokine, cutaneous T-cell-attracting chemokine, and interleukin-10 Ann Allergy Asthma Immunol 113 2014 204 208 24932689 34 Wang F. Cai R. He D. Serum IFN-gamma-inducible chemokines CXCL9 and CXCL10 are elevated in non-immediate drug hypersensitivity reactions Asian Pac J Allergy Immunol 34 2016 236 241 27001652 35 Tisoncik J.R. Korth M.J. Simmons C.P. Into the eye of the cytokine storm Microbiol Mol Biol Rev 76 2012 16 32 22390970 36 Price K.N. Frew J.W. Hsiao J.L. COVID-19 and immunomodulator/immunosuppressant use in dermatology J Am Acad Dermatol 82 2020 e173 e175 32224277 37 Mehta P. McAuley D.F. Brown M. COVID-19: consider cytokine storm syndromes and immunosuppression Lancet 395 2020 1033 1034 32192578 38 Ferrara J.L. Cytokine dysregulation as a mechanism of graft-versus-host disease Curr Opin Immunol 5 1993 794 799 8240742 39 Luetke-Eversloh M. Killig M. Romagnani C. Signatures of human NK cell development and terminal differentiation Front Immunol 4 2013 499 24416035 40 Cunningham B.A. Hemperly J.J. Murray B.A. Neural cell adhesion molecule: structure, immunoglobulin-like domains, cell surface modulation, and alternative RNA splicing Science 236 1987 799 806 3576199 41 Secher T. Soluble N.C.A.M. Adv Exp Med Biol 663 2010 227 242 20017026
PMC007xxxxxx/PMC7303035.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)31150-6 10.1016/j.jaad.2020.06.052 JAAD Online When interferon tiptoes through COVID-19: Pernio-like lesions and their prognostic implications during SARS-CoV-2 infection Damsky William MD, PhD ∗∗ Peterson Danielle MD King Brett MD, PhD ∗ Department of Dermatology, Yale School of Medicine, New Haven, Connecticut ∗ Correspondence to: Brett King, MD, PhD, 333 Cedar St, LCI 501, PO Box 208059, New Haven, CT 06510 ∗∗ Correspondence to: William Damsky, MD, PhD, 333 Cedar St, LCI 501, PO Box 208059, New Haven, CT 06510 19 6 2020 9 2020 19 6 2020 83 3 e269e270 © 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 was recently reported that patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can develop cutaneous lesions resembling pernio (popularly called “COVID toes”).1, 2, 3, 4, 5 Recent work has suggested that SARS-CoV-2 infection is sometimes characterized by a muted antiviral type I and III interferon (IFN) response,6 , 7 which may explain progression to severe clinical manifestations in some patients; whereas a robust type I IFN response was associated with rapid viral clearance and bland disease course.6 Here, we describe pernio-like lesions as they have been reported in the literature and consider other settings where pernio is observed, including familial chilblains lupus (FCL), an interferonopathy syndrome. Together, these data suggest that COVID toes may be a marker of patients who are able to mount a robust antiviral immune response to SARS-CoV-2 and reflect a milder course of coronavirus disease 2019 (COVID-19). Sporadic pernio (also known as chilblains) is an idiopathic cold-sensitive inflammatory disorder that presents with red-to-violaceous macules or papules on acral sites; vesiculation and ulceration may occur. These lesions are typically located on the distal toes but can also occur on fingers, heels, and even the nose and ears. Histopathology reveals edema in the superficial dermis and marked superficial and deep perivascular and perieccrine lymphocytic inflammation (Fig 1 , A). Interface change or vasculopathic changes (eg, focal thrombosis), or both, may be present.Fig 1 Clinical presentation of pernio-like lesions, histology, and disease course, depending on type I interferon response. A, Histology of pernio and pernio-like lesions. There is a moderately dense superficial and deep perivascular lymphocytic or lymphohistiocytic inflammatory infiltrate. There is also perieccrine lymphocytic inflammation. A mild vacuolar interface dermatitis can also be seen. B, Interferon (IFN) and clinical manifestations of coronavirus disease 2019 (COVID-19). A strong, early type I IFN response is associated with viral clearance and a mild course, whereas an insufficient type I IFN response may lead to severe disease, possibly through development of a cytokine release syndrome and subsequent end-organ damage. Pernio-like lesions, or COVID toes, which we know can result from elevated type I IFN signaling in the body, may be a marker of those who respond effectively to the virus. Similar cold-induced lesions are a feature of FCL, caused by mutations in TREX1. TREX1-FCL is one of several interferonopathies, genetic syndromes characterized by excessive, type I IFN production.8 Type I IFNs (IFN-α, IFN-β) are essential inducers of antiviral immunity but also can drive autoimmunity when activated inappropriately. The clinical and histologic manifestations of pernio in TREX1-FCL are similar to sporadic pernio but can be more severe. Therefore, pernio can be a manifestation of a systemically elevated type I IFN response. Furthermore, others have shown that recombinant type I IFN therapy can induce thrombotic microangiopathy in some patients through direct effects on the microvasculature.9 Pernio-like lesions in the setting of SARS-CoV-2 infection have primarily been described in relatively younger patients who tend to have a milder disease course.1, 2, 3, 4, 5 Similar to idiopathic pernio and TREX1-FCL, histopathology reveals superficial and deep perivascular and perieccrine lymphocytic inflammation and mild vacuolar interface change with occasional microthrombi.2 , 3 Lesions often resolve over days to weeks. Interpretation of this particular manifestation of COVID-19 has been somewhat hampered by low rates of SARS-CoV-2 confirmation in reported cases, but the apparent relationship of pernio-like lesions and a mild disease course may be explained by a high type I IFN response in such patients. Recent observations suggest that a strong early type I IFN response is associated with early viral control and a mild course, whereas an insufficient type I IFN response may be associated with progression to more severe disease (Fig 1, B).6 , 7 Therefore, we hypothesize that pernio-like lesions, which can occur with elevated type I IFN signaling, are the result of a robust antiviral response in patients with COVID-19 and, therefore, are associated with a favorable disease course, as observed in these patients. Funding sources: This work was supported by the Ranjini and Ajay Poddar Fund for Dermatologic Diseases Research to Dr King. Dr Damsky is supported by the 10.13039/100001582 Dermatology Foundation . Conflicts of interest: Dr Damsky has research funding from Pfizer, but it did not support this work, and is a consultant for Eli Lilly and Company. Dr King is an investigator for Concert Pharmaceuticals Inc, Eli Lilly and Company, and Pfizer Inc, and is a consultant to and/or has served on advisory boards for Aclaris Therapeutics, Arena Pharmaceuticals, Bristol-Meyers Squibb, Concert Pharmaceuticals Inc, Dermavant Sciences, Eli Lilly and Company, and Pfizer Inc, and is on speakers bureaus for Regeneron and Sanofi Genzyme. Dr Peterson has no conflicts of interest to declare. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Fernandez-Nieto D. Jimenez-Cauhe J. Suarez-Valle A. 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 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 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 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 5 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 6 Trouillet-Assant S. Viel S. Gaymard A. Type I IFN immunoprofiling in COVID-19 patients J Allergy Clin Immunol 146 1 2020 206 208.e2 32360285 7 Blanco-Melo D. Nilsson-Payant B.E. Liu W.-C. Imbalanced host response to SARS-CoV-2 drives development of COVID-19 Cell 181 5 2020 1036 1045.e9 32416070 8 Rice G. Newman W.G. Dean J. Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutières syndrome Am J Hum Genet 80 4 2007 811 815 17357087 9 Kavanagh D. McGlasson S. Jury A. Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature Blood 128 24 2016 2824 2833 27663672
PMC007xxxxxx/PMC7306731.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)31161-0 10.1016/j.jaad.2020.06.063 JAAD Online Comment on: “To consider varicella-like exanthem associated with COVID-19, virus varicella zoster and virus herpes simplex must be ruled out. Characterization of herpetic lesions in hospitalized COVID-19 patients” Fernandez-Nieto Diego MD ∗ Ortega-Quijano Daniel MD Suarez-Valle Ana MD Burgos-Blasco Patricia MD Jimenez-Cauhe Juan MD Fernandez-Guarino Montserrat MD, PhD From the Dermatology Department, Ramon y Cajal University Hospital, Alcala University, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain ∗ Correspondence to: Diego Fernandez-Nieto, MD, Dermatology Department, Ramon y Cajal University Hospital, Carretera Colmenar Viejo km 9.100, 28034 Madrid, Spain 22 6 2020 9 2020 22 6 2020 83 3 e257e259 © 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 have read with great interest the articles by Llamas-Velasco et al1 and Marzano et al2 about the current controversy regarding coronavirus disease 2019 (COVID-19) vesicular exanthems and the role of herpesvirus in the etiology of these lesions. Llamas-Velasco et al1 report 3 cases of vesicular lesions in patients hospitalized with COVID-19, suggesting that complementary tests, such as Tzanck smear, virus culture, polymerase chain reaction (PCR), or skin biopsy should be performed to rule out other viral infections. Marzano and Genovese2 were not able to perform PCR tests in their previous study of varicella-like exanthem3 due to logistic reasons but also due to clinical presentation not being suggestive of varicella. We previously conducted a prospective study of vesicular COVID-19 rashes, all with a positive nasopharyngeal swab for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in our hospital from March 1 to April 20, 2020.4 Of a total of 53 patients, 15 were excluded because of an alternative herpes simplex/zoster clinical diagnosis (clinical data are summarized in Table I ). All 15 patients presented typical clinical lesions and symptoms of herpes simplex/zoster. Only 1 patient (6.7%) had a previous history of immunosuppression. Latency time between COVID-19 symptoms and herpetic lesions was variable (median, 16 days; range, 6-32 days). Despite performing PCR tests for SARS-CoV-2 from the content of the vesicles in only 3 patients, all of the results were negative.Table I Summary of patient clinical data Patient Sex Age, y Relevant medical history Chest x-ray Total number of days since onset of COVID-19 symptoms Diagnosis Multiplex herpes PCR/SARS-CoV-2 rt-PCR from the vesicles Medication 1 (Fig 1, A) Male 69 None Bilateral interstitial pneumonia (required ICU stay) 16 Recurrent herpes simplex (orolabial) HSV1/negative Hydroxychloroquine, azithromycin, ceftriaxone, acyclovir 2 Female 96 Hypertension, chronic kidney disease, hyperuricemia Bilateral interstitial pneumonia 27 Recurrent herpes simplex (orolabial) HSV1/negative Hydroxychloroquine, azithromycin, prednisone 3 Female 77 Primary biliary cholangitis, Alzheimer disease Bilateral interstitial pneumonia 14 Recurrent herpes simplex (orolabial) HSV1/not done Hydroxychloroquine, lopinavir/ritonavir, azithromycin, prednisone 4 Male 65 Hypertension, dyslipidemia Bilateral interstitial pneumonia (required ICU stay) 32 Recurrent herpes simplex (orolabial) HSV1/not done Lopinavir/ritonavir, azithromycin, prednisone, tocilizumab, remdesivir, acyclovir 5 Male 38 Colorectal cancer (on chemotherapy treatment) Bilateral interstitial pneumonia 9 Recurrent herpes simplex (orolabial) HSV1/not done Lopinavir/ritonavir, tocilizumab, remdesivir, prednisone, acyclovir 6 Male 61 None Bilateral interstitial pneumonia (required ICU stay) 15 Recurrent herpes simplex (orolabial) HSV1/not done Hydroxychloroquine, lopinavir/ritonavir, tocilizumab, prednisone, acyclovir 7 Female 45 None Bilateral interstitial pneumonia 18 Recurrent herpes simplex (orolabial) Not done/not done Hydroxychloroquine 8 Male 76 Hypertension, dyslipidemia Bilateral interstitial pneumonia 24 Recurrent herpes simplex (orolabial) Not done/not done Hydroxychloroquine 9 (Fig 1, B) Female 56 None Bilateral interstitial pneumonia 22 Localized herpes zoster HSV3/negative Hydroxychloroquine, valacyclovir 11 Male 52 None Normal 14 Localized herpes zoster HSV3/not done Valacyclovir 10 Female 63 Hypertension Normal 26 Localized herpes zoster (ophthalmic) Not done/not done Valacyclovir 12 Male 56 dyslipidemia Normal 26 Localized herpes zoster (ophthalmic) Not done/not done Valacyclovir 13 Male 82 Hypertension, diabetes Bilateral interstitial pneumonia 7 Localized herpes zoster Not done/not done Hydroxychloroquine, acyclovir 14 Female 73 Dyslipidemia Bilateral interstitial pneumonia 12 Localized herpes zoster Not done/not done Hydroxychloroquine, prednisone, acyclovir 15 Male 78 Hypertension Bilateral interstitial pneumonia 6 Localized herpes zoster Not done/not done Hydroxychloroquine, acyclovir COVID-19, Coronavirus disease 2016; HSV1, herpes simplex virus 1; HSV3, herpes simplex virus 3; ICU, intensive care unit; PCR, polymerase chain reaction; rt-PCR, reverse-transcriptase polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. Regarding vesicular rashes or varicella-like COVID-19 exanthems,3 we previously reported 4 cases in which we performed both PCR multiplex for herpesvirus and reverse-transcriptase PCR for SARS-CoV-2 directly from the content of the vesicles. Interestingly, results for both techniques were negative in all 4 cases.4 This reasonably rules out a role of herpes viruses3 and a potential infective ability of SARS-CoV-2 through the vesicles. We agree with the authors that there is a potential role for herpetic viral infections and superinfections in patients with COVID-19. In fact, some presumed COVID-19 vesicular lesions have been later proven to be caused by herpetic infections.1 , 5 In our prospective study,4 from a total of 96 COVID-19 dermatologic consultations in the reported period, 15.6% corresponded to herpes simplex/zoster diagnoses. However, we cannot categorically affirm that there is an incidence increase of these diagnoses in patients with COVID-19 due to the lack of a control group. In our current experience, the diagnosis of herpesvirus infection in patients with COVID-19 does not usually involve diagnostic doubts, due to the clinical presentation and reported symptoms being typical of the disease, even when lesions are extensive (Fig 1 ).Fig 1 A, A 69-year-old man with COVID-19 pneumonia and extensive orolabial herpes simplex virus 1 reactivation. B, A 56-year-old woman with COVID-19 pneumonia and herpes zoster on the trunk. In conclusion, complementary diagnostic tests for herpesvirus and even SARS-CoV-2 may prove useful for clinical research and should be encouraged if the necessary resources are available. However, we believe that regarding clinical practice, we should reserve these techniques for atypical clinical presentations or cases where therapeutic management would change significantly. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Llamas-Velasco M. Rodríguez-Jiménez P. Chicharro P. 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 3 2020 e253 e254 32442700 2 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 3 2020 e255 e256 32442697 3 Marzano A.V. Genovese G. Fabbrocini G. Varicella-like exanthem as a specific COVID-19-associated skin manifestation: multicenter case series of 22 patients J Am Acad Dermatol 83 1 2020 280 285 32305439 4 Fernandez-Nieto D, Ortega-Quijano D, Jimenez-Cauhe J, et al. Clinical and histological characterization of vesicular COVID-19 rashes: a prospective study in a tertiary care hospital [e-pub ahead of print]. Clin Exp Dermatol. https://doi.org/10.1111/ced.14277. Accessed May 27, 2020. 5 Galván Casas C, Català A, Carretero Hernández G, et al. Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases [e-pub ahead of print]. Br J Dermatol. https://doi.org/10.1111/bjd.19163. Accessed May 27. 2020.
PMC007xxxxxx/PMC7311902.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)31168-3 10.1016/j.jaad.2020.06.070 Ethics Journal Club Medical student dermatology rotations in the context of COVID-19 Muzumdar Sonal BS a Grant-Kels Jane M. MD b Feng Hao MD, MHS b∗ a University of Connecticut School of Medicine, Farmington, Connecticut b Department of Dermatology, University of Connecticut Health Center, Farmington, Connecticut ∗ Reprint requests: Hao Feng, MD, MHS, Department of Dermatology, University of Connecticut Health Center, 21 South Rd, 2nd Floor, Farmington, CT 06032 24 6 2020 11 2020 24 6 2020 83 5 15571558 © 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 pmc Dear Dr Dermatoethicist: We frequently have medical students rotate through our department but, because of the COVID-19 pandemic, we are hesitant to accept rotating students at this time. Although we want to optimize the educational opportunities these students receive, we do not want to endanger trainees, staff, and our patients. Additionally, we are concerned about the impact that this may have on students interested in applying to dermatology. What should we do? —Worried Program Director Dear Worried Program Director: Deciding whether to accept medical students in your department is challenging. Beneficence is at play because rotating through dermatology benefits medical students, and it is an excellent way for students to learn more about the field and help them determine if dermatology is in fact the specialty they would like to pursue. Additionally, rotations help students obtain letters of recommendation from academic dermatologists. Since the start of the pandemic, medical students rotating in dermatology have been temporarily sidelined as clinics have closed and are seeing only patients with emergencies. As we reopen, far fewer in-person patient visits are being scheduled, and many appointments are now virutal.1 As a result, students may not benefit significantly from in-person rotations, and creative solutions are needed. Nonmaleficence, or the avoidance of intentional harm, must also be considered. With the COVID-19 pandemic, there is a risk that medical students may become infected themselves and subsequently infect their patients and fellow health care workers if allowed to participate in clinical rotations.2 Because medical students are learners and are not considered essential personnel, limiting their exposure to infectious patients is paramount. Regarding the ethical principle of justice, limiting student rotations will harm certain groups of students more than others. Dermatology is a competitive specialty, and rotations and specialty-specific letters of recommendation have been cited as important factors in resident selection.3 Limiting rotations may thus disproportionately affect those with limited or no prior experience in the field. Similarly, students without home dermatology departments, who typically rely on away rotations to secure letters of recommendation, are likely to be disadvantaged as well. Follow the guidance of your medical school and institution when deciding whether to allow medical students to rotate in person and ensure that they have access to appropriate personal protective equipment during in-person encounters if allowed. Prioritize safety while optimizing medical student education. Creative options include 1) sitting in on virtual lectures and grand rounds sessions, 2) participating in teledermatology care, 3) engaging in case-based learning, and 4) performing scholarly activities. Organizations such as the Association of Program Directors are devising novel ways to involve students in learning experiences at different institutions. Because many students will not have the opportunity to rotate at various dermatology programs or obtain dermatology letters of recommendation before applying, this is an opportune time to endeavor to evaluate the applicants based more upon intrinsic values beyond their academic achievements and credentials, including their backgrounds and challenges overcome, whether their school has fewer dermatology opportunities, ties to a particular region, unique skills or interests, and aspirations. —Dr Dermatoethicist Funding sources: None. Disclosure: Dr Feng is a consultant and medical monitor for Cytrellis Biosystems Inc and Soliton Inc. Ms Muzumdar and Dr Grant-Kels have no conflicts of interest to declare. IRB approval status: Not applicable. ==== Refs References 1 Muddasani S. Housholder A. Fleischer A.B. Jr. An assessment of United States dermatology practices during the COVID-19 outbreak J Dermatol Treat 31 2020 436 438 2 Miller D.G. Pierson L. Doernberg S. The role of medical students during the COVID-19 pandemic Ann Intern Med 173 2 2020 145 146 32259194 3 National Resident Matching Program Results of the 2018 NRMP program director survey Available at: https://www.nrmp.org/wp-content/uploads/2018/07/NRMP-2018-Program-Director-Survey-for-WWW.pdf 2018
PMC007xxxxxx/PMC7320686.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)32090-9 10.1016/j.jaad.2020.06.990 JAAD Online Using cyclosporine in the COVID era: An emergent need for caution Khurana Ananta MD, DNB ∗ Sethia Khushboo MBBS Department of Dermatology, Dr. Ram Manohar Lohia Hospital & Atal Bihari Vajpayee Institute of Medical Sciences, New Delhi, India ∗ Correspondence to: Ananta Khurana, MD, DNB, Department of Dermatology, Dr. Ram Manohar Lohia Hospital & ABVIMS, New Delhi 110001, India 27 6 2020 10 2020 27 6 2020 83 4 e315e316 © 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 the paper “Cyclosporine therapy during the COVID-19 pandemic is not a reason for concern” by Rudnicka et al1 and wish to highlight some interpretations that can encourage complacency in the use of a drug where caution is needed. As rightly pointed out, there are in vitro data showing inhibitory effects of cyclosporine A (CsA) on coronaviruses (CoVs); along with many other classes of virus, prominently hepatitis C virus and HIV.2 CsA binds to cyclophilins, a family of ubiquitous proteins present in all prokaryotes and eukaryotes. Functional interactions between viral proteins (chiefly the nonstructural protein 1) and members of cyclophilin family form an important part of the virus-host interaction.2 Genome-wide analysis of protein-protein interactions between severe acute respiratory syndrome (SARS)-CoV and human host proteins identified both cyclophilins and FK506-binding protein (FKBP) as interaction partners for SARS-CoV proteins.3 The exact function of cyclophilins' viral pathogenicity is not known, but they are probably essential for viral growth and replication. The immunosuppressive action of calcineurin inhibitors (CNIs), on the other hand, relies on calcineurin inhibition by the CsA-cyclophilin A complex, which blocks the translocation of nuclear factor of activated T cells to the nucleus and prevents the transcription of cytokine genes, prominently interleukin 2. Thus, the antiviral effect of CsA, via binding cyclophilin, largely occurs a step upstream of that essential for their immunosuppressive effect. Trials of some novel cyclophilin inhibitors and nonimmunosuppressive analogs of CsA have been undertaken for potential use in hepatitis C virus and other viral infections.4 There are well-researched aspects regarding the intricacies of the interaction of viruses with host cells. Interestingly, mycophenolic acid and 6-thioguanine also have in vitro activity against CoVs, but again, the clinical implications are unclear.5 , 6 Another important point to consider for clinical use of immunosuppressives during the ongoing pandemic is the effect on host antiviral immune responses.7 The cytotoxic T lymphocytes and natural killer cells are the most important immune cells in this regard, along with antibody-dependent cellular cytotoxicity and certain cytokines, prominently interferons.7 CsA not only suppresses the helper T cells and precursors of cytotoxic T lymphocytes but also causes depression of innate immune response via an inhibitory effect on natural killer cells. Increased risk of viral infections, such as multiple viral warts and Epstein-Barr virus reactivations in transplant patients, and of cytomegalovirus infections in transplant recipients and ulcerative colitis patients taking CsA is probably related to this.7 Further, animal models have demonstrated an inability to mount an effective immune response to viral infections with administration of CsA.8 Thus, the prominent interference with host antiviral responses by CsA should not be ignored. Further, none of the immunosuppressives have so far been conclusively shown to be beneficial for the “cytokine storm” associated with severe coronavirus disease 2019 (COVID-19) infection, and use on that premise is speculative. Hence, we believe that the use of immunosuppressive drugs requires a guarded approach during the ongoing pandemic, with initiation only in most essential cases and with continued close monitoring for infectious adverse effects. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Rudnicka L. Goldust M. Glowacka P. Cyclosporine therapy during the COVID-19 pandemic is not a reason for concern [e-pub ahead of print] J Am Acad Dermatol 83 2 2020 e151 e512 32376422 2 de Wilde A.H. Zevenhoven-Dobbe J.C. van der Meer Y. Cyclosporin A inhibits the replication of diverse coronaviruses J Gen Virol 92 2011 2542 2548 21752960 3 Pfefferle S. Schöpf J. Kögl M. The SARS-coronavirus-host interactome: identification of cyclophilins as target for pan-coronavirus inhibitors PLoS Pathog 7 2011 e1002331 22046132 4 Gallay P.A. Cyclophilin inhibitors: a novel class of promising host-targeting anti-HCV agents Immunol Res 52 2011 200 210 5 Hart B.J. Dyall J. Postnikova E. Interferon-β and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays J Gen Virol 95 2014 571 577 24323636 6 Chen X. Chou C.Y. Chang G.G. Thiopurine analogue inhibitors of severe acute respiratory syndrome-coronavirus papain-like protease, a deubiquitinating and deISGylating enzyme Antivir Chem Chemother 19 2009 151 156 19374142 7 Khurana A. Saxena S. Immunosuppressive agents for dermatological indications in the ongoing COVID 19 pandemic: rationalizing use and clinical applicability [e-pub ahead of print] Dermatol Ther 2020 10.1111/dth.13639 8 Kim J.H. Perfect J.R. Infection and cyclosporine Rev Infect Dis 11 1989 677 690 2682942
PMC007xxxxxx/PMC7320688.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)32089-2 10.1016/j.jaad.2020.06.989 JAAD Online Time to revisit the Health Insurance Portability and Accountability Act (HIPAA)? Accelerated telehealth adoption during the COVID-19 pandemic Bhate Chinmoy MD a∗ Ho Chin Hung MD b Brodell Robert T. MD c a Dermatology and Pathology & Laboratory Medicine, Rutgers New Jersey Medical School, Newark, New Jersey b Physician Assistant Studies, Clarkson University, and Dermatologist, St. Lawrence Health System, Potsdam, New York c Dermatology and Pathology, University of Mississippi Medical Center, Jackson, Mississippi ∗ Correspondence to: Chinmoy Bhate, MD, 185 S Orange Ave, Newark, NJ 07103 27 6 2020 10 2020 27 6 2020 83 4 e313e314 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: Throughout the coronavirus disease 2019 (COVID-19) pandemic, campaigns to promote social distancing and sheltering-in-place in the United States forced most dermatology offices to change the way they operate. These measures, combined with a temporary easing of the enforcement of the Health Insurance Portability and Accountability Act (HIPAA) for telehealth during the public health emergency, motivated dermatologists to embrace teledermatology in all its forms. Despite the return of in-office evaluation, telemedicine will likely remain a part of our new normal. Enacted nearly 25 years ago, HIPAA impacted every aspect of health care,1 , 2 including, but not limited to, the design of software for medical record keeping, insurance claim review, research, and communication. While technologic innovation, video conferencing, and telework were embraced in some industries, the patient-facing elements of health care lagged behind, partly because of the impact of regulatory requirements on medical communication software. Early in the pandemic, health care providers in the United States scrambled to find avenues for “telehealth at home” by any means necessary to serve their patients and support their staff. Many adopted video conferencing applications, independent of electronic medical record systems, as essential patient care tools. Most electronic medical record systems did not offer these services or they were inefficient or expensive, or both. Many everyday teleconferencing applications not native to health care contain robust privacy elements such as end-to-end encryption; however, these are not necessarily HIPAA-compliant if they do not feature the audit controls required in the privacy rule: system administrators must be able to record and follow audit trails whenever protected health information is created, modified, accessed, shared, or deleted.2 This includes encrypted communications with patients. For this same reason, private text messaging is not HIPAA-compliant. Conventional audit control rules require health care workers or their organizations to enter into a Business Associate Agreement with the third party handling protected health information. Because these third parties generally will not enter into such agreements, the burden of liability for breaches or other violations falls entirely onto health care staff and their organizations. In medicine, risks are weighed against benefits. Patient care may be compromised when health care providers disproportionately fear the consequences of HIPAA violations, which include professional, legal, and monetary penalties. Some suggest the misinterpretation of HIPAA can lead to a “code of silence,”3 , 4 impeding the sharing of medical information. Did the easing in its enforcement actually improve communication among colleagues and with patients? Should the ongoing use of agile teleconferencing software, independent of electronic medical records, be embraced in the provider-patient relationship? Protecting patient privacy is important. The revision of audit controls in HIPAA could allow for the protection of privacy while also permitting patient and caregiver to exercise judgment in making decisions about the provision of health care. Such changes, and the general expansion of telemedicine, raise additional questions; for example, liability, cybersecurity, appropriateness of use, and scope of practice. They may, however, directly address existing problems in access to dermatologic care for underserved individuals. A careful review and amendment of HIPAA could allow health care providers to continue optimizing telemedicine services for the benefit of patients during and beyond COVID-19.5 Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Edemekong P.F. Haydel M.J. Health Insurance Portability and Accountability Act (HIPAA) StatPearls 2020 StatPearls Publishing Treasure Island, FL 2 HIPAA Privacy rule. 45 CFR parts 160 and 164, Subparts A, C and E. 3 Berwick D.M. Gaines M.E. How HIPAA harms care, and how to stop it JAMA 320 2018 229 230 29926093 4 Span P. HIPAA's use as code of silence often misinterprets the law New York Times. July 17, 2015. Available at: https://www.nytimes.com/2015/07/21/health/hipaas-use-as-code-of-silence-often-misinterprets-the-law.html 5 Portnoy J. Waller M. Elliot T. Telemedicine in the era of COVID-19 J Allergy Clin Immunol Pract 8 2020 1489 1491 32220575
PMC007xxxxxx/PMC7320706.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)32086-7 10.1016/j.jaad.2020.06.986 JAAD Online Experience in patients with hidradenitis suppurativa and COVID-19 symptoms Galán José Luis MD ∗ Silvente Catiana MD González Mónica MD García Claudia MD Díez Kevin MD Martín María Ángeles MD Velázquez Diana MD de la Cueva Pablo PhD Hospital Universitario Infanta Leonor, Madrid, Spain ∗ Correspondence to: José Luis Galán, MD, Hospital Universitario Infanta Leonor, Calle Gran Vía del Este, 80, CP 28031 Madrid, Spain 27 6 2020 10 2020 27 6 2020 83 4 e309e311 © 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 letter written by Seltzer et al1 about the risk of severe forms of coronavirus disease 2019 (COVID-19) in patients with hidradenitis suppurativa (HS) and would like to share our experience. COVID-19 is an illness caused by severe acute respiratory syndrome coronavirus 2, which has spread quickly across the globe. This disease has a variable severity spectrum. A severe form develops in a subgroup of patients (especially elderly people and patients with underlying medical comorbidities) characterized by interstitial pneumonia, acute respiratory distress syndrome, and septic shock. HS is a chronic and recurring pathology of the pilosebaceous follicle. It is usually associated with several comorbidities, including obesity, smoking, diabetes mellitus, and cardiovascular pathology, among others, that, at the same time, are risk factors for the development of severe forms of COVID-19.1 , 2 To assess the severity of COVID-19 in HS patients, we reviewed the medical records of the 75 patients with HS who were monitored in our center from February 15 to April 15, 2020. The data were collected directly from the electronic medical record. Verification of data was made by telephone contact with the 75 patients with HS. Of the 75 patients with HS, 12 received biologic treatment, 30 were treated with nonbiologic systemic drugs, and 33 underwent topical treatment. Data highly suggestive of COVID-19 infection were present in 8 patients, including at least 1 of the following: symptoms of febrile acute respiratory infection, anosmia, ageusia, and compatible analytic or radiographic changes. None of them were tested for diagnostic confirmation, because only those patients who required hospital admission were tested at our center during this time frame. We collected some data from these 8 patients, which are summarized in Table I . We must specify that, according to the protocol of our center, unilobar pneumonia was not considered a severe form of COVID-19.Table I Data of patients with hidradenitis suppurativa with symptoms suggestive of COVID-19 Variable Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Age, y 60 32 30 69 50 37 21 53 Suggestive data of COVID-19 Febrile acute respiratory infection Febrile acute respiratory infection and anosmia Febrile acute respiratory infection Febrile acute respiratory infection Febril acute respiratory infection, ageusia and anosmia Febril acute respiratory infection Febril acute respiratory infection Febril acute respiratory infection and compatible radiographic changes Close contact with confirmed COVID + patient No No No Yes No Yes No No COVID-19 risk factors Age, AH, DM, DL, smoking No No Age, AH, DL, IHD, COPD, smoking, obesity AH, DM, obesity NO NO AH, smoking Treatment received Clindamycin 300 mg/12 h Doxycycline 200 mg/24 h Ethinylestradiol/levonorgestrel 150/30 mcg/24 h Clindamycin 300 mg/12 h Adalimumab, 40 mg/7d Doxycycline, 200 mg/24 h Acitretin, 10 mg/24 h Adalimumab, 40 mg/7 d First date symptoms 4/6/2020 3/21/2020 2/25/2020 3/25/2020 3/18/2020 3/26/2020 3/13/2020 3/27/2020 End date symptoms 4/20/2020 4/17/2020 2/28/2020 4/03/2020 4/16/2020 4/8/2020 3/23/2020 3/31/2020 Pneumonia No No No No No No No Yes, unilobar Hospitalization No No No No No No No No AH, Arterial hypertension; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; DM, diabetes mellitus; DL, dyslipidemia; IHD, ischemic heart disease. Regarding treatment, we highlight that there does not seem to be an increased risk of severe COVID-19 infection in our 2 patients with biologic treatment, but the sample size is too small for generalizability. In any case, following the evidence available to date, the current recommendation would be not to withdraw the biologic treatment in patients with HS who present with symptoms of COVID-19 as in other immune-mediated skin pathologies such as psoriasis.3, 4, 5 We are aware of the limitations of this study, including the small sample size, the absence of statistical analysis, and the lack of serologies or molecular research to confirm the diagnosis of COVID-19 infection. However, the main interest of this work is that in a population area of the southeast of Madrid very widely affected by the pandemic (with 2176 confirmed severe cases during this period), we observe that there have not been any severe cases within a series of 75 patients with HS, even when these pathologies share risk factors, regardless of the treatment they receive. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: None disclosed. Reprints not available from the authors. ==== Refs References 1 Seltzer J.A. Okeke C.A.V. Perry J.D. Shipman W.D. Okoye G.A. Byrd A.S. Exploring the risk of severe COVID-19 infection in hidradenitis suppurativa patients J Am Acad Dermatol 83 2 2020 e153 e154 32389715 2 Goldburg S.R. Strober B.E. Payette M.J. Hidradenitis suppurativa: epidemiology, clinical presentation, and pathogenesis J Am Acad Dermatol 82 5 2020 1045 1058 31604104 3 Blaszczak A. Trinidad J.C.L. Cartron A.M. Adalimumab for treatment of hidradenitis suppurativa during the COVID-19 pandemic: safety considerations J Am Acad Dermatol 83 1 2020 e31 32283230 4 Amerio P. Prignano F. Giuliani F. Gualdi G. COVID-19 and psoriasis: should we fear for patients treated with biologics? Dermatol Ther 2020 e13434 10.1111/dth.13434 32314483 5 Gisondi P. Facheris P. Dapavo P. The impact of COVID-19 pandemic on patients with chronic plaque psoriasis being treated with biologic therapy: the Northern Italy experience Br J Dermatol 183 2 2020 373 374 32343839
PMC007xxxxxx/PMC7320848.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)32083-1 10.1016/j.jaad.2020.06.983 JAAD Online Strategies to prevent SARS-CoV-2 transmission during dermatologic head and neck surgery Do Mytrang H. PhD a Minkis Kira MD, PhD b Petukhova Tatyana A. MD, MS b Lipner Shari R. MD, PhD b∗ a Tri-Institutional MD-PhD program, New York, New York b Department of Dermatology, Weill Cornell Medicine, New York, New York ∗ Correspondence to: Shari R. Lipner, MD, PhD, Department of Dermatology, Weill Cornell Medicine, 1305 York Ave, 9th Floor, New York, NY 10021 27 6 2020 10 2020 27 6 2020 83 4 e307e308 © 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 article by Garcia-Doval1 and support the emphasis on preventive measures against disease transmission when performing head and neck surgery during the coronavirus disease 2019 (COVID-19) pandemic. Because severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted through droplets and aerosols,2 dermatologic surgeons are at increased risk when performing surgery on the head and neck regions (Table I ). Furthermore, the patient's mouth and nose are often exposed because a mask would obscure the surgical site. We discuss here additional considerations for dermatologic surgery during the pandemic.3 Table I Risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission in various dermatologic procedures Procedure Risk Mohs micrographic surgery/cancer excisions in the head and neck regions where surgeon's face directly opposes patient's face (within 12-18 inches) that last longer than 10 minutes High Ablative laser and cosmetic procedures with substantial surgical smoke plumes∗ High Procedures where mucous membranes are breached (e.g., lip injections)∗ High Shave and punch biopsies† Low ∗ Not recommended at this time. † Can be considered high risk in selective patients, needs to be evaluated case-by-case. We concur with Garcia-Doval1 on the importance of personal protective equipment in preventing SARS-CoV-2 transmission. However, numerous viruses have been detected in surgical smoke,3 suggesting that SARS-CoV-2 may be transmitted similarly. Therefore, electrosurgery units should be adjusted to the lowest effective settings to minimize surgical smoke plume production.3 , 4 In addition, use of smoke evacuators and high-efficiency particle air filters for recirculated air are recommended to mitigate against aerosolized transmission. Garcia-Doval1 suggested clinical features for SARS-CoV-2 screening and testing before surgery, but there are limitations to these recommendations. Because up to one-third of SARS-CoV-2 infections are asymptomatic,5 clinical features are helpful but cannot substitute for preoperative testing. Viral and serology testing detect active and previous SARS-CoV-2 infections. However, the sensitivity of viral testing with reverse transcription-polymerase chain reaction (RT-PCR) depends on the disease stage and sampling techniques; therefore, negative results should be interpreted in the appropriate clinical context.5 Serology testing does not detect early infections because antibodies typically take several weeks to develop. A multipronged approach is necessary, including preoperative screening/testing, appropriate personal protective equipment use, smoke evacuators, and high-efficiency particle air filtration, to protect dermatologic surgeons and staff. Patients should be tested within 72 hours before surgery with RT-PCR of nasopharyngeal swaps,6 although practical considerations can make this challenging. Therefore, universal COVID-19 precautions should always be followed. For infected patients, surgery should be postponed until the infection is cleared. Urgent operations in infected patients should be performed in specialized operating rooms with appropriate personal protective equipment and intubation to avoid viral spread, and infectious disease specialists should be consulted.6 An N95 mask with goggles or a face shield, a gown with a hood, and shoe coverings should be worn, and a smoke evacuator and high-efficiency particle air filtration should be used, even for patients with negative test results. Telemedicine should be used for postoperative care when feasible. Use of dissolvable sutures, cyanoacrylate adhesives, and patient education regarding wound care may help decrease the need for in-office visits. Garcia-Doval also recommends testing professionals, although sporadic testing may be futile and regular testing would be more useful. Ideally, routine RT-PCR testing of team members would help identify asymptomatic infections; however, this may be difficult to enforce. Instead, daily symptom screening and temperature checks should always be performed. RT-PCR testing should be performed upon reopening and after any SARS-CoV-2 exposure or symptom development. We hope these suggestions provide the best possible protection for dermatologic surgeons and teams performing essential operations. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Garcia-Doval I. Head and neck surgery is a high-risk procedure for COVID-19 transmission and there is a need for a preventive strategy to protect professionals J Am Acad Dermatol 83 2 2020 705 706 32422223 2 Wang W. Xu Y. Gao R. Detection of SARS-CoV-2 in different types of clinical specimens JAMA 323 18 2020 1843 1844 32159775 3 Do M.H. Minkis K. Petukhova T.A. Lipner S.R. Recommendations for personal protective equipment and smoke evacuation for dermatologic surgeries amid the COVID-19 crisis Dermatol Ther 2020 e13592 32413200 4 American College of Surgeons COVID-19: Considerations for Optimum Surgeon Protection Before, During, and After Operation Available at: https://www.facs.org/covid-19/clinical-guidance/surgeon-protection 2020 5 Centers for Disease Control and Prevention Coronavirus (COVID-19). Get the Facts About Coronavirus Available at: https://www.cdc.gov/coronavirus/2019-ncov/ 2020 6 American Academy of Dermatology Reopening the dermatologic surgery office in the COVID-19 era 2020 Available at: https://www.aad.org/dw/dw-insights-and-inquiries/2020-archive/may/reopening-the-dermatologic-surgery-office
PMC007xxxxxx/PMC7341034.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)32172-1 10.1016/j.jaad.2020.07.008 JAAD Online Conducting inpatient dermatology consultations and maintaining resident education in the COVID-19 telemedicine era Hammond Margaret I. MD Sharma Timmie R. MD Cooper Kevin D. MD Beveridge Mara G. MD ∗ Department of Dermatology, Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, Ohio ∗ Correspondence to: Mara G. Beveridge, MD, 11100 Euclid Ave, Lakeside 3500, Cleveland, OH 44106 8 7 2020 10 2020 8 7 2020 83 4 e317e318 © 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: Telemedicine is being used to provide care while minimizing coronavirus disease 2019 (COVID-19) exposure to patients and providers and preserving scarce personal protective equipment. This has led to anxiety among providers about how to accomplish this without sacrificing quality of care. The commentary by Lee et al1 summarized steps for outpatient telemedicine using existing platforms, prioritizing high-risk or urgent visits, and postponing nonessential visits. Here we aim to supplement their work by sharing our experience with inpatient teledermatology and maintaining trainee involvement in telehealth. Inpatient dermatology consult services, like other health care providers during this crisis, can take steps to conserve personal protective equipment. Telemedicine can be used to triage consults and determine who needs an in-person consultation (Fig 1 ). For patients who can be managed with telemedicine, a live interactive encounter supplemented by photographs is preferred. Video allows evaluation from multiple angles and maintains a “face-to-face” interaction, while photographs add greater detail. When video is not possible, adding direct audio interaction with the patient while viewing their photographs helps maintain the usual history taking and counseling.Fig 1 Proposed telemedicine workflow for inpatient consults. COVID-19, Coronavirus disease 2019. The feasibility of performing telemedicine may vary across institutions. Obtaining photographs may be a challenge. Many health systems have the ability to easily and securely send photographs between providers. Alternatively, photographs can be requested directly from the patient. For a live interactive visit, patients will need a video-compatible device. While 81% of American adults own a smartphone, including 53% of those older than 65 years,2 many hospitals are now providing tablets to patients in isolation and have seen a resultant 50% reduction in personal protective equipment use.3 Health Insurance Portability and Accountability Act-compliant telehealth platforms are listed in the American Academy of Dermatology Teledermatology Toolkit.4 Billing for these services is evolving as payers loosen restrictions. The Centers for Medicare and Medicaid Services have temporary waivers for initial hospital care and initial/subsequent observation codes. Restrictions on frequency of subsequent inpatient care have also been temporarily lifted.5 Hospital billing departments, the Centers for Medicare and Medicaid Services website,5 and the American Academy of Dermatology Teledermatology Toolkit4 are excellent resources. The pandemic poses unique challenges in trainee education. Residents learn by being included in clinical and ethical discussions where they can contribute meaningfully. Residents can create and execute triage algorithms for telehealth or live visits with patients. To maintain resident preceptorship, we created a workflow (Table I )4 that mimics an in-person encounter. In addition, video conferencing promotes faculty attendance and engagement in didactics by reducing time and travel constraints.Table I Telemedicine workflow maintaining resident preceptorship Component of encounter Description of workflow Initial history and examination The resident initiates the video call with the patient and conducts the history taking and physical examination portion of the visit. Staffing with attending The resident then virtually leaves the patient encounter to discuss the case with the attending, either through the same video platform or even over a simple phone call. This allows the typical flow of resident-patient interactions, followed by attending staffing, to continue. The attending, resident, and patient then reconvene in a group call over the videoconferencing platform during which the visit is completed. The AAD's Teledermatology Toolkit provides a list of HIPAA-compliant telehealth platforms, some of which have waived their fees.4 Patient counseling As in live appointments, the attending may leave the room after completing their examination and detailing the plan of care, allowing the resident to remain in the call to perform patient education. Documentation After the call, the resident completes documentation and other clinical duties such as sending prescriptions or communicating with specialists as they normally would. AAD, American Academy of Dermatology; HIPAA, Health Insurance Portability and Accountability Act. In summary, telemedicine can be used judiciously in the inpatient setting to meet the needs of the current health crisis. Telehealth could even be used after the pandemic to provide access to dermatology for remote hospitals. The teledermatologist could assist the primary team with their clinical decision making but still recommend transfer if needed. Residents can play a valuable role in the transition to telehealth while continuing to meet educational objectives. Preserving preceptorship and didactic education can lead to fulfillment for both resident and attending physicians alike. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Lee I. Kovarik C. Tejasvi T. Pizarro M. Lipoff J.B. Telehealth: helping your patients and practice survive and thrive during the COVID-19 crisis with rapid quality implementation J Am Acad Dermatol 82 5 2020 1213 1214 32229278 2 Pew Research Center Internet and Technology. Mobile Fact Sheet. Survey conducted Jan. 8 to Feb. 7, 2019 Available at: https://www.pewresearch.org/internet/fact-sheet/mobile/ 3 Martineau P. iPads Are Crucial Health Care Tools in Combating Covid-19. Wired. April 8, 2020 Available at: https://www.wired.com/story/ipads-crucial-health-tools-combating-covid-19/ 4 American Academy of Dermatology Teledermatology Toolkit. Dermatologists can use telemedicine during COVID-19 outbreak Available at: https://www.aad.org/member/practice/telederm/toolkit 5 CMS Interim Final Rule and Waivers Available at: https://www.cms.gov/about-cms/emergency-preparedness-response-operations/current-emergencies/coronavirus-waivers
PMC007xxxxxx/PMC7345366.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)32175-7 10.1016/j.jaad.2020.07.011 Research Letter Applying to dermatology residency during the COVID-19 pandemic Kearns Donovan G. BA a Chat Vipawee S. BS b Uppal Shelley MD c Wu Jashin J. MD d∗ a Loma Linda University School of Medicine, California b Medical College of Georgia at Augusta University, California c Albany Medical College, New York d Dermatology Research and Education Foundation, Irvine, California ∗ Correspondence to: Jashin J. Wu, MD 8 7 2020 10 2020 8 7 2020 83 4 12141215 © 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: As the coronavirus disease 2019 pandemic continues to unfold, the medical community has been forced to make a number of social and institutional adaptations to reduce the risk to patients and providers. Changes to the residency application process are particularly influential on students pursuing competitive specialties such as dermatology. In April 2020, the Dermatology Residency Program Directors released a consensus statement regarding the 2020-2021 application cycle.1 In this announcement, program directors acknowledged disruptions that may occur in extracurriculars, such as in-person clinical projects and community outreaches, research, United States Medical Licensing Examination (USMLE) step 2, and subinternships of dermatology applicants, calling for understanding from residency programs in this coming application cycle and making suggestions for how to best fill the gaps from missed opportunities. Away rotations have been opportunities for students to foster relationships with faculty, residents, and programs; obtain letters of recommendation; and demonstrate a strong interest in specific dermatology programs. Because of the delay in or cancellation of away rotations and research conferences, the ability for students to establish professional connections outside of their institution has become challenging. In lieu of typical in-person rotations, it has been suggested that students be offered virtual away rotations. Virtual rotations include online didactics, use of the American Academy of Dermatology's online modules, and interactive sessions led by residents and faculty.2 According to the Dermatology Residency Program Directors, away rotations “should not be perceived as required or necessary for matching into dermatology residency,” with the exception of applicants without a home dermatology program.1 Similarly, the Association of American Medical Colleges has officially recommended that programs conduct all residency interviews virtually via telephone or video conference. This essential recommendation adds an additional layer of difficulty for both programs and applicants as they seek ways to determine their best fit. To help standardize and optimize the process, the American Academy of Dermatology has released a proposal detailing how web-based interviews should be conducted.3 Furthermore, the Association of American Medical Colleges has provided virtual interviewing tips to assist applicants navigating this application cycle.4 Applicants should familiarize themselves with the technology being used during the interviews and ensure that they have a stable internet connection. The interview should be conducted in a private and well-lit space in which the applicant is clearly visible to the interviewer. Additionally, applicants should wear professional clothing and come prepared with relevant interview materials just as they would for an in-person residency interview. Among the uncertainty and anxiety surrounding this unusual application cycle, some residency programs are pushing for reexamination of the characteristics used to stratify and select applicants. It has been suggested that applicants be evaluated by a holistic process, taking into consideration the personal and professional journey that led them to dermatology. An emphasis should be placed on seeking out applicants who “exhibit selflessness or grit and will enhance the robustness and diversity of our workforce.”5 Dermatology applicants and residencies must remain understanding, flexible, and willing to adapt, as all of medicine must do in these unprecedented times. Funding sources: None. Conflicts of interest: The corresponding stated the authors had no relevant conflicts of interest for this letter. ==== Refs References 1 Dermatology Residency Program Director Consensus Statement on 2020-21 Application Cycle 2020 Available at: 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. Accessed July 23, 2020 2 Stewart C.R. Chernoff K.A. Wildman H.F. Lipner S.R. Recommendations for medical student preparedness and equity for dermatology residency applications during the COVID-19 pandemic J Am Acad Dermatol 83 3 2020 e225 e226 32450096 3 PAAMC. Virtual Interviews: Tips for Interviewers. Available at: https://www.aamc.org/system/files/2020-05/Virtual_Interview_Tips_for_Program_Directors_05142020.pdf. Accessed July 23, 2020. 4 Muzumdar S. Grant-Kels J.M. Feng H. Dear dermatoethicist: web-based dermatology residency interviews in the time of COVID-19 J Am Acad Dermatol 83 2020 707 708 32413445 5 Karasik D. O'Connor D.M. Nathan N.R. What matters most: why the COVID-19 pandemic should prompt us to revisit the dermatology resident selection process J Am Acad Dermatol 83 1 2020 e55 32348822
PMC007xxxxxx/PMC7361079.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)32185-X 10.1016/j.jaad.2020.07.021 Research Letter Treatment discontinuation and rate of disease transmission in psoriasis patients receiving biologic therapy during the COVID-19 pandemic: A Canadian multicenter retrospective study Georgakopoulos Jorge R. MD a Mufti Asfandyar MD a Vender Ron MD, FRCPC bc Yeung Jensen MD, FRCPC adef∗ a Division of Dermatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada b Department of Dermatology, McMaster University, Hamilton, Ontario, Canada c Dermatrials Research Inc & Venderm Innovations in Psoriasis, Hamilton, Ontario, Canada d Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada e Women's College Hospital, Toronto, Ontario, Canada f Probity Medical Research Inc, Waterloo, Ontario, Canada ∗ Correspondence to: Jensen Yeung, MD, FRCPC, Department of Dermatology, Women's College Hospital, 76 Grenville St, Fifth Floor, Toronto, Ontario, Canada, M5S 1B2 15 7 2020 10 2020 15 7 2020 83 4 12121214 © 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: Limited data are available to guide use of biologics for moderate to severe plaque psoriasis in the current coronavirus disease 2019 (COVID-19) health care landscape.1 , 2 We aimed to further understand the rate of patient-driven biologic discontinuation in moderate to severe psoriasis because of concerns regarding COVID-19 complications. Furthermore, our goal was to add to the limited but increasing body of literature on whether biologic use should be considered a risk factor for greater susceptibility to COVID-19. After research ethics approval, a multicenter retrospective study was undertaken of all patients from 2 tertiary academic hospitals affiliated with the University of Toronto, Canada, and a community practice in Hamilton, Canada. Inclusion criteria were patients aged 18 years or older with moderate to severe psoriasis who received at least 1 dose of a biologic before February 1, 2020. Data were retrospectively obtained from Patient Support Program case managers of all major suppliers of biologic agents for psoriasis. February 1, 2020, was the starting point of data collection (5 documented COVID-19 cases and 0 deaths in Canada) and patients were followed up until June 1, 2020 (91,703 cumulative cases and 7594 deaths).3 As of February 1, 2020, there were 2095 patients receiving biologic therapy for psoriasis who met inclusion criteria. Total number of patients who temporarily discontinued their biologic at any point during the 4-month period because of COVID-19–related concerns was 23 (1.1%) (Table I ). Of the 23 patients who temporarily discontinued their biologic, 7 did so in February, 11 in March, 3 in April, and 2 in May. This corresponded to a total of 17 (0.81%), 18 (0.86%), and 18 (0.86%) patients discontinuing treatment at each of April 1, May 1, and June 1, 2020 timepoints, respectively. Biologic discontinuation by class included tumor necrosis factor α inhibitors (8/749, 1.07%), interleukin 12 and 23 inhibitors (5/371, 1.35%), interleukin 17 inhibitors (4/482, 0.83%), and interleukin 23 inhibitors (6/493, 1.22%) (Table II ). Mean duration of biologic treatment before discontinuation was 50.6 ± 35.7 months. Five patients who temporarily discontinued their biologic elected to restart the same biologic before June 1 compared with 18 who remained without treatment. All patients who restarted their biologic (5/5, 100%) did so because of a flare of their psoriasis. Of the 23 patients who temporarily discontinued treatment, 14 (60.9%) were men, mean age was 56.4 ± 12.6 years, and 1 (4.3%) also had psoriatic arthritis. Of the 2095 patients in our cohort (2072 [98.9%] of whom continued to receive a biologic throughout the entire follow-up period), 0 had a confirmed positive diagnosis of COVID-19. All patients who developed COVID-19–related symptoms received testing, results of which were negative. Of the 16 new biologic treatment initiations between April 1 and June 1, 2020, the majority were interleukin 17 inhibitors (n = 13, 81.2%), followed by tumor necrosis factor α inhibitors (n = 2, 12.5%) and interleukin 23 inhibitors (n = 1, 6.2%).Table I Demographics of psoriasis patients who temporarily discontinued biologic treatment because of coronavirus disease 2019 concerns Discontinuation month, 2020 Biologic Sex Age, years Diagnosis Duration, months Restart before June 1 February Adalimumab Man 56 Ps 78 Yes Adalimumab Man 70 Ps 90 No Adalimumab Man 43 Ps 88 No Guselkumab Man 56 Ps 19 No Guselkumab Man 67 Ps 23 No Infliximab Man 63 Ps 133 No Ustekinumab Man 45 Ps 43 No March Adalimumab Man 46 Ps 92 No Adalimumab Woman 65 Ps + PsA 83 No Adalimumab Woman 65 Ps 43 Yes Guselkumab Woman 64 Ps 24 No Guselkumab Man 48 Ps 17 No Guselkumab Woman 69 Ps 22 No Ixekizumab Woman 66 Ps 26 Yes Ixekizumab Man 70 Ps 23 Yes Ustekinumab Man 30 Ps 100 No Ustekinumab Man 49 Ps 2 No Ustekinumab Woman 51 Ps 36 Yes April Guselkumab Man 56 Ps 18 No Ustekinumab Woman 71 Ps 35 No Secukinumab Woman 73 Ps 56 No May Adalimumab Man 43 Ps 91 No Ixekizumab Woman 32 Ps 21 No Biologics reviewed included adalimumab, brodalumab, certolizumab, etanercept, guselkumab, infliximab, ixekizumab, risankizumab, secukinumab, and ustekinumab. Ps, Psoriasis; PsA, psoriatic arthritis. Table II Percentage of patient-driven temporary biologic treatment discontinuation during the coronavirus disease 2019 pandemic Variable Combined Adalimumab Brodalumab Certolizumab Etanercept Guselkumab Infliximab Ixekizumab Risankizumab Secukinumab Ustekinumab Total patients∗ 2095 290 29 46 365 388 48 249 105 204 371 Discontinued before April 1 17 (0.81) 5 (1.7) 0 0 0 5 (1.3) 1 (2.1) 2 (0.8) 0 0 4 (1.08) Discontinued before May 1 18 (0.86) 5 (1.7) 0 0 0 6 (1.5) 1 (2.1) 0 0 1 (0.5) 5 (1.35) Discontinued before June 1 18 (0.86) 5 (1.7) 0 0 0 6 (1.5) 1 (2.1) 1 (0.4) 0 1 (0.5) 4 (1.08) Total no. of restarts 5 2 0 0 0 0 0 2 0 0 1 Combined all months† 23 (1.1) 7 (2.4) 0 0 0 6 (1.5) 1 (2.1) 3 (1.2) 0 1 (0.5) 5 (1.35) Data are presented as No. (%) unless otherwise indicated. ∗ Total number of patients receiving a biologic for psoriasis as of February 1, 2020, and followed throughout the entire 4-month study period. † Total number of patients who discontinued their biologic, including those who restarted before June 1. The results of this study demonstrate that the rate of patient-driven biologic discontinuation during the peak of COVID-19 cases in Canada remained low during the entire 4-month follow-up period. Although interleukin 17 inhibitors had the lowest rate of temporary discontinuation, there did not appear to be a major class-specific difference in rates. Our findings provide some of the earliest evidence supporting current COVID-19 biologic treatment guidelines and encourage continuation of biologics in asymptomatic patients with negative COVID-19 test results despite the risk of future outbreaks.4 , 5 Discontinuation of treatment out of concerns about contracting COVID-19 is not supported because it may lead to decreased efficacy outcomes with reintroduction or a flare of psoriasis, as observed with our cohort. Low volumes of new biologic initiations highlight the need for improved access to nonurgent care during the pandemic. Funding sources: None. Conflicts of interest: Dr Vender has been a speaker, consultant, advisory board member, and investigator for AbbVie, Actelion, Amgen, Astellas, Celgene, Dermira, Eli Lilly, Galderma, Janssen Ortho, Leo, Merck, Novartis, Pfizer, Regeneron, and Takeda. Dr Yeung has been a speaker, consultant, and investigator for AbbVie, Allergan, Amgen, Astellas, Boehringer Ingelheim, Celgene, Centocor, Coherus, Dermira, Eli Lilly, Forward, Galderma, GSK, Janssen, Leo, Medimmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Takeda, UCB, Valeant, and Xenon. Drs Georgakopoulos and Mufti have no conflicts of interest to declare. Reprints not available from the authors. ==== Refs References 1 Warren R.B. Gooderham M. Burge R. Comparison of cumulative clinical benefits of biologics for the treatment of psoriasis over 16 weeks: results from a network meta-analysis J Am Acad Dermatol 82 5 2019 1138 1149 31884091 2 Kim H.J. Lebwohl M.G. Biologics and psoriasis: the beat goes on Dermatol Clin 37 1 2019 29 36 30466686 3 Johns Hopkins Coronavirus Resource Center COVID-19 case tracker Available at: https://coronavirus.jhu.edu/ 2020 4 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 5 2020 1217 1218 32199889 5 Shah P. Zampella J.G. Use of systemic immunomodulatory therapies during the coronavirus disease 2019 (COVID-19) pandemic J Am Acad Dermatol 82 6 2020 e203 e204 32244021
PMC007xxxxxx/PMC7362801.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)32190-3 10.1016/j.jaad.2020.07.026 JAAD Online Caution in the time of rashes and COVID-19 Vesely Matthew D. MD, PhD ∗ Perkins Sara H. MD Department of Dermatology, Yale School of Medicine, New Haven, Connecticut ∗ Correspondence to: Matthew D. Vesely, MD, PhD, Department of Dermatology, Yale School of Medicine, 333 Cedar St, PO Box 208059, New Haven, CT 06520 15 7 2020 10 2020 15 7 2020 83 4 e321e322 © 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 applaud the authors of a recent report in JAAD 1 who performed a systematic literature review of the highly variable cutaneous manifestations of coronavirus disease 2019 (COVID-19). Since the global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), dermatologists have mobilized to identify, catalog, and disseminate potential cutaneous manifestations of SARS-CoV-2 infection. Lack of widespread testing and potential limitations in assays that detect acute and previous infections underscore the utility of identifying skin manifestations of COVID-19. These limitations, however, make it difficult to definitively conclude that skin manifestations of COVID-19 are due to SARS-CoV-2. In fact, the most commonly reported cutaneous manifestation, pernio-like lesions (so-called COVID toes),1 seem to generally occur in patients who test negative for viral infection by polymerase chain reaction and subsequent serologic testing.2 However, detection of SARS-CoV-2 in endothelial cells of these lesions suggests direct viral invasion.3 On the other hand, patients who have confirmed SARS-CoV-2 infection have been reported to develop a wide variety of cutaneous manifestations, including morbilliform eruption, urticaria, petechiae, retiform purpura, periorbital erythema, vesicular, livedo reticularis, digitate papulosquamous, erythema multiforme, pernio-like lesions, and androgenic alopecia1, 2, 3 (Fig 1 ). It remains to be determined which skin manifestations are a sign of SARS-CoV-2 infection due to direct tissue injury from viral tropism or to sequela of infection such as coagulopathy and immune injury.3 Fig 1 Reported cutaneous manifestations of coronavirus disease (COVID-19). These skin findings have been reported by clinicians as potential signs of COVID-19. Most of these highly variable and rare findings reported in case reports and small case series may not be specific to severe acute respiratory syndrome coronavirus 2 infection. We urge caution and continued scholarship moving forward to decipher what impact COVID-19 has on skin. We recommend caution when concluding that cutaneous findings are specifically due to SARS-CoV-2. Without question, SARS-CoV-2 is a unique and devastating virus with multiple tissue tropism and heterogeneous immune activation. With further clinical studies, more widespread testing, and a better understanding of the natural course of the virus, these skin manifestations will likely settle into 2 types: virus-specific and nonspecific. To determine virus-specific mechanisms, direct detection of viral particles within cutaneous lesions is needed.3 Furthermore, these studies should use control tissue of similar lesions (eg, perniosis) that occurred before the pandemic. In the absence of direct viral detection, unique immune signatures identified within patients with COVID-19 should be investigated in patients who develop skin manifestations. Cutaneous lesions that are nonspecific should be grouped into those that are suggestive of COVID-19 vs those that are not. The COVID-19 Dermatology Registry will be critical to identifying which cutaneous manifestations are most suggestive of COVID-19. The difficulty in classifying the cutaneous manifestations of a systemic, complex, and heterogenous immune-mediated disease is reminiscent of systemic lupus erythematosus (SLE). Although distinct in etiology, disease course, and treatment, the lessons learned from studying SLE may be applied to understanding the cutaneous manifestations of COVID-19. In 1992, Dr Robert A. Greenwald commented that “anything happening to a patient with SLE which is not immediately otherwise explicable will automatically be blamed on the lupus, regardless of pathophysiologic validity.”4 This became known as Greenwald's law of lupus. Subsequently, Dr Richard Sontheimer provided a corollary to Greenwald's law that anything happening to patient with a positive anti-nuclear antibody will be blamed on lupus.5 Now it appears that anything happening to a patient's skin during the COVID-19 pandemic will be attributed to SARS-CoV-2 infection, rightly or wrongly. We thank Dr Jean Bolognia for input on the figure. Biorender.com was used to generate the figure with academic subscription. Funding sources: Dr Vesely is supported by the 10.13039/100001582 Dermatology Foundation , the 10.13039/100005190 Melanoma Research Alliance , and 10.13039/100000002 National Institutes of Health 10.13039/100006108 National Center for Advancing Translational Sciences (KL2-TR-001862). Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Jia J.L. Kamceva M. Rao S.A. Linos E. Cutaneous manifestations of COVID-19: a preliminary review J Am Acad Dermatol 83 2 2020 687 690 32422225 2 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 3 Colmenero I. Santonja C. Alonso-Riano M. SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultraestructural study of 7 paediatric cases [e-pub ahead of print] Br J Dermatol 2020 10.1111/bjd.19327 4 Greenwald R.A. Greenwald's law of lupus J Rheumatol 19 9 1992 1490 5 Sontheimer R.D. Greenwald's law of lupus: the Sontheimer amendment J Rheumatol 20 7 1993 1258 1259 8240543
PMC007xxxxxx/PMC7362843.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)32191-5 10.1016/j.jaad.2020.07.027 JAAD Online Dermatology in the Black barbershop: A potential opportunity for expanding access and bridging gaps Okoji Uchenna K. MPH a Lipoff Jules B. MD b∗ a Drexel University College of Medicine, Philadelphia, Pennsylvania b Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania ∗ Correspondence to: Jules B. Lipoff, MD, Penn Medicine University City, 3737 Market St, Ste 1100, Philadelphia, PA 19104 15 7 2020 11 2020 15 7 2020 83 5 e369e370 © 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 barbershop, a place of refuge for Black men, is an archetypal safe Black space, where patrons can be vulnerable, seek counsel, and speak freely while attending to grooming needs. Research has established barbershops, historically common sites for medical practice such as bloodletting and cauterization during the Middle Ages, as culturally appropriate venues for education, training, and screening to address health disparities.1 While studies have examined cardiovascular health, prostate cancer, and diabetes, few have considered the barbershop for expansion of dermatologic care access (eg, salons as clinical sites for skin cancer screening).2 , 3 The limited data on dermatologic health disparities suggest that people of color have worse health outcomes and less outpatient care compared with White patients.4 Certainly, the cause is multifactorial, including access to care. We propose that bringing dermatology to the barbershop could bridge access gaps and open opportunities for better care for this population. Given the recent extra attention and widespread calls for action against racism and social injustice, this moment represents an auspicious time to push for changes toward health equity, at the very least, small incremental ones. Many Black men visit barbershops frequently—weekly or biweekly. This consistency lends itself to longitudinal data collection. Possible interventions include (1) providing educational material to barbers and patrons on conditions disproportionately affecting Black men (eg, pseudofolliculitis barbae and acne keloidalis nuchae), (2) educating barbers to identify common conditions (eg, atopic dermatitis, acne vulgaris, and androgenic alopecia), (3) establishing referral services between barbers and dermatologists specializing in skin of color, and (4) developing “in-house” dermatology services in barbershops during peak times. Barbershop-centered interventions would not only increase awareness of dermatology in this community, but also could improve the comfort and access to medical care by providing services at a familiar location outside of a traditional medical office. Communities of color are well known to have higher levels of health care system distrust,5 so such community collaboration could be helpful in establishing better connections. Further, this education could dispel myths and inaccuracies about skin conditions and care perpetuated by media and folklore. For instance, Adotama et al2 found that although most barbers could correctly identify pseudofolliculitis barbae, their ideas about treatment varied considerably. Consistent, evidence-based education could close knowledge gaps. With coronavirus disease 2019 (COVID-19), engagement with barbershops must proceed cautiously and when appropriate. Still, bringing dermatology to barbershops could build trust, when done culturally appropriately, and especially if led by dermatologists connected to the communities. It is important that these activities are driven by these physicians with built-in community ties and personal buy-in, but the burden of caring for these underserved populations should not alone rest on dermatologists of color, who constitute a small fraction of the workforce. True systemic change will depend on continued support and commitment from dermatology organizations and the dermatology workforce at large to push for greater awareness and resources to better center care for patients of color. We encourage establishing these forward-thinking interventions as active approaches towards greater patient diversity and inclusivity, making clear that all are welcome. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the author(s). ==== Refs References 1 Luque J.S. Ross L. Gwede C.K. Qualitative systematic review of barber-administered health education, promotion, screening and outreach programs in African-American communities J Community Health 39 1 2014 181 190 23913106 2 Adotama P. Tinker D. Mitchell K. Barber knowledge and recommendations regarding pseudofolliculitis barbae and acne keloidalis nuchae in an urban setting JAMA Dermatol 153 12 2017 1325 1326 29049485 3 Turrisi R. Gunn H. Hultgren B. The style project: feasibility of collaborating with salons for prevention and early detection of skin cancer Arch Dermatol 148 10 2012 1206 1207 23069967 4 Tripathi R. Knusel K.D. Ezaldein H.H. Association of demographic and socioeconomic characteristics with differences in use of outpatient dermatology services in the United States JAMA Dermatol 154 11 2018 1286 1291 30267073 5 Armstrong K. McMurphy S. Dean L.T. Differences in the patterns of health care system distrust between blacks and whites J Gen Intern Med 23 6 2008 827 833 18299939
PMC007xxxxxx/PMC7363593.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)32188-5 10.1016/j.jaad.2020.07.024 Health Policy & Practice Guiding principles for prioritization of limited in-person dermatology appointments during the COVID-19 pandemic Stoff Benjamin K. MD, MAB abc∗ Blalock Travis W. MD ab Swerlick Robert A. MD a MacKelfresh Jamie B. MD a Lawley Leslie P. MD a Chen Suephy C. MD, MS ab a Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia b Veterans Affairs Health System, Atlanta, Georgia c Emory Center for Ethics, Atlanta, Georgia ∗ Correspondence and reprint requests to: Benjamin K. Stoff, MD, MA, Department of Dermatology, Emory University School of Medicine, 1525 Clifton Rd, NE, Atlanta, GA 30312. 16 7 2020 10 2020 16 7 2020 83 4 12281230 8 7 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. Key words COVID-19 Delphi method in-person appointments justice maximizing benefits resource allocation Abbreviations used COVID-19 coronavirus disease 2019 TBSE total-body skin examination screening ==== Body pmcCoronavirus disease 2019 (COVID-19) has led dermatology practices to severely limit in-person appointments due to social distancing and shelter-in-place measures.1 Even as infection rates fall and practices reopen, epidemiologic modeling predicts future resurgences of COVID-19, likely compelling practices to intermittently restrict in-person appointments again.2 Principles of scarce health care resource distribution have been applied during the COVID-19 pandemic, commonly for critical care resources.3 , 4 However, these principles have not been modified for or applied to limited in-person dermatology appointments during the pandemic. Guiding principles can inform dermatologists about how to prioritize patients and skin diseases in this context. Our department convened an in-person appointment prioritization workgroup including the Department Chair (R.A.S.), Vice Chair (S.C.C.), Residency Program Director (J.B.M.), Pediatric Dermatology Director (L.P.L.), Dermatologic Surgery Director (T.W.B.), and Dermatopathology Head of Operations (B.K.S.), who is a Fellow at the Emory Center for Ethics and chaired the workgroup. Many institutions have encouraged telehealth during the pandemic. As suggested by our institution, the workgroup assumed that any dermatologic problem that could be adequately addressed using teledermatology would be handled in that fashion. Using a modified Delphi approach with 2 rounds, the workgroup chair drafted guiding principles that were sent to workgroup members for anonymous feedback. The workgroup then met virtually for discussion and voting on areas of disagreement. The document was revised and recirculated until consensus was reached via simple majority. The workgroup chair presented the principles to the department and then sent them to faculty, trainees, administrators, nursing representatives, and select patients for further feedback and revision before they were finalized (Table I ).Table I Guiding principles for allocation of limited in-person dermatology appointments during the COVID-19 pandemic Guiding principle Examples 1. Health care providers, other health care employees, and public health officials should be given priority, especially if their skin disease interferes with delivering care or other essential duties, because of their instrumental value to the health of others. • A hospitalist with an inflamed epidermoid cyst on the face interfering with masking and requiring intralesional corticosteroid injection or incision and drainage • An emergency department nurse with new-onset tense bullae on the lower extremities causing pain and edema 2. Diagnostic procedures, including but not limited to skin biopsies, should be prioritized because pathologic and/or microbiologic diagnosis often allows for better characterization of risk of morbidity and mortality of malignancies, serious infections, and severe inflammatory disorders. 2A. Clinical lesions or eruptions for which the differential diagnosis incudes high-risk malignancies, serious infections, or severe inflammatory disorders should be prioritized. • A patient at high risk for melanoma with a changing pigmented lesion • An immunosuppressed patient with a tender nodule concerning for severe infection requiring biopsy and/or tissue culture • A patient with acute-onset tense bullae • A patient with mycosis fungoides with new nodules or erythroderma 3. Patients with severe skin disease that is life-threatening, function-limiting, and/or emotionally debilitating who would benefit most from an in-person evaluation should be prioritized over patients with mild disease or patients with severe disease who would gain less in order to maximize benefits. • A patient with moderate hidradenitis suppurativa with an acute abscess on the buttocks preventing sitting and requiring incision and drainage • A solid-organ transplant recipient with a high-risk squamous cell carcinoma on the scalp requiring excision • A patient with an enlarging keloid on the chest causing severe pain and requiring intralesional corticosteroid injection • An infant with a high-risk vascular lesion 4. For patients with similar prognoses, consider a random selection process for determining who gets a particular in-person appointment. • For a list of patients with low-risk basal cell carcinoma awaiting treatment, random selection can be used to determine when each patient is scheduled for definitive treatment. 5. Patients with skin disease burden resulting in substantial functional and/or emotional morbidity who do not have access to or cannot effectively use teledermatology platforms should be prioritized. • A patient without a smartphone, tablet, computer, and/or internet connectivity with widespread dermatitis The first 3 principles are grounded in maximizing benefits, an essential guiding principle for health care utilization during pandemics.4 Health care workers have instrumental value to society because they care for others. Diagnostic procedures permit triage decisions about which subsequent treatments are most impactful. Prioritizing patients with severe disease who would gain most from in-person intervention maximizes benefits as well. The final 2 principles are rooted in justice and respond to health care access disparities during the pandemic.5 Random allocation has been promoted for distributing resources because of recognized injustices associated with a first-come, first-served distribution method, such as favoring those who can travel quickly and wait.3 To illustrate how our practice has put into operation this principle, which is uncommonly deployed in health care, providers were given a list of patients requiring in-person appointments and assigned each to a priority tier 1 to 3 based on the other principles. Schedulers then randomized patients within each tier and assigned them to appointment slots, such that tier 1 priority patients got the first available appointments and so on. Finally, allocating some in-person appointments to patients lacking access to or capability for teledermatology accommodates medically underserved populations during pandemics and may alleviate burdens on other specialties, such as emergency medicine. Although cancer screening is often delayed during pandemics, the workgroup addressed total-body skin examination screening. The workgroup concluded that if sufficient in-person appointment capacity for total-body skin examination screening exists, a tiered prioritization scheme that balances risk of skin cancer with risk of severe COVID-19 (Table II ) can be considered.Table II Application of guiding principles to total-body skin examination screening (TBSE) during the COVID-19 pandemic Tier Description Example 1 (highest priority) Patients at very high risk for skin cancer (primary, recurrent, or metastatic) A patient with a history of invasive melanoma or high-risk squamous cell carcinoma within the last 6 months 2 Patients with a low to moderate risk of skin cancer with strong preferences for TBSE and relatively low risk for severe COVID-19 A healthy 45-year-old patient with a family history of melanoma requesting TBSE 3 Patients with low risk for skin cancer and high risk of severe COVID-19∗ An elderly patient with chronic lung disease and few risk factors for skin cancer COVID-19, Coronavirus disease 2019; TBSE, total-body skin examination screening. ∗ Risk factors for severe COVID-19: age >65 years, residency in a nursing home, underlying diseases: chronic lung disease, coronary artery disease, liver disease, chronic kidney disease, diabetes mellitus, obesity, hypertension, and immunosuppression. Several limitations apply to these principles. First, principles are not rules and should not dictate all appointment allocation decisions. Further, translating these principles into operations may not be immediately possible or may require adaptations for different practices. These principles may not apply when there is less appointment scarcity due to increased supply of appointments, decreased demand for them, or both. These principles provide a framework for in-person appointment prioritization during times of appointment scarcity, such as the COVID-19 pandemic. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. ==== Refs References 1 Chen Y. Pradhan S. Xue S. What are we doing in the dermatology outpatient department amidst the raging of the 2019 novel coronavirus? J Am Acad Dermatol 82 4 2020 1034 32081700 2 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 3 Persad G. Wertheimer A. Emanuel E.J. Principles for allocation of scarce medical interventions Lancet 373 9661 2009 423 431 19186274 4 Emanuel E.J. Persad G. Upshur R. Fair allocation of scarce medical resources in the time of Covid-19 N Engl J Med 382 21 2020 2049 2055 32202722 5 Dorn A.V. Cooney R.E. Sabin M.L. COVID-19 exacerbating inequalities in the US Lancet 395 10232 2020 1243 1244 32305087
PMC007xxxxxx/PMC7363597.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)32197-6 10.1016/j.jaad.2020.06.1025 JAAD Online Prevalence of cheilitis in health care workers treating patients with COVID-19 Singh Mehak MD a Bothra Atul MD b Pawar Manoj MD c∗ Maheswari Anshu MD d Tiwari Apoorv MD e Adhicari Pankaj MD f a Department of Dermatology, JK Medical College and LN Hospital, Bhopal, India b Department of Dermatology, Gauhati Medical College and Hospital, Guwahati, Assam, India c Department of Dermatology, MVP's Dr MVP Medical College and Hospital and Research Centre, Nashik, India d Private Practice, New Delhi, India e Department of Medicine, All India Institute of Medical Sciences, Bhopal, India f Department of Dermatology, Gauhati Medical College and Hospital, Guwahati, Assam, India ∗ Correspondence to: Manoj Pawar, MD, Flat no. 11, Manomay Apartment, Savatanagar, CIDCO, Nashik-422008, Maharashtra State, India 16 7 2020 11 2020 16 7 2020 83 5 e373e374 © 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 pmcTothe Editor: The COVID-19 pandemic heralded the use of personal protective equipment (PPE) by front-line health care workers (HCWs) working tirelessly for long hours. The extended use of PPE has led to various kinds of occupational dermatoses, including facial dermatitis, pressure injury, acne, and frictional injury, in up to 97% of HCWs.1 , 2 In this study, we report preliminary data of HCWs experiencing various types of cheilitis due to the use of face masks. From April 15 through May 15, 2020, we came across 33 HCWs, engaged in COVID-19 duties, who complained of dryness, itching, smarting, and/or tightness of the lips after the use of face masks. The history, occupation, and clinical features including onset, duration, pattern of cheilitis, exacerbating factors, and duration of PPE worn were recorded, and final clinical diagnosis was made. Patch testing could not be performed. In the 33 HCWs, the most common presenting symptoms were tightness (63.64%) and chapping (57.57%), followed by burning sensation, smarting, and itching. The most common signs were flaking 24 (72.73%), scaling 15 (45.46%), and swelling 13 (39.39%). Generalized lip dryness, that is, cheilitis simplex (n = 21, 63.64%), was the most frequent pattern of cheilitis. Angular cheilitis was seen in 12 patients (36.36%), whereas progression to perioral involvement was seen in 5 patients (15.15%). Cheilitis venenata was observed in 10 (30.30%) patients, attributed here to N95 mask contact. Associated lip edema was present in 7 patients (21.21%). Secondary infections (27.27%) and hyperpigmentation (18.18%) were the most common sequelae (Supplemental Fig 1; available via Mendeley at https://doi.org/10.17632/655bpmbggv.1). Spicy food and hot beverages (n = 26, 78.79%) were the most common aggravating factors, followed by habitual picking/peeling (51.52%) and associated contact dermatitis to N95 masks (30.30%). Most of the HCWs admitted to extended work hours, with a mean of 8.92 ± 2.15 hours of face mask worn per day and 5.01 ± 1.11 hours of rotation per day (Table I). The patients were treated with liberal use of bland emollients and counseling to eliminate inciting factor(s) and break the wet-dry cycle by repeated application of saliva. Topical corticosteroids, topical calcineurin inhibitors, oral antihistamines, antibiotics, and vitamin B supplements were used as and when justified. Our study denotes generalized lip dryness to be the most common presentation of lip cheilitis, which might progress to perioral involvement. PPE forms the major armamentarium for HCWs' protection in the fight against COVID-19. PPE-induced dermatoses lead to frequent irritation and subsequent touching of the face, which might increase disease transmission.3 The inadequate workforce, coupled with a relative shortage of PPE kits, results in the long duty hours of the HCWs and leads to constant chapping of the lips. An unconscious repeated contact with saliva follows, which macerates the skin and removes the protective oils, leading to a constant wet-dry cycle and resulting in disruption of skin barrier function and inflammation, which further perpetuates the cycle. Dehydration, air-conditioned rooms, and the humid environment created by the PPE also contribute (Supplemental Fig 2; available via Mendeley at https://doi.org/10.17632/phwh6mj87y.1). The authors would like to suggest that HCWs liberally use a bland emollient such as petrolatum jelly to moisturize the lips, avoid repeated lip licking, and increase hydration to prevent such occupational dermatoses. Table I Summary of demographic and clinical features, causative agents, and treatments Parameters Value % Number of patients 33 — Age, y, mean ± SD 32.28 ± 16.67 — Sex, male:female 14:19 — Occupation Doctors 11 33.33 Nurses 12 36.36 Allied services (ward assistants, cleaners, transport teams, etc) 4 12.12 Symptoms Burning sensation 13 39.39 Smarting 8 24.24 Itching 9 27.27 Tightness 21 63.64 Chapping 19 57.57 Signs Flaking 24 72.73 Scaling 15 45.46 Fissures 13 39.39 Perioral accentuations 5 15.15 Swelling 12 36.36 Pattern of cheilitis observed Cheilitis simplex 21 63.64 Angular cheilitis 12 36.36 Perioral involvement 5 15.15 Cheilitis venenata 10 30.30 Type of cheilitis Irritant contact dermatitis 24 72.73 Allergic contact dermatitis 3 09.09 Friction dermatitis∗ 6 18.18 Associated sequelae Hyperpigmentation 6 18.18 Secondary infection 9 27.27 Photosensitivity 8 24.24 Exacerbating factors Habitual peeling/picking: exfoliative cheilitis 17 51.52 Aggravation due to spicy food/hot beverages 26 78.79 Duration of PPE worn/d, h, mean ± SD 8.92 ± 2.15 — Duration of rotation/d, h, mean ± SD 5.01 ± 1.11 — History of dermatitis/allergic predisposition Atopy 2 06.06 Asthma 6 18.18 Food allergies 4 12.12 Lipstick/lip products allergy 5 15.15 Contact dermatitis to components of PPE Gloves 5 15.15 Gown 4 12.12 Face shield 1 03.03 Face mask (including straps, nose piece, and the body) 12 36.36 N95 masks 8 66.67 Surgical masks 2 16.67 Homemade fabric masks (dye dermatitis) 2 16.67 Medications prescribed Barrier emollient 31 93.94 Topical corticosteroid 3 09.09 Topical calcineurin inhibitor 9 27.27 Topical antibiotic 9 27.27 Oral antihistamine 11 33.33 Vitamin B complex supplements 14 42.42 PPE, Personal protective equipment; SD, standard deviation. ∗ Friction dermatitis may be caused by the constant rubbing by mask or by sweat wiping. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: NA. Reprints not available from the authors. ==== Refs References 1 Singh M. Pawar M. Bothra A. Personal protective equipment induced facial dermatoses in healthcare workers managing COVID-19 cases J Eur Acad Dermatol Venereol 34 2020 e378 e380 32396675 2 Lan J. Song Z. Miao X. Skin damage among healthcare workers managing coronavirus disease–2019 J Am Acad Dermatol 82 2020 1215 1216 32171808 3 Kantor J. Behavioral considerations and impact on personal protective equipment use: early lessons from the coronavirus (COVID-19) pandemic J Am Acad Dermatol 82 2020 1087 1088 32171806
PMC007xxxxxx/PMC7363613.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)32195-2 10.1016/j.jaad.2020.06.1023 Research Letter Multidisciplinary care of epidermolysis bullosa during the COVID-19 pandemic—Consensus: Recommendations by an international panel of experts Murrell Dedee F. BMBCh, MD, FRCP a∗ Lucky Anne W. MD b Salas-Alanis Julio C. MD, PhD c Woodley David T. MD d Palisson Francis MD ef Natsuga Ken MD, PhD g Nikolic Milos MD, PhD h Ramirez-Quizon Mae MD i Paller Amy S. MD j Lara-Corrales Irene MD, FRCPC k Barzegar Mohammadreza Amir MD l Sprecher Eli MD, PhD m Has Cristina MD, PhD n Laimer Martin MD, MSc o Bruckner Anna L. MD, MSCS p Bilgic Asli MD q Nanda Arti MD r Purvis Diana MD s Hovnanian Alain MD, PhD tu Murat-Sušić Slobodna MD, PhD v Bauer Johannes MD o Kern Johannes S. MD, PhD, FACD wx Bodemer Christine MD, PhD yz Martin Linda K. FACD aa Mellerio Jemima BSc, MD, FRCP bb Kowaleski Cezary MD PhD cc Robertson Susan J. FACD wdd Bruckner-Tuderman Leena MD n Pope Elena MSc, FRCPC k Marinkovich M. Peter MD ee Tang Jean Y. MD, PhD ee Su John FACD, FRACP, MCRIFRCPC xff Uitto Jouni MD, PhD gghh Eichenfield Lawrence F. MD iijj Teng Joyce MD, PhD ee Aan Koh Mark Jean MD kk Lee Sang Eun MD, PhD ll Khuu Phuong MD ee Rishel Heather I. MD, PhD mm Sommerlund Mette MD, PhD nn Wiss Karen MD oo Hsu Chao-Kai MD, PhD pp Chiu Tor Wo BMBCh, FRCS, FCSHK, FHKAM qq Martinez Anna E. FRCPCH rr a Department of Dermatology, St George Hospital, University of New South Wales, Sydney, New South Wales, Australia b Cincinnati Children's Epidermolysis Bullosa Center, Cincinnati Children's Hospital, Cincinnati, Ohio c DebRA (Dystrophic Epidermolysis Bullosa Research Association) Mexico, Monterrey, Mexico d Department of Dermatology, University of Southern California, Los Angeles, California e Dystrophic Epidermolysis Bullosa Research Association DebRA (Dystrophic Epidermolysis Bullosa Research Association) Chile f Clinica Alemana, Universidad del Desarrollo, Santiago, Chile g Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan h Deptartment of Dermatovenereology, University of Belgrade School of Medicine, Belgrade, Serbia i Department of Dermatology, University of the Philippines, Philippines General Hospital, Manila, Philippines j Departments of Dermatology and Pediatrics, Children's Hospital, Northwestern University, Chicago, Illinois k Section of Dermatology, Hospital for Sick Children, Toronto, Ontario, Canada l Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran m Department of Dermatology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel n Department of Dermatology, Medical Center-University of Freiburg, Freiburg, Germany o EB Haus, Department of Dermatology, Paracelsus University, Salzburg, Austria p Pediatric Dermatology Department, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, Colorado q Department of Dermatology, Akdeniz University, Antalya, Turkey r Pediatric Dermatology Unit, As'ad Al-Hamad Dermatology Center, Kuwait s Department of Dermatology, Starship Children's Health, Auckland, New Zealand t Department of Genetics, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 1163, Laboratory of Genetic Skin Diseases, Paris, France u Institut des Maladies Génétiques (IMAGINE), University of Paris, Paris, France v Department of Dermatovenereology, University Hospital Centre, Zagreb, Croatia w Dermatology Department, The Royal Melbourne Hospital, Melbourne, Victoria, Australia x The University of Melbourne, Parkville, Victoria, Australia y Department of Dermatology, Necker Enfants Malades Hospital, University of Paris, Paris, France z Reference Centre for Genodermatoses and Rare Skin Diseases (MAGEC), Paris, France aa Department of Dermatology, Sydney Children's Hospital, University of New South Wales Faculty of Medicine, Sydney, New South Wales, Australia bb Adult Epidermolysis Bullosa Service, St John's Institute of Dermatology, St Thomas' Hospital, London, United Kingdom cc Department of Dermatology and Immunodermatology, University of Warsaw, Warsaw, Poland dd Department of Dermatology, The Royal Children's Hospital, Melbourne, Victoria, Australia ee Department of Dermatology, Stanford University Medical Center, Palo Alto, California ff Monash University, Eastern Health, Melbourne, Victoria, Australia gg Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania hh Sidney Kimmel Medical College, Philadelphia, Pennsylvania ii Departments of Dermatology and Pediatrics, University of California, San Diego, California jj Department of Pediatric Dermatology, Rady Children's Hospital, San Diego, California kk Dermatology Service, KK Women's & Children's Hospital, Singapore ll Department of Dermatology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea mm Rishel Pediatric Dermatology, PC, Rishel Enterprises, LLC, San Francisco, California nn Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark oo Department of Dermatology, University of Massachusetts Medical School, Worcester, Massachusetts pp Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan qq Chinese University of Hong Kong, Hong Kong, China rr Paediatric Dermatology Department, Great Ormond Street National Health Service Foundation Trust, London, United Kingdom ∗ Correspondence and reprint requests to: Dedee F. Murrell, BMBCh, MD, FRCP, Department of Dermatology, St George Hospital, University of NSW Faculty of Medicine, Sydney, NSW 2217, Australia 16 7 2020 10 2020 16 7 2020 83 4 12221224 © 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. Graphical abstract ==== Body pmcTo the Editor: The 2019 novel coronavirus (COVID-19) pandemic became apparent in China during the International Congress on Epidermolysis Bullosa (EB) in London, in January 2020. Many patients with EB have medical problems that make them a vulnerable population of patients.1 We developed an international consensus to suggest the best management of patients with EB during the pandemic. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters host cells using its spike protein binding to the cell receptor angiotensin converting enzyme 2 (ACE2), which is expressed in several tissues. Mucosae have high ACE2 expression, particularly the nasal epithelium. ACE2 is also expressed in the basal layer of keratinocytes and sebaceous glands of normal skin as well as in vascular endothelial cells, but its expression in wounded EB skin has not been studied.2 A questionnaire was drafted by an author (D.M.) into a table of suggested modifications to the management of EB during the COVID-19 pandemic. Fifty-seven well-known experts on EB were selected based on membership of the international Clin-et group or clinical expertise in EB, or both, demonstrated at International EB Congress participation. Responses and reasons for each response were requested individually to the lead author based on an ideal scenario, rather than what actually may happen in some centers with financial constraints. A priori, consensus was considered to be the agreement of more than 70% of respondents with the suggestion. Questionnaires were returned by 44 of the 57 EB experts, representing several areas of clinical expertise in EB (dermatology, pediatrics, internal medicine, and surgery) from 5 continents. After addition and revision of some items and 3 cycles of revoting, consensus was achieved for all items, which are summarized in Supplementary Table I (available via Mendeley at https://data.mendeley.com/datasets/zmpncb6zpr/2). The main change in usual practice was the introduction of photographs from the patient/family and teledermatology as the primary visit for patients with less severe EB, with dressing supplies sent to the patients directly. For those patients with EB with significant internal disease, monitoring tests (blood and urine) must continue but can be obtained by local laboratories or family doctors close to home.3 If telehealth images are insufficient to assess lesions, assessments should be conducted at the EB center.4 One of the greatest fears of families caring for patients with severe forms of EB is how they will be perceived on admission to hospitals, especially institutions with limited resources, including ventilators. Because patients with EB often appear frail and emaciated, health care workers unfamiliar with the condition may underestimate their resilience and incorrectly assume that they have a low likelihood of survival.5 If a patient with EB required anticoagulation to manage COVID-19, there might be additional bleeding from the skin or mucosae, but blood transfusions will compensate for this. Supplemental Table I details protection for the skin and mucosae that is required for wearing masks and ventilation. Funding sources: None. Conflicts of interest: Dr Lucky is an investigator/advisor board member for Abeona, Amryt, and Lenus. Dr Paller is an investigator/advisory board member for Abeona. Dr Anna Bruckner is an investigator for Fibrocell, ProQR, and Phoenix Tissue Repair. Authors Murrell, Salas-Alanis, Woodley, Palisson, Natsuga, Nikolic, Ramirez-Quizon, Lara-Corrales, Barzegar, Sprecher, Has, Laimer, Bruckner, Nanda, Purvis, Hovnanian, Murat-Sušić, Bauer, Kern, Bodemer, Mellerio, Kowaleski, Robertson, Bruckner-Tuderman, Pope, Marinkovich, Tang, Su, Uitto, Eichenfield Teng, Koh, Lee, Khuu, Rishel, Sommerlund, Wiss, Hsu, Chiu, and Martinez have no conflicts of interest to declare. IRB approval status: Not applicable. ==== Refs References 1 Has C. Bauer J.W. Bodemer C. Consensus reclassification of epidermolysis bullosa and other disorders with skin fragility Br J Dermatol 2020 10.1111/bjd.18921 2 Hamming I. Timens W. Bulthuis M.L.C. Lely A.T. Navis G.J. van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis J Pathol 203 2004 631 637 15141377 3 Ramirez M. Murrell D.F. Fine J.D. Management of epidermolysis bullosa Exp Opin Orph Drugs 1 4 2013 279 293 4 Mellerio J.E. Robertson S.J. Bernardis C. Management of cutaneous squamous cell carcinoma in patients with epidermolysis bullosa—best clinical practice guidelines Br J Dermatol 174 1 2016 56 67 26302137 5 Bruckner A.L. Losow M. Wisk J. The challenges of living with and managing epidermolysis bullosa: insights from patients and caregivers Orphanet J Rare Dis 15 1 2020 1 31900176
PMC007xxxxxx/PMC7365061.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)32217-9 10.1016/j.jaad.2020.07.048 Research Letter Lack of association between chilblains outbreak and severe acute respiratory syndrome coronavirus 2: Histologic and serologic findings from a new immunoassay Hébert Vivien MD a∗ Duval-Modeste Anne-Bénédicte MD a Joly Pascal MD, PhD a Lemée Véronique MD b Cellier Lucie MD c Jouen Fabienne MD d Veber Benoit MD, PhD e Drouot Laurent PhD d Boyer Olivier MD, PhD d a Normandie University, UNIROUEN, Inserm, U1234, FOCIS Center of Excellence PAn'THER, Rouen University Hospital, Department of Dermatology, Rouen, France b Department of Virology, Rouen University Hospital, Rouen, France c Department of Pathology, Rouen University Hospital, Rouen, France d Normandie University, UNIROUEN, Inserm, U1234, FOCIS Center of Excellence PAn'THER, Department of Immunology and Biotherapy, Rouen University Hospital, Rouen, France e Department of Resuscitation, Rouen University Hospital, Rouen, France ∗ Correspondence to: Vivien Hébert, MD, Clinique dermatologique, CHU de Rouen, 1 rue de Germont, 76031 Rouen, France 16 7 2020 11 2020 16 7 2020 83 5 14341436 © 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: COVID-19, which is due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a worldwide pandemic on March 11, 2020.1 , 2 Recently, numerous cases of acute chilblains-like lesions have been reported on social networks from Belgium, France, and Italy. Despite weak evidence, particularly the absence of serologic studies, the hypothesis that these lesions were potentially related to the COVID-19 infection, as a paucisymptomatic form, rapidly grew.3, 4, 5 An alert letter was even sent to the French Ministry of Health and to French dermatologists by the National Union of Dermatologists. Because 33 patients (14 women, 19 men) with chilblains were referred to our dermatology department within 1 week, we studied the relationship between these lesions and the COVID-19 infection. All patients (mean ± standard deviation age, 23.4 ± 8.7 y) presented erythematous and purpuric papules localized on the toes alone or toes and fingers (12 patients, 36.4%) (Fig 1 ). Edema was present in 12 (36.4%) and pruritus or burning sensation in 18 (54.5%) patients. The median delay between the onset of dermatologic features and the first consultation was 8 days (interquartile range, 6.5-18 d). Chilblains were the only clinical manifestation in 23 cases (69.7%); 10 (30.3%) patients presented other symptoms, which occurred before (n = 6), concomitantly with (n = 1), or after skin symptoms (n = 3): asthenia (n = 4), cough (n = 3), diarrhea (n = 3), fever (n = 2), myalgia (n = 2), headache (n = 1), and odynophagia (n = 1). No patient reported contact with COVID-19–infected patients. Three patients had recently been tested for COVID-19 infection and had negative results on sinus reverse-transcription polymerase chain reaction (RT-PCR).Fig 1 Examples of 4 patients referred for chilblains. Blood cell count results were normal in 26 patients. A mild lymphopenia (mean, 1.15 ± 0.21 giga per liter) was observed in 7 patients. C-reactive protein and erythrocyte sedimentation rate results were negative for all patients. Two patients had positive results for antinuclear antibodies, and 3 patients had antibodies for a type III cryoglobulinemia. Histology performed in 5 patients showed lymphocytic infiltrate in the superficial dermis around the vessels and eccrine glands in all cases, reminiscent of idiopathic chilblains. Direct immunofluorescence showed fibrinogen and C3 deposits on endothelial cells in 2 cases. Results of indirect immunofluorescence assay using the serum from a patient with anti–SARS-CoV-2 immunoglobulin (Ig) G antibodies and RT-PCR on lesional skin were negative. We developed an ALBIA-Spike S1 for detecting anti–SARS-CoV-2 antibodies that allowed a 96% sensitivity and 98% specificity (Drouot et al, personal communication, May 2020). Test results for anti–SARS-CoV-2 IgG antibodies were negative in all 33 sera, and in 1 of 33, the result was positive for IgM at the first consultation and at the second consultation 14 days later. No seroconversion was observed (Fig 2 ). Our findings were then confirmed by using the Abbott (Abbott Park, IL) SARS-CoV-2 IgG immunoassay performed on the day 14 sera, without detectable seropositivity.Fig 2 Severe acute respiratory syndrome coronavirus 2 serology. Sera from negative control patients (circles, n = 130; health donors of blood collected by the French Établissement Franҫais du Sang before the pandemic), patients with COVID-19 (squares, n = 18; patients with reverse-transcription polymerase chain reaction results from Rouen University Hospital), and patients with chilblains (triangles, n = 33 at day 0 and n = 31 at day 14) were assayed for the presence of anti-Spike S1 antibodies. A, Immunoglobulin M. B, Immunoglobulin G. The dotted line marks the threshold of positivity of the assay. AU, Arbitrary units; Ig, immunoglobulin. The present data provide no argument for any link between these chilblains and infection with SARS-CoV-2. Clinical and histologic features were those of idiopathic chilblains. The results of RT-PCR and indirect immunofluorescence on lesional skin, when performed, were negative. None of the 33 sera tested contained anti–SARS-CoV-2 IgG antibodies, and only 1 had IgM twice (3%), consistent with the current estimation of a rate of SARS-CoV-2 infection of 5% to 10% in the general population in France.6 We think that this hypothesis of COVID-19–related chilblains could be explained by a cumulation of (1) a temporality bias in this early spring period, when the average temperature differences were the widest; (2) a confounding bias related to the young age, because paucisymptomatic forms of the infection are observed in young people; and (3) a recruitment bias related to the shortening of dermatology consultation delays due to the quarantine period. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Institute for Research and Innovation in Biomedicine. 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 8 2020 727 733 31978945 2 Huang C. Wang Y. Li X. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Lancet 395 10223 2020 497 506 31986264 3 Bouaziz J. Duong T. Jachiet M. Vascular skin symptoms in COVID-19: a French observational study J Eur Acad Dermatol Venereol 2020 10.1111/jdv.16544 4 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 2020 667 670 32380219 5 Kolivras A. Dehavay F. Delplace D. Coronavirus (COVID-19) infection-induced chilblains: a case report with histopathological findings JAAD Case Rep 6 2020 489 492 32363225 6 Institut Pasteur Une modélisation indique qu'entre 3% et 7% des Français ont été infectés https://www.pasteur.fr/fr/espace-presse/documents-presse/covid-19-modelisation-indique-que-pres-6-francais-ont-ete-infectes 2020
PMC007xxxxxx/PMC7365088.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)32204-0 10.1016/j.jaad.2020.07.035 Research Letter Risk assessment of outpatient dermatology practice in the setting of the COVID-19 pandemic Gerami Pedram MD ab∗ Liszewski Walter MD a a Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois b Robert H. Lurie Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois ∗ Reprint requests: Pedram Gerami, MD, Department of Dermatology, Northwestern University, 676 N St Clair St, Suite 1765, Chicago, IL 60611 16 7 2020 11 2020 16 7 2020 83 5 15381539 © 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: Severe acute respiratory syndrome coronavirus 2 has had a mortality rate of 2.2% in China and 7.2% in Italy. Mortality and severity of infection are associated with older age and comorbidities.1 Infectivity is estimated at 2% to 3.58% of exposures. Health care workers, representing up to 20% of those infected, are at elevated risk. The high rates of infectivity and mortality raise questions on how outpatient clinics can reduce risk. We created a model to assess the weekly risk of exposure in a dermatology practice. In the United States, testing is limited in many places to patients who are highly symptomatic. The largest study to date, which mainly focused on testing symptomatic individuals from Wuhan, reported 81% to have mild disease and 19% to have severe illness.1 Additionally, many may be completely asymptomatic. In New York on April 27, 2020, the reported number of positive cases was 298,004. The same day, a seroprevalence study showed a positivity rate of 14.9% in the state of 19.45 million people, roughly translating to 2,898,050 infections. These studies suggest that current reporting may be capturing only 10% to 20% of all infections. There are surmounting data that the number of infections is far greater than reported. To help dermatologists better grasp the impact of COVID-19, we created 2 models: a dermatologist practicing in Chicago (city population of 2,700,000) and one practicing in a metropolitan area of 100,000. The model assumes each physician sees 145 patients per week, which is the national average.2 The model displays a range that assumes the ratio of symptomatic-to-asymptomatic infections is 1:4 or 1:9, which are based on data from Wuhan and New York, respectively. The range also uses current data that the sensitivity of the polymerase chain reaction test may be as low as 70% or as high as 95%.3 The number of asymptomatic or mildly symptomatic patients in a population and the number of these patients a dermatologist is likely to encounter in a given week are shown for Chicago (Table I ) and a metropolitan area of 100,000 (Table II ). When there are 4425 average daily new positive cases in Chicago and 165 in the smaller metropolitan area, a conservative estimate would suggest that a dermatologist could expect to encounter 1 mildly symptomatic or asymptomatic patient with COVID per week.Table I Expected exposure rates in the city of Chicago Number of positive cases Number of undiagnosed, mild, or minimally symptomatic cases, range Patient exposure, weekly, range 100 421-1286 0.02-0.071 500 2105-6429 0.11-0.35 1000 4211-12,857 0.23-0.69 4425 18,632-56,893 1.00-2.25 5000 21,053-64,286 1.13-3.45 10,000 42,105-128,571 2.26-6.90 50,000 210,526-642,587 11.31-34.52 100,000 421,053-1,285,714 22.61-69.05 Bold represents when the threshold when a dermatologist can anticipate to encounter at least one active COVID patient per week. Table II Expected exposure rates in a metropolitan area of 100,000 people Number of positive cases Number of undiagnosed, mild, or minimally symptomatic cases, range Patient exposure, weekly, range 10 42-129 0.06-0.19 50 211-643 0.31-0.93 100 421-1286 0.61-1.86 165 695-2121 1.00-1.08 500 2105-6429 3.05-9.32 1000 4211-12,857 6.11-18.64 5000 21,053-64,286 30.53-93.21 10,000 42,105-128,571 61.05-186.43 Bold represents when the threshold when a dermatologist can anticipate to encounter at least one active COVID patient per week. The virus is transmitted through airborne aerosols, including speaking, which can travel for at least 6 feet.3 Furthermore, viral loads are similar in both symptomatic and asymptomatic individuals.4 Surgical masks can decrease transmission by 75%,5 and N95 masks are even more protective. However, depending on the type and fit of PPE, dermatologists and their staff could be exposed to the virus if a patient with COVID is seen. If in-person clinic volumes return to prequarantine levels and if new infections continue in the community, exposure to COVID-positive patients is inevitable. However, there are steps we can take to mitigate the risk. Screening patients for symptoms and recent close contacts with COVID is essential. Universal PPE for dermatologists and their staff, ideally N95 masks, is also needed. Funding sources: None. Disclosure: Dr Gerami has served as a consultant for Myriad Genomics, DermTech, Merck, and Castle Biosciences and has received honoraria for this. Dr Liszewski has no conflicts of interest to declare. IRB approval status: Not applicable. ==== Refs References 1 Wu C. Chen X. Cai Y. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China JAMA Intern Med 180 7 2020 1 11 2 Jacobson C.C. Resneck J.S. Kimball A.B. Generational differences in practice patterns of dermatologists in the United States Arch Dermatol 140 2004 1477 1482 15611425 3 Down B. Kulkarni S. Khan A.H.A. Barker B. Tang I. Novel coronavirus (COVID-19) infection: what a doctor on the frontline needs to know Ann Med Surg (Lond) 55 2020 24-29 32405411 4 Zou L. Ruan F. Huang M. SARS-CoV-2 Viral load in upper respiratory specimens of infected patients N Engl J Med 382 2020 1177 1179 32074444 5 Chan J.F. Zhang A.J. Yuan S. Simulation of the clinical and pathological manifestations of coronavirus disease 2019 (COVID-19) in golden Syrian hamster model: implications for disease pathogenesis and transmissibility Clin Infect Dis 2020 10.1093/cid/ciaa325
PMC007xxxxxx/PMC7365110.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)32212-X 10.1016/j.jaad.2020.07.043 JAAD Online The digital divide: How COVID-19's telemedicine expansion could exacerbate disparities Bakhtiar Mina BA a Elbuluk Nada MD, MSc b Lipoff Jules B. MD c∗ a Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania b Department of Dermatology, Keck School of Medicine of University of Southern California, Los Angeles, California c Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania ∗ Correspondence to: Jules B. Lipoff, MD, Penn Medicine University City, 3737 Market St, Suite 1100, Philadelphia, PA 19104 16 7 2020 11 2020 16 7 2020 83 5 e345e346 © 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 recent months, closure of nonessential outpatient practices prompted the Centers for Medicare & Medicaid Services to ease regulations on telemedicine. The resultant rapid adoption and investment in telemedicine may normalize telemedicine for the mainstream by increasing patient and physician familiarity and introduce clinical changes that endure after the threat of COVID-19 subsides. Advancement of teledermatology should intuitively expand access to care, given its convenience, cost effectiveness, and triage capabilities.1 However, despite increasing access, we must consider how increased telemedicine could paradoxically create or exacerbate health disparities, with early evidence raising concern.2 Health disparities in dermatology already exist for minority patients and those with low income; for example, for African American patients, this includes inadequate physician training with skin of color, unequal access, and increased mortality.3 For direct-to-patient telemedicine, not all patients have equal access. Consider the equipment needed for video visits: smartphones, tablets, or computers and a reliable internet connection. Device ownership and internet use correlate with age, education, and income: 26% of Americans with an annual income of less than $30,000 rely exclusively on smartphone internet access.4 Furthermore, US Federal Communications Commission reports confirm significant household income differences between those with and without broadband internet.5 Although most without internet access live in rural areas, digital infrastructure barriers also affect urban settings: in New York City, almost 50% of low-income households lack internet access.6 Not only does poor infrastructure limit access, but wealthier consumers' use could drive up costs and crowd out physicians' limited clinical time from the underserved patients who need it most. Beyond digital access, telehealth services must meet quality standards, and inconsistent quality may burden vulnerable populations more. The American Telemedicine Association's guidelines for teledermatology emphasize the importance of high-quality images, lighting, and positioning, with challenges for evaluating moles (especially in difficult-to-photograph areas, such as hair-bearing skin). As we expand, we must ensure that high quality standards (including technologic and compliance with the Health Insurance Portability and Accountability Act) remain paramount. We concede that although we strive to provide excellent care, ensuring internet access for everyone is beyond our reach. Still, as telemedicine is poised to transform the clinical landscape, to encourage health equity, we must advocate for digital equity, and we must anticipate and address disparities before they grow. Solutions may include greater use of store-and-forward telemedicine compared to video visits, which require greater bandwidth; additional clinical appointments for those without proper devices; and nonprofit partnerships to redistribute refurbished devices, as in public education. Beyond devices, physicians should encourage digital literacy as an acquired skill, providing educational training on telemedicine, and consider technical support staff for practices. Further, as Congress considers increased broadband infrastructure in rural areas, we must remind lawmakers that cities also have digital inequities. Doctors and public health advocates should encourage equitable telemedicine access as it expands now. Dermatology is especially poised to lead the way, given its large body of research and experience. We must anticipate the risks of exacerbating disparities and of delivering less and lower-quality care to our most underserved patients. If we do not, internet access and device ownership could become social determinants of health. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 Lee J. English J.C. Teledermatology: a review and update Am J Clin Dermatol 19 2 2018 253 260 28871562 2 Eberly L.A. Khatana S.A.M. Nathan A.S. Telemedicine outpatient cardiovascular care during the COVID-19 pandemic: bridging or opening the digital divide? Circulation 2020 10.1161/CIRCULATIONAHA.120.048185 3 Dawes S.M. Tsai S. Gittleman H. Barnholtz-Sloan J.S. Bordeaux J.S. Racial disparities in melanoma survival J Am Acad Dermatol 75 5 2016 983 991 27476974 4 Anderson M. Kumar M. Digital divide persists even as lower-income Americans make gains in tech adoption. Pew Research Center Available at: https://www.pewresearch.org/fact-tank/2019/05/07/digital-divide-persists-even-as-lower-income-americans-make-gains-in-tech-adoption/ 2019 5 Federal Communications Commission 2020 Broadband Deployment Report Available at: https://docs.fcc.gov/public/attachments/FCC-20-50A1.pdf 2020 6 City of New York. De Blasio Administration Releases Internet Master Plan For City's Broadband Future Available at: https://www1.nyc.gov/office-of-the-mayor/news/010-20/de-blasio-administration-releases-internet-master-plan-city-s-broadband-future 2020
PMC007xxxxxx/PMC7365112.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(20)30369-9 10.1016/j.reval.2020.07.001 Note Clinique L’allergologue face à l’épidémie de COVID-19 : quel impact et quelles précautions prendre ? The allergist facing the COVID-19 pandemic: What impact and what precautions should be taken?Fontaine J.F. ab* Fromentin E. c Lefevre S. d Demoly P. e a Cabinet d’allergologie, 113, rue de Vesle, Reims, France b Service de pneumologie et allergologie, CHU de Reims, Reims, France c Cabinet d’allergologie, 32, place Sébastopol, Lille, France d Institut régional d’allergologie, CHR Metz-Thionville, Metz, France e Département de pneumologie, unité d’exploration des allergies, hôpital Arnaud-de-Villeneuve, hôpital universitaire de Montpellier, université Montpellier, UMR-S 1136 Inserm-Sorbonne université, Équipe EPAR - IPLESP, Paris, France ⁎ Auteur correspondant. Département de pneumologie, unité d’exploration des allergies, hôpital Arnaud-de-Villeneuve, hôpital universitaire de Montpellier, Univ Montpellier, UMR-S 1136 Inserm-Sorbonne université, Equipe EPAR - IPLESP, Paris, France. 16 7 2020 12 2020 16 7 2020 60 8 625629 27 6 2020 1 7 2020 © 2020 Published by Elsevier Masson SAS. 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. Dans l’environnement sanitaire inhabituel de la pandémie COVID 19 les allergologues doivent adapter leur exercice et leurs locaux de consultation, en renforçant les précautions d’hygiène et de distanciation. En cas de confinement la téléconsultation est un nouvel outil qui peut, dans un grand nombre de cas, faciliter la prise en charge des patients. Néanmoins, chaque praticien doit définir un plan d’urgence et les priorités de consultation en fonction de sa pratique et du contexte épidémique. In the unusual health environment of the COVID 19 pandemic, allergists must adapt their exercise and their office or clinic, by strengthening hygiene and distancing precautions. In case of sanitary containment telehealth can, in many cases, replace face-to-face visits. Nevertheless, each practitioner must define the contingency planning and the priorities according to his own practice and the epidemic context. Mots clés SARS-CoV-2 COVID-19 Téléconsultation Hygiène Allergie asthme Rhinite allergique Allergie alimentaire Keywords SARS-CoV-2 COVID-19 Telehealth Hygiene Allergy Asthma Allergic rhinitis Food allergy ==== Body pmcLa pandémie COVID-19 à laquelle nous sommes confrontés crée pour l’ensemble de la société un environnement sanitaire inhabituel et préoccupant. C’est particulièrement vrai pour les soignants qui, en dehors d’une courte expérience de préparation à la grippe H1N1 en 2009, n’avaient pas encore eu à gérer une épidémie de cette ampleur. 1 Un environnement sanitaire inhabituel Dans les premières semaines de crise, la situation s’est progressivement avérée de plus en plus problématique et anxiogène :• pour les autorités, qui semblent avoir découvert la contagiosité du virus et la gravité potentielle de l’infection au fur et à mesure de la progression de l’épidémie, et qui ont connu très rapidement des difficultés logistiques liées au manque de stocks de masques, de gel hydroalcoolique, et de tension sur l’approvisionnement en certains médicaments, notamment les curares et les hypnotiques ; • pour les soignants, qui ont accompagné la mise en place progressive de mesures de prévention, initialement sans matériel adapté (masques FFP2, solution hydroalcoolique), et se sont impliqués dans la mise en place des filières COVID hospitalières et libérales ; • pour les patients, qui ont suivi l’évolution de la pandémie dans les médias, et pour lesquels la gravité potentielle de l’infection et la fréquence des formes asymptomatiques ont donné à la COVID-19 la dimension d’un risque vital omniprésent et insaisissable. L’organisation de crise du système de soins français a d’abord reposé sur une prise en charge des patients et des appels téléphoniques par les services d’urgence et le centre 15, et sur une réorganisation hospitalière donnant une priorité aux lits de réanimation et aux besoins en personnels dédiés : médecins et infirmier(e)s-anesthésistes, aide-soignant(e)s formés à la prise en charge des malades lourds et au contexte infectieux. De nombreuses unités ont été transformées en services dédiés COVID-19 pour la prise en charge de malades autres que ceux nécessitant des soins de réanimation. En secteur libéral, des filières dédiées aux patients suspects de COVID-19 se sont mises en place, notamment à l’initiative de collègues spécialistes de médecine générale, et le nombre de consultations pour les autres pathologies a fortement chuté dans les cabinets qui ont maintenu une activité. 2 Une nécessaire adaptation de l’exercice de l’allergologie Dans ce contexte, les allergologues ont été amenés à adapter leur exercice. Tous se sont retrouvés dans l’« esprit soignant » et l’élan de solidarité qui a prévalu au sein de la communauté médicale et paramédicale, en s’impliquant lorsque c’était utile et possible dans les filières dédiées à la COVID-19, en participant à la régulation ou au suivi post-infection, et/ou en apportant une aide logistique. Comme tous les soignants ils ont également suivi l’évolution de la pandémie et des données épidémiologiques et physiopathologiques avec d’autant plus d’intérêt que l’affection s’est révélée toucher des organes concernés par les maladies allergiques et impliquer des mécanismes immunologiques auxquels la profession est sensibilisée. Les activités de soin en allergologie ont dû être réorganisées [1], [2], avec une déprogrammation des actes hospitaliers non urgents, dont ceux d’allergologie, une annulation et/ou un report des consultations présentielles, et des incertitudes quant à la date et aux modalités de reprise d’un exercice normal. 2.1 La téléconsultation La téléconsultation a été, comme dans toutes les autres spécialités, un outil efficace en période de confinement pour gérer les pathologies chroniques et renouvellements d’ordonnance, mais aussi pour prendre en charge de nouveaux patients dans un certain nombre de cas. Il est probable qu’elle restera utilisée après la crise, bien plus qu’elle ne l’était antérieurement. Ces consultations à distance, sans possibilité d’examen clinique autre que visuel, permettent de gérer diverses situations, et notamment :• de donner des conseils relatifs à la prise en charge des maladies allergiques en période de COVID-19 : facteurs de risques, adaptation thérapeutique, trousse d’urgence… ; • d’assurer le suivi d’allergies respiratoires ou alimentaires stables, sans nouvel incident dans les 12 à 18 derniers mois ; • d’assurer le renouvellement des traitements symptomatiques et/ou d’immunothérapie allergénique ; • d’effectuer des primo-consultations pour lesquelles le diagnostic peut être approché, voire posé, à l’anamnèse et/ou à l’examen visuel, comme c’est par exemple le cas pour une dermatite atopique, une suspicion d’eczéma de contact, une urticaire chronique notamment à type de dermographisme, une rhino-conjonctivite saisonnière avec allergie alimentaire évocatrice de sensibilisation aux PR-10 et/ou profilines, une rhinite perannuelle avec allergie alimentaire associée, une rhinite et/ou un asthme dont l’apparition coïncide avec l’adoption d’un animal… ; • de prescrire un bilan biologique, en remplacement des tests cutanés qui n’auraient pu être effectués pour cause d’indisponibilité sous forme d’extraits commerciaux (latex, rongeurs, aliments, …), pour diagnostic moléculaire, ou avant réalisation ultérieure des tests cutanés (d’autant plus justifiée pour les pollens qu’ils trouvent leur principale utilité thérapeutique après la saison pollinique). 2.2 Les consultations présentielles Les consultations présentielles restent cependant indispensables dans certains cas, en particulier :• pour des actes difficiles à différer comme les injections de venins d’hyménoptères, les tests cutanés médicamenteux urgents (curares, chimiothérapies, biothérapies, produits de contraste iodés, …) pour des molécules dont le réemploi serait nécessaire dans les mois à venir, ou des tests de réintroduction indispensables pour raison nutritionnelle en cas d’allergie alimentaire ou exploration urgente de tolérance médicamenteuse ; • pour des situations nécessitant un examen clinique comme une première consultation pour toux et/ou dyspnée, une exacerbation sévère d’un asthme, le bilan d’un angio-œdème sévère ou d’une anaphylaxie idiopathique récidivante, la prise en charge d’une dermatite atopique sévère suspecte de surinfection, ou le diagnostic d’une éruption cutanée non identifiable en visioconsultation, et/ou nécessitant une analyse plus fine des lésions. Après déconfinement, et avec la reprise progressive des activités de consultation, l’alternance de téléconsultations et de consultations présentielles peut apparaître comme une solution aux difficultés que pose une gestion raisonnée des flux de patients pour limiter les contacts et le risque de résurgence de l’épidémie. Elle implique une orientation téléphonique préalable en fonction des motifs de consultation, pourra se baser sur une priorisation des actes (Tableau 1 ), et sera adaptée en fonction de la pression épidémique locale, du degré d’inquiétude des patients, et des capacités d’accueil de la structure.Tableau 1 Proposition de priorisation des actes d’allergologie en situation de crise sanitaire pour cause d’épidémie de COVID-19 (d’après Shaker et al. [1], modifié). Tableau 1 Contexte clinique Proposition de prise en charge Asthme Priorité 1 Exacerbation sévère d’asthme Consultation présentielle en milieu adapté, permettant la réalisation d’examens complémentaires (dont EFR) si nécessaires, et un diagnostic Covid-19 Priorité 2 Exacerbation modérée d’asthme Privilégier si possible la téléconsultation pour une adaptation thérapeutique et réévaluation rapide dans les suites Priorité 3 Asthme avec recours aux services d’urgence ou hospitalisation pour exacerbation dans les 3 à 6 derniers mois, ou plus de deux cures de corticoïdes oraux dans les 3 à 6 derniers mois, ou ayant nécessité une augmentation de palier thérapeutique dans les 3 à 6 derniers mois Privilégier si possible la téléconsultation pour une adaptation thérapeutique et réévaluation rapide dans des suites Priorité 4 Asthme bien contrôlé dans les 6 à 12 derniers mois, sans recours aux services d’urgence, avec moins d’une cure de corticoïdes oraux et/ou moins de deux exacerbations dans les 12 derniers mois Privilégier la téléconsultation pour poursuite et adaptation éventuelle du traitement de fond et de secours, et différer la consultation présentielle Priorité 5 Asthme léger à modéré, ou bien contrôlé Téléconsultation pour assurer le suivi du traitement. Report des consultations présentielles Rhino-conjonctivite allergique Priorité 0 Rhino-conjonctivite allergique Téléconsultation pour traitement symptomatique et éventuelle prescription de recherche d’IgE spécifiques. Différer consultations présentielles et tests cutanés Allergie alimentaire : consultations et tests de réintroduction Priorité 1 Anaphylaxie grade 2 ou supérieur, ou anaphylaxie récidivante évocatrice d’allergie alimentaire Consultation présentielle et tests cutanés, éventuellement précédés d’une téléconsultation et de tests biologiques Priorité 2 Anaphylaxie grade 1 pour laquelle le diagnostic d’allergie alimentaire a été évoqué Privilégier la téléconsultation et des tests biologiques en première approche Priorité 3 Suspicion d’allergie alimentaire non-IgE dépendante (SEIPA, œsophagite à éosinophiles) ou d’intolérance alimentaire (FODMAPs) Privilégier la téléconsultation et les régimes d’éviction d’épreuve en première approche Priorité 4 Suivi d’une allergie alimentaire sans nouvel incident ni signe évocateur d’une nouvelle allergie au cours des 12 à 18 derniers mois Privilégier la téléconsultation Priorité 1 Suspicion d’allergie posant un problème nutritionnel chez l’enfant, et nécessitant des tests cutanés et/ou de réintroduction Consultations présentielles pour tests cutanés et biologiques, et/ou test de réintroduction et/ou induction de tolérance en milieu sécurisé sur le plan infectieux Lait et hydrolysats Éviction alimentaire inadéquate et à risque de carences (notamment œuf et blé) Priorité 2 Evaluation du seuil de tolérance d’un aliment dont l’éviction a été mise en place au vu d’une simple sensibilisation, chez un enfant à haut risque allergique Consultation présentielle et test de réintroduction en milieu sécurisé sur le plan infectieux Priorité 3 Allergie alimentaire nécessitant une évaluation du seuil de réactivité, mais sans risque nutritionnel immédiat ni altération significative de la qualité de vie Privilégier la téléconsultation pour réévaluation et suivi, et différer le test de réintroduction Allergie médicamenteuse Priorité 1 Suspicion d’allergie à un médicament dont le réemploi serait nécessaire à court terme (antibiotiques, curares, chimiothérapie, biothérapie, …) Consultation présentielle, tests cutanés et éventuel test de réintroduction/tolérance Priorité 2 Suspicion d’allergie à un médicament dont le réemploi n’est pas nécessaire à court terme et/ou pour lequel il existe une alternative thérapeutique Privilégier la téléconsultation pour évaluation de l’imputabilité, et différer les tests cutanés Affections cutanées Priorité 1 Première consultation pour angio-œdème, en particulier avec atteinte pharyngo-laryngée, abdominale, et/ou génitale Consultation présentielle pour évaluation diagnostique et bilan biologique à la recherche d’un angio-œdème héréditaire Possibilité de téléconsultation en première approche en cas d’angio-œdème peu sévère Priorité 1 Dermatite atopique sévère et/ou suspecte de surinfection Consultation présentielle de dermato-allergologie Priorité 2 Suivi d’angio-œdème héréditaire bien contrôlé sans nouvel incident au cours des 6 derniers mois Privilégier la téléconsultation Priorité 3 Première consultation pour urticaire chronique Privilégier la téléconsultation et une optimisation du traitement antihistaminique en première approche Priorité 4 Consultation de suivi pour urticaire chronique Privilégier la téléconsultation pour adaptation du traitement Priorité 4 Dermatite atopique modérée Privilégier la téléconsultation pour conseils, traitement local et suivi, et différer les consultations présentielles Immunothérapie allergénique Priorité 1 Injections de venin d’hyménoptères dans le cadre d’une immunothérapie allergénique en cours Poursuite des injections en consultation présentielle, ou par le médecin traitant si souhaité par le patient et possibilité de délivrance des extraits hors milieu hospitalier Priorité 2 Initiation d’une immunothérapie allergénique aux venins d’hyménoptères À discuter, sur décision de l’allergologue, en tenant compte du rapport bénéfice/risque, de la capacité d’accueil sécurisé en milieu hospitalier, et du risque de réaction anaphylactique nécessitant une prise en charge par les services d’urgence Priorité 3 Renouvellement d’une immunothérapie allergénique sublinguale en cours Privilégier la téléconsultation Priorité 3 Suivi d’une immunothérapie orale alimentaire Privilégier la téléconsultation. Il est déconseillé de procéder à une augmentation de doses en période de confinement en raison d’un accès plus restreint aux conseils de l’allergologue et aux services d’urgence Priorité 0 Initiation d’une immunothérapie allergénique aux pneumallergènes ou initiation d’une immunothérapie orale alimentaire Il est conseillé de différer la mise en route d’une ITA aux pneumallergènes ou d’une ITO alimentaire, de sorte que d’éventuels effets indésirables puissent être pris en charge dans de bonnes conditions de sécurité sanitaire À adapter par chaque praticien et pour chaque patient en fonction du contexte épidémique local, du degré de confinement préconisé par les autorités, et des capacités de la structure d’accueil. Priorité 0 : non-prioritaire ; priorité X décroissante de 1 à X. Les priorités données à tel ou tel acte ne constituent qu’une base de réflexion initiée en période de confinement et sont susceptibles d’évoluer avec l’état d’urgence sanitaire et la capacité matérielle des cabinet et structures hospitalières à reprendre progressivement une activité normale. Elles permettent néanmoins de structurer une prise en charge adaptée et coordonnée de tous les patients allergiques dans ce contexte difficile. 3 Des mesures de protection et d’hygiène renforcées En parallèle de cette réflexion qui vise à limiter les déplacements des patients, la mise en place de mesures de protection individuelles et collectives au sein des cabinets de consultation est impérative pour la reprise des activités présentielles, et comprend notamment un renforcement des mesures d’hygiène habituelles des locaux. En effectuant la synthèse de diverses recommandations ou publications [3], [4] on peut notamment émettre un certain nombre de conseils, qui ont été diffusés par le CNP d’Allergologie le 8 mai 2020 [5] pour la reprise des consultations après déconfinement (Fig. 1 ).Fig. 1 Recommandations du CNP d’Allergologie pour la reprise des consultations après déconfinement dans le cadre de la pandémie de COVID-19 [5]. 3.1 Protection individuelle 3.1.1 Secrétaire, assistant(e) • Masques chirurgicaux (un par demi-journée) ou FFP2 (pour les actes de soins). • Tenue lavable à 60 °C, restant au cabinet, et mise dans un sac plastique pour lavage au domicile. • Solution hydroalcoolique (SHA norme NF EN 14476) : avant prise en charge d’un patient et après manipulation d’objets (carte vitale, documents, carte bancaire…). • Stylos et fournitures de bureau individuelles, sans échange. 3.1.2 Médecin • Masques FFP2 (pour les actes de soins à risque) ou chirurgicaux, lunettes de protection ou visière, gants non stériles. • Tenue lavable à 60 °C, restant au cabinet et lavée à 60 °C. • Solution hydro-alcoolique (SHA norme NF EN 14476). 3.2 Réorganisation des locaux et du parcours patient 3.2.1 Affichage des mesures barrière et consignes en cas de symptômes de COVID-19 • Orientation immédiate vers une filière dédiée en cas de symptômes évocateurs de COVID-19 : • Solution hydroalcoolique à disposition, masque dès l’arrivée en cas de symptômes 3.2.2 Secrétariat • Marquage au sol pour respect des distances entre patients. • Protection plexiglas si nécessaire. • Nettoyage des surfaces de travail et du matériel de bureau (claviers, lecteurs de carte vitale et bancaire, téléphones …) avec un produit virucide en fin de demi-journée, et enveloppement éventuel de certains matériels dans un film plastique nettoyé régulièrement avec une solution désinfectante et changé chaque jour. 3.2.3 Salle d’attente et toilettes • Retrait de tous les objets non indispensables en salle d’attente (revues, jouets…). • Espacement des chaises pour respect des consignes de distanciation • Solution hydroalcoolique. • Poubelles avec sac et couvercle. • Accès limité aux toilettes, essentiellement pour lavage des mains, et mise à disposition d’essuie-mains en papier. 3.2.4 Climatisation En l’état actuel des connaissance l’usage d’une climatisation est déconseillé si l’air est recyclé. 3.3 Gestion des rendez-vous • Espacement des rendez-vous avec si possible alternance de téléconsultations et de consultations présentielles. • Demande faite au patient de venir à l’heure précise du rendez-vous, si possible avec un masque, de prévoir un règlement par carte bancaire (sans contact si possible), d’avoir son propre stylo… • Limitation du nombre de personnes en salle d’attente et respect de la distanciation : pas d’accompagnants sauf nécessité (enfant, handicap). 3.4 Entretien des locaux • Aération régulière de toutes les pièces, au moins deux fois par jour (20 à 30 mn), et conseil de laisser un maximum de portes ouvertes pour assurer la circulation d’air et limiter les contacts avec les poignées de porte. • Nettoyage quotidien du sol, des paillasses, du mobilier, des lavabos, et du matériel avec solution désinfectante ou javélisée ; l’utilisation d’un aspirateur ou d’un balai non humide est déconseillée. • Nettoyage après chaque patient, avec un produit virucide, des surfaces potentiellement contaminées : lit d’examen, stéthoscope, saturomètre, siège, bureau, poignées de porte… • Évacuation des déchets dans un double sac poubelle. 4 Un examen du patient adapté à la situation Au-delà des précautions d’hygiène générales et des mesures-barrière au premier rang desquelles figurent le lavage des mains, l’usage de solution hydro-alcoolique, le port systématique d’un masque chirurgical par le patient et le médecin, d’une blouse, et d’un masque FFP2 par le soignant en cas de symptômes potentiellement évocateurs d’infection à SARS-CoV-2, l’examen clinique évitera autant que faire se peut les risques de projection de sécrétions nasales, buccales ou bronchiques. La rhinoscopie antérieure habituellement pratiquée avec l’otoscope, qui peut être à l’origine d’éternuements, n’est que rarement indispensable. De même les indications d’explorations fonctionnelles respiratoires, qui exposent au risque de projections dans l’air ambiant et sur le matériel lors de l’expiration forcée, en cas de toux après l’examen, ou en cas de déconnexion du filtre antimicrobien, seront réfléchies. La pléthysmographie cabine fermée est, à cet égard, plus sécurisante pour le personnel soignant que la spirométrie simple mais nécessitera une désinfection complète du matériel au décours de l’examen. La pratique des tests cutanés et épicutanés, pour peu qu’elle respecte les mesures-barrière lors de la manipulation du matériel et que patient comme médecin soient masqués, ne paraît pas particulièrement à risque de contamination. 5 Conclusion La pandémie COVID-19 créé un environnement sanitaire inhabituel, complexe et inquiétant, auquel les soignants en général et les médecins allergologues en particulier doivent faire face pour prendre en charge leurs patients de façon optimale et les accompagner dans leurs questionnements. Elle bouleverse les conditions de vie et d’exercice, dominées par la nécessité de limiter les risques de contamination, et impose notamment un réapprentissage des règles d’hygiène de base et de gestion d’épidémie, une réorganisation des activités de soin et une réflexion quant à l’avenir du système de santé et de nos sociétés. Déclaration de liens d’intérêts Les auteurs déclarent ne pas avoir de liens d’intérêts. ==== Refs Références 1 Shaker M.S. Oppenheimer J. Grayson M. COVID-19 : Pandemic Contingency Planning for the Allergy and Immunology Clinic J Allergy Clin Immunol Pract 8 5 2020 10.1016/j.jaip.2020.03.012 1477-1488.e5, Epub 2020 Mar 26 2 World Allergy Organization (WAO): preparing your office for the COVID-19 Pandemic (24 March 2020): https://www.worldallergy.org/UserFiles/file/Preparing_your_office_COVID-19.pdf. 3 Centre d’Appui pour la Prévention des Infections associées aux Soins. COVID-19 et précautions d’hygiène (02/04/2020): https://rhc-arlin.pasman.fr/wp-content/uploads/2020/04/prev_COVID-19_MED-LIB_RHC-Cpias-CVDL03042020.pdf. 4 https://solidarites-sante.gouv.fr/IMG/pdf/consignes-hygiene-cabinets-ville-covid19.pdf 5 CNP d’Allergologie. Covid-19 et recommandations pour la reprise des consultations dans les cabinets d’allergologie (8 mai 2020) : https://app.advicemedica.com/media/mailbox_attachments/2020/05/08/88c7f3407d01482b9825963e02cf9f60.pdf.
PMC007xxxxxx/PMC7366092.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)32206-4 10.1016/j.jaad.2020.07.037 JAAD Online COVID toes: Phenomenon or epiphenomenon? Deutsch Alana BA a Blasiak Rachel MD, MPH ab Keyes Ashley MD c Wu Julia MD d Marmon Shoshana MD, PhD efg Asrani Falguni MD e Moy Janet MD h Russo Marian MD h McLellan Beth N. MD ab∗ a Albert Einstein College of Medicine, Bronx, New York b Jacobi Medical Center, Division of Dermatology, Bronx, New York c Lincoln Medical Center, Department of Dermatology, Bronx, New York d Elmhurst Medical Center, Department of Dermatology, Elmhurst, New York e Woodhull Medical Center, Department of Dermatology, Brooklyn, New York f Coney Island Medical Center, Department of Dermatology, Brooklyn, New York g Cumberland Medical Center, Department of Dermatology, Brooklyn, New York h Metropolitan Medical Center, Department of Dermatology, New York, New York ∗ Reprint requests: Beth N. McLellan, MD, 1400 Pelham Pkwy S, Rm 4W4D, Bronx, NY, 10467 17 7 2020 11 2020 17 7 2020 83 5 e347e348 © 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: As of June 15, there have been 206,606 cases and 22,103 deaths from COVID-19 in New York City.1 The boroughs of the Bronx, Queens, and Brooklyn, as well as Harlem in upper Manhattan, have been epicenters of disease since its emergence due to socioeconomic factors that dictate their populations' baseline health and limit the ability to maintain infection control measures. Accordingly, these areas account for 80.8% and 81.2% of cases and deaths from COVID-19 in New York City, respectively.1 As dermatologists representing the New York City Health+Hospitals municipal health care system throughout these heavily affected areas, we have observed that the mounting phenomenon of acral perniosis, colloquially known as COVID toes, has been virtually absent in our patient populations despite noteworthy subjugation in less affected areas.2 Illustratively, the 7 medical centers we represent have seen no cases of COVID toes. Although usual dermatologic services have been curtailed during this pandemic period, inpatient consults and ambulatory televisits have been used to maintain the provision of care; therefore, lack of access to dermatologic services cannot account for this finding. Between March 16 and June 5, 2020, there were a total of 5635 dermatology televisits completed among our 7 hospitals, ranging from 222 to 1250 televisits per hospital (Fig 1 ).Fig 1 Total number of ambulatory dermatology televisits at New York City Health+Hospitals neighborhood hospitals from March 16, 2020, to June 5, 2020. Importantly, an overwhelming majority of the serviced population is Hispanic and black (Table I ). A notable racial imbalance among reported cases of COVID toes is glaringly apparent in a large, registry-based case series3 of 318 patients, of whom only 2.7% were Hispanic and 0.7% were black, thus, suggesting this phenomenon as a disease manifestation in white individuals. However, even if findings are resolute that this phenomenon is specific to a single ethnic group, there is still the question of whether its relation to disease is one of direct causality.Table I Racial/ethnic breakdown, %, of represented New York City Health+Hospitals neighborhood hospitals as reported in the NYC Health+Hospitals 2016 Community Health Needs Assessment5 NYC H+H Hospital Hispanic Non-Hispanic black Non-Hispanic white Asian/Pacific Islander American Indian or Native Multirace/other Patient declined to answer Jacobi 41.1 33.2 8.5 5.6 1.5 4.9 5.2 Coney Island 23.3 18.2 36.7 8.4 0.2 9.1 4.1 Woodhull 55.2 29.3 7.3 1.9 0.6 3.5 2.3 Lincoln 62.7 27.8 1.3 1.2 0.3 3.9 2.8 Elmhurst 52.1 6.5 9.7 14.9 1.0 10.7 5.1 Metropolitan 51.8 21.1 6.9 5.1 0.1 5.1 3.3 Cumberland 15.6 20.2 49.6 8.9 0.1 4.0 1.6 In the authors' opinion, it remains difficult to qualify COVID toes as a direct manifestation of the disease at this time, especially because the rate of COVID-19 antigen test positivity among affected patients is low. Although recent reports corroborate low rates of confirmed disease, they also explanatorily suggest that this manifestation occurs in otherwise mildly ill or asymptomatic individuals late in the disease course, which precludes antigen testing in a timely fashion.3 , 4 There are other factors that could explain our findings—perhaps our population has been less exposed to lay media reports of acral perniosis and its possible association with COVID-19, or perhaps greater experience with severe COVID-19 in their communities made these patients less likely to be concerned about mild manifestations. Furthermore, our patients often seek care in the emergency department and fear of exposure to infection may have prevented them from seeking evaluation. Nevertheless, based on presently available data, it may be most appropriate to circumscribe this phenomenon of COVID toes as, rather, an epiphenomenon—an accompanying symptom without causal relation. Continued reporting of COVID toes cases, as well as antigen and antibody testing of these individuals and ongoing pursuit of plausible alternative explanations, remains crucial so that when a comprehensive, retrospective study becomes achievable, the deductions can accurately portray the pathophysiology of disease and its manifestations. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: No IRB information. ==== Refs References 1 City of New York COVID-19: Data Available at: https://www1.nyc.gov/site/doh/covid/covid-19-data.page 2 Cordoro K.M. Reynolds S.D. Wattier R. McCalmont T.H. Clustered cases of acral perniosis: clinical features, histopathology and relationship to COVID-19 Pediatr Dermatol 37 2020 419 423 32396999 3 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 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 2020 71 77 32348545 5 2016 Community Health Needs Assessment Available at: https://www.nychealthandhospitals.org/2016-community-health-needs-assessment/
PMC007xxxxxx/PMC7371582.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)32266-0 10.1016/j.jaad.2020.07.066 JAAD Online Approaching the dermatology residency application process during a pandemic Rosman Ilana S. MD a∗ Schadt Courtney R. MD b Samimi Sara S. MD c Rosenbach Misha MD c a Division of Dermatology, Washington University School of Medicine, St. Louis, Missouri b Division of Dermatology, University of Louisville, Louisville, Kentucky c Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania ∗ Correspondence to: Ilana S. Rosman, MD, 660 S. Euclid Ave, Campus Box 8118, St Louis, MO 63110 21 7 2020 11 2020 21 7 2020 83 5 e351e352 © 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 presents an unprecedented crisis that has caused significant disruptions to medical education. Continued uncertainty around travel restrictions, clerkship scheduling, and resumption of clinical activities has heightened medical student anxiety about the upcoming residency application process. Dermatology is consistently one of the most competitive specialties, with a 28% unmatched rate in 2018.1 Given this environment and the emphasis placed on personal knowledge of applicants,2 many applicants complete away rotations to gain exposure to outside programs, secure letters of recommendation, and collaborate on research projects. On average, applicants to dermatology have among the highest number of publications and research and volunteer experiences across all specialties.1 Many of these opportunities are in jeopardy this cycle given rotation cancellations, altered or limited volunteer opportunities, and interrupted or halted research. To address students' concerns about the upcoming cycle, we (ISR and CRS) released a dermatology program director consensus statement to be shared with medical students and medical school faculty and deans.3 Statements from obstetrics and gynecology, otolaryngology, emergency medicine, neurosurgery, and pediatrics have also been published.3 These statements are in line with recommendations released by the Coalition for Physician Accountability, composed of representatives from several national medical organizations.4 Given the ongoing crisis, we suggest changes to the application and recruitment process for academic dermatology programs around the country to consider.• Away rotations: We recommend that dermatology programs reserve away rotation opportunities for students without home institution dermatology options and encourage such students to seek rotations with the closest dermatology practice or program. Additionally, we encourage the creation of virtual experiences to allow for recruitment of students from other institutions. These may be noncredit bearing, be shorter in length than typical rotations, and include a variety of activities, including but not limited to participation in virtual educational conferences, remote panels or meetings with selected faculty and residents, teledermatology clinical care, and virtual tours of facilities. • Interview process: We strongly recommend that programs develop plans for remote interviews via currently available videoconferencing platforms. The capacity to conduct remote interviews will be critical moving forward, even beyond the current pandemic situation, by reducing student costs (which may aid in recruiting applicants from broader socioeconomic backgrounds), allowing for greater scheduling flexibility, and aligning with environmentally sound practices in light of the climate crisis. As program directors, we understand the difficulty in enacting novel and possibly temporary policies. We also sympathize with the inclination for a wait-and-see approach as parts of the country modify physical distancing and shelter-in-place orders. However, application season is upon us, and with the likelihood of the pandemic continuing in some capacity for the next several months, it is imperative that we take a proactive approach. Expecting students to travel during an overlapping COVID-19 and influenza season risks their health and risks exposure and transmission of infection to faculty and residents. We propose that these suggestions be adopted broadly to alleviate medical student concerns, address potential inequities in applicant opportunities, and implement socially responsible measures that will position us well for future challenges. Funding sources: None. Disclosure: Dr Rosman is the dermatology residency program director at Washington University. Dr Schadt is the dermatology residency program director at University of Louisville. Drs Rosman and Schadt cofounded and cochair the Association of Professors of Dermatology Program Director Task Force; their views are their own. Dr Samimi is the associate dermatology residency program director at the University of Pennsylvania. Dr Rosenbach is the dermatology residency program director at the University of Pennsylvania, a member of the American Academy of Dermatology's (AAD's) Ad Hoc Task Force on COVID-19, and cochair of the AAD's Climate Change Expert Resource Group; his views are his own. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 National Resident Matching Program Chart 3 Charting Outcomes in the Match: US Allopathic Seniors 2018 https://www.nrmp.org/wp-content/uploads/2018/06/Charting-Outcomes-in-the-Match-2018-Seniors.pdf 2 National Resident Matching Program Figures D-1 and D-2 Results of the 2018 NRMP Program Director Survey 2018 24-25. https://www.nrmp.org/wp-content/uploads/2018/07/NRMP-2018-Program-Director-Survey-for-WWW.pdf 3 Specialty response to Covid-19. Association of American Medical Colleges http://students-residents.aamc.org/applying-residency/article/specialty-response-covid-19 4 Coalition for Physician Accountability publishes recommendations on movement across institutional for 2020-2021. Accreditation Council for Graduate Medical Education https://acgme.org/Newsroom/Newsroom-Details/ArticleID/10252/Coalition-for-Physician-Accountability-Publishes-Recommendations-for-2020-2021
PMC007xxxxxx/PMC7373692.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)32256-8 10.1016/j.jaad.2020.07.057 Review Hand hygiene during COVID-19: Recommendations from the American Contact Dermatitis Society Rundle Chandler W. MD a Presley Colby L. BA, BS b Militello Michelle MS b Barber Cara MPH c Powell Douglas L. MD d Jacob Sharon E. MD efg Atwater Amber Reck MD h Watsky Kalman L. MD i Yu Jiade MD j Dunnick Cory A. MD ak∗ a Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado b Rocky Vista University College of Osteopathic Medicine, Parker, Colorado c Michigan State University College of Human Medicine, Grand Rapids, Michigan d Department of Dermatology, University of Utah, Salt Lake City, Utah e Loma Linda Veterans Affairs Medical Center, Loma Linda, California f Department Medicine and Pediatrics, University of California, Riverside, California g Department of Dermatology, Loma Linda University Center, Loma Linda, California h Department of Dermatology, Duke University Medical Center, Durham, North Carolina i Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut j Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts k Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado ∗ Correspondence to: Cory A. Dunnick, MD, University of Colorado Anschutz Medical Campus, Department of Dermatology, 1665 Aurora Court F703, Aurora, CO 80045. 22 7 2020 12 2020 22 7 2020 83 6 17301737 17 7 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 recent COVID-19 pandemic has resulted in increased hand hygiene and hand cleansing awareness. To prevent virus transmission, the Centers for Disease Control and Prevention recommends frequent hand washing with soap and water. Hand hygiene products are available in a variety of forms, and while each of these formulations may be effective against COVID-19, they may also alter skin barrier integrity and function. As health care workers and the general population focus on stringent hand hygiene, the American Contact Dermatitis Society anticipates an increase in both irritant contact and allergic contact hand dermatitis. Alcohol-based hand sanitizers with moisturizers have the least sensitizing and irritancy potential when compared to soaps and synthetic detergents. This article provides an overview of the most frequently used hand hygiene products and their associations with contact dermatitis as well as recommendations from the American Contact Dermatitis Society on how to treat and prevent further dermatitis. Key words allergic contact dermatitis COVID-19 detergents hand washing irritant contact dermatitis soap Abbreviations used ABHS alcohol-based hand sanitizer ACD allergic contact dermatitis ACDS American Contact Dermatitis Society CDC Centers for Disease Control and Prevention ICD irritant contact dermatitis SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 TEWL transepidermal water loss ==== Body pmc Capsule Summary • Hand hygiene is an accepted practice to prevent the transmission of infectious disease. • Increased hand washing related to coronavirus 2019 may result in elevated rates of hand dermatitis. • The American Contact Dermatitis Society recommends best practices for proper hand hygiene, skin disease prevention, and skin restoration. The recent COVID-19 pandemic has resulted in worldwide hand hygiene and hand cleansing awareness. Hand hygiene is a widely accepted principle in the prevention of disease transmission because proper hand hygiene has a 24% to 31% likelihood of decreasing the spread of transmissible disease.1 , 2 COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an enveloped, unsegmented, positive-sense RNA virus.3 According to the Centers for Disease Control and Prevention (CDC), the virus is currently believed to spread via direct contact, indirect contact, and droplet contact. To prevent virus transmission, the CDC recommends frequent hand washing with soap and water for 20 seconds; alternatively, if soap and water are unavailable, hand sanitizer containing at least 60% alcohol can be used.4 Hand hygiene products are available in various forms: liquid or bar soaps, synthetic detergents, antiseptic handwashes, and alcohol-based hand sanitizers (ABHSs). Although each formulation may be effective against COVID-19, they may alter skin barrier integrity and function, increasing the risk of hand dermatitis. Here, experts from the American Contact Dermatitis Society (ACDS) review best hand hygiene practices to mitigate COVID-19–related skin disease. Types of hand hygiene products Soaps Soaps are made of lye and natural fats. The term soap is used to refer to any cleanser; however, this is incorrect because soap designates a specific chemical composition.5 Soap is created when a fat interacts with an alkali, resulting in a fatty acid salt with cleansing properties. The typical pH of a true soap is approximately 9 to 10.6 Soap removes dirt and inactivates viruses by disrupting the lipid membrane and intracellular lipids. There is evidence to support soap as a more effective method of hand hygiene than hand sanitizer.7 Hand washing with soap and water has the added benefit of physically washing away debris and pathogens with running water. Although soaps are effective in removing debris, they also remove beneficial intracellular lipids and damage proteins found in the stratum corneum layer of the skin.6 Removing these beneficial lipids and proteins compromises the stratum corneum and increases skin sensitivity and irritation.6 Synthetic detergents Synthetic detergents, derived from petrolatum mixed with surfactants, contain less than 10% soap and have a pH of 5.5 to 7, which is similar to the pH of healthy skin.6 Synthetic detergents contain chemical surfactants, which function similarly to soap. The hydrophobic end of synthetic surfactants fuses with the lipid membrane of the virus.8 This leads to disruption of the viral membrane but may also remove natural lipids found in the stratum corneum.5 Synthetic detergents have been shown to be efficacious in the killing of lipid-enveloped viruses and most protozoa. However, they are ineffective against non–lipid-enveloped viruses. COVID-19, a lipid-enveloped virus, should therefore be susceptible to synthetic detergents.9, 10, 11 Examples of common surfactants in synthetic detergents include sodium lauroyl sarcosinate, cocamide diethanolamine, sodium lauroyl oat amino acids, disodium cocoamphodiacetate, decyl glucoside, sodium cocoyl glutamate, lauryl glucoside, and cetrimonium chloride.9 A subset of synthetic detergents are the lipid-free cleansers. Lipid-free cleansers contain no soap (no fat or oil), clean without water, and leave a thin moisturizing residue containing glycerin or glycol.6 , 12 Many synthetic detergents contain added lipophilic moisturizing ingredients (eg, petrolatum, vegetable oils, shea butter).5 The addition of moisturizing ingredients to synthetic detergent cleansers allows for effective skin cleansing with minimal stripping of the essential stratum corneum components.6 The degree of induced skin xerosis, irritation, and inflammation depends on the specific surfactant concentrations.6 Antiseptic handwashes Antiseptic handwashes are soaps or synthetic detergents that have an added antimicrobial component. These antimicrobial ingredients disrupt the integrity of the viral membrane.13 , 14 Various antimicrobial ingredients were reviewed and rated for their relative efficacy as a virucidal agent and potential allergenicity (Table I ). Alcohols, bleach, and iodophor-containing solutions are the most effective against viruses.15 The antiviral activity of alcohol is attributed to its ability to denature proteins.16 The antiviral activity of povidone iodine is noted to rapidly penetrate the cells of microorganisms, inactivate cellular replication, and impair protein synthesis.17 Table I Activity of antimicrobial ingredients against enveloped viruses such as coronaviruses Ingredient Virucidal activity against enveloped viruses11,43∗ Allergenicity† Chloroxylenol High + Ethanol High - Povidone iodine High +/- Sodium hypochlorite (bleach) (0.21%) High - Triclosan/triclocarban High +/- Benzalkonium chloride Moderate + Chlorhexidine digluconate Moderate + Benzethonium chloride Low - Phenolic compounds Low - Quaternary ammonium compounds Low - ∗ High virucidal activity: <1 minute; moderate virucidal activity: 1 to 30 minutes; low virucidal activity: >30 minutes. † The + symbol indicates that the ingredient is found in the American Contact Dermatitis Society core patch testing panels, +/- indicates scattered reports of contact allergy and the - symbol indicates that allergenicity is rare.15,16 ABHS ABHSs work by penetrating the viral membrane to denature and coagulate proteins, disrupt cellular metabolism, and induce lysis of the viral particle.14 In 2017, a study evaluated the virucidal activity of ABHSs against a variety of viral pathogens, including SARS-CoV. This study determined that ethanol-based and isopropyl ABHSs were effective disinfectants during the previous 2002 SARS-CoV outbreak.18 With respect to COVID-19, the CDC recommends that ethanol greater than 60% or isopropanol greater than 70% be used on the hands in health care.19 Isopropyl alcohol percentage is calculated by weight or by volume. For example, 70% alcohol by weight is equivalent to 76.8% by volume if prepared at 15°C or 80.5% if prepared at 25°C.13 Additionally, the CDC recommends ABHSs that contain emollients or moisturizers with low allergenicity, as discussed in articles by Rodriguez-Homs and Atwater20 and Xu et al,21 as an alternative to harsher soaps and detergents, to minimize irritant contact dermatitis (ICD).21 , 22 With respect to hand dermatitis, well-formulated ABHSs conferred lower rates of ICD compared to other hand hygiene methods, such as soap and water.16 Disinfectant wipes Disinfectant wipes are commonly used for disinfection. Hand wipes and baby wipes are formulated for skin use. These wipes contain antibacterial active ingredients, such as benzethonium chloride or alcohol, to disinfect. Hand wipes containing antimicrobial ingredients break down the COVID-19 virus by disrupting the viral membrane. Similarly, alcohol-based hand wipes also degrade the integrity of the viral membrane in the same method as ABHS, making them a viable opponent to COVID-19. Appropriate use of wipes is necessary for skin ICD to be avoided. Wipes designed for surface cleaning should not be used on the skin. The wipes commonly sold by household disinfectant companies use harsh active ingredients such as N-alkyl dimethyl benzyl ammonium chloride as their antimicrobial agents. Due to the harsh disinfectants being documented as sources of chemical irritation, they should not be used in hand hygiene.23 Skin barrier function A major component of a healthy skin barrier is the stratum corneum, composed of keratin and lipids. The epidermis maintains an acidic cutaneous pH (acid mantle) that provides structural integrity and buffers against harsh environmental substances that can negatively affect skin barrier function, including alkaline soaps and detergents, hot water (and very cold water), low humidity, repeated glove use, friction, wet work, and rough paper towels.24 Stringent hand hygiene can cause an acute loss of surface lipids due to lipid-emulsifying detergents and lipid-dissolving alcohols.13 As the lipid barrier of the stratum corneum is depleted and proteins are denatured, the attenuated skin barrier will exhibit increased transepidermal water loss (TEWL) and increased epidermal penetration of irritants and allergens, propagating an inflammatory response, resulting in hand dermatitis.25 With respect to the inflammatory response, topical steroids may be necessary to mitigate inflammatory skin disease. However, topical steroids can also have direct implications related to epidermal barrier function. These include epidermal atrophy, reduced keratinocyte size, decreased free fatty acids, and increased TEWL.26 Hand hygiene-induced dermatitis As health care workers and the general population focus on stringent hand hygiene, the ACDS anticipates an increase in both ICD and ACD. During the COVID-19 outbreak in China, 66.1% of health care workers washed their hands more than 10 times per day, but only 22.1% applied moisturizers after hand washing.2 , 27 The higher frequency of hand washing in contrast with the lower frequency of moisturizer application provides an imbalance that predisposes to an increased risk of hand dermatitis. ICD ICD risk secondary to hand hygiene increases relative to the concentration, duration, and intensity of contact with the eliciting substance. The majority of occupational skin diseases are due to contact dermatitis, with ICD being the most common cause (80% of cases).28 , 29 In a study in which occupational dermatitis was evaluated in health care workers, the hands are most commonly affected. This most likely occurred because frequent hand washing, gloves, disinfectants, and detergents are known irritants.30 Health care workers are in one of the highest-risk professions for developing occupational skin disease, with an estimated prevalence of 30%.30 A combination of chemical and physical irritants (eg, detergents and hot water) results in keratinocyte release of proinflammatory cytokines that instigate skin barrier disruption, cellular changes, and additional cytokine release. Reported irritants include iodophors, antimicrobial soaps (chlorhexidine, chloroxylenol, triclosan), detergents, alcohol-based products, and other additives in hand cleansing products. Use of detergent-based substances leads to the highest rates of dermatitis by reducing moisture in the stratum corneum and stripping away protective lipids, thereby making the skin more vulnerable to irritation.31 ABHSs are believed to be safer than detergents with regard to risk of ICD because of lesser lipid-dissolving effects.13 , 18 ABHSs with moisturizers may result in a decreased risk of ICD versus hand sanitizer without moisturizer. It is imperative to check the ingredients of products to prevent hand dermatitis. Allergic contact dermatitis Allergic contact dermatitis (ACD) is a risk with frequent hand washing. The development of contact allergy requires sensitization to a specific allergen, followed by elicitation of the inflammatory response upon secondary exposure to the allergen. There are a variety of hand hygiene components reported to cause hand ACD, including preservatives, surfactants, and antimicrobial ingredients (Tables I and II ).32, 33, 34, 35 ABHSs may also contain allergens, including propylene glycol and fragrance.32 Most health care facilities have switched to nitrile gloves to avoid sensitization to latex. However, rubber accelerators are still used in the manufacturing of nitrile gloves and are a common causes of glove ACD. Vinyl gloves are considered to be safer with respect to ACD, because they usually do not contain rubber accelerators; however, there are rare reports of ACD to vinyl gloves.36, 37, 38 Furthermore, the CDC reports that nitrile, natural rubber, and neoprene (polychloroprene) gloves all maintain greater minimum tensile and elongation requirements when compared to vinyl gloves.33 , 39 Therefore, medical gloves made of neoprene or nitrile may be implemented as rubber-free options that also protect against viral exposure.33 , 38 Table II Allergens commonly encountered with regular hand hygiene Gloves30,32 Soaps, synthetic detergents, and antiseptics33∗ Hand sanitizers27 I. Latex II. Rubber accelerators• Thiurams • Carbamates • Diphenylguanidine • Mixed dialkyl thioureas • Benzothiazoles III. Fragrance IV. Surfactants• Cocamidopropyl betaine • Cocamide diethanolamine • Decyl glucoside • Dimethylaminopropylamine • Oleamidopropyl dimethylamine V. Preservatives• Dimethyloldimethyl hydantoin • Diazolidinyl • Formaldehyde • Iodopropynyl butylcarbamate • Imidazolidinyl urea • Isothiazolinones • Quaternium-15 Fragrance Benzoates Cetyl stearyl alcohol Tocopherol ∗ These allergens were the top North American Contact Dermatitis Group screening allergens found in skin cleansers for the years 2000 to 2014.33 Individuals exposed to hand hygiene–related irritants or allergens may experience any 1 of the following morphologic patterns of ICD or ACD: acute (erythema, edema, vesicle formation) (Fig 1 ), subacute (crust formation, scaling), and chronic (lichenification). Those with recalcitrant hand dermatitis, a change in baseline hand dermatitis, a new hand dermatitis, or suspect contact allergy should seek dermatologic care and should be considered for patch testing.Fig 1 Hand dermatitis from antiseptic hand wash in a health care worker. Moisturizers Moisturizers both prevent and treat xerosis and dermatitis due to hand hygiene.24 Moisturizers can be categorized into different formulations, including ointments, creams, lotions, and gels. In general, ointments are considered the most moisturizing, with creams, lotions, and gels following, respectively. Those with severe xerosis or eczema should consider ointment. Moisturizing ingredients include occlusive, humectant, emollient, and protein rejuvenators. Occlusives (eg, petrolatum, beeswax) serve as a physical barrier to decrease TEWL, resulting in the replenishment of stratum corneum water content. Humectants (eg, urea, glycerin), are effective hydrophilic compounds that attract water from the deeper dermis and the outside environment of the epidermis.40 This newly attracted moisture decreases TEWL, improving the skin barrier. Emollients (eg, ceramides, free fatty acids) are primarily lipids and oils that replenish the disrupted lipid outer membranes to prevent skin dehydration. Protein rejuvenators (eg, collagen, keratin) are small-molecular-weight proteins that are thought to replenish essential skin barrier proteins lost in hand hygiene. Soaps can be irritating and cause dryness to the skin. Adding a humectant to this formula can help mitigate skin irritation. Barrier creams and regular moisturizing lotions have been shown to be equivocal in the prevention of ICD, and either may be used after hand washing.13 A combination of these ingredients is effective to replenish skin barrier integrity and function. Best practices and alternatives To mitigate the expected rise in dermatitis from repetitive hand washing in response to COVID-19, good hand hygiene techniques are imperative. The CDC recommends that individuals wash their hands with soap and lukewarm water for at least 20 seconds.4 Special attention is required to equally wash all areas of the hand. Results from Wong et al41 showed that the fingertips, hypothenar eminence, and dorsum of the hand were commonly missed areas in hand washing. Particular care during hand washing should be directed toward these missed areas. An extensive list of ACDS-recommended hand hygiene practices can be found in Table III .Table III American Contact Dermatitis Society hand hygiene recommendations Use of soaps and synthetic detergents• Wash hands with lukewarm or cool water and soap for at least 20 seconds. • Avoid hot and very cold water. • Nonfrictional, pat drying (don't rub). • Immediate application of moisturizer after cleansing practices is recommended. • Products with antibacterial ingredients are not necessary for proper hand hygiene. • Look for soaps or synthetic detergents that are devoid of allergenic surfactants, preservatives, fragrances, or dyes. • Look for synthetic detergents with added moisturizers. • Dry hands are common with frequent use of soaps or synthetic detergents. Use of ABHS• At least 60% alcohol is recommended. • Look for hand sanitizers that are devoid of allergenic surfactants, preservatives, fragrances, or dyes. • Look for ABHSs with added moisturizers. • Dry hands are common with frequent use. Application of a moisturizer after hand washing is recommended. Use of moisturizers• Avoid moisturizers in jars to prevent double dipping into and potentially contaminating the product. • Use moisturizers packaged in tubes instead. • Look for pocket-sized moisturizers to keep on one's person for frequent reapplication. • At night, apply moisturizer followed by cotton or loose plastic gloves (eg, plastic clear, disposable food gloves) to create an occlusive barrier. • For health care workers, a moisturizer under gloves can also be effective. Moisturizers with a water base are safe under all gloves; however, oil-based moisturizers can break down latex and rubber by making the material swell or become brittle. • Latex, vinyl, and nitrile gloves are resistant to breakdown from ethanol or isopropyl alcohol. • Soak and smear: soak the hands in plain water for 20 minutes and immediately apply moisturizer of choice to damp skin nightly for up to 2 weeks. Glove ACD• For glove ACD, accelerator-free gloves should be used, such as rubber-free neoprene or nitrile gloves. • Apply moisturizer after washing hands and before wearing gloves. • Consider a cotton glove liner or loose plastic gloves (eg, plastic clear, disposable food gloves). • Individuals with suspected hand ACD should be patch tested. Treatment of hand dermatitis• ACD○ For hand dermatitis that is allergic in nature, allergens should be identified and avoided. ○ Application of a topical steroid may be recommended to mitigate flares of dermatitis. ○ Individuals with recalcitrant hand dermatitis should seek a dermatology consultation and be evaluated for patch testing. ○ Individuals with suspected ACD should be patch tested to evaluate for a clinically relevant causal allergen. ○ For recalcitrant cases, a stronger topical steroid, phototherapy, systemic therapy, or occupational modification may be necessary. • ICD○ For hand dermatitis that is irritant in nature, awareness of the irritating nature of wet work and exposure to surfactants and detergents is imperative. ○ Irritants should be identified and avoided. ○ The use of barrier creams (eg, restorative creams such as humectants) may be helpful; however, their use is equivalent to regular moisturizers. ○ Switching to less-irritating products should be attempted. ○ Application of a topical steroid can be considered if conservative measures fail; however, consider potential topical steroid-induced damage to the skin barrier. ○ Individuals with recalcitrant hand dermatitis should seek a dermatology consultation. ○ For recalcitrant cases, phototherapy, systemic therapy, or occupational modification may be necessary. Risk factors for induction or worsening of hand ACD and/or ICD• Hand washing○ Frequent hand washing ○ Washing hands with dish detergent or other known irritants ○ Washing hands with very hot or very cold water ○ Use of disinfectant wipes to clean hands ○ Working with known irritants such as bleach • Application of known allergens• Products containing topical antibiotics (eg, neomycin, bacitracin) • Applications of superglue (ethyl cyanoacrylate) to glue inflammatory or healing fissures • Occluding fingers with adhesive bandage impregnated with bacitracin or benzalkonium chloride • Occlusion○ Increased duration of glove occlusion (without underlying moisturizer application) ○ Hands treated with a detergent or soap before glove occlusion (without underlying moisturizer application) ○ Occluding hands with self-adherent wraps • Underlying skin disease• Pre-existing atopic dermatitis of the hands • Picking at dermatitis-induced scale ABHS, Alcohol-based hand sanitizer; ACD, allergic contact dermatitis; ICD, irritant contact dermatitis. Water temperature does not affect microbe removal; therefore, it is recommended that cold or lukewarm water be used to avoid skin irritation.4 , 42 Higher water temperatures (greater than 40°C) affect the stratum corneum by lipid fluidization, or disordered lipid structure, leading to increased skin permeability.43 Washing hands with soap and water immediately before or after using an alcohol-based product is unnecessary and increases the risk of hand dermatitis. Applying gloves when hands are still wet from either hand washing or alcohol sanitizer is also not recommended, because the risk for skin irritation due to trapping of irritating ingredients increases.13 A full list of exacerbating hand dermatitis factors is provided in Table III. Universal precautions should be used because many COVID-19–positive patients may be asymptomatic. For health care professionals, hands should be washed both before and after patient encounters using a strong ABHS and antiseptics with antiviral activity.13 , 22 To effectively use moisturizing agents after hand washing and nonfrictional (pat) drying, apply a minimum amount of 2 fingertip units of moisturizer to each hand, as shown in Fig 2 . Evenly spread a thin layer across the hand, between fingers, on cuticles, and on fingertips and wait 1 to 3 minutes before resuming activity. Moisturizer should be reapplied every 3 to 4 hours and/or after each hand washing. The American Academy of Dermatology recommends fragrance-free moisturizers with petrolatum or mineral oil as the most effective and least allergenic.13 , 44 Additionally, further recommendations about low-allergenicity products can be found in the literature (Xu et al21 and Rodriguez-Homs and Atwater20), but product selection is ultimately based on user preference and tolerability. Of note, petrolatum and mineral oils should not be used under latex or rubber medical gloves, because these products are known to compromise glove integrity.45 However, latex, vinyl, and nitrile gloves are resistant to breakdown from ethanol or isopropyl alcohol.46 , 47 Fig 2 One fingertip unit. Two fingertip units is the appropriate amount of moisturizer to apply to hands after hand washing. Conclusion Hand hygiene is essential for reducing COVID-19 transmission. There are a variety of hand hygiene products available; however, their safety and efficacy vary. With respect to hand dermatitis, ABHSs with moisturizers have the least sensitizing and irritancy potential compared to soaps and synthetic detergents. Wet work and synthetic detergents may be the greatest contributors to hand dermatitis because of the potential inclusion of surfactant, preservative, or fragrance allergens. Strategies for hand dermatitis prevention include using products devoid of common allergens, using products with added moisturizers, and applying moisturizers immediately after hand washing or before glove occlusion. Cases of recalcitrant hand dermatitis should be evaluated and managed by a dermatologist. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: not applicable. Reprints not available from the authors. ==== Refs References 1 Lin Huang G.K. Stewardson A.J. Lindsay Grayson M. Back to basics: hand hygiene and isolation Curr Opin Infect Dis 27 4 2014 379 389 24945613 2 Kantor J. Behavioral considerations and impact on personal protective equipment use: early lessons from the coronavirus (COVID-19) pandemic J Am Acad Dermatol 82 5 2020 1087 1088 32171806 3 Guo Y.-R. Cao Q.-D. Hong Z.-S. 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PMC007xxxxxx/PMC7385551.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)32287-8 10.1016/j.jaad.2020.07.086 JAAD Online Assessing the risk of adalimumab use for hidradenitis suppurativa during the COVID-19 pandemic Kearns Donovan G. BA a Chat Vipawee S. BS b Uppal Shelley MD c Wu Jashin J. MD d∗ a Loma Linda University School of Medicine, Loma Linda, California b Medical College of Georgia at Augusta University, Augusta, California c Albany Medical College School of Medicine, Albany, New York d Dermatology Research and Education Foundation, Irvine, California ∗ Reprint requests: Jashin J. Wu, MD, Dermatology Research and Education Foundation, Irvine, California 28 7 2020 12 2020 28 7 2020 83 6 e433e434 © 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 prolonged quarantines and social restrictions, the COVID-19 pandemic continues to persist in the United States and globally. Questions still remain regarding the safety of various immunosuppressive medications for those with chronic conditions. With limited real-life data from COVID-19 infection in patients with hidradenitis suppurativa (HS) receiving adalimumab, we can use previous drug trials to extrapolate the potential risk to patients based on the change in infection rate when compared to placebo. Adalimumab, a tumor necrosis factor alpha (TNF-α) antagonist, is the only biologic treatment approved by the US Food and Drug Administration for patients 12 years and older with moderate to severe HS. TNF-α is a pleiotropic cytokine with proinflammatory functions that serves to protect against bacterial, fungal, and viral infection. Primary infection or reactivation of HIV, varicella zoster virus, Epstein-Barr virus, hepatitis, cytomegalovirus, John Cunningham (JC), and human papillomavirus have all been reported in patients receiving TNF-α therapy.1 TNF-α has been shown to be significantly elevated in patients with the severe acute respiratory infection coronavirus 2 (SARS-CoV-2), and serum levels are positively correlated with disease severity.2 It is currently uncertain whether elevated TNF-α is necessary for resolution of SARS-CoV-2 infection or if it plays a pathologic role in the development of the cytokine storm. In 2 placebo-controlled phase III clinical trials (PIONEER I/II), 633 adults with moderate to severe HS were randomly assigned to receive adalimumab (40 mg) or placebo. The trials were divided into 2 periods. In period 1, patients received either 40 mg of adalimumab weekly or placebo for 12 weeks. In period 2, patients received adalimumab (40 mg) weekly, received adalimumab (40 mg) every other week, or received placebo for 24 weeks. At the end of period 1, infection developed in 24.8% and 25.2% of those receiving adalimumab weekly, compared to 28.3% and 32.5% of patients receiving placebo, in PIONEER 1 and 2, respectively. At the end of period 2, infection occurred in 29.2% and 35.3% of patients receiving adalimumab weekly, 25.0% and 35.8% of patients receiving the medication every other week, and 32.7% and 25.5% of patients in the placebo control group, in PIONEER 1 and 2, respectively.3 There was no increase in serious infection or nasopharyngitis observed in active treatment groups. In both trials, it was concluded that the rate of infection was not increased in patients treated with adalimumab compared to placebo (Table I ).Table I Rate of infections with adalimumab for hidradenitis suppurativa compared to placebo∗ Infections, overall Serious infection Nasopharyngitis Adalimumab, n (%) Placebo, n (%) Adalimumab, n (%) Placebo, n (%) Adalimumab, n (%) Placebo, n (%) 185 (23) 160 (28) 3 (0.4) 4 (0.7) 39 (5) 41 (7) ∗ These data are a combined average of 2 phase III trials. The adalimumab group is a combined average of 2 treatment schedules (once per week or once per 2 weeks). This study's analysis was limited by the original research from the adalimumab trials, because the authors of the trials did not specify whether the cause of infection was bacterial or viral. However, the findings support the notion that otherwise healthy patients with HS, without risk factors, who use adalimumab during the COVID-19 pandemic are not predisposed to infection or nasopharyngitis (Table I). This is consistent with a recent case series documenting mild, uncomplicated disease in a small cohort of patients with HS receiving adalimumab.4 Clinicians considering discontinuing adalimumab in high-risk patients should be aware that discontinuation of biologics has been shown to result in decreased response to treatment and the development of antidrug antibodies. Funding sources: None. Disclosure: 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. Drs Kearns, Chat, and Uppal have no conflicts of interest to declare. IRB approval status: Not applicable. ==== Refs References 1 Kim S.Y. Solomon D.H. Tumor necrosis factor blockade and the risk of viral infection Nat Rev Rheumatol 6 3 2010 165 174 20142812 2 Huang C. Wang Y. Li X. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Lancet 395 10223 2020 497 506 31986264 3 Kimball A.B. Okun M.M. Williams D.A. Two phase 3 trials of adalimumab for hidradenitis suppurativa N Engl J Med 375 5 2016 422 434 27518661 4 Galán Sánchez J.L. San Nicasio C.S. Olivares M.G. Experience in patients with hidradenitis suppurativa and COVID-19 symptoms J Am Acad Dermatol 2020 10.1016/j.jaad.2020.06.986
PMC007xxxxxx/PMC7385924.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)32290-8 10.1016/j.jaad.2020.07.089 Original Article Antecedent immunosuppressive therapy for immune-mediated inflammatory diseases in the setting of a COVID-19 outbreak Veenstra Jesse MD, PhD a∗ Buechler Connor R. BS b Robinson Gabrielle MD a Chapman Stephanie MD a Adelman Madeline BS b Tisack Aaron BS b Dimitrion Peter MS b Todter Erika MS c Kohen Laurie MD a Lim Henry W. MD a a Department of Dermatology, Henry Ford Health System, Detroit, Michigan b Wayne State University School of Medicine, Detroit, Michigan c Department of Public Health Sciences, Henry Ford Health System, Detroit, Michigan ∗ Correspondence to: Jesse Veenstra, MD, PhD, Department of Dermatology, Henry Ford Medical Center–New Center One, 3031 W Grand Blvd, Suite 800, Detroit, MI 48202. 28 7 2020 12 2020 28 7 2020 83 6 16961703 23 7 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 Finite clinical data and understanding of COVID-19 immunopathology has led to limited, opinion-based recommendations for the management of patients with immune-mediated inflammatory disease (IMID) receiving immunosuppressive (IS) therapeutics. Objective To determine if IS therapeutic type affects COVID-19 risk among patients with IMID. Methods We conducted a retrospective cohort analysis of Henry Ford Health System patients tested for COVID-19 between February 1 and April 18, 2020, treated with IS medication for IMID. Therapeutic class of IS medication, comorbidities, and demographic factors were combined into multivariate models to determine predictors of COVID-19 infection, admission, ventilation, and mortality. Results Of 213 patients with IMID, 36.2% tested positive for COVID-19, and they had no greater odds of being hospitalized or requiring ventilation relative to the general population. No IS therapeutic worsened the course of disease after multivariate correction, although multidrug regimens and biologics predicted an increased and decreased rate of hospitalization, respectively, with the latter driven by tumor necrosis factor α inhibitors. Limitations A single-center study somewhat limits the generalization to community-based settings. Only patients tested for COVID-19 were analyzed. Conclusion IS therapies for IMIDs are not associated with a significantly greater risk of SARS-CoV-2 or severe sequelae when controlling for other factors, and tumor necrosis factor α inhibitors may decrease the odds of severe infection. Key words autoimmune disease biologics coronavirus COVID-19 DMARDs immune-mediated inflammatory diseases immunosuppression SARS-CoV-2 Abbreviations used CI confidence interval DMARD disease-modifying antirheumatic drug HFHS Henry Ford Health System IL interleukin IMID immune-mediated inflammatory disease IS immunosuppressive OR odds ratio PCR polymerase chain reaction SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 TNF tumor necrosis factor ==== Body pmc Capsule Summary • Little is known about the impact of systemic immunosuppressive (IS) medications common to dermatology on COVID-19 risk. • IS medications for immune-mediated inflammatory disease were not associated with increased risk of SARS-CoV-2 infection or severe sequelae, and anti–tumor necrosis factor α monotherapy was associated with decreased admission rate. Patients can be reassured when continuing these medications during the COVID-19 pandemic. The COVID-19 pandemic has sparked uncertainty throughout society and the medical community on how to best quell the spread of the virus, allocate critical resources, and care for high-risk populations, especially as new cases surge.1, 2, 3, 4 Concerns about potential increased risk for patients receiving immunosuppressive (IS) treatment for immune-mediated inflammatory disease (IMID) are warranted. Several professional societies suggest that clinicians should discontinue or reduce the use of IS agents in patients who test positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),1 , 5 , 6 although there is insufficient evidence to recommend discontinuation of IS therapy in others. Although immunosuppression predisposes individuals to infection by influenza and rhinoviruses, it has not been reported as a risk factor in previous coronavirus outbreaks, and it did not appear as a frequent comorbidity in studies of the initial outbreak of SARS-CoV-2 in China.7 , 8 Current guidance relies on expert opinion and incidences of infection from previous clinical trials for these therapies.9 , 10 In the absence of a clinical or mechanistic understanding of SARS-CoV-2 immunopathology, this information may not be sufficient to guide clinical practice. Discontinuation of IS treatment could lead to disease flares in patients with previously controlled IMID or to the development of antidrug antibodies, severely affecting quality of life.2 , 11 Furthermore, the effect of perturbing a proinflammatory state in an already dysregulated immune system during a disease flare might provoke a cytokine storm in patients with mild or asymptomatic COVID-19, as has been seen in patients with cancer who contract COVID-19 soon after receiving immunotherapy.12 Targeted immunomodulation may even prove beneficial, evidenced by data from previous coronaviruses and ongoing clinical trials.13, 14, 15 Given this uncertainty, there is a great need for more data concerning patient outcomes in the early stages of the outbreak to guide clinical decision making. During the COVID-19 pandemic, Detroit has had a high incidence of cases and is thus an excellent population from which to draw a single-center study, reducing the possible effect of confounding environmental factors. From February 1 to April 18, 2020, the Henry Ford Health System (HFHS) in Detroit, Michigan, tested a total of 15,345 individuals for SARS-CoV-2 using polymerase chain reaction (PCR), of whom 5881 (38.3%) had positive results. Of positive cases, 2650 (45.1%) patients were admitted, 522 (8.9%) required a ventilator, and 322 (5.5%) died (Supplemental Fig 1; all supplemental material available via Mendeley at https://doi.org/10.17632/hwf6mwdccj.1). Methods Study population We performed a retrospective cohort study (Fig 1 ) using a chart review of patients tested for SARS-CoV-2 with laboratory PCR at HFHS between February 1 and April 18, 2020, who were being treated with IS drugs commonly used in dermatologic treatment and patients with IMID (Supplemental Table I) as documented in the electronic medical record. IS medications of interest included disease-modifying antirheumatic drugs (DMARDs) and biologics. DMARDs included apremilast, azathioprine, methotrexate, mycophenolate, cyclosporine, tofacitinib, and intravenous immunoglobulin. Biologics were subcategorized into tumor necrosis factor (TNF) α inhibitors (adalimumab, etanercept, infliximab, and certolizumab), interleukin (IL) 17 inhibitors (ixekizumab, secukinumab, and brodalumab), IL-12/23 inhibitors (ustekinumab, guselkumab, risankizumab, and tildrakizumab), and others (abatacept, dupilumab, omalizumab, belimumab, rituximab); no patients treated with IL-1 or IL-6 inhibitors were identified. For inclusion, patients were required to be treated with an IS medication at least 1 month before testing, which was validated through review of the treating physician notes and patient communications without reliance on autopopulated medication lists. Systemic corticosteroid use was not used as an independent identifying medication to avoid capturing patients on short-term corticosteroid regimens; however, some patients with IMID were concurrently treated with long-term corticosteroid regimens of at least 2 months in conjunction with another IS medication and were noted as such. Any patients receiving chemotherapy or those whose IS medication could not be verified as current were excluded. IMID status was verified via review of physician notes, and those taking IS medications for non-IMID indications, such as for the prevention of transplant rejection, were not included. A total of 213 patients with IMID treated with IS therapeutics were included and will be referred to as the IMID cohort (Table I ). Individuals tested at HFHS during this time were under high suspicion for COVID-19, which included symptomatic patients or those with a known exposure presenting to the emergency department for testing, patients admitted, and HFHS health care providers seeking testing for concern of potential exposure. Asymptomatic patients without a verified exposure were not tested during this time. The policy for testing, admission, or ventilation did not vary based on comorbidities, demographics, or immunosuppressive treatments during this time. For patients tested multiple times, any positive result was considered a COVID-19–positive case. All research activities were conducted with approval of the HFHS institutional review board (no. 13768). We tracked outcomes for each patient via review of physician notes.Fig 1 Flow diagram of the study. Patients were deemed to be positive for COVID-19 if any test result was positive for SARS-CoV-2 RNA and negative for COVID-19 if all test results were negative. DMARD, Disease-modifying antirheumatic drug; HFHS, Henry Ford Health System; IMID, immune-mediated inflammatory disease. Table I Characteristics of the study population of patients tested for COVID-19 Characteristics Patients with IMID on IS therapy (N = 213) Age, y, mean ± SD 53 ± 15 Age >65 y, n (%) 50 (23.5) Female sex, n (%) 155 (72.8) Race or ethnic group, n (%) White 112 (52.6) Black 74 (34.7) Hispanic 3 (1.4) Asian 2 (0.9) Middle Eastern 3 (1.4) Other/unknown 19 (8.9) COVID-19 positive, n (%) 77 (36.2) Hydroxychloroquine use, n (%)∗ 28 (13.1) IS medication class, n (%)† Biologics 96 (45.1) TNF-α inhibitors 56 (26.3) TNF-α inhibitor monotherapy 45 (21.1) IL-17 inhibitors 7 (3.3) IL-12/23 inhibitors 7 (3.3) Biologic monotherapy 73 (34.3) DMARDs 138 (64.8) Apremilast 10 (4.7) Azathioprine 25 (11.7) Methotrexate 65 (30.5) Methotrexate monotherapy 45 (21.1) Mycophenolate 23 (10.8) DMARD monotherapy 100 (46.9) Multidrug therapy‡ 40 (18.8) Systemic corticosteroids∗ 22 (10.3) Comorbidity class, n (%) Cardiac 109 (51.2) Pulmonary 75 (35.2) Renal 11 (5.2) Gastrointestinal 45 (21.1) Endocrine 133 (62.4) Cancer 11 (5.2) IMID classification, n (%) Rheumatoid arthritis/spondylitis 72 (33.8) Psoriasis/psoriatic arthritis 29 (13.6) Inflammatory bowel disease 38 (17.8) SLE/DM, PM/MCTD/ILD/Scl 33 (15.5) Others§ 45 (21.1) DM, Dermatomyositis; DMARD, disease-modifying antirheumatic drug; IL, interleukin; ILD, interstitial lung disease; IMID, immune-mediated inflammatory disease; IS, immunosuppressive; MCTD, mixed connective tissue disease; PM, polymyositis; Scl, scleroderma and systemic sclerosis; SD, standard deviation; SLE, systemic lupus erythematosus; TNF, tumor necrosis factor. ∗ Concomitant use with IS medication. † Any patient taking a medication from a therapeutic class (Supplemental Table I) was included in the respective group, regardless of additional medications taken. Biologics and DMARDs were further subcategorized as shown. Monotherapy designates a patient using a medication without an additional biologic or DMARD. Therapeutics with fewer than 5 patients treated are not shown. ‡ Patients taking medications from both the biologics and DMARD groups or multiple DMARDs within the IMID cohort were also included in the multidrug therapy group. § Others includes patients treated with IS therapy for autoimmune blistering conditions, autoimmune hepatitis, atopic conditions, hidradenitis suppurativa, myasthenia gravis, sarcoidosis, urticaria, and uveitis. Analyses The outcomes of interest were COVID-19 status (positive or negative) via PCR test, admission status (admitted or not admitted), ventilatory status (requiring or not requiring invasive mechanical ventilation), and vital status (living or deceased). We used 2-group comparisons to assess the overall outcomes for the IMID cohort against the general population tested at HFHS. For the purposes of this comparison, admission status, ventilator status, and mortality data were used only for those who tested positive for COVID-19. We then categorized IS medications into 2 primary groups—biologics and DMARDs, with hydroxychloroquine classified as an independent non-IS medication, given its potential use in both IMID and COVID-19. We subcategorized our cohort into those with rheumatoid arthritis/spondylitis, psoriasis/psoriatic arthritis, systemic lupus erythematosus/dermatomyositis/polymyositis/mixed connective tissue disorder/interstitial lung disease/scleroderma, inflammatory bowel disease, or others; others included autoimmune blistering conditions, autoimmune hepatitis, atopic conditions, hidradenitis suppurativa, myasthenia gravis, sarcoidosis, urticaria, and uveitis (Table I). We performed 2-group comparisons to assess the odds ratios of outcomes of interest as a function of IMID type or IS therapy present (Table II ), with admission status, ventilator status, and mortality again being used only for those who tested positive for COVID-19. We additionally assessed admission status as a function of IS therapy class among the IMID cohort as a whole to determine if effects on admission rates were affected by COVID-19 status (Supplemental Table II). These comparisons were performed using chi-square testing, with Fisher's exact test used when expected counts were less than 5. Further investigation was performed by using multivariate logistic regression models while controlling for age, race, sex, COVID-19 status, IS medication, and comorbidities as documented in physician notes, including cardiac, pulmonary, renal, gastrointestinal, endocrine, and history of cancer (Supplemental Table III). For all analyses, statistical significance was determined if P was less than .05. All analyses were performed with SAS 9.4 (SAS Institute Inc, Cary, NC) or GraphPad Prism software, version 8 (GraphPad Software, Inc, La Jolla, CA).Table II Outcomes by paired analysis among COVID-19–positive cases within the IMID cohort, OR (95% CI)∗ Therapeutic class and IMID condition (COVID-19 cases, n) COVID-19† Admission Ventilator Mortality Biologics (30) 0.94 (0.55-1.67) 0.42 (0.16-1.09)‡ 1.06 (0.27-4.45) 0.61 (0.11-2.77) TNF-α inhibitors (16) 0.63 (0.33-1.20) 0.22 (0.07-0.73)‡ 0.61 (0.05-4.49) 0.75 (0.06-6.53) TNF-α monotherapy (11) 0.50 (0.23-1.03) 0.15 (0.03-0.70)‡ 0.00 (0.00-3.79) 0.00 (0.00-3.37) Biologics monotherapy (23) 0.73 (0.41-1.32) 0.44 (0.17-1.21) 0.93 (0.18-5.72) 0.45 (0.04-3.73) DMARDs (53) 1.33 (0.74-2.36) 2.54 (0.95-6.73) 1.15 (0.21-6.10) 2.40 (0.29-29.33) Azathioprine (6) 0.52 (0.21-13.2) 0.87 (0.19-3.93) 16.8 (2.90-84.4)‡,§ 2.64 (0.19-20.7) Methotrexate (23) 0.95 (0.52-1.75) 0.94 (0.34-2.52) 0.93 (0.17-5.04) 1.19 (0.21-5.43) Methotrexate monotherapy (15) 0.79 (0.40-1.58) 1.00 (0.34-2.93) 0.67 (0.055-4.96) 0.81 (0.065-7.2) Mycophenolate (12) 2.10 (0.91-4.83) 1.94 (0.57-6.20) 0.89 (0.07-6.10) 3.05 (0.52-14.83) DMARD monotherapy (34) 0.84 (0.49-1.48) 1.21 (0.50-2.87) 0.19 (0.02-1.29) 0.61 (0.11-2.77) Systemic corticosteroids (12) 2.33 (1.01-5.73) 5.48 (1.28-26.1)‡ 5.08 (1.10-20.9) 3.05 (0.52-14.8) Multidrug therapy (21) 2.31 (1.14-4.75)‡ 2.15 (0.73-5.59) 4.16 (1.01-17.41) 2.94 (0.63-13.29) Hydroxychloroquine (7) 0.55 (0.21-1.38) 2.36 (0.45-12.4) 5.2 (0.83-26.8) 2.17 (0.16-15.5) RA/spondylitis (26) 1.00 (0.56-1.78) 1.04 (0.41-2.73) 0.77 (0.14-4.10) 2.09 (0.45-9.39) Psoriasis/PsA (13) 1.52 (0.69-3.47) 0.71 (0.20-2.26) 0.81 (0.07-6.16) 0.00 (0.00-2.69) IBD (10) 0.58 (0.27-1.27) 0.54 (0.16-1.94) 0.00 (0.00-3.18) 1.38 (0.12-9.48) SLE/DM/PM/MCTD/ILD/Scl (11) 0.77 (0.35-1.69) 1.65 (0.54-8.51) 1.13 (0.45-5.38) 0.00 (0.00-3.83) Bold values represent significant values. CI, Confidence interval; DM, dermatomyositis; DMARD, disease-modifying antirheumatic drug; ILD, interstitial lung disease; IMID, immune-mediated inflammatory disease; MCTD, mixed connective tissue disease; OR, odds ratio; PM, polymyositis; PsA, psoriatic arthritis; RA, rheumatoid arthritis; Scl, scleroderma and systemic sclerosis; SLE, systemic lupus erythematosus; TNF, tumor necrosis factor. ∗ The ORs and 95% CIs drawn from 2-group comparison have not been adjusted and should not be used to infer definitive effects. † COVID-19 positivity among all patients with IMID. ‡ P < .05. § Three of 6 patients admitted requiring a ventilator. Results Of the 213 patients included in the IMID cohort, 77 (36.2%) tested positive for COVID-19 (Fig 1). Forty-one positive cases required admission (53.2% of positive cases), with 7 (9.1% of positive cases) necessitating ventilator use. Thirty-one patients with COVID-19–related admissions were subsequently discharged, 6 died, and 4 remained admitted and continued to receive care. Among 136 patients with IMID who tested negative for SARS-CoV-2, 29 (21.3% of negative cases) were admitted for continued suspicion of COVID-19 or reasons unrelated to COVID-19, and 2 (1.5% of negative cases) required a ventilator; any subsequent COVID-19 testing result was also negative. Twenty-five of these admitted patients were discharged, and 4 died of non–COVID-19–related reasons. Relevant additional information can be found in Supplemental Table IV. Relative to the general population, the IMID cohort did not have significantly greater odds of testing positive (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.69-1.2), hospital admission after testing positive (OR, 1.39; 95% CI, 0.91-2.16), need for invasive mechanical ventilation after testing positive (OR, 1.03; 95% CI, 0.47-2.19), or COVID-19–related mortality (OR, 1.47; 95% CI, 0.68-3.25) (Supplemental Table V). Although not corrected for additional variables, the following results from the 2-group comparison within the study cohort bear noting. The use of systemic corticosteroids compared to nonuse significantly increased the odds of admission within the cohort generally and among those who tested positive for COVID-19 (OR, 5.48; 95% CI, 1.28-26.1) (Table II). Receiving DMARD compared to non-DMARD therapy and multidrug therapy compared to monotherapy each led to increased odds of admission within the cohort generally, although this was not true when analysis was restricted to only those who tested positive for COVID-19 (Table II). Multidrug therapy compared to monotherapy also gave greater odds of a positive COVID-19 test result within the cohort (OR, 2.46; 95% CI, 1.20-5.06) (Supplemental Table II); no single medication among patients using multidrug therapy accounted for this result. Use of biologics compared to nonbiologic therapy was associated with lower odds of admission among patients with IMID generally as well as among those who tested positive (OR, 0.33; 95% CI, 0.14-0.82) (Supplemental Table II). No IMID type was associated with a particular outcome (Table II and Supplemental Table II). When logistic regression was performed within the cohort to correct for contributing variables, significant positive predictors of admission status included age older than 65 years, SARS-CoV-2 status, multidrug therapy, and presence of a pulmonary comorbidity, whereas biologic therapy proved to be a negative predictor of admission (OR, 0.26; 95% CI, 0.066-0.95) (Fig 2 , A). In turn, race was the only factor that proved able to predict COVID-19 status, with African American patients (OR, 2.8; 95% CI, 1.5-5.2) having greater odds of a positive test result (Supplemental Table VI, A). However, neither race nor any other factor besides age older than 65 years was a significant predictor of mortality (OR, 13; 95% CI, 2.3-122) for patients with IMID as a whole (Supplemental Table VI, B). When patients receiving monotherapy were compared to one another to remove the confounding effects of additional IS medications, patients treated with TNF-α inhibitor monotherapy had significantly lower odds of admission (OR, 0.16; 95% CI, 0.032-0.72) (Fig 2, B). There were no other significant effects on outcomes of interest due to IS medications after multivariate analysis.Fig 2 Multivariate analysis of factors associated with hospital admission among patients with IMID treated with IS medication tested for COVID-19 by (A) IS therapeutic class and (B) IS monotherapy. ∗Any patient taking a medication from a therapeutic class was included in the respective group, regardless of additional medications taken. Bold values indicate statistical significance. †P < .05. ‡Patients taking multiple biologics and/or DMARDs were included in the multidrug therapy group. DMARD, Disease-modifying antirheumatic drug; GI, gastrointestinal; IS, immunosuppressive; TNF, tumor necrosis factor. Discussion Our study provides strong empirical evidence that the current perception of predisposition to contracting COVID-19 and developing associated sequelae among those receiving IS therapies common to dermatology may be overestimated. Among patients with IMID treated with IS therapy, those tested for COVID-19 had no greater odds of a positive test result or developing severe disease relative to the general population tested at HFHS. Additionally, biologic therapies led to decreased odds of admission after multivariate correction, an effect likely driven by TNF-α inhibitor therapies, which significantly lowered the odds of admission after correction when used as a monotherapy. This finding mirrors the recent results found in convenience-based sampling from large databases of rheumatology patients.16 A similar significant decrease was not shown with IL-17 or IL-12/23 inhibitors on paired comparison, although too few of such patients were present in the data set to allow for meaningful multivariate analysis. It has previously been postulated that certain biologic therapies might assist in the control of COVID-19, preventing the development of severe disease by acting to mitigate the development of cytokine storm,17 , 18 and biologics including IL-17, IL-6, and TNF-α inhibitors are now currently under investigation for the treatment of COVID-19–related sequalae.14 In recently published cohorts of patients with IMID with COVID-19, those who were hospitalized as opposed to being treated on an outpatient basis tended to be older; had a greater number of comorbidities; and were more likely to use systemic corticosteroids, hydroxychloroquine, or methotrexate.16 , 19 In our study, corticosteroids and multidrug therapy appeared on paired analysis to increase the odds of hospitalization among patients with IMID who were infected, but only multidrug therapy proved predictive of disease course when controlling for other contributing variables. A possible explanation for this seeming discrepancy is our accounting for a greater variety of contributing comorbidities than either prior study, including several thought to affect the course of COVID-19, such as kidney impairment,20 , 21 chronic liver disease,22 , 23 history of malignancy,24 , 25 and pre-existing pulmonary compromise beyond chronic obstructive pulmonary disease. Each of these was present within our data set, and we have no reason to believe they would not be present among similar patient populations as well. Once these variables were accounted for, any negative contribution of individual classes of IS medications to the course of COVID-19 disappeared. Because significant comorbid conditions were grouped by organ system, we were unable to infer conclusions about any single comorbid disease. Although multidrug therapy did portend a higher risk of hospitalization as compared to monotherapies, this result could be due to either additive immunosuppression or a greater burden of disease and overall lower functional status among patients receiving such combination regimens. However, the result remains instructive for dermatologists, who may want to consider abridging therapeutic regimens to monotherapy whenever possible or advising patients whose care necessitates multidrug regimens about their higher risk for hospitalization. No other therapeutic or IMID condition showed an effect on outcomes from COVID-19 among those treated for IMIDs, including those with potentially more severe pre-existing pulmonary compromise, such as patients with connective tissue disease. This finding mirrors other recently published data16 and suggests that those being treated in dermatology clinics for IMID conditions should not be considered high-risk for COVID-19 based on that IMID condition alone. Several reports have suggested that IS therapy does not increase the prevalence of COVID-19 in patients with IMID.26 , 27 However, these studies had the potential to miss many COVID-19 cases, because they surveyed patients with IMID for any history of a diagnosis, regardless of testing, and were unable to account for asymptomatic carriers or sheltering among patients with IMID. By restricting our study only to patients suspected of having and tested for SARS-CoV-2, we excluded asymptomatic or sheltered individuals entirely and gained a cohort of patients with both positive and negative test results, from which we are able to conclude that no IS therapy increased the odds of testing positive after controlling for other contributing factors. Although this strategy creates a selection bias and cannot be used to infer the absolute incidence of COVID-19 among this population, it does allow for important comparisons between COVID-19–negative and –positive patients as opposed to only analyzing positive cases. Only race predicted COVID-19 status on multivariate analysis, with African American individuals at greater odds of testing positive (Supplemental Table VI, A). This association was likely in part due to the epidemiology of SARS-CoV-2 in Detroit, which is roughly 78% African American and has had the greatest density of COVID-19 cases in Michigan,28 although further expansion is beyond the scope of this article. Performing a single-center retrospective chart review limits the total number of patients in our study and the number of patients using any given therapeutic, which somewhat limits the generalizability to community-based settings, yet also removes confounding variables such as the differences between hospital systems and environmental exposures that could affect disease course and outcome in larger databases involving multiple hospitals. The fact that HFHS is located in a SARS-CoV-2 hotspot allowed us to collect a substantial cohort of patients nonetheless and perform analysis from which to inform clinical care. Based on the available data from our study and others, there appears to be no need to discontinue use of particular IS medications in an attempt to reduce risk of COVID-19 and related illness, although consideration should be given to reducing multidrug regimens to monotherapy wherever possible. Furthermore, TNF-α inhibitors may reduce the risk of more severe disease among patients with IMID requiring IS therapy. Funding sources: None. Conflicts of interest: None disclosed. IRB approval status: Reviewed and approved by Henry Ford Health System IRB (no. 13768). Reprints not available from the authors. ==== Refs References 1 American Academy of Dermatology Guidance on the use of biologic agents during COVID-19 outbreak Available at: https://assets.ctfassets.net/1ny4yoiyrqia/PicgNuD0IpYd9MSOwab47/023ce3cf6eb82cb304b4ad4a8ef50d56/Biologics_and_COVID-19.pdf 2 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 5 2020 1217 1218 32199889 3 Kirby T. Rheumatologists rapidly adjust patient care during COVID-19 pandemic Lancet Rheumatol 2 5 2020 e258 32518921 4 Kumar D. Manuel O. Natori Y. COVID-19: a global transplant perspective on successfully navigating a pandemic Am J Transplant 20 2020 1773 1779 32202064 5 American Society of Transplantation American Society of Transplantation statement on COVID-19 Available at: https://imana.org/COVID-19/ast-statement/ 6 American College of Rheumatology COVID-19 clinical guidance for adult patients with rheumatic diseases Available at: https://www.rheumatology.org/Portals/0/Files/ACR-COVID-19-Clinical-Guidance-Summary-Patients-with-Rheumatic-Diseases.pdf 7 D'Antiga L. Coronaviruses and immunosuppressed patients. The facts during the third epidemic Liver Transpl 26 2020 832 834 32196933 8 Guan W.-j. Liang W.-h. Zhao Y. Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis Eur Respir J 55 4 2020 2000547 32217650 9 Brownstone N.D. Thibodeaux Q.G. Reddy V.D. Novel coronavirus disease (COVID-19) and biologic therapy in psoriasis: infection risk and patient counseling in uncertain times Dermatol Ther (Heidelb) 10 2020 1 11 31701473 10 Price K.N. Frew J.W. Hsiao J.L. Shi V.Y. COVID-19 and immunomodulator/immunosuppressant use in dermatology J Am Acad Dermatol 82 5 2020 e173 e175 32224277 11 Bashyam A.M. Feldman S.R. Should patients stop their biologic treatment during the COVID-19 pandemic? J Dermatolog Treat 31 2020 317 318 32191143 12 Dai M.-Y. Liu D. Liu M. Patients with cancer appear more vulnerable to SARS-CoV-2: a multi-center study during the COVID-19 outbreak Cancer Discov 10 2020 783 791 32345594 13 Hussell T. Pennycook A. Openshaw P.J. Inhibition of tumor necrosis factor reduces the severity of virus-specific lung immunopathology Eur J Immunol 31 9 2001 2566 2573 11536154 14 Lythgoe M.P. Middleton P. Ongoing clinical trials for the management of the COVID-19 pandemic Trends Pharmacol Sci 41 2020 363 382 32291112 15 Schett G. Sticherling M. Neurath M.F. COVID-19: risk for cytokine targeting in chronic inflammatory diseases? Nat Rev Immunol 20 2020 271 272 32296135 16 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 17 Feldmann M. Maini R.N. Woody J.N. Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed Lancet 395 10234 2020 1407 1409 32278362 18 Pacha O. Sallman M.A. Evans S.E. COVID-19: a case for inhibiting IL-17? Nat Rev Immunol 20 2020 345 346 32358580 19 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 20 Henry B.M. Lippi G. Chronic kidney disease is associated with severe coronavirus disease 2019 (COVID-19) infection Int Urol Nephrol 52 2020 1193 1194 32222883 21 Cheng Y. Luo R. Wang K. Kidney disease is associated with in-hospital death of patients with COVID-19 Kidney Int 97 5 2020 829 838 32247631 22 Wang T. Du Z. Zhu F. Comorbidities and multi-organ injuries in the treatment of COVID-19 Lancet 395 10228 2020 e52 32171074 23 Albillos A. Lario M. Álvarez-Mon M. Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance J Hepatol 61 6 2014 1385 1396 25135860 24 Liang W. Guan W. Chen R. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China Lancet Oncol 21 3 2020 335 337 32066541 25 Alipour S. COVID-19 and cancer patients: delving into burning questions Arch Breast Cancer 7 1 2020 1 3 26 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 biological treatment and renal transplanted recipients in maintenance immunosuppressive treatment J Am Acad Dermatol 83 2020 285 287 32330632 27 Monti S. Balduzzi S. Delvino P. Bellis E. Quadrelli V.S. Montecucco C. Clinical course of COVID-19 in a series of patients with chronic arthritis treated with immunosuppressive targeted therapies Ann Rheum Dis 79 5 2020 667 668 32241793 28 Michigan Department of Health and Human Services Coronavirus: Michigan data. Available at: https://www.michigan.gov/coronavirus/0,9753,7-406-98163_98173---,00.html
PMC007xxxxxx/PMC7387278.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)32303-3 10.1016/j.jaad.2020.07.101 JAAD Online Reply to research letter Rivera-Oyola Ryan MS ∗ Koschitzky Merav BA Lebwohl Mark MD Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mt Sinai Hospital, New York, New York ∗ Correspondence to: Ryan David Rivera-Oyola, MS, The Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, 5 E 98th St, 5th Floor, New York 10029 29 7 2020 12 2020 29 7 2020 83 6 e443e443 © 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 light of the current coronavirus disease 2019 (COVID-19) pandemic, scientists have debated the safety of immunosuppressive biologic therapies. We read with interest the letter by Wan et al,1 “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.” We agree that caution should be used when exposing patients to systemic biologic agents in the setting of not only COVID-19 but also any acute or chronic infection, as Kaushik and Lebwohl2 have previously emphasized. In the authors' analysis, ixekizumab treatment groups did not report a significantly increased rate of respiratory tract infections (RTIs). Despite an elevated rate of RTIs in the brodalumab and secukinumab treatment groups, the study included oropharyngitis, oropharyngeal pain, and pharyngolaryngeal pain in their definition of RTI. Interleukin 17 is known to be associated with monilial infections3; therefore, thrush and esophagitis could potentially explain these increased rates and should have been excluded from the analysis. Furthermore, the rate of infection was higher in the placebo group in some studies. For example, the AMAGINE-2 (P3 Study Brodalumab in Treatment of Moderate to Severe Plaque Psoriasis) trial reported an increased rate of upper RTI and rhinitis of 7.44% and 0.65% in placebo groups vs 5.39% and 0.33% in treatment groups, respectively. Similarly, the AMAGINE-3 (Efficacy and Safety of Brodalumab Compared With Placebo and Ustekinumab in Moderate to Severe Plaque Psoriasis Subjects) trial reported increased rates of nasopharyngitis and influenza of 5.11% and 1.92% in the placebo groups vs 4.97% and 1.28% in the brodalumab treatment groups, respectively. Placebo groups also experienced increased rates of nasopharyngitis (8.47% vs 5.08%), upper RTIs (1.69% vs 0%), and nasal congestion (1.69% vs 0%) compared with treatment groups during the FEATURE (First study of sEcukinumAb in prefilled syringes in subjecTs with chronic plaqUe-type psoriasis Response) trial. We realize that data can be included or excluded to display a certain desired outcome and hope such findings do not discourage clinicians from treating patients with the most efficacious biologic therapies available. Funding sources: None. Conflicts of interest: Dr Lebwohl is an employee of Mount Sinai and receives research funds from 10.13039/100006483 AbbVie , 10.13039/100002429 Amgen , 10.13039/100004312 Eli Lilly and Company , 10.13039/100005205 Janssen Research & Development , LLC, Novartis, Ortho Dermatologics, and UCB, Inc, and has been the principal investigator for numerous clinical trials but has no personal financial gain. Authors Rivera-Oyola and Koschitzky have no conflicts of interest to declare. IRB approval status: Not applicable. Reprints not available from the authors. ==== Refs References 1 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 2 2020 677 679 32416207 2 Kaushik S.B. Lebwohl M.G. Psoriasis: which therapy for which patient: focus on special populations and chronic infections J Am Acad Dermatol 80 1 2019 43 53 30017706 3 Yiu Z.Z. Griffiths C.E. Interleukin 17-A inhibition in the treatment of psoriasis Expert Rev Clin Immunol 12 1 2016 1 4 26561053

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