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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypertension'. | A virtual-hybrid approach to launching a cardio-oncology clinic during a pandemic.
BACKGROUND
As cardiovascular disease is a leading cause of death in cancer survivors, the new subspecialty of Cardio-Oncology has emerged to address prevention, monitoring, and management of cardiovascular toxicities to cancer therapies. During the coronavirus disease of 2019 (COVID-19) pandemic, we developed a Virtual-Hybrid Approach to build a de novo Cardio-Oncology Clinic.
METHODS
We conceptualized a Virtual-Hybrid Approach including three arms: information seeking in locations with existing Cardio-Oncology clinics, information gathering at the location for a new clinic, and information sharing to report clinic-building outcomes. A retrospective review of outcomes included collection and synthesis of data from our first 3 months (at pandemic peak) on types of appointments, cancers, drugs, and cardiotoxicities. Data were presented using descriptive statistics.
RESULTS
A de-novo Cardio-Oncology clinic was developed structured from the ground up to integrate virtual and in-person care in a hybrid and innovative model, using the three arms of the Virtual-Hybrid Approach. First, we garnered in-person and virtual preparation through hands-on experiences, training, and discussions in existing Cardio-Oncology Clinics and conferences. Next, we gleaned information through virtual inquiry and niche-building. With partners throughout the institution, a virtual referral process was established for outpatient referrals and inpatient e-consult referrals to actualize a hybrid care spectrum for our patients administered by a multidisciplinary hybrid care team of clinicians, ancillary support staff, and clinical pharmacists. Among the multi-subspecialty clinic sessions, approximately 50% were in Cardio-Oncology, 20% in Preventive Cardiology, and 30% in General Cardiology. In the hybrid model, the Heart & Vascular Center had started to re-open, allowing for 65% of our visits to be in person. In additional analyses, the most frequent cardiovascular diagnosis was cardiomyopathy (34%), the most common cancer drug leading to referral was trastuzumab (29%), and the most prevalent cancer type was breast cancer (42%).
CONCLUSIONS
This Virtual-Hybrid Approach and retrospective review provides guidance and information regarding initiating a brand-new Cardio-Oncology Clinic during the pandemic for cancer patients/survivors. This report also furnishes virtual resources for patients, virtual tools for oncologists, cardiologists, and administrators tasked with starting new clinics during the pandemic, and innovative future directions for this digital pandemic to post-pandemic era.
Introduction
Cardio-Oncology care has been adjusted in the COVID-19 pandemic with limited in-person clinic or hospital visits, increased use of teleconsultation, less frequent imaging, increased reliance on biomarkers, and considerations of differential diagnoses involving COVID-19 when evaluating cancer patients or survivors for possible cardiovascular toxicity [1]. Monitoring and management algorithms have been developed to help guide virtual care [2–4]. In the pandemic, we have changed the way in which we provide healthcare services at our clinics and institutions. This has challenged us to restructure current systems for the safety of our patients.
Various forms of innovation have come to bear in the pandemic, including telemedicine, digital health, artificial intelligence, social media, informatics, big data, and precision medicine [5, 6]. Telemedicine is the primary form of innovation that has been most developed in the pandemic [2, 5, 7]. Social media has been very helpful for dissemination of information, as well as education, and has been integral for creating online groups for support and determining the best ways for proceeding in the pandemic and advocating for our patients and colleagues in this period [5, 6]. In addition, the Doximity social media application has been valuable to practices across the nation, due to its telehealth platform (Doximity Video and Phone; https://www.doximity.com/dialer-video).
Despite the growing need, and allowances made during the pandemic, many centers do not have formal Cardio-Oncology clinics. Starting a new clinic can be challenging. The COVID-19 pandemic has made the process significantly more difficult, with the need to minimize exposure and maximize patient safety.
Currently, limited information is available on how to start a Cardio-Oncology Clinic during a pandemic, albeit given the high risk of morbidity or mortality in COVID-19-positive patients who also have cancer or CVD [8–13]. Several institutions have published on their experiences with starting in-person Cardio-Oncology clinics prior to the pandemic [8, 14–17]. One group has reported on their conversion from existing in-person Cardio-Oncology visits to telemedicine consultations, seeing 11 patients virtually within a few weeks [7]. Many have considered implications of the pandemic on the practice and study of cardio-oncology [2, 4, 5, 18–20], and two groups have suggested models for clinics converting from existing in-person care to televisits [4, 5]. Yet, no groups have directly addressed steps for de novo virtual-hybrid clinic formation within the limitations of the pandemic and without conversion of a pre-existing Cardio-Oncology clinic.
Our report offers a template for other centers to develop their own new Cardio-Oncology clinics during the pandemic. We determined a Virtual-Hybrid Approach to clinic launch, with both virtual and in-person elements of three key arms: information seeking where there are existing Cardio-Oncology Clinics in place, information gathering where the clinic will be built, and information sharing to report on initial patient data demonstrating the success of the launch (Fig. 1). We then performed retrospective chart review to collect and synthesize data on the types of appointments (new versus established, virtual versus in-person), cancers (e.g., breast, prostate, leukemia, lung), cancer drugs, and cardiovascular toxicities (e.g., cardiomyopathy, hypertension) for patients seen virtually or in person in our new Cardio-Oncology clinic at Froedtert Hospital and Medical College of Wisconsin (F&MCW). Here, we will discuss our findings in the context of previous publications on launching Cardio-Oncology Clinics prior to the pandemic. Our results will present distributions of cancer drugs and types, and cardiovascular diagnoses, similar to previous publications on Cardio-Oncology clinic-building. However, we will differentiate and illuminate the techniques that leverage the virtual underpinnings of pandemic clinic-building. We submit that it is feasible to establish a new Cardio-Oncology Clinic for cancer patients or survivors with or at risk for cardiovascular toxicity from cancer therapy during a pandemic, providing optimal care for new patients in the midst of the need for safety and minimizing exposure. We also propose virtual resources for patients and clinicians and describe innovative future directions in the pandemic and post-pandemic period.
Fig. 1 The Virtual-Hybrid Approach to Cardio-Oncology Clinic-building in the pandemic
Methods
Virtual-hybrid approach
We pursued a Virtual-Hybrid Approach of information seeking, information gathering, and information sharing (Fig. 1). For information seeking, we focused on institutions that already had a Cardio-Oncology clinic in place. Prior to the COVID-19 pandemic, substantial experience was gained at an established in-person Cardio-Oncology clinic at a world-renowned leading hospital. Published manuscripts on pre-pandemic building and operations of Cardio-Oncology clinics at other institutions were reviewed. Extensive networking with leaders of Cardio-Oncology clinics around the United States and in the United Kingdom was accomplished at regional, national, and international meetings in person and on social media in a hybrid approach. These meetings were attended in person pre-COVID-19 and virtually during the pandemic. For information gathering, we addressed the location in which the new Cardio-Oncology clinic would be built. We learned about existing resources in the destination Heart & Vascular Center and existing needs and patients in the destination partner cancer center. We networked with physicians, advanced practice providers (APPs), nurses, service line leaders, and administrators in the Heart & Vascular Center and the cancer center, as well as in primary care and other supporting specialties. The subsequent Cardio-Oncology clinic sessions were intermingled with other subspecialty areas, to optimize availability for patient visits while filling clinic slots and tailoring spectrum of care to emerging patient needs. Cardio-Oncology patient visits were included in multi-subspecialty clinics.
Retrospective study design
For quantitative data, we pursued a retrospective observational study to determine the distribution of outpatient visits in the first 3 months of our virtual-hybrid Cardio-Oncology Clinic. We reviewed data from charts of patients (all were 18 years of age or older) who received outpatient care from the new Director of Cardio-Oncology at F&MCW between April 15, 2020 and July 17, 2020 to determine which of these patients were considered to be in Cardio-Oncology, Preventive Cardiology, or General Cardiology. We collated all three to determine the percentage of patients seen in Cardio-Oncology, compared to the other two specialties. Preventive Cardiology was collated as a partner clinic to help build the Preventive Cardio-Oncology component of the Cardio-Oncology Clinic, to help apply established principles for prevention. From among the multi-subspecialty clinic sessions, we determined the proportion of patients who were specifically cancer patients or survivors with or at risk for cardiovascular toxicity from cancer therapy and thereby seen in the Cardio-Oncology Clinic. Next, we identified the distribution of cardiovascular toxicities in cancer patients or survivors seen in the Cardio-Oncology Clinic. We also evaluated the spectrum of cancer drugs received by cancer patients or survivors seen in the Cardio-Oncology Clinic. In addition, we summarized the types of cancers in patients seen in the Cardio-Oncology Clinic. Finally, we assessed the frequency of virtual visits during the course of the pandemic over our first 3 months for patients seen in the Cardio-Oncology Clinic. This retrospective review was approved by the F&MCW IRB; HIPAA informed consent was waived for this minimal risk study, which did not involve any form of intervention and was conducted in compliance with good clinical and research practice. The team designed and carried out the study with reliance on virtual communication tools.
Data collection and analysis
Data gathering, management, and analysis were conducted at F&MCW. We collected patient-related, disease-related, treatment-related, and outcome-related data, particularly patient sex, type of appointment (new versus established, virtual versus in-person), type of cancer (e.g., breast, prostate, leukemia, lung), type of cancer drug, and type of cardiovascular toxicity (e.g., cardiomyopathy, hypertension). In order to minimize any risk of breaching patient confidentiality, all data collection occurred on institutional-based computing environments with de-identified data used for analyses. There were no alternative procedures for the subjects as this is a retrospective review of data that are not amenable to prospective collection and review. Descriptive graphs or tables of patient-, disease-, treatment-, and outcome-related variables distributions were prepared, with no comparisons made needing statistical tests.
Results
Virtual preparation
Preparation for starting the Cardio-Oncology clinic followed a Virtual-Hybrid Approach (Fig. 1, left). Five overarching factors employing virtual communication methods emerged to ensure the successful launching of the clinic. Team and individual experience and exposure to various areas of interest in Cardio-Oncology were achieved and assessed before and during the pandemic. Far-reaching connections to experts and potential collaborators in the field were developed and exercised. Close contact with the institution launching this clinic was important to determine the resources available; these resources dictated the strategy and potential outcomes of the clinic. Importantly, the expectations of others for the Cardio-Oncology clinic were determined and incorporated. Finally, recognition of the limitations that exist at the destination institution guided care and goal setting.
Virtual inquiry
Before initiating the Cardio-Oncology clinic in the destination institution, existing structures, patient base, and needs in the Heart & Vascular Center as well as the Cancer Center were evaluated, adhering to pandemic protocols (Fig. 1, middle). Pre-existing building blocks for the planned Cardio-Oncology clinic were assessed, and the partner Preventive Cardiology clinic was investigated. We also evaluated characteristics of the cancer center patient population to best position the clinic for success.
Virtual niche-building
Five main aspects of niche-building were pursued. Partnerships with Vascular and Cancer Center physicians, advanced practice providers, and service line leaders were developed to initiate and grow the clinic (Fig. 1, middle). The Cardio-Oncology team and clinic flexibility were demonstrated through openness to taking quicksteps. Presentations were made at Grand Rounds and rounds across the institution in Cardiology, Hematology/Oncology, Radiation Oncology, Surgical Oncology, Internal Medicine, and Family Medicine to promote the clinic capabilities. Collaborative solutions for problems facing fields complementing Cardio-Oncology developed trust and collaboration. Teamwork was developed by leveraging diversity of perspectives and virtual communication technologies, to establish effective patient care despite COVID-19 limitations.
Hybrid care Spectrum
The hybrid F&MCW Cardio-Oncology Clinic was initiated and established in the outpatient setting, in close partnership with the Preventive Cardiology Clinic, Cancer Center, and inpatient Cardiology Consult and Hematology/Oncology teams (Fig. 1, right).
Initial and subsequent visits have been completed in person or by video, with phone visits also available for virtual return visits if patients without adept and available smartphone use have limited ability to appear in person. Virtual patient visits over our first 3 months occurred with the use of telemedicine platforms integrated with Epic (via MyChart for patients and Haiku/Canto for clinicians), or using the Doximity video call function. Patients with in-person appointments are screened appropriately on arrival for signs or symptoms of COVID-19 or exposure, following institutional protocols. Wearing masks is required of all patients, and each patient can be accompanied by a family member; some choose to also wear gloves or face shields. There is sufficient room for maintaining social distancing in the clinic waiting room and hallways.
Innovation
Current innovation in the clinic also includes Virtual Clinician Tools and Virtual Patient Resources (Fig. 2). For clinicians, the links for an AHA CME course on Novel Concepts, Current Debates and Treatment Considerations in Cardio-Oncology, an online Cardio-Oncology Compendium hosting risk assessment clinical decision aids, Cardio-Oncology Drug Regimen and Acronym Databases, and UPTODATE access for reviewing Cardio-Oncology drug information are supplied. For patients, the video from the International Cardio-Oncology Society explaining the Cardio-Oncology subspecialty, American College of Cardiology (ACC) mobile health (mHealth) CardioSmart education app and website, Cancer Heart Talk mini-podcast series accessed via SoundCloud app and website, Cardio-Oncology Frequently Asked Questions, and ChemoCare website are provided for patient-facing Cardio-Oncology and heart anatomy and physiology education, engagement, and awareness. Virtual Resources for Preventive Cardio-Oncology are also made available to our patients. These include the American Heart Association (AHA) Physical Activity Recommendations, AHA Life’s Simple 7 Webpages, American Society For Preventive Cardiology Online Coaching Webpages in partnership with Intervent, and the Become An Ex Smoking Cessation Support Webpages in partnership with Mayo Clinic. The resources are provided in the Epic patient portal MyChart, and more ways to make the resources accessible to a broad and diverse patient population are in development. Future innovation in the clinic will explore contemporary initiatives connecting patients and their safely guarded data with their permission with wearable devices, health information technology, informatics, artificial intelligence, personalized medicine, and additional mobile health (mHealth) applications.
Fig. 2 Virtual patient and clinician education and resources. Available online as PDF with hot links in the CardioOnc Compendium (https://tinyurl.com/CardioOncCompendium)
Virtual visit infrastructure and timeline
There was no pre-existing Cardio-Oncology program at the time of launching our de novo Virtual/Hybrid Cardio-Oncology Clinic. The newly recruited Director of Cardio-Oncology was tasked with the responsibility of launching the new clinic, with support from the Heart & Vascular Center clinic administrators, medical director, and Cardiology Division and Department of Medicine leadership. Prior to opening the Cardio-Oncology Clinic, the Heart & Vascular Center initiated virtual conversion then additionally collaborated with Inception Health (MCW’s innovation lab company) over the course of 4 weeks to iteratively develop the clinical informatics infrastructure for virtual visits. The video visits were designed to function using clinician’s personal smartphones, iPads, and tablets, with direct web browser video links from the electronic health record mobile application. Direct video calls through the Doximity mobile application were also approved. Existing Inception Health personnel re-allocated their time in order to adopt and maintain responsibility for the virtual component of all ambulatory clinics across the health system, in partnership with medical and administrative directors of each clinic area, such as the Heart & Vascular Center. No additional costs or hires were pursued to facilitate the development of the virtual visit infrastructure and timeline. Existing resources and personnel were re-allocated to virtual visit design to enable building the virtual clinics in the Heart & Vascular Center. To assist clinicians and billing compliance colleagues, note templates were created for video and phone visits to indicate patient informed consent for virtual visits due to the pandemic, as well as to capture limited appropriate physical examinations, in addition to the amount of time spent on records review and real-time medical counseling.
Initial consults were electronically triaged by either a cardiologist or a cardiology fellow supervised by a cardiologist. Each triage team determined which consults would be appropriate as virtual video visits, versus in-person to occur once the Heart and Vascular Center started re-opening routine physical visits, or whether patients needed to be evaluated urgently in person. During the first week of operation, the brand-new Cardio-Oncology Clinic started entirely virtually with only video and phone visits. As the Heart and Vascular Center re-opened for physical patient visits the following week, from week 2 through the remainder of the first 3 months the Cardio-Oncology Clinic had both virtual and in-person visits integrated throughout each clinic session weekly, based on whether patients were new and whether they had smart device or computer functionality available.
Virtual referral network and process
Cardio-Oncology patient assessment begins within a referral network before the patient arrives at a Cardio-Oncology clinic. Consequently, forming a virtual referral network and enacting a user-friendly virtual referral process was a key component of building the Cardio-Oncology clinic during the pandemic. All referral patterns and networks for our de novo Cardio-Oncology Clinic were built from the ground up. Initial referrals were from within our health system; this quickly expanded to consults from outside of our health system encompassing the entire state. Patients were referred to our Clinic by clinicians or by self-referrals. Some of our local patients connected to us after being introduced to us by their clinicians in other states or through family members in other states who learned about us from their own clinicians or community-based Cardiology society outreach events.
Referrals across the institution and outside of our health system have come to us from the Divisions of Hematology and Oncology, Internal Medicine, Family Medicine, Surgical Oncology/Breast Clinic, and Survivorship Clinics. From the cancer center’s perspective, there may be many “triggers” that would warrant a Cardio-Oncology referral. For example, an abnormal ECG, an abnormal echocardiogram, cardiovascular symptoms, previous cardiovascular history (e.g., coronary artery disease, hypertension, cardiomyopathy) particularly in a patient who previously underwent treatment or is beginning new treatment with cardiotoxic neoplastic medications or radiation therapy and is at high risk of cardiovascular toxicity, or those in preparation for stem cell transplant, or oncologic surgery. Referral protocols were determined based on standard practice, discussions with colleagues in Medical and Radiation Oncology, Hematology, Bone Marrow Transplant, Surgical Oncology/Breast Clinic, Children’s Hospital, Radiation Oncology, Primary Care, and updated literature reviews.
Cancer survivors are at a higher risk than the general population for cardiovascular morbidity and mortality. If a cancer survivor needing to be evaluated is already under the care of a cardiologist, the referring provider can reach out to their cardiologist for guidance on the appropriate CV surveillance. If they do not already have a cardiologist, a Cardio-Oncology consult should be requested. The Cardio-Oncology consult can be placed using a direct Cardio-Oncology button within the universally available Cardiovascular Consult order panel. Referrers can also place a General Cardiology consult and mention the Cardio-Oncology physician by name as requested by the clinician or patient. An E-Consult functionality is also being implemented for those patients who need to be assessed sooner than the next available appointment, or for those patients who may not need a full Cardio-Oncology evaluation, or if referring providers are uncertain. The e-consult can also be placed as a second opinion requested by the inpatient Cardiology Consult team.
The inpatient Cardiology Consult service will continue to directly address inpatient consults from the inpatient hematology/oncology services. The inpatient Cardiology Consult service can collaborate with the Cardio-Oncology Clinic via formal Cardio-Oncology E-consults in the electronic health record Epic if a specific focused question arises regarding Cardio-Oncology relevant to the care of individual currently hospitalized patients that have already been formally evaluated by the inpatient Cardiology Consult service. After a patient has been formally evaluated by the inpatient Cardiology Consult service, if the patient is appropriate for outpatient follow up in the Cardiology clinic with Cardio-Oncology, this should be communicated to the primary Hematology/Oncology service. If appropriate at the time of consultation, the inpatient cardiology consult service can make the follow-up appointment. Oftentimes, this patient population remains in the inpatient setting for several weeks. If this is the case, the Cardiology clinic phone number and clinician information should be provided to the primary service to do so prior to the patient being discharged from the hospital.
Virtual-hybrid multidisciplinary team
It is important to develop a multidisciplinary team and initially focus on allocation of pre-existing resources. Accordingly, some roles among our Cardio-Oncology clinic personnel are shared with other subspecialties. Our virtual-hybrid multidisciplinary Cardio-Oncology Clinic personnel include physicians, a nurse practitioner (NP), a nurse, a research support specialist, medical assistants, pharmacists, administrative assistants, and administrators. All personnel with pre-existing in-person roles and practices re-allocated a portion of their time to the development and practice of virtual visits.
Our clinic and partners consist of board-certified Cardiologists with special training in various cardiac subspecialties (e.g., cardio-oncology, preventive cardiology, heart failure and transplant, electrophysiology, interventional cardiology), who collaborate closely with our cancer experts. Our physicians together specialize in the prevention, diagnosis, and treatment of heart and vascular disorders resulting from side effects of cancer therapy. Our comprehensive team of advanced practice providers, nurses, and pharmacists work alongside our physicians to care for patients from the moment of cancer diagnosis through life’s survivorship journey. The NP typically sees established patients when needed to follow up on imaging, intervention, or diagnostic and management plans, and may also see select new patients. In complex cases, the NP discusses the care of established patients with both the cardio-oncologist and the referring clinician. The nurse assists with patient triage and communications (including addressing patient requests and queries), liaises closely with the nurse practitioner and pharmacists, and educates patients on Cardio-Oncology using virtual materials. Our clinical pharmacists function at the highest level of their advanced training, similar to all clinic personnel, and assist with medication education, review, titration, discussion, and prescription, particularly for heart failure, hypertension, hyperlipidemia, and smoking cessation, as well as commenting on potential drug interactions.
For Preventive Cardio-Oncology, we additionally partner with our dietitians and exercise physiologists to help advise our patients on nutrition and exercise plans, as well as our colleagues in cardiopulmonary stress testing where applicable. Further, in the pandemic, we provide patients with free online coaching options for lifestyle modification (Fig. 2). We also direct patients to AHA webpages with guidance on pursuing ideal cardiovascular health.
Virtual-hybrid patient flow
Once a referral is placed by the designated order buttons in the electronic health record, central schedulers or the Cardio-Oncology Clinic administrative assistant schedule the new patient for a video or in-person visit (Fig. 3). The clinic administrative assistant works closely with our health professionals in our interdisciplinary advanced subspecialty clinic to gather relevant clinical reports and history pertinent to patient appointments. Virtual medical assistants contact patients a few days before their appointments to confirm and troubleshoot virtual connectivity. On the appointment day, medical assistants then ‘room’ patients for virtual or in-person visits by preparing patients for their medical visits (including reviewing medications and in-person or at-home virtual vital signs), and also rechecking virtual connectivity for video visits. The clinician then completes the visit virtually or in-person and introduces the patient to the range of electronic resources available. Following the visit, the clinical administrative assistant arranges follow-up testing and appointments.
Fig. 3 Virtual-Hybrid Patient Flow Chart. Admin = Administrative; MA = Medical Assistant; MD = Medical Doctor; NP = Nurse Practitioner
Virtual risk assessment
Baseline risk assessment and follow-up start with oncology and primary care [21]. Asymptomatic low risk patients with low-risk treatment plans can have continued assessment and follow-up by oncology and primary care in partnership. Patients who have symptoms, are at high risk based on their history, or are planned for high-risk treatment plans should be referred to Cardio-Oncology for prevention, monitoring, and management recommendations. Recommendations should adhere to society expert consensus, scientific statements, and guidelines for prevention, surveillance, and survivorship, and optimize CVD risk and medications [21]. A putative risk score based on medication-related and patient-related risk factors can be used to guide monitoring and management recommendations for most Cardio-Oncology patients [22], and can be used in a virtual clinical decision aid (https://tinyurl.com/CardioOncCDA) (Fig. 4). Specific risk scores are also available for adults treated with anthracyclines, trastuzumab, or other drugs, or for adult survivors of childhood cancers [9–13].
Fig. 4 Virtual Cardio-Oncology clinical decision aid (CDA). Risk assessment (https://tinyurl.com/CardioOncCDA) to guide monitoring and management recommendations regarding development of cardiomyopathy for most Cardio-Oncology patients; a CDA specifically for women with early breast cancer is also available in the CardioOnc Compendium (https://tinyurl.com/CardioOncCompendium)
Virtual management algorithms
Evidence-based management algorithms have been selected or developed as adjunctive resources for inpatient teams. They are available online in a virtual collection for use in the inpatient setting by the inpatient Cardiology Consult service or hematology/oncology teams to assist with diagnosis and treatment of cardiovascular toxicities from cancer therapies or cancer itself. The algorithms cover cardiomyopathy from anthracyclines or trastuzumab, planned chemotherapy with pre-existing cardiomyopathy, neurohormonal therapy or dexrazoxane for cardioprotection, myocarditis, persistent malignant pericardial effusion, hypertension, surveillance after radiation therapy or drugs that cause ischemia, malignant pericardial effusion, and other salient topics frequently encountered.
Virtual community engagement
The local, regional, national, and international community was virtually engaged via social media posts on Twitter (using #MCWCardioOnc on @DrBrownCares or @PrevCardioOnc), podcasts hosted by the MCW CTSI (available on iTunes, Google, and Apple podcast platforms), Heart Success podcast series, and Cancer Heart Talk brief 15-min mini-podcast series (available on SoundCloud). Perspectives were also published for international community engagement in the Women Heart Alliance newsletter, as well as on the AHA Early Career Blog, ACC Women in Cardiology Blog, CardioOncTrain.Com Blog, and PrevCardioOnc.Com Blog. Virtual continuing medical education (CME) presentations were also given at the Wisconsin state ACC annual conference meeting, Midwest ACC annual conference meeting, Southeast ACC annual conference meeting, Brazilian Cardio-Oncology Symposium, and the Ohio State Cardio-Oncology CME conference, then subsequently at the AHA and ACC annual national scientific sessions.
Distribution of patient data
In our multi-subspecialty clinic visits (virtual and in-person integrated and combined; n = 182; 136 new and 47 returns), approximately 50% of patient visits were in Cardio-Oncology, 20% were in Preventive Cardio-Oncology, and 30% were in General Cardiology (Fig. 5a). Overall among Cardio-Oncology visits, 65% were in person, consistent with early and safe clinic re-opening in a hybrid model, with 19% by video and 16% by phone, with the fraction by phone decreasing over time as patients and clinic personnel became more adept with troubleshooting video. Of new patients, 77% were in person, and the remainder by video. No Cardio-Oncology patients presenting in person developed any signs or symptoms concerning for COVID-19.
Fig. 5 Initial Clinic-Building Outcomes Using the Virtual-Hybrid Approach. a Distribution of Cardio-Oncology, Preventive Cardio-Oncology, and General Cardiology patients seen in our multi-subspecialty clinic visits. b Distribution of cardiovascular diagnosis or indication for referral. c Distribution of cancer drugs. d Distribution of cancer types
The most frequent cardiovascular diagnosis or indication for referral was cardiomyopathy (34%) (Fig. 5b). Other diagnoses included decrease in global longitudinal strain, diastolic congestive heart failure, hypertension, myocarditis, dyspnea, chest pain, palpitations, survivorship, risk assessment, and pre-bone marrow transplant, among other cardiovascular diagnoses or visit indications. The most frequent cancer drug was trastuzumab (29%) (Fig. 5c), managed according to a novel algorithm developed in our de novo Virtual-Hybrid Cardio-Oncology Clinic based on the recent publication indicating the safety of continuation of trastuzumab for left ventricular ejection fraction of 40% or greater [23] (Fig. 6). The second most frequent cancer drug was anthracycline (24%). Other drugs included, tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), endocrine therapies, and investigational therapeutics, among others. The most frequent cancer type in our clinic was breast cancer (42%) (Fig. 5d). These trends in cardiovascular diagnosis or indication and cancer drugs or types were similar in assessments of virtual visits alone, with the most frequent being cardiomyopathy (43%), trastuzumab (41%), and breast cancer (44%), respectively. The findings of similar cardiovascular and cancer distributions in virtual versus in-person visits indicated an optimal qualitative return on resource and personnel investment.
Fig. 6 Algorithm for Continuation of Trastuzumab Therapy with Mild LV Dysfunction
Imaging and medication titration
In our clinic, a distribution of cardiovascular diagnoses determines the imaging needed for each patient (Fig. 5b). Therefore, a number of imaging modalities are useful to our patients (e.g., echocardiography, computed tomography with or without angiography, magnetic resonance imaging, coronary angiography, myocardial perfusion imaging). Our most frequently used imaging modality is echocardiography. The frequency of obtaining echocardiograms has depended on each patient’s condition and cancer treatment. A substantial portion of patients coming to us on trastuzumab have needed an echocardiogram every 1–3 months, depending on the extent of adverse effects on left ventricular ejection fraction (LVEF) or strain In these patients, medication titration has occurred approximately every 2 weeks, and for very symptomatic patients with volume overload, they have often been seen weekly..
In our management algorithms, early referral prior to the onset of symptoms has been emphasized, especially in cancer patients or survivors with a history of cardiovascular disease, cardiotoxic neoplastic agents, or a high risk of cardiovascular toxicity. This has provided an opportunity for us to assess and discuss ways to optimize the benefit to risk ratio of continuing with the current cancer treatment plan, and more importantly how and when to put cardioprotective measures in place to facilitate safe cancer therapy. Such discussions have also resulted in closer monitoring. Some conditions have warranted proceeding to other modalities of non-invasive imaging, such as cardiac MRI if myocarditis is suspected. For cases in which coronary artery disease is suspected, our patients undergo functional assessment of their coronaries with a stress test or anatomical assessment with a coronary CT scan or invasive coronary angiography. In our practice, only exercise stress tests were halted due to the pandemic. Every other form of imaging including rest and stress echo, as well as MRI and nuclear medicine have remained readily available for those with cardiovascular toxicities or individuals considered to be at moderate or high risk. This allowed us to adhere to pre-pandemic imaging recommendations tailored during the pandemic to limit imaging if possible to those who are at higher risk for cardiovascular toxicities or who have already been diagnosed with these adverse effects [1–4] (e.g., Fig. 6).
Discussion
The COVID-19 pandemic has inevitably compelled leaders of healthcare clinics to rethink and restructure approaches to deliver optimal care for patients. Our brand-new Cardio-Oncology clinic has been built to thrive in this new pandemic landscape by utilizing virtual technology as one of the key components of our clinic-building and care model since its inception. While existing clinics have reinvented their operations through the uptake of technology, our clinic has been able to capitalize on this resource to deliver virtual-hybrid care from the start. Virtual communication has proved useful to coordinate referral networks and care among providers within a multidisciplinary team across different clinics and departments. We see a variety of cancer patients, types, and drugs (Fig. 5), and our distribution results are generally congruent with reports from other leading cardio-oncology clinics [8, 14, 15, 17, 22].
Various methods have been developed for risk assessment to help guide providers and patients in determining the appropriate guidelines for care. We offer the use of virtual risk assessment tools such as the computed risk scores based on medication- and patient-related risk factors [22] (Fig. 4) (https://tinyurl.com/CardioOncCompendium), as well as recommendations for establishing cross-provider partnerships to continuously evaluate risk [21]. Other online databases containing useful information and guidelines are readily accessible and can help guide clinical practices. We encourage use of these virtual tools, which can further facilitate collaborative Cardio-Oncology care in the pandemic. Our conversations with international colleagues have suggested additional utility of these virtual tools beyond the pandemic. The online resources can be very helpful in settings where clinical practitioners work alone without support from nurses, pharmacists, nutrition specialists, or exercise physiologists.
Virtual-hybrid care has extended the care team’s capabilities for delivering and maintaining patient education and follow-up. The internet continues to be a robust resource, containing a wealth of health information that is easily accessible to the general population. Various mobile applications and electronic devices have also been developed in recent years to educate, track, and manage patients’ health and lifestyles. While these tools provide patients with greater accessibility and independence, they also create a valuable opportunity for healthcare providers to further engage patients. In a virtual-hybrid model, this becomes increasingly important, as patients may frequently transition between virtual and in-person visits. Forming care partnerships with patients through these virtual information and health-tracking resources becomes crucial in the continuity of care and proper health maintenance as we move through the pandemic.
Our most frequent cardiovascular diagnosis was cardiomyopathy (34%), which is reflective of the management need that first helped start the emerging field of Cardio-Oncology, and is similar to the most frequent cardiovascular diagnosis noted by clinicians from several other leading centers (20–35%) [24, 25]. However, Cardio-Oncology has grown remarkably over the last 10–20 years, with a wide spectrum of cardiovascular diagnoses and indications for referral (Fig. 5b) [8, 14]. Accordingly, at some other leading centers, the most frequent cardiovascular diagnosis or indication for referral has been reported as hypertension [14], arrythmia [17], or comprehensive risk assessment prior to beginning of therapy to optimize cardioprotection [8] in the practice of Preventive Cardio-Oncology [21]. This illustrates an opportunity for growth in our Clinic, to increase the fraction of high-risk patients who undergo comprehensive cardiovascular risk evaluation and management of risk factors prior to administration of cardiotoxic therapy.
Our clinic cares for patients with a range of cancer types (Fig. 5d). Individuals with breast, lung, and hematologic cancers represent a substantial proportion of our patient population, similar to other Cardio-Oncology clinics [8, 14, 22, 26]. The most frequent cancer diagnosis, breast cancer (43%), is consistent with reports from other leading cardio-oncology clinics such as the Mayo Clinic (39.2%) [15] and the Cleveland Clinic in Florida (44.3%) [14]. While hematologic malignancies such as leukemia and lymphoma represented 29% of our patients and was the second most prevalent cancer within our cohort, they comprised the most frequent forms of cancer at other cardio-oncology clinics such as at the Moffitt Cancer Center (31%) [8] and at UCLA (32.70%) [25]. However, the absolute difference was relatively insignificant. Overall, similar to these established cardio-oncology clinics, we receive patients from across a variety of cancers.
A wide breadth of cancer therapeutics is associated with cardiotoxicity [21]. Anthracyclines associate with cardiomyopathy, especially when used with trastuzumab. Targeted therapies (e.g., TKIs) can cause new or worsening of pre-existing hypertension. ICIs are associated with an increased incidence of myocarditis. Some cytotoxic chemotherapeutics, such as cisplatin, increase the risk of venous thromboembolism, and antimetabolites such as fluoropyrimidines have long been associated with a broad range of cardiotoxicities. Radiation therapy is associated with ischemic heart disease, valve dysfunction, conduction abnormalities, pericardial disease, and cardiomyopathy. Patients with cancer who have developed cardiovascular toxicity or who may be at high risk for cardiovascular toxicity should be referred to the Cardio-Oncology clinic for close follow-up.
The most frequently used cancer medication used among our patients was trastuzumab (29%), with the second most frequent being anthracyclines (24%). This was similar to other institutions, with anthracyclines and trastuzumab among the most common cancer drugs in their Cardio-Oncology clinics. Yet, anthracyclines were typically noted more commonly than trastuzumab. The Cleveland Clinic in Florida saw patients most commonly treated with radiation (40%), followed by anthracyclines (26.8%) [14]. The Moffitt Cancer Center most frequently had patients who were treated with anthracyclines (52%), with HER2 targeted therapies representing 27% of the cancer drugs [8]. This difference may reflect a high frequency of patients with HER+ breast cancer in our population (diagnosed by a ratio of HER2 to chromosome 17 signals on dual probe fluorescent in situ hybridization ≥2 or ≥ 6 HER2 signals/cell [27]), as well as the keen attention to a substantial fall in left ventricular ejection fraction or global longitudinal strain as a potential prognostic factor in our patients, per American Society of Echocardiography (ASE) guidelines [28].
All of these patient data distributions were obtained in the context of the Virtual-Hybrid patient flow in our de novo Cardio-Oncology Clinic (Fig. 3), that can be modeled by other future Virtual-Hybrid Cardio-Oncology clinics initiated during the pandemic. Table 1 compares the first few weeks of our de novo C-O clinic setup model with two published manuscripts describing conversion of pre-existing in-person C-O clinics to providing telehealth visits as an option for patients. The table shows similar numbers of patients seen in the initial periods of the clinics, although the numbers in our new clinic went from 0 to 10 in the first 3 weeks, compared to going from up to 40 patients weekly to 11 patients in 2.5 weeks for a group that converted their in-person clinic to a virtual option. Overall, CV diagnoses and cancer types were comparable; distributions of cancer drugs were not reported by the other group. Important differences were noted. Most of our patients in the pandemic were new (90%), given the de novo status of the Cardio-Oncology Clinic, while the converted virtual clinic of another group initially focused on established patients for > 50% of their patient visits. While key personnel were also the same (e.g., physician, advanced practice provider, nurse or nurse coordinator), we also report virtual versions of supportive staffing patterns, including the virtual scheduling and rooming process and pharmacy and lifestyle modification visits. Additionally, trainees have been integrally involved in the establishment of our Cardio-Oncology Clinic, with residents training in program-building, and medical students and fellows training in ambulatory cardio-oncology clinical practice and cardio-oncology critical thinking, respectively. Finally, besides the patient flow (Fig. 3) and de novo nature of our Virtual-Hybrid clinic initiated in the pandemic, our unique contribution may be the virtual resources, compared to the essential “webside manner” [7] or an alternative algorithm [4] for triaging virtual or in-person visits to the physician or advanced practice provider (Table 1).
Table 1 Comparisons Among Clinic Models Described In The Pandemic
Virtual-Hybrid Clinic Telehealth Clinic (14) Triage Clinic (4)
Model Type De Novo Conversion Conversion
Time Frame Compared 3 weeks 2.5 weeks Not reported
Number of Patients 10 11 Not reported
New Visits (%) 90 45 Not reported
Variety of CV Diagnoses Yes Yes Not reported
Variety of CA Types Yes Yes Not reported
Variety of CA Drugs Yes Unknown Not reported
Referrals Yes Unknown Yes
Scheduling Yes Unknown Not reported
Rooming Process Yes Unknown Not Reported
Virtual AA Yes Unknown Not Reported
Virtual MA Yes Unknown Not Reported
Virtual Physician Yes Yes Yes
Virtual APP Yes Unknown Yes
Virtual Pharmacist Yes Unknown Not Reported
Virtual Nurse (Coordinator) Yes Unknown Yes
Unique Contribution Virtual Resources Webside Manner Triage Algorithm
Similar to the formation or conversion of Cardio-Oncology clinics, many protocols for treatment regimens and cancer patients are yet to be standardized. While no standard protocols have been widely adopted at Cardio-Oncology practices, various institutions and writing groups have proposed some approaches (e.g., ASE or ASCO guidelines). We have collaboratively developed institutional algorithms for various cardiovascular toxicities and medications based on existing scientific statements, society guidelines, expert consensus statements, and manuscripts from leading cardio-oncology research institutions. The goal is to adopt, adapt, develop, and continuously update these algorithms, as new literature arises in order to establish best practices and an institutional standard of care.
Conclusion
Starting a new Cardio-Oncology Clinic in the pandemic has its challenges, and yet for our patients can be invaluable. Appropriately competing priorities in the pandemic can limit the scheduling of meetings and gathering of people together in one virtual room to discuss a mutual vision. Gathering resources for patient and clinician education can also be formidable, as can social distancing and obtaining important imaging. However, multiple virtual one-on-one or small group meetings can be beneficial for building institutional relationships. Similarly, virtual visits have risen to the challenge to ensure maintenance of patient care throughout the pandemic. Modifications have also been made to enable safety and distancing during imaging. With the benefit of these adjustments to address the challenge, this report provides a foundation for initiating a cardio-oncology clinic in the pandemic, with virtual resources and tools to equip patients and clinicians.
In the future, we will also lay out a roadmap for initiation of comprehensive cardio-oncology programs with the five pillars of patient care, education, research, community engagement, and innovation in the era of digital transformation accelerated by the pandemic. Novel risk modifiers and risk attenuation methods, such as breast arterial calcification, clonal hematopoiesis of indeterminate potential, and Cardio-Oncology prehabilitation, habilitation, and rehabilitation will also be addressed. Future innovation to implement recommendations from clinical trials across the nation currently underway that utilize mobile health or web-based diet and physical activity interventions and/or seek to determine the impact of cardioprotective pharmacotherapy in Preventive Cardio-Oncology will also be assessed (ClinicalTrials.Gov: NCT01988571, NCT02943590, NCT02562716, NCT01968200, NCT03265574, NCT03760588, NCT03386383, NCT02244411, NCT03223753). Many of these studies incorporate virtual technologies that will be very helpful during and after the pandemic as we continue pursuit of digital transformation.
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Acknowledgements
We are grateful to the following individuals, as well as all of the departments and divisions at Froedtert & MCW that have rallied together to help us establish the hybrid Cardio-Oncology clinic or to see our patients needing subspecialty care, or to partner with us in referrals from the inpatient service, especially the following clinicians: Stacey Gardiner MD, Jason Rubenstein MD, David Ishizawar MD, Jalaj Garg MD, Andrew Rosenblum MD. We are also grateful to Nicole Lohr MD PhD and the clinical sections at the Zablocki Veterans Administration Medical Center that have also helped us establish an affiliate Cardio-Oncology Clinic in tandem at the VAMC in Milwaukee, WI.
Authors’ contributions
SAB conceived of the study, obtained, analyzed and interpreted the data, and made a substantial contribution to the writing of the manuscript; SP made a substantial contribution to the writing of the manuscript; DR made a substantial contribution to the writing of the manuscript; SZ obtained the data and made a substantial contribution to the writing of the manuscript; ML interpreted the data and made a substantial contribution to the writing of the manuscript; TN made a substantial contribution to the writing of the manuscript; BS analyzed the data and made a substantial contribution to the writing of the manuscript; RM made a substantial contribution to the writing of the manuscript; JMac made a substantial contribution to the writing of the manuscript; KD made a substantial contribution to the writing of the manuscript; JMes made a substantial contribution to the writing of the manuscript; DM made a substantial contribution to the writing of the manuscript; JS made a substantial contribution to the writing of the manuscript. All authors read and approved the final manuscript.
Funding
No funding was associated with this work.
Availability of data and materials
The datasets during and/or analyzed during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The study was approved by the Froedtert & MCW Institutional Review Board (ID PRO00038807); HIPAA informed consent was waived for this minimal risk study.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests. | TRASTUZUMAB | DrugsGivenReaction | CC BY | 33441188 | 18,793,759 | 2021-01-13 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Left ventricular failure'. | A virtual-hybrid approach to launching a cardio-oncology clinic during a pandemic.
BACKGROUND
As cardiovascular disease is a leading cause of death in cancer survivors, the new subspecialty of Cardio-Oncology has emerged to address prevention, monitoring, and management of cardiovascular toxicities to cancer therapies. During the coronavirus disease of 2019 (COVID-19) pandemic, we developed a Virtual-Hybrid Approach to build a de novo Cardio-Oncology Clinic.
METHODS
We conceptualized a Virtual-Hybrid Approach including three arms: information seeking in locations with existing Cardio-Oncology clinics, information gathering at the location for a new clinic, and information sharing to report clinic-building outcomes. A retrospective review of outcomes included collection and synthesis of data from our first 3 months (at pandemic peak) on types of appointments, cancers, drugs, and cardiotoxicities. Data were presented using descriptive statistics.
RESULTS
A de-novo Cardio-Oncology clinic was developed structured from the ground up to integrate virtual and in-person care in a hybrid and innovative model, using the three arms of the Virtual-Hybrid Approach. First, we garnered in-person and virtual preparation through hands-on experiences, training, and discussions in existing Cardio-Oncology Clinics and conferences. Next, we gleaned information through virtual inquiry and niche-building. With partners throughout the institution, a virtual referral process was established for outpatient referrals and inpatient e-consult referrals to actualize a hybrid care spectrum for our patients administered by a multidisciplinary hybrid care team of clinicians, ancillary support staff, and clinical pharmacists. Among the multi-subspecialty clinic sessions, approximately 50% were in Cardio-Oncology, 20% in Preventive Cardiology, and 30% in General Cardiology. In the hybrid model, the Heart & Vascular Center had started to re-open, allowing for 65% of our visits to be in person. In additional analyses, the most frequent cardiovascular diagnosis was cardiomyopathy (34%), the most common cancer drug leading to referral was trastuzumab (29%), and the most prevalent cancer type was breast cancer (42%).
CONCLUSIONS
This Virtual-Hybrid Approach and retrospective review provides guidance and information regarding initiating a brand-new Cardio-Oncology Clinic during the pandemic for cancer patients/survivors. This report also furnishes virtual resources for patients, virtual tools for oncologists, cardiologists, and administrators tasked with starting new clinics during the pandemic, and innovative future directions for this digital pandemic to post-pandemic era.
Introduction
Cardio-Oncology care has been adjusted in the COVID-19 pandemic with limited in-person clinic or hospital visits, increased use of teleconsultation, less frequent imaging, increased reliance on biomarkers, and considerations of differential diagnoses involving COVID-19 when evaluating cancer patients or survivors for possible cardiovascular toxicity [1]. Monitoring and management algorithms have been developed to help guide virtual care [2–4]. In the pandemic, we have changed the way in which we provide healthcare services at our clinics and institutions. This has challenged us to restructure current systems for the safety of our patients.
Various forms of innovation have come to bear in the pandemic, including telemedicine, digital health, artificial intelligence, social media, informatics, big data, and precision medicine [5, 6]. Telemedicine is the primary form of innovation that has been most developed in the pandemic [2, 5, 7]. Social media has been very helpful for dissemination of information, as well as education, and has been integral for creating online groups for support and determining the best ways for proceeding in the pandemic and advocating for our patients and colleagues in this period [5, 6]. In addition, the Doximity social media application has been valuable to practices across the nation, due to its telehealth platform (Doximity Video and Phone; https://www.doximity.com/dialer-video).
Despite the growing need, and allowances made during the pandemic, many centers do not have formal Cardio-Oncology clinics. Starting a new clinic can be challenging. The COVID-19 pandemic has made the process significantly more difficult, with the need to minimize exposure and maximize patient safety.
Currently, limited information is available on how to start a Cardio-Oncology Clinic during a pandemic, albeit given the high risk of morbidity or mortality in COVID-19-positive patients who also have cancer or CVD [8–13]. Several institutions have published on their experiences with starting in-person Cardio-Oncology clinics prior to the pandemic [8, 14–17]. One group has reported on their conversion from existing in-person Cardio-Oncology visits to telemedicine consultations, seeing 11 patients virtually within a few weeks [7]. Many have considered implications of the pandemic on the practice and study of cardio-oncology [2, 4, 5, 18–20], and two groups have suggested models for clinics converting from existing in-person care to televisits [4, 5]. Yet, no groups have directly addressed steps for de novo virtual-hybrid clinic formation within the limitations of the pandemic and without conversion of a pre-existing Cardio-Oncology clinic.
Our report offers a template for other centers to develop their own new Cardio-Oncology clinics during the pandemic. We determined a Virtual-Hybrid Approach to clinic launch, with both virtual and in-person elements of three key arms: information seeking where there are existing Cardio-Oncology Clinics in place, information gathering where the clinic will be built, and information sharing to report on initial patient data demonstrating the success of the launch (Fig. 1). We then performed retrospective chart review to collect and synthesize data on the types of appointments (new versus established, virtual versus in-person), cancers (e.g., breast, prostate, leukemia, lung), cancer drugs, and cardiovascular toxicities (e.g., cardiomyopathy, hypertension) for patients seen virtually or in person in our new Cardio-Oncology clinic at Froedtert Hospital and Medical College of Wisconsin (F&MCW). Here, we will discuss our findings in the context of previous publications on launching Cardio-Oncology Clinics prior to the pandemic. Our results will present distributions of cancer drugs and types, and cardiovascular diagnoses, similar to previous publications on Cardio-Oncology clinic-building. However, we will differentiate and illuminate the techniques that leverage the virtual underpinnings of pandemic clinic-building. We submit that it is feasible to establish a new Cardio-Oncology Clinic for cancer patients or survivors with or at risk for cardiovascular toxicity from cancer therapy during a pandemic, providing optimal care for new patients in the midst of the need for safety and minimizing exposure. We also propose virtual resources for patients and clinicians and describe innovative future directions in the pandemic and post-pandemic period.
Fig. 1 The Virtual-Hybrid Approach to Cardio-Oncology Clinic-building in the pandemic
Methods
Virtual-hybrid approach
We pursued a Virtual-Hybrid Approach of information seeking, information gathering, and information sharing (Fig. 1). For information seeking, we focused on institutions that already had a Cardio-Oncology clinic in place. Prior to the COVID-19 pandemic, substantial experience was gained at an established in-person Cardio-Oncology clinic at a world-renowned leading hospital. Published manuscripts on pre-pandemic building and operations of Cardio-Oncology clinics at other institutions were reviewed. Extensive networking with leaders of Cardio-Oncology clinics around the United States and in the United Kingdom was accomplished at regional, national, and international meetings in person and on social media in a hybrid approach. These meetings were attended in person pre-COVID-19 and virtually during the pandemic. For information gathering, we addressed the location in which the new Cardio-Oncology clinic would be built. We learned about existing resources in the destination Heart & Vascular Center and existing needs and patients in the destination partner cancer center. We networked with physicians, advanced practice providers (APPs), nurses, service line leaders, and administrators in the Heart & Vascular Center and the cancer center, as well as in primary care and other supporting specialties. The subsequent Cardio-Oncology clinic sessions were intermingled with other subspecialty areas, to optimize availability for patient visits while filling clinic slots and tailoring spectrum of care to emerging patient needs. Cardio-Oncology patient visits were included in multi-subspecialty clinics.
Retrospective study design
For quantitative data, we pursued a retrospective observational study to determine the distribution of outpatient visits in the first 3 months of our virtual-hybrid Cardio-Oncology Clinic. We reviewed data from charts of patients (all were 18 years of age or older) who received outpatient care from the new Director of Cardio-Oncology at F&MCW between April 15, 2020 and July 17, 2020 to determine which of these patients were considered to be in Cardio-Oncology, Preventive Cardiology, or General Cardiology. We collated all three to determine the percentage of patients seen in Cardio-Oncology, compared to the other two specialties. Preventive Cardiology was collated as a partner clinic to help build the Preventive Cardio-Oncology component of the Cardio-Oncology Clinic, to help apply established principles for prevention. From among the multi-subspecialty clinic sessions, we determined the proportion of patients who were specifically cancer patients or survivors with or at risk for cardiovascular toxicity from cancer therapy and thereby seen in the Cardio-Oncology Clinic. Next, we identified the distribution of cardiovascular toxicities in cancer patients or survivors seen in the Cardio-Oncology Clinic. We also evaluated the spectrum of cancer drugs received by cancer patients or survivors seen in the Cardio-Oncology Clinic. In addition, we summarized the types of cancers in patients seen in the Cardio-Oncology Clinic. Finally, we assessed the frequency of virtual visits during the course of the pandemic over our first 3 months for patients seen in the Cardio-Oncology Clinic. This retrospective review was approved by the F&MCW IRB; HIPAA informed consent was waived for this minimal risk study, which did not involve any form of intervention and was conducted in compliance with good clinical and research practice. The team designed and carried out the study with reliance on virtual communication tools.
Data collection and analysis
Data gathering, management, and analysis were conducted at F&MCW. We collected patient-related, disease-related, treatment-related, and outcome-related data, particularly patient sex, type of appointment (new versus established, virtual versus in-person), type of cancer (e.g., breast, prostate, leukemia, lung), type of cancer drug, and type of cardiovascular toxicity (e.g., cardiomyopathy, hypertension). In order to minimize any risk of breaching patient confidentiality, all data collection occurred on institutional-based computing environments with de-identified data used for analyses. There were no alternative procedures for the subjects as this is a retrospective review of data that are not amenable to prospective collection and review. Descriptive graphs or tables of patient-, disease-, treatment-, and outcome-related variables distributions were prepared, with no comparisons made needing statistical tests.
Results
Virtual preparation
Preparation for starting the Cardio-Oncology clinic followed a Virtual-Hybrid Approach (Fig. 1, left). Five overarching factors employing virtual communication methods emerged to ensure the successful launching of the clinic. Team and individual experience and exposure to various areas of interest in Cardio-Oncology were achieved and assessed before and during the pandemic. Far-reaching connections to experts and potential collaborators in the field were developed and exercised. Close contact with the institution launching this clinic was important to determine the resources available; these resources dictated the strategy and potential outcomes of the clinic. Importantly, the expectations of others for the Cardio-Oncology clinic were determined and incorporated. Finally, recognition of the limitations that exist at the destination institution guided care and goal setting.
Virtual inquiry
Before initiating the Cardio-Oncology clinic in the destination institution, existing structures, patient base, and needs in the Heart & Vascular Center as well as the Cancer Center were evaluated, adhering to pandemic protocols (Fig. 1, middle). Pre-existing building blocks for the planned Cardio-Oncology clinic were assessed, and the partner Preventive Cardiology clinic was investigated. We also evaluated characteristics of the cancer center patient population to best position the clinic for success.
Virtual niche-building
Five main aspects of niche-building were pursued. Partnerships with Vascular and Cancer Center physicians, advanced practice providers, and service line leaders were developed to initiate and grow the clinic (Fig. 1, middle). The Cardio-Oncology team and clinic flexibility were demonstrated through openness to taking quicksteps. Presentations were made at Grand Rounds and rounds across the institution in Cardiology, Hematology/Oncology, Radiation Oncology, Surgical Oncology, Internal Medicine, and Family Medicine to promote the clinic capabilities. Collaborative solutions for problems facing fields complementing Cardio-Oncology developed trust and collaboration. Teamwork was developed by leveraging diversity of perspectives and virtual communication technologies, to establish effective patient care despite COVID-19 limitations.
Hybrid care Spectrum
The hybrid F&MCW Cardio-Oncology Clinic was initiated and established in the outpatient setting, in close partnership with the Preventive Cardiology Clinic, Cancer Center, and inpatient Cardiology Consult and Hematology/Oncology teams (Fig. 1, right).
Initial and subsequent visits have been completed in person or by video, with phone visits also available for virtual return visits if patients without adept and available smartphone use have limited ability to appear in person. Virtual patient visits over our first 3 months occurred with the use of telemedicine platforms integrated with Epic (via MyChart for patients and Haiku/Canto for clinicians), or using the Doximity video call function. Patients with in-person appointments are screened appropriately on arrival for signs or symptoms of COVID-19 or exposure, following institutional protocols. Wearing masks is required of all patients, and each patient can be accompanied by a family member; some choose to also wear gloves or face shields. There is sufficient room for maintaining social distancing in the clinic waiting room and hallways.
Innovation
Current innovation in the clinic also includes Virtual Clinician Tools and Virtual Patient Resources (Fig. 2). For clinicians, the links for an AHA CME course on Novel Concepts, Current Debates and Treatment Considerations in Cardio-Oncology, an online Cardio-Oncology Compendium hosting risk assessment clinical decision aids, Cardio-Oncology Drug Regimen and Acronym Databases, and UPTODATE access for reviewing Cardio-Oncology drug information are supplied. For patients, the video from the International Cardio-Oncology Society explaining the Cardio-Oncology subspecialty, American College of Cardiology (ACC) mobile health (mHealth) CardioSmart education app and website, Cancer Heart Talk mini-podcast series accessed via SoundCloud app and website, Cardio-Oncology Frequently Asked Questions, and ChemoCare website are provided for patient-facing Cardio-Oncology and heart anatomy and physiology education, engagement, and awareness. Virtual Resources for Preventive Cardio-Oncology are also made available to our patients. These include the American Heart Association (AHA) Physical Activity Recommendations, AHA Life’s Simple 7 Webpages, American Society For Preventive Cardiology Online Coaching Webpages in partnership with Intervent, and the Become An Ex Smoking Cessation Support Webpages in partnership with Mayo Clinic. The resources are provided in the Epic patient portal MyChart, and more ways to make the resources accessible to a broad and diverse patient population are in development. Future innovation in the clinic will explore contemporary initiatives connecting patients and their safely guarded data with their permission with wearable devices, health information technology, informatics, artificial intelligence, personalized medicine, and additional mobile health (mHealth) applications.
Fig. 2 Virtual patient and clinician education and resources. Available online as PDF with hot links in the CardioOnc Compendium (https://tinyurl.com/CardioOncCompendium)
Virtual visit infrastructure and timeline
There was no pre-existing Cardio-Oncology program at the time of launching our de novo Virtual/Hybrid Cardio-Oncology Clinic. The newly recruited Director of Cardio-Oncology was tasked with the responsibility of launching the new clinic, with support from the Heart & Vascular Center clinic administrators, medical director, and Cardiology Division and Department of Medicine leadership. Prior to opening the Cardio-Oncology Clinic, the Heart & Vascular Center initiated virtual conversion then additionally collaborated with Inception Health (MCW’s innovation lab company) over the course of 4 weeks to iteratively develop the clinical informatics infrastructure for virtual visits. The video visits were designed to function using clinician’s personal smartphones, iPads, and tablets, with direct web browser video links from the electronic health record mobile application. Direct video calls through the Doximity mobile application were also approved. Existing Inception Health personnel re-allocated their time in order to adopt and maintain responsibility for the virtual component of all ambulatory clinics across the health system, in partnership with medical and administrative directors of each clinic area, such as the Heart & Vascular Center. No additional costs or hires were pursued to facilitate the development of the virtual visit infrastructure and timeline. Existing resources and personnel were re-allocated to virtual visit design to enable building the virtual clinics in the Heart & Vascular Center. To assist clinicians and billing compliance colleagues, note templates were created for video and phone visits to indicate patient informed consent for virtual visits due to the pandemic, as well as to capture limited appropriate physical examinations, in addition to the amount of time spent on records review and real-time medical counseling.
Initial consults were electronically triaged by either a cardiologist or a cardiology fellow supervised by a cardiologist. Each triage team determined which consults would be appropriate as virtual video visits, versus in-person to occur once the Heart and Vascular Center started re-opening routine physical visits, or whether patients needed to be evaluated urgently in person. During the first week of operation, the brand-new Cardio-Oncology Clinic started entirely virtually with only video and phone visits. As the Heart and Vascular Center re-opened for physical patient visits the following week, from week 2 through the remainder of the first 3 months the Cardio-Oncology Clinic had both virtual and in-person visits integrated throughout each clinic session weekly, based on whether patients were new and whether they had smart device or computer functionality available.
Virtual referral network and process
Cardio-Oncology patient assessment begins within a referral network before the patient arrives at a Cardio-Oncology clinic. Consequently, forming a virtual referral network and enacting a user-friendly virtual referral process was a key component of building the Cardio-Oncology clinic during the pandemic. All referral patterns and networks for our de novo Cardio-Oncology Clinic were built from the ground up. Initial referrals were from within our health system; this quickly expanded to consults from outside of our health system encompassing the entire state. Patients were referred to our Clinic by clinicians or by self-referrals. Some of our local patients connected to us after being introduced to us by their clinicians in other states or through family members in other states who learned about us from their own clinicians or community-based Cardiology society outreach events.
Referrals across the institution and outside of our health system have come to us from the Divisions of Hematology and Oncology, Internal Medicine, Family Medicine, Surgical Oncology/Breast Clinic, and Survivorship Clinics. From the cancer center’s perspective, there may be many “triggers” that would warrant a Cardio-Oncology referral. For example, an abnormal ECG, an abnormal echocardiogram, cardiovascular symptoms, previous cardiovascular history (e.g., coronary artery disease, hypertension, cardiomyopathy) particularly in a patient who previously underwent treatment or is beginning new treatment with cardiotoxic neoplastic medications or radiation therapy and is at high risk of cardiovascular toxicity, or those in preparation for stem cell transplant, or oncologic surgery. Referral protocols were determined based on standard practice, discussions with colleagues in Medical and Radiation Oncology, Hematology, Bone Marrow Transplant, Surgical Oncology/Breast Clinic, Children’s Hospital, Radiation Oncology, Primary Care, and updated literature reviews.
Cancer survivors are at a higher risk than the general population for cardiovascular morbidity and mortality. If a cancer survivor needing to be evaluated is already under the care of a cardiologist, the referring provider can reach out to their cardiologist for guidance on the appropriate CV surveillance. If they do not already have a cardiologist, a Cardio-Oncology consult should be requested. The Cardio-Oncology consult can be placed using a direct Cardio-Oncology button within the universally available Cardiovascular Consult order panel. Referrers can also place a General Cardiology consult and mention the Cardio-Oncology physician by name as requested by the clinician or patient. An E-Consult functionality is also being implemented for those patients who need to be assessed sooner than the next available appointment, or for those patients who may not need a full Cardio-Oncology evaluation, or if referring providers are uncertain. The e-consult can also be placed as a second opinion requested by the inpatient Cardiology Consult team.
The inpatient Cardiology Consult service will continue to directly address inpatient consults from the inpatient hematology/oncology services. The inpatient Cardiology Consult service can collaborate with the Cardio-Oncology Clinic via formal Cardio-Oncology E-consults in the electronic health record Epic if a specific focused question arises regarding Cardio-Oncology relevant to the care of individual currently hospitalized patients that have already been formally evaluated by the inpatient Cardiology Consult service. After a patient has been formally evaluated by the inpatient Cardiology Consult service, if the patient is appropriate for outpatient follow up in the Cardiology clinic with Cardio-Oncology, this should be communicated to the primary Hematology/Oncology service. If appropriate at the time of consultation, the inpatient cardiology consult service can make the follow-up appointment. Oftentimes, this patient population remains in the inpatient setting for several weeks. If this is the case, the Cardiology clinic phone number and clinician information should be provided to the primary service to do so prior to the patient being discharged from the hospital.
Virtual-hybrid multidisciplinary team
It is important to develop a multidisciplinary team and initially focus on allocation of pre-existing resources. Accordingly, some roles among our Cardio-Oncology clinic personnel are shared with other subspecialties. Our virtual-hybrid multidisciplinary Cardio-Oncology Clinic personnel include physicians, a nurse practitioner (NP), a nurse, a research support specialist, medical assistants, pharmacists, administrative assistants, and administrators. All personnel with pre-existing in-person roles and practices re-allocated a portion of their time to the development and practice of virtual visits.
Our clinic and partners consist of board-certified Cardiologists with special training in various cardiac subspecialties (e.g., cardio-oncology, preventive cardiology, heart failure and transplant, electrophysiology, interventional cardiology), who collaborate closely with our cancer experts. Our physicians together specialize in the prevention, diagnosis, and treatment of heart and vascular disorders resulting from side effects of cancer therapy. Our comprehensive team of advanced practice providers, nurses, and pharmacists work alongside our physicians to care for patients from the moment of cancer diagnosis through life’s survivorship journey. The NP typically sees established patients when needed to follow up on imaging, intervention, or diagnostic and management plans, and may also see select new patients. In complex cases, the NP discusses the care of established patients with both the cardio-oncologist and the referring clinician. The nurse assists with patient triage and communications (including addressing patient requests and queries), liaises closely with the nurse practitioner and pharmacists, and educates patients on Cardio-Oncology using virtual materials. Our clinical pharmacists function at the highest level of their advanced training, similar to all clinic personnel, and assist with medication education, review, titration, discussion, and prescription, particularly for heart failure, hypertension, hyperlipidemia, and smoking cessation, as well as commenting on potential drug interactions.
For Preventive Cardio-Oncology, we additionally partner with our dietitians and exercise physiologists to help advise our patients on nutrition and exercise plans, as well as our colleagues in cardiopulmonary stress testing where applicable. Further, in the pandemic, we provide patients with free online coaching options for lifestyle modification (Fig. 2). We also direct patients to AHA webpages with guidance on pursuing ideal cardiovascular health.
Virtual-hybrid patient flow
Once a referral is placed by the designated order buttons in the electronic health record, central schedulers or the Cardio-Oncology Clinic administrative assistant schedule the new patient for a video or in-person visit (Fig. 3). The clinic administrative assistant works closely with our health professionals in our interdisciplinary advanced subspecialty clinic to gather relevant clinical reports and history pertinent to patient appointments. Virtual medical assistants contact patients a few days before their appointments to confirm and troubleshoot virtual connectivity. On the appointment day, medical assistants then ‘room’ patients for virtual or in-person visits by preparing patients for their medical visits (including reviewing medications and in-person or at-home virtual vital signs), and also rechecking virtual connectivity for video visits. The clinician then completes the visit virtually or in-person and introduces the patient to the range of electronic resources available. Following the visit, the clinical administrative assistant arranges follow-up testing and appointments.
Fig. 3 Virtual-Hybrid Patient Flow Chart. Admin = Administrative; MA = Medical Assistant; MD = Medical Doctor; NP = Nurse Practitioner
Virtual risk assessment
Baseline risk assessment and follow-up start with oncology and primary care [21]. Asymptomatic low risk patients with low-risk treatment plans can have continued assessment and follow-up by oncology and primary care in partnership. Patients who have symptoms, are at high risk based on their history, or are planned for high-risk treatment plans should be referred to Cardio-Oncology for prevention, monitoring, and management recommendations. Recommendations should adhere to society expert consensus, scientific statements, and guidelines for prevention, surveillance, and survivorship, and optimize CVD risk and medications [21]. A putative risk score based on medication-related and patient-related risk factors can be used to guide monitoring and management recommendations for most Cardio-Oncology patients [22], and can be used in a virtual clinical decision aid (https://tinyurl.com/CardioOncCDA) (Fig. 4). Specific risk scores are also available for adults treated with anthracyclines, trastuzumab, or other drugs, or for adult survivors of childhood cancers [9–13].
Fig. 4 Virtual Cardio-Oncology clinical decision aid (CDA). Risk assessment (https://tinyurl.com/CardioOncCDA) to guide monitoring and management recommendations regarding development of cardiomyopathy for most Cardio-Oncology patients; a CDA specifically for women with early breast cancer is also available in the CardioOnc Compendium (https://tinyurl.com/CardioOncCompendium)
Virtual management algorithms
Evidence-based management algorithms have been selected or developed as adjunctive resources for inpatient teams. They are available online in a virtual collection for use in the inpatient setting by the inpatient Cardiology Consult service or hematology/oncology teams to assist with diagnosis and treatment of cardiovascular toxicities from cancer therapies or cancer itself. The algorithms cover cardiomyopathy from anthracyclines or trastuzumab, planned chemotherapy with pre-existing cardiomyopathy, neurohormonal therapy or dexrazoxane for cardioprotection, myocarditis, persistent malignant pericardial effusion, hypertension, surveillance after radiation therapy or drugs that cause ischemia, malignant pericardial effusion, and other salient topics frequently encountered.
Virtual community engagement
The local, regional, national, and international community was virtually engaged via social media posts on Twitter (using #MCWCardioOnc on @DrBrownCares or @PrevCardioOnc), podcasts hosted by the MCW CTSI (available on iTunes, Google, and Apple podcast platforms), Heart Success podcast series, and Cancer Heart Talk brief 15-min mini-podcast series (available on SoundCloud). Perspectives were also published for international community engagement in the Women Heart Alliance newsletter, as well as on the AHA Early Career Blog, ACC Women in Cardiology Blog, CardioOncTrain.Com Blog, and PrevCardioOnc.Com Blog. Virtual continuing medical education (CME) presentations were also given at the Wisconsin state ACC annual conference meeting, Midwest ACC annual conference meeting, Southeast ACC annual conference meeting, Brazilian Cardio-Oncology Symposium, and the Ohio State Cardio-Oncology CME conference, then subsequently at the AHA and ACC annual national scientific sessions.
Distribution of patient data
In our multi-subspecialty clinic visits (virtual and in-person integrated and combined; n = 182; 136 new and 47 returns), approximately 50% of patient visits were in Cardio-Oncology, 20% were in Preventive Cardio-Oncology, and 30% were in General Cardiology (Fig. 5a). Overall among Cardio-Oncology visits, 65% were in person, consistent with early and safe clinic re-opening in a hybrid model, with 19% by video and 16% by phone, with the fraction by phone decreasing over time as patients and clinic personnel became more adept with troubleshooting video. Of new patients, 77% were in person, and the remainder by video. No Cardio-Oncology patients presenting in person developed any signs or symptoms concerning for COVID-19.
Fig. 5 Initial Clinic-Building Outcomes Using the Virtual-Hybrid Approach. a Distribution of Cardio-Oncology, Preventive Cardio-Oncology, and General Cardiology patients seen in our multi-subspecialty clinic visits. b Distribution of cardiovascular diagnosis or indication for referral. c Distribution of cancer drugs. d Distribution of cancer types
The most frequent cardiovascular diagnosis or indication for referral was cardiomyopathy (34%) (Fig. 5b). Other diagnoses included decrease in global longitudinal strain, diastolic congestive heart failure, hypertension, myocarditis, dyspnea, chest pain, palpitations, survivorship, risk assessment, and pre-bone marrow transplant, among other cardiovascular diagnoses or visit indications. The most frequent cancer drug was trastuzumab (29%) (Fig. 5c), managed according to a novel algorithm developed in our de novo Virtual-Hybrid Cardio-Oncology Clinic based on the recent publication indicating the safety of continuation of trastuzumab for left ventricular ejection fraction of 40% or greater [23] (Fig. 6). The second most frequent cancer drug was anthracycline (24%). Other drugs included, tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), endocrine therapies, and investigational therapeutics, among others. The most frequent cancer type in our clinic was breast cancer (42%) (Fig. 5d). These trends in cardiovascular diagnosis or indication and cancer drugs or types were similar in assessments of virtual visits alone, with the most frequent being cardiomyopathy (43%), trastuzumab (41%), and breast cancer (44%), respectively. The findings of similar cardiovascular and cancer distributions in virtual versus in-person visits indicated an optimal qualitative return on resource and personnel investment.
Fig. 6 Algorithm for Continuation of Trastuzumab Therapy with Mild LV Dysfunction
Imaging and medication titration
In our clinic, a distribution of cardiovascular diagnoses determines the imaging needed for each patient (Fig. 5b). Therefore, a number of imaging modalities are useful to our patients (e.g., echocardiography, computed tomography with or without angiography, magnetic resonance imaging, coronary angiography, myocardial perfusion imaging). Our most frequently used imaging modality is echocardiography. The frequency of obtaining echocardiograms has depended on each patient’s condition and cancer treatment. A substantial portion of patients coming to us on trastuzumab have needed an echocardiogram every 1–3 months, depending on the extent of adverse effects on left ventricular ejection fraction (LVEF) or strain In these patients, medication titration has occurred approximately every 2 weeks, and for very symptomatic patients with volume overload, they have often been seen weekly..
In our management algorithms, early referral prior to the onset of symptoms has been emphasized, especially in cancer patients or survivors with a history of cardiovascular disease, cardiotoxic neoplastic agents, or a high risk of cardiovascular toxicity. This has provided an opportunity for us to assess and discuss ways to optimize the benefit to risk ratio of continuing with the current cancer treatment plan, and more importantly how and when to put cardioprotective measures in place to facilitate safe cancer therapy. Such discussions have also resulted in closer monitoring. Some conditions have warranted proceeding to other modalities of non-invasive imaging, such as cardiac MRI if myocarditis is suspected. For cases in which coronary artery disease is suspected, our patients undergo functional assessment of their coronaries with a stress test or anatomical assessment with a coronary CT scan or invasive coronary angiography. In our practice, only exercise stress tests were halted due to the pandemic. Every other form of imaging including rest and stress echo, as well as MRI and nuclear medicine have remained readily available for those with cardiovascular toxicities or individuals considered to be at moderate or high risk. This allowed us to adhere to pre-pandemic imaging recommendations tailored during the pandemic to limit imaging if possible to those who are at higher risk for cardiovascular toxicities or who have already been diagnosed with these adverse effects [1–4] (e.g., Fig. 6).
Discussion
The COVID-19 pandemic has inevitably compelled leaders of healthcare clinics to rethink and restructure approaches to deliver optimal care for patients. Our brand-new Cardio-Oncology clinic has been built to thrive in this new pandemic landscape by utilizing virtual technology as one of the key components of our clinic-building and care model since its inception. While existing clinics have reinvented their operations through the uptake of technology, our clinic has been able to capitalize on this resource to deliver virtual-hybrid care from the start. Virtual communication has proved useful to coordinate referral networks and care among providers within a multidisciplinary team across different clinics and departments. We see a variety of cancer patients, types, and drugs (Fig. 5), and our distribution results are generally congruent with reports from other leading cardio-oncology clinics [8, 14, 15, 17, 22].
Various methods have been developed for risk assessment to help guide providers and patients in determining the appropriate guidelines for care. We offer the use of virtual risk assessment tools such as the computed risk scores based on medication- and patient-related risk factors [22] (Fig. 4) (https://tinyurl.com/CardioOncCompendium), as well as recommendations for establishing cross-provider partnerships to continuously evaluate risk [21]. Other online databases containing useful information and guidelines are readily accessible and can help guide clinical practices. We encourage use of these virtual tools, which can further facilitate collaborative Cardio-Oncology care in the pandemic. Our conversations with international colleagues have suggested additional utility of these virtual tools beyond the pandemic. The online resources can be very helpful in settings where clinical practitioners work alone without support from nurses, pharmacists, nutrition specialists, or exercise physiologists.
Virtual-hybrid care has extended the care team’s capabilities for delivering and maintaining patient education and follow-up. The internet continues to be a robust resource, containing a wealth of health information that is easily accessible to the general population. Various mobile applications and electronic devices have also been developed in recent years to educate, track, and manage patients’ health and lifestyles. While these tools provide patients with greater accessibility and independence, they also create a valuable opportunity for healthcare providers to further engage patients. In a virtual-hybrid model, this becomes increasingly important, as patients may frequently transition between virtual and in-person visits. Forming care partnerships with patients through these virtual information and health-tracking resources becomes crucial in the continuity of care and proper health maintenance as we move through the pandemic.
Our most frequent cardiovascular diagnosis was cardiomyopathy (34%), which is reflective of the management need that first helped start the emerging field of Cardio-Oncology, and is similar to the most frequent cardiovascular diagnosis noted by clinicians from several other leading centers (20–35%) [24, 25]. However, Cardio-Oncology has grown remarkably over the last 10–20 years, with a wide spectrum of cardiovascular diagnoses and indications for referral (Fig. 5b) [8, 14]. Accordingly, at some other leading centers, the most frequent cardiovascular diagnosis or indication for referral has been reported as hypertension [14], arrythmia [17], or comprehensive risk assessment prior to beginning of therapy to optimize cardioprotection [8] in the practice of Preventive Cardio-Oncology [21]. This illustrates an opportunity for growth in our Clinic, to increase the fraction of high-risk patients who undergo comprehensive cardiovascular risk evaluation and management of risk factors prior to administration of cardiotoxic therapy.
Our clinic cares for patients with a range of cancer types (Fig. 5d). Individuals with breast, lung, and hematologic cancers represent a substantial proportion of our patient population, similar to other Cardio-Oncology clinics [8, 14, 22, 26]. The most frequent cancer diagnosis, breast cancer (43%), is consistent with reports from other leading cardio-oncology clinics such as the Mayo Clinic (39.2%) [15] and the Cleveland Clinic in Florida (44.3%) [14]. While hematologic malignancies such as leukemia and lymphoma represented 29% of our patients and was the second most prevalent cancer within our cohort, they comprised the most frequent forms of cancer at other cardio-oncology clinics such as at the Moffitt Cancer Center (31%) [8] and at UCLA (32.70%) [25]. However, the absolute difference was relatively insignificant. Overall, similar to these established cardio-oncology clinics, we receive patients from across a variety of cancers.
A wide breadth of cancer therapeutics is associated with cardiotoxicity [21]. Anthracyclines associate with cardiomyopathy, especially when used with trastuzumab. Targeted therapies (e.g., TKIs) can cause new or worsening of pre-existing hypertension. ICIs are associated with an increased incidence of myocarditis. Some cytotoxic chemotherapeutics, such as cisplatin, increase the risk of venous thromboembolism, and antimetabolites such as fluoropyrimidines have long been associated with a broad range of cardiotoxicities. Radiation therapy is associated with ischemic heart disease, valve dysfunction, conduction abnormalities, pericardial disease, and cardiomyopathy. Patients with cancer who have developed cardiovascular toxicity or who may be at high risk for cardiovascular toxicity should be referred to the Cardio-Oncology clinic for close follow-up.
The most frequently used cancer medication used among our patients was trastuzumab (29%), with the second most frequent being anthracyclines (24%). This was similar to other institutions, with anthracyclines and trastuzumab among the most common cancer drugs in their Cardio-Oncology clinics. Yet, anthracyclines were typically noted more commonly than trastuzumab. The Cleveland Clinic in Florida saw patients most commonly treated with radiation (40%), followed by anthracyclines (26.8%) [14]. The Moffitt Cancer Center most frequently had patients who were treated with anthracyclines (52%), with HER2 targeted therapies representing 27% of the cancer drugs [8]. This difference may reflect a high frequency of patients with HER+ breast cancer in our population (diagnosed by a ratio of HER2 to chromosome 17 signals on dual probe fluorescent in situ hybridization ≥2 or ≥ 6 HER2 signals/cell [27]), as well as the keen attention to a substantial fall in left ventricular ejection fraction or global longitudinal strain as a potential prognostic factor in our patients, per American Society of Echocardiography (ASE) guidelines [28].
All of these patient data distributions were obtained in the context of the Virtual-Hybrid patient flow in our de novo Cardio-Oncology Clinic (Fig. 3), that can be modeled by other future Virtual-Hybrid Cardio-Oncology clinics initiated during the pandemic. Table 1 compares the first few weeks of our de novo C-O clinic setup model with two published manuscripts describing conversion of pre-existing in-person C-O clinics to providing telehealth visits as an option for patients. The table shows similar numbers of patients seen in the initial periods of the clinics, although the numbers in our new clinic went from 0 to 10 in the first 3 weeks, compared to going from up to 40 patients weekly to 11 patients in 2.5 weeks for a group that converted their in-person clinic to a virtual option. Overall, CV diagnoses and cancer types were comparable; distributions of cancer drugs were not reported by the other group. Important differences were noted. Most of our patients in the pandemic were new (90%), given the de novo status of the Cardio-Oncology Clinic, while the converted virtual clinic of another group initially focused on established patients for > 50% of their patient visits. While key personnel were also the same (e.g., physician, advanced practice provider, nurse or nurse coordinator), we also report virtual versions of supportive staffing patterns, including the virtual scheduling and rooming process and pharmacy and lifestyle modification visits. Additionally, trainees have been integrally involved in the establishment of our Cardio-Oncology Clinic, with residents training in program-building, and medical students and fellows training in ambulatory cardio-oncology clinical practice and cardio-oncology critical thinking, respectively. Finally, besides the patient flow (Fig. 3) and de novo nature of our Virtual-Hybrid clinic initiated in the pandemic, our unique contribution may be the virtual resources, compared to the essential “webside manner” [7] or an alternative algorithm [4] for triaging virtual or in-person visits to the physician or advanced practice provider (Table 1).
Table 1 Comparisons Among Clinic Models Described In The Pandemic
Virtual-Hybrid Clinic Telehealth Clinic (14) Triage Clinic (4)
Model Type De Novo Conversion Conversion
Time Frame Compared 3 weeks 2.5 weeks Not reported
Number of Patients 10 11 Not reported
New Visits (%) 90 45 Not reported
Variety of CV Diagnoses Yes Yes Not reported
Variety of CA Types Yes Yes Not reported
Variety of CA Drugs Yes Unknown Not reported
Referrals Yes Unknown Yes
Scheduling Yes Unknown Not reported
Rooming Process Yes Unknown Not Reported
Virtual AA Yes Unknown Not Reported
Virtual MA Yes Unknown Not Reported
Virtual Physician Yes Yes Yes
Virtual APP Yes Unknown Yes
Virtual Pharmacist Yes Unknown Not Reported
Virtual Nurse (Coordinator) Yes Unknown Yes
Unique Contribution Virtual Resources Webside Manner Triage Algorithm
Similar to the formation or conversion of Cardio-Oncology clinics, many protocols for treatment regimens and cancer patients are yet to be standardized. While no standard protocols have been widely adopted at Cardio-Oncology practices, various institutions and writing groups have proposed some approaches (e.g., ASE or ASCO guidelines). We have collaboratively developed institutional algorithms for various cardiovascular toxicities and medications based on existing scientific statements, society guidelines, expert consensus statements, and manuscripts from leading cardio-oncology research institutions. The goal is to adopt, adapt, develop, and continuously update these algorithms, as new literature arises in order to establish best practices and an institutional standard of care.
Conclusion
Starting a new Cardio-Oncology Clinic in the pandemic has its challenges, and yet for our patients can be invaluable. Appropriately competing priorities in the pandemic can limit the scheduling of meetings and gathering of people together in one virtual room to discuss a mutual vision. Gathering resources for patient and clinician education can also be formidable, as can social distancing and obtaining important imaging. However, multiple virtual one-on-one or small group meetings can be beneficial for building institutional relationships. Similarly, virtual visits have risen to the challenge to ensure maintenance of patient care throughout the pandemic. Modifications have also been made to enable safety and distancing during imaging. With the benefit of these adjustments to address the challenge, this report provides a foundation for initiating a cardio-oncology clinic in the pandemic, with virtual resources and tools to equip patients and clinicians.
In the future, we will also lay out a roadmap for initiation of comprehensive cardio-oncology programs with the five pillars of patient care, education, research, community engagement, and innovation in the era of digital transformation accelerated by the pandemic. Novel risk modifiers and risk attenuation methods, such as breast arterial calcification, clonal hematopoiesis of indeterminate potential, and Cardio-Oncology prehabilitation, habilitation, and rehabilitation will also be addressed. Future innovation to implement recommendations from clinical trials across the nation currently underway that utilize mobile health or web-based diet and physical activity interventions and/or seek to determine the impact of cardioprotective pharmacotherapy in Preventive Cardio-Oncology will also be assessed (ClinicalTrials.Gov: NCT01988571, NCT02943590, NCT02562716, NCT01968200, NCT03265574, NCT03760588, NCT03386383, NCT02244411, NCT03223753). Many of these studies incorporate virtual technologies that will be very helpful during and after the pandemic as we continue pursuit of digital transformation.
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Acknowledgements
We are grateful to the following individuals, as well as all of the departments and divisions at Froedtert & MCW that have rallied together to help us establish the hybrid Cardio-Oncology clinic or to see our patients needing subspecialty care, or to partner with us in referrals from the inpatient service, especially the following clinicians: Stacey Gardiner MD, Jason Rubenstein MD, David Ishizawar MD, Jalaj Garg MD, Andrew Rosenblum MD. We are also grateful to Nicole Lohr MD PhD and the clinical sections at the Zablocki Veterans Administration Medical Center that have also helped us establish an affiliate Cardio-Oncology Clinic in tandem at the VAMC in Milwaukee, WI.
Authors’ contributions
SAB conceived of the study, obtained, analyzed and interpreted the data, and made a substantial contribution to the writing of the manuscript; SP made a substantial contribution to the writing of the manuscript; DR made a substantial contribution to the writing of the manuscript; SZ obtained the data and made a substantial contribution to the writing of the manuscript; ML interpreted the data and made a substantial contribution to the writing of the manuscript; TN made a substantial contribution to the writing of the manuscript; BS analyzed the data and made a substantial contribution to the writing of the manuscript; RM made a substantial contribution to the writing of the manuscript; JMac made a substantial contribution to the writing of the manuscript; KD made a substantial contribution to the writing of the manuscript; JMes made a substantial contribution to the writing of the manuscript; DM made a substantial contribution to the writing of the manuscript; JS made a substantial contribution to the writing of the manuscript. All authors read and approved the final manuscript.
Funding
No funding was associated with this work.
Availability of data and materials
The datasets during and/or analyzed during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The study was approved by the Froedtert & MCW Institutional Review Board (ID PRO00038807); HIPAA informed consent was waived for this minimal risk study.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests. | TRASTUZUMAB | DrugsGivenReaction | CC BY | 33441188 | 18,793,759 | 2021-01-13 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myocarditis'. | A virtual-hybrid approach to launching a cardio-oncology clinic during a pandemic.
BACKGROUND
As cardiovascular disease is a leading cause of death in cancer survivors, the new subspecialty of Cardio-Oncology has emerged to address prevention, monitoring, and management of cardiovascular toxicities to cancer therapies. During the coronavirus disease of 2019 (COVID-19) pandemic, we developed a Virtual-Hybrid Approach to build a de novo Cardio-Oncology Clinic.
METHODS
We conceptualized a Virtual-Hybrid Approach including three arms: information seeking in locations with existing Cardio-Oncology clinics, information gathering at the location for a new clinic, and information sharing to report clinic-building outcomes. A retrospective review of outcomes included collection and synthesis of data from our first 3 months (at pandemic peak) on types of appointments, cancers, drugs, and cardiotoxicities. Data were presented using descriptive statistics.
RESULTS
A de-novo Cardio-Oncology clinic was developed structured from the ground up to integrate virtual and in-person care in a hybrid and innovative model, using the three arms of the Virtual-Hybrid Approach. First, we garnered in-person and virtual preparation through hands-on experiences, training, and discussions in existing Cardio-Oncology Clinics and conferences. Next, we gleaned information through virtual inquiry and niche-building. With partners throughout the institution, a virtual referral process was established for outpatient referrals and inpatient e-consult referrals to actualize a hybrid care spectrum for our patients administered by a multidisciplinary hybrid care team of clinicians, ancillary support staff, and clinical pharmacists. Among the multi-subspecialty clinic sessions, approximately 50% were in Cardio-Oncology, 20% in Preventive Cardiology, and 30% in General Cardiology. In the hybrid model, the Heart & Vascular Center had started to re-open, allowing for 65% of our visits to be in person. In additional analyses, the most frequent cardiovascular diagnosis was cardiomyopathy (34%), the most common cancer drug leading to referral was trastuzumab (29%), and the most prevalent cancer type was breast cancer (42%).
CONCLUSIONS
This Virtual-Hybrid Approach and retrospective review provides guidance and information regarding initiating a brand-new Cardio-Oncology Clinic during the pandemic for cancer patients/survivors. This report also furnishes virtual resources for patients, virtual tools for oncologists, cardiologists, and administrators tasked with starting new clinics during the pandemic, and innovative future directions for this digital pandemic to post-pandemic era.
Introduction
Cardio-Oncology care has been adjusted in the COVID-19 pandemic with limited in-person clinic or hospital visits, increased use of teleconsultation, less frequent imaging, increased reliance on biomarkers, and considerations of differential diagnoses involving COVID-19 when evaluating cancer patients or survivors for possible cardiovascular toxicity [1]. Monitoring and management algorithms have been developed to help guide virtual care [2–4]. In the pandemic, we have changed the way in which we provide healthcare services at our clinics and institutions. This has challenged us to restructure current systems for the safety of our patients.
Various forms of innovation have come to bear in the pandemic, including telemedicine, digital health, artificial intelligence, social media, informatics, big data, and precision medicine [5, 6]. Telemedicine is the primary form of innovation that has been most developed in the pandemic [2, 5, 7]. Social media has been very helpful for dissemination of information, as well as education, and has been integral for creating online groups for support and determining the best ways for proceeding in the pandemic and advocating for our patients and colleagues in this period [5, 6]. In addition, the Doximity social media application has been valuable to practices across the nation, due to its telehealth platform (Doximity Video and Phone; https://www.doximity.com/dialer-video).
Despite the growing need, and allowances made during the pandemic, many centers do not have formal Cardio-Oncology clinics. Starting a new clinic can be challenging. The COVID-19 pandemic has made the process significantly more difficult, with the need to minimize exposure and maximize patient safety.
Currently, limited information is available on how to start a Cardio-Oncology Clinic during a pandemic, albeit given the high risk of morbidity or mortality in COVID-19-positive patients who also have cancer or CVD [8–13]. Several institutions have published on their experiences with starting in-person Cardio-Oncology clinics prior to the pandemic [8, 14–17]. One group has reported on their conversion from existing in-person Cardio-Oncology visits to telemedicine consultations, seeing 11 patients virtually within a few weeks [7]. Many have considered implications of the pandemic on the practice and study of cardio-oncology [2, 4, 5, 18–20], and two groups have suggested models for clinics converting from existing in-person care to televisits [4, 5]. Yet, no groups have directly addressed steps for de novo virtual-hybrid clinic formation within the limitations of the pandemic and without conversion of a pre-existing Cardio-Oncology clinic.
Our report offers a template for other centers to develop their own new Cardio-Oncology clinics during the pandemic. We determined a Virtual-Hybrid Approach to clinic launch, with both virtual and in-person elements of three key arms: information seeking where there are existing Cardio-Oncology Clinics in place, information gathering where the clinic will be built, and information sharing to report on initial patient data demonstrating the success of the launch (Fig. 1). We then performed retrospective chart review to collect and synthesize data on the types of appointments (new versus established, virtual versus in-person), cancers (e.g., breast, prostate, leukemia, lung), cancer drugs, and cardiovascular toxicities (e.g., cardiomyopathy, hypertension) for patients seen virtually or in person in our new Cardio-Oncology clinic at Froedtert Hospital and Medical College of Wisconsin (F&MCW). Here, we will discuss our findings in the context of previous publications on launching Cardio-Oncology Clinics prior to the pandemic. Our results will present distributions of cancer drugs and types, and cardiovascular diagnoses, similar to previous publications on Cardio-Oncology clinic-building. However, we will differentiate and illuminate the techniques that leverage the virtual underpinnings of pandemic clinic-building. We submit that it is feasible to establish a new Cardio-Oncology Clinic for cancer patients or survivors with or at risk for cardiovascular toxicity from cancer therapy during a pandemic, providing optimal care for new patients in the midst of the need for safety and minimizing exposure. We also propose virtual resources for patients and clinicians and describe innovative future directions in the pandemic and post-pandemic period.
Fig. 1 The Virtual-Hybrid Approach to Cardio-Oncology Clinic-building in the pandemic
Methods
Virtual-hybrid approach
We pursued a Virtual-Hybrid Approach of information seeking, information gathering, and information sharing (Fig. 1). For information seeking, we focused on institutions that already had a Cardio-Oncology clinic in place. Prior to the COVID-19 pandemic, substantial experience was gained at an established in-person Cardio-Oncology clinic at a world-renowned leading hospital. Published manuscripts on pre-pandemic building and operations of Cardio-Oncology clinics at other institutions were reviewed. Extensive networking with leaders of Cardio-Oncology clinics around the United States and in the United Kingdom was accomplished at regional, national, and international meetings in person and on social media in a hybrid approach. These meetings were attended in person pre-COVID-19 and virtually during the pandemic. For information gathering, we addressed the location in which the new Cardio-Oncology clinic would be built. We learned about existing resources in the destination Heart & Vascular Center and existing needs and patients in the destination partner cancer center. We networked with physicians, advanced practice providers (APPs), nurses, service line leaders, and administrators in the Heart & Vascular Center and the cancer center, as well as in primary care and other supporting specialties. The subsequent Cardio-Oncology clinic sessions were intermingled with other subspecialty areas, to optimize availability for patient visits while filling clinic slots and tailoring spectrum of care to emerging patient needs. Cardio-Oncology patient visits were included in multi-subspecialty clinics.
Retrospective study design
For quantitative data, we pursued a retrospective observational study to determine the distribution of outpatient visits in the first 3 months of our virtual-hybrid Cardio-Oncology Clinic. We reviewed data from charts of patients (all were 18 years of age or older) who received outpatient care from the new Director of Cardio-Oncology at F&MCW between April 15, 2020 and July 17, 2020 to determine which of these patients were considered to be in Cardio-Oncology, Preventive Cardiology, or General Cardiology. We collated all three to determine the percentage of patients seen in Cardio-Oncology, compared to the other two specialties. Preventive Cardiology was collated as a partner clinic to help build the Preventive Cardio-Oncology component of the Cardio-Oncology Clinic, to help apply established principles for prevention. From among the multi-subspecialty clinic sessions, we determined the proportion of patients who were specifically cancer patients or survivors with or at risk for cardiovascular toxicity from cancer therapy and thereby seen in the Cardio-Oncology Clinic. Next, we identified the distribution of cardiovascular toxicities in cancer patients or survivors seen in the Cardio-Oncology Clinic. We also evaluated the spectrum of cancer drugs received by cancer patients or survivors seen in the Cardio-Oncology Clinic. In addition, we summarized the types of cancers in patients seen in the Cardio-Oncology Clinic. Finally, we assessed the frequency of virtual visits during the course of the pandemic over our first 3 months for patients seen in the Cardio-Oncology Clinic. This retrospective review was approved by the F&MCW IRB; HIPAA informed consent was waived for this minimal risk study, which did not involve any form of intervention and was conducted in compliance with good clinical and research practice. The team designed and carried out the study with reliance on virtual communication tools.
Data collection and analysis
Data gathering, management, and analysis were conducted at F&MCW. We collected patient-related, disease-related, treatment-related, and outcome-related data, particularly patient sex, type of appointment (new versus established, virtual versus in-person), type of cancer (e.g., breast, prostate, leukemia, lung), type of cancer drug, and type of cardiovascular toxicity (e.g., cardiomyopathy, hypertension). In order to minimize any risk of breaching patient confidentiality, all data collection occurred on institutional-based computing environments with de-identified data used for analyses. There were no alternative procedures for the subjects as this is a retrospective review of data that are not amenable to prospective collection and review. Descriptive graphs or tables of patient-, disease-, treatment-, and outcome-related variables distributions were prepared, with no comparisons made needing statistical tests.
Results
Virtual preparation
Preparation for starting the Cardio-Oncology clinic followed a Virtual-Hybrid Approach (Fig. 1, left). Five overarching factors employing virtual communication methods emerged to ensure the successful launching of the clinic. Team and individual experience and exposure to various areas of interest in Cardio-Oncology were achieved and assessed before and during the pandemic. Far-reaching connections to experts and potential collaborators in the field were developed and exercised. Close contact with the institution launching this clinic was important to determine the resources available; these resources dictated the strategy and potential outcomes of the clinic. Importantly, the expectations of others for the Cardio-Oncology clinic were determined and incorporated. Finally, recognition of the limitations that exist at the destination institution guided care and goal setting.
Virtual inquiry
Before initiating the Cardio-Oncology clinic in the destination institution, existing structures, patient base, and needs in the Heart & Vascular Center as well as the Cancer Center were evaluated, adhering to pandemic protocols (Fig. 1, middle). Pre-existing building blocks for the planned Cardio-Oncology clinic were assessed, and the partner Preventive Cardiology clinic was investigated. We also evaluated characteristics of the cancer center patient population to best position the clinic for success.
Virtual niche-building
Five main aspects of niche-building were pursued. Partnerships with Vascular and Cancer Center physicians, advanced practice providers, and service line leaders were developed to initiate and grow the clinic (Fig. 1, middle). The Cardio-Oncology team and clinic flexibility were demonstrated through openness to taking quicksteps. Presentations were made at Grand Rounds and rounds across the institution in Cardiology, Hematology/Oncology, Radiation Oncology, Surgical Oncology, Internal Medicine, and Family Medicine to promote the clinic capabilities. Collaborative solutions for problems facing fields complementing Cardio-Oncology developed trust and collaboration. Teamwork was developed by leveraging diversity of perspectives and virtual communication technologies, to establish effective patient care despite COVID-19 limitations.
Hybrid care Spectrum
The hybrid F&MCW Cardio-Oncology Clinic was initiated and established in the outpatient setting, in close partnership with the Preventive Cardiology Clinic, Cancer Center, and inpatient Cardiology Consult and Hematology/Oncology teams (Fig. 1, right).
Initial and subsequent visits have been completed in person or by video, with phone visits also available for virtual return visits if patients without adept and available smartphone use have limited ability to appear in person. Virtual patient visits over our first 3 months occurred with the use of telemedicine platforms integrated with Epic (via MyChart for patients and Haiku/Canto for clinicians), or using the Doximity video call function. Patients with in-person appointments are screened appropriately on arrival for signs or symptoms of COVID-19 or exposure, following institutional protocols. Wearing masks is required of all patients, and each patient can be accompanied by a family member; some choose to also wear gloves or face shields. There is sufficient room for maintaining social distancing in the clinic waiting room and hallways.
Innovation
Current innovation in the clinic also includes Virtual Clinician Tools and Virtual Patient Resources (Fig. 2). For clinicians, the links for an AHA CME course on Novel Concepts, Current Debates and Treatment Considerations in Cardio-Oncology, an online Cardio-Oncology Compendium hosting risk assessment clinical decision aids, Cardio-Oncology Drug Regimen and Acronym Databases, and UPTODATE access for reviewing Cardio-Oncology drug information are supplied. For patients, the video from the International Cardio-Oncology Society explaining the Cardio-Oncology subspecialty, American College of Cardiology (ACC) mobile health (mHealth) CardioSmart education app and website, Cancer Heart Talk mini-podcast series accessed via SoundCloud app and website, Cardio-Oncology Frequently Asked Questions, and ChemoCare website are provided for patient-facing Cardio-Oncology and heart anatomy and physiology education, engagement, and awareness. Virtual Resources for Preventive Cardio-Oncology are also made available to our patients. These include the American Heart Association (AHA) Physical Activity Recommendations, AHA Life’s Simple 7 Webpages, American Society For Preventive Cardiology Online Coaching Webpages in partnership with Intervent, and the Become An Ex Smoking Cessation Support Webpages in partnership with Mayo Clinic. The resources are provided in the Epic patient portal MyChart, and more ways to make the resources accessible to a broad and diverse patient population are in development. Future innovation in the clinic will explore contemporary initiatives connecting patients and their safely guarded data with their permission with wearable devices, health information technology, informatics, artificial intelligence, personalized medicine, and additional mobile health (mHealth) applications.
Fig. 2 Virtual patient and clinician education and resources. Available online as PDF with hot links in the CardioOnc Compendium (https://tinyurl.com/CardioOncCompendium)
Virtual visit infrastructure and timeline
There was no pre-existing Cardio-Oncology program at the time of launching our de novo Virtual/Hybrid Cardio-Oncology Clinic. The newly recruited Director of Cardio-Oncology was tasked with the responsibility of launching the new clinic, with support from the Heart & Vascular Center clinic administrators, medical director, and Cardiology Division and Department of Medicine leadership. Prior to opening the Cardio-Oncology Clinic, the Heart & Vascular Center initiated virtual conversion then additionally collaborated with Inception Health (MCW’s innovation lab company) over the course of 4 weeks to iteratively develop the clinical informatics infrastructure for virtual visits. The video visits were designed to function using clinician’s personal smartphones, iPads, and tablets, with direct web browser video links from the electronic health record mobile application. Direct video calls through the Doximity mobile application were also approved. Existing Inception Health personnel re-allocated their time in order to adopt and maintain responsibility for the virtual component of all ambulatory clinics across the health system, in partnership with medical and administrative directors of each clinic area, such as the Heart & Vascular Center. No additional costs or hires were pursued to facilitate the development of the virtual visit infrastructure and timeline. Existing resources and personnel were re-allocated to virtual visit design to enable building the virtual clinics in the Heart & Vascular Center. To assist clinicians and billing compliance colleagues, note templates were created for video and phone visits to indicate patient informed consent for virtual visits due to the pandemic, as well as to capture limited appropriate physical examinations, in addition to the amount of time spent on records review and real-time medical counseling.
Initial consults were electronically triaged by either a cardiologist or a cardiology fellow supervised by a cardiologist. Each triage team determined which consults would be appropriate as virtual video visits, versus in-person to occur once the Heart and Vascular Center started re-opening routine physical visits, or whether patients needed to be evaluated urgently in person. During the first week of operation, the brand-new Cardio-Oncology Clinic started entirely virtually with only video and phone visits. As the Heart and Vascular Center re-opened for physical patient visits the following week, from week 2 through the remainder of the first 3 months the Cardio-Oncology Clinic had both virtual and in-person visits integrated throughout each clinic session weekly, based on whether patients were new and whether they had smart device or computer functionality available.
Virtual referral network and process
Cardio-Oncology patient assessment begins within a referral network before the patient arrives at a Cardio-Oncology clinic. Consequently, forming a virtual referral network and enacting a user-friendly virtual referral process was a key component of building the Cardio-Oncology clinic during the pandemic. All referral patterns and networks for our de novo Cardio-Oncology Clinic were built from the ground up. Initial referrals were from within our health system; this quickly expanded to consults from outside of our health system encompassing the entire state. Patients were referred to our Clinic by clinicians or by self-referrals. Some of our local patients connected to us after being introduced to us by their clinicians in other states or through family members in other states who learned about us from their own clinicians or community-based Cardiology society outreach events.
Referrals across the institution and outside of our health system have come to us from the Divisions of Hematology and Oncology, Internal Medicine, Family Medicine, Surgical Oncology/Breast Clinic, and Survivorship Clinics. From the cancer center’s perspective, there may be many “triggers” that would warrant a Cardio-Oncology referral. For example, an abnormal ECG, an abnormal echocardiogram, cardiovascular symptoms, previous cardiovascular history (e.g., coronary artery disease, hypertension, cardiomyopathy) particularly in a patient who previously underwent treatment or is beginning new treatment with cardiotoxic neoplastic medications or radiation therapy and is at high risk of cardiovascular toxicity, or those in preparation for stem cell transplant, or oncologic surgery. Referral protocols were determined based on standard practice, discussions with colleagues in Medical and Radiation Oncology, Hematology, Bone Marrow Transplant, Surgical Oncology/Breast Clinic, Children’s Hospital, Radiation Oncology, Primary Care, and updated literature reviews.
Cancer survivors are at a higher risk than the general population for cardiovascular morbidity and mortality. If a cancer survivor needing to be evaluated is already under the care of a cardiologist, the referring provider can reach out to their cardiologist for guidance on the appropriate CV surveillance. If they do not already have a cardiologist, a Cardio-Oncology consult should be requested. The Cardio-Oncology consult can be placed using a direct Cardio-Oncology button within the universally available Cardiovascular Consult order panel. Referrers can also place a General Cardiology consult and mention the Cardio-Oncology physician by name as requested by the clinician or patient. An E-Consult functionality is also being implemented for those patients who need to be assessed sooner than the next available appointment, or for those patients who may not need a full Cardio-Oncology evaluation, or if referring providers are uncertain. The e-consult can also be placed as a second opinion requested by the inpatient Cardiology Consult team.
The inpatient Cardiology Consult service will continue to directly address inpatient consults from the inpatient hematology/oncology services. The inpatient Cardiology Consult service can collaborate with the Cardio-Oncology Clinic via formal Cardio-Oncology E-consults in the electronic health record Epic if a specific focused question arises regarding Cardio-Oncology relevant to the care of individual currently hospitalized patients that have already been formally evaluated by the inpatient Cardiology Consult service. After a patient has been formally evaluated by the inpatient Cardiology Consult service, if the patient is appropriate for outpatient follow up in the Cardiology clinic with Cardio-Oncology, this should be communicated to the primary Hematology/Oncology service. If appropriate at the time of consultation, the inpatient cardiology consult service can make the follow-up appointment. Oftentimes, this patient population remains in the inpatient setting for several weeks. If this is the case, the Cardiology clinic phone number and clinician information should be provided to the primary service to do so prior to the patient being discharged from the hospital.
Virtual-hybrid multidisciplinary team
It is important to develop a multidisciplinary team and initially focus on allocation of pre-existing resources. Accordingly, some roles among our Cardio-Oncology clinic personnel are shared with other subspecialties. Our virtual-hybrid multidisciplinary Cardio-Oncology Clinic personnel include physicians, a nurse practitioner (NP), a nurse, a research support specialist, medical assistants, pharmacists, administrative assistants, and administrators. All personnel with pre-existing in-person roles and practices re-allocated a portion of their time to the development and practice of virtual visits.
Our clinic and partners consist of board-certified Cardiologists with special training in various cardiac subspecialties (e.g., cardio-oncology, preventive cardiology, heart failure and transplant, electrophysiology, interventional cardiology), who collaborate closely with our cancer experts. Our physicians together specialize in the prevention, diagnosis, and treatment of heart and vascular disorders resulting from side effects of cancer therapy. Our comprehensive team of advanced practice providers, nurses, and pharmacists work alongside our physicians to care for patients from the moment of cancer diagnosis through life’s survivorship journey. The NP typically sees established patients when needed to follow up on imaging, intervention, or diagnostic and management plans, and may also see select new patients. In complex cases, the NP discusses the care of established patients with both the cardio-oncologist and the referring clinician. The nurse assists with patient triage and communications (including addressing patient requests and queries), liaises closely with the nurse practitioner and pharmacists, and educates patients on Cardio-Oncology using virtual materials. Our clinical pharmacists function at the highest level of their advanced training, similar to all clinic personnel, and assist with medication education, review, titration, discussion, and prescription, particularly for heart failure, hypertension, hyperlipidemia, and smoking cessation, as well as commenting on potential drug interactions.
For Preventive Cardio-Oncology, we additionally partner with our dietitians and exercise physiologists to help advise our patients on nutrition and exercise plans, as well as our colleagues in cardiopulmonary stress testing where applicable. Further, in the pandemic, we provide patients with free online coaching options for lifestyle modification (Fig. 2). We also direct patients to AHA webpages with guidance on pursuing ideal cardiovascular health.
Virtual-hybrid patient flow
Once a referral is placed by the designated order buttons in the electronic health record, central schedulers or the Cardio-Oncology Clinic administrative assistant schedule the new patient for a video or in-person visit (Fig. 3). The clinic administrative assistant works closely with our health professionals in our interdisciplinary advanced subspecialty clinic to gather relevant clinical reports and history pertinent to patient appointments. Virtual medical assistants contact patients a few days before their appointments to confirm and troubleshoot virtual connectivity. On the appointment day, medical assistants then ‘room’ patients for virtual or in-person visits by preparing patients for their medical visits (including reviewing medications and in-person or at-home virtual vital signs), and also rechecking virtual connectivity for video visits. The clinician then completes the visit virtually or in-person and introduces the patient to the range of electronic resources available. Following the visit, the clinical administrative assistant arranges follow-up testing and appointments.
Fig. 3 Virtual-Hybrid Patient Flow Chart. Admin = Administrative; MA = Medical Assistant; MD = Medical Doctor; NP = Nurse Practitioner
Virtual risk assessment
Baseline risk assessment and follow-up start with oncology and primary care [21]. Asymptomatic low risk patients with low-risk treatment plans can have continued assessment and follow-up by oncology and primary care in partnership. Patients who have symptoms, are at high risk based on their history, or are planned for high-risk treatment plans should be referred to Cardio-Oncology for prevention, monitoring, and management recommendations. Recommendations should adhere to society expert consensus, scientific statements, and guidelines for prevention, surveillance, and survivorship, and optimize CVD risk and medications [21]. A putative risk score based on medication-related and patient-related risk factors can be used to guide monitoring and management recommendations for most Cardio-Oncology patients [22], and can be used in a virtual clinical decision aid (https://tinyurl.com/CardioOncCDA) (Fig. 4). Specific risk scores are also available for adults treated with anthracyclines, trastuzumab, or other drugs, or for adult survivors of childhood cancers [9–13].
Fig. 4 Virtual Cardio-Oncology clinical decision aid (CDA). Risk assessment (https://tinyurl.com/CardioOncCDA) to guide monitoring and management recommendations regarding development of cardiomyopathy for most Cardio-Oncology patients; a CDA specifically for women with early breast cancer is also available in the CardioOnc Compendium (https://tinyurl.com/CardioOncCompendium)
Virtual management algorithms
Evidence-based management algorithms have been selected or developed as adjunctive resources for inpatient teams. They are available online in a virtual collection for use in the inpatient setting by the inpatient Cardiology Consult service or hematology/oncology teams to assist with diagnosis and treatment of cardiovascular toxicities from cancer therapies or cancer itself. The algorithms cover cardiomyopathy from anthracyclines or trastuzumab, planned chemotherapy with pre-existing cardiomyopathy, neurohormonal therapy or dexrazoxane for cardioprotection, myocarditis, persistent malignant pericardial effusion, hypertension, surveillance after radiation therapy or drugs that cause ischemia, malignant pericardial effusion, and other salient topics frequently encountered.
Virtual community engagement
The local, regional, national, and international community was virtually engaged via social media posts on Twitter (using #MCWCardioOnc on @DrBrownCares or @PrevCardioOnc), podcasts hosted by the MCW CTSI (available on iTunes, Google, and Apple podcast platforms), Heart Success podcast series, and Cancer Heart Talk brief 15-min mini-podcast series (available on SoundCloud). Perspectives were also published for international community engagement in the Women Heart Alliance newsletter, as well as on the AHA Early Career Blog, ACC Women in Cardiology Blog, CardioOncTrain.Com Blog, and PrevCardioOnc.Com Blog. Virtual continuing medical education (CME) presentations were also given at the Wisconsin state ACC annual conference meeting, Midwest ACC annual conference meeting, Southeast ACC annual conference meeting, Brazilian Cardio-Oncology Symposium, and the Ohio State Cardio-Oncology CME conference, then subsequently at the AHA and ACC annual national scientific sessions.
Distribution of patient data
In our multi-subspecialty clinic visits (virtual and in-person integrated and combined; n = 182; 136 new and 47 returns), approximately 50% of patient visits were in Cardio-Oncology, 20% were in Preventive Cardio-Oncology, and 30% were in General Cardiology (Fig. 5a). Overall among Cardio-Oncology visits, 65% were in person, consistent with early and safe clinic re-opening in a hybrid model, with 19% by video and 16% by phone, with the fraction by phone decreasing over time as patients and clinic personnel became more adept with troubleshooting video. Of new patients, 77% were in person, and the remainder by video. No Cardio-Oncology patients presenting in person developed any signs or symptoms concerning for COVID-19.
Fig. 5 Initial Clinic-Building Outcomes Using the Virtual-Hybrid Approach. a Distribution of Cardio-Oncology, Preventive Cardio-Oncology, and General Cardiology patients seen in our multi-subspecialty clinic visits. b Distribution of cardiovascular diagnosis or indication for referral. c Distribution of cancer drugs. d Distribution of cancer types
The most frequent cardiovascular diagnosis or indication for referral was cardiomyopathy (34%) (Fig. 5b). Other diagnoses included decrease in global longitudinal strain, diastolic congestive heart failure, hypertension, myocarditis, dyspnea, chest pain, palpitations, survivorship, risk assessment, and pre-bone marrow transplant, among other cardiovascular diagnoses or visit indications. The most frequent cancer drug was trastuzumab (29%) (Fig. 5c), managed according to a novel algorithm developed in our de novo Virtual-Hybrid Cardio-Oncology Clinic based on the recent publication indicating the safety of continuation of trastuzumab for left ventricular ejection fraction of 40% or greater [23] (Fig. 6). The second most frequent cancer drug was anthracycline (24%). Other drugs included, tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), endocrine therapies, and investigational therapeutics, among others. The most frequent cancer type in our clinic was breast cancer (42%) (Fig. 5d). These trends in cardiovascular diagnosis or indication and cancer drugs or types were similar in assessments of virtual visits alone, with the most frequent being cardiomyopathy (43%), trastuzumab (41%), and breast cancer (44%), respectively. The findings of similar cardiovascular and cancer distributions in virtual versus in-person visits indicated an optimal qualitative return on resource and personnel investment.
Fig. 6 Algorithm for Continuation of Trastuzumab Therapy with Mild LV Dysfunction
Imaging and medication titration
In our clinic, a distribution of cardiovascular diagnoses determines the imaging needed for each patient (Fig. 5b). Therefore, a number of imaging modalities are useful to our patients (e.g., echocardiography, computed tomography with or without angiography, magnetic resonance imaging, coronary angiography, myocardial perfusion imaging). Our most frequently used imaging modality is echocardiography. The frequency of obtaining echocardiograms has depended on each patient’s condition and cancer treatment. A substantial portion of patients coming to us on trastuzumab have needed an echocardiogram every 1–3 months, depending on the extent of adverse effects on left ventricular ejection fraction (LVEF) or strain In these patients, medication titration has occurred approximately every 2 weeks, and for very symptomatic patients with volume overload, they have often been seen weekly..
In our management algorithms, early referral prior to the onset of symptoms has been emphasized, especially in cancer patients or survivors with a history of cardiovascular disease, cardiotoxic neoplastic agents, or a high risk of cardiovascular toxicity. This has provided an opportunity for us to assess and discuss ways to optimize the benefit to risk ratio of continuing with the current cancer treatment plan, and more importantly how and when to put cardioprotective measures in place to facilitate safe cancer therapy. Such discussions have also resulted in closer monitoring. Some conditions have warranted proceeding to other modalities of non-invasive imaging, such as cardiac MRI if myocarditis is suspected. For cases in which coronary artery disease is suspected, our patients undergo functional assessment of their coronaries with a stress test or anatomical assessment with a coronary CT scan or invasive coronary angiography. In our practice, only exercise stress tests were halted due to the pandemic. Every other form of imaging including rest and stress echo, as well as MRI and nuclear medicine have remained readily available for those with cardiovascular toxicities or individuals considered to be at moderate or high risk. This allowed us to adhere to pre-pandemic imaging recommendations tailored during the pandemic to limit imaging if possible to those who are at higher risk for cardiovascular toxicities or who have already been diagnosed with these adverse effects [1–4] (e.g., Fig. 6).
Discussion
The COVID-19 pandemic has inevitably compelled leaders of healthcare clinics to rethink and restructure approaches to deliver optimal care for patients. Our brand-new Cardio-Oncology clinic has been built to thrive in this new pandemic landscape by utilizing virtual technology as one of the key components of our clinic-building and care model since its inception. While existing clinics have reinvented their operations through the uptake of technology, our clinic has been able to capitalize on this resource to deliver virtual-hybrid care from the start. Virtual communication has proved useful to coordinate referral networks and care among providers within a multidisciplinary team across different clinics and departments. We see a variety of cancer patients, types, and drugs (Fig. 5), and our distribution results are generally congruent with reports from other leading cardio-oncology clinics [8, 14, 15, 17, 22].
Various methods have been developed for risk assessment to help guide providers and patients in determining the appropriate guidelines for care. We offer the use of virtual risk assessment tools such as the computed risk scores based on medication- and patient-related risk factors [22] (Fig. 4) (https://tinyurl.com/CardioOncCompendium), as well as recommendations for establishing cross-provider partnerships to continuously evaluate risk [21]. Other online databases containing useful information and guidelines are readily accessible and can help guide clinical practices. We encourage use of these virtual tools, which can further facilitate collaborative Cardio-Oncology care in the pandemic. Our conversations with international colleagues have suggested additional utility of these virtual tools beyond the pandemic. The online resources can be very helpful in settings where clinical practitioners work alone without support from nurses, pharmacists, nutrition specialists, or exercise physiologists.
Virtual-hybrid care has extended the care team’s capabilities for delivering and maintaining patient education and follow-up. The internet continues to be a robust resource, containing a wealth of health information that is easily accessible to the general population. Various mobile applications and electronic devices have also been developed in recent years to educate, track, and manage patients’ health and lifestyles. While these tools provide patients with greater accessibility and independence, they also create a valuable opportunity for healthcare providers to further engage patients. In a virtual-hybrid model, this becomes increasingly important, as patients may frequently transition between virtual and in-person visits. Forming care partnerships with patients through these virtual information and health-tracking resources becomes crucial in the continuity of care and proper health maintenance as we move through the pandemic.
Our most frequent cardiovascular diagnosis was cardiomyopathy (34%), which is reflective of the management need that first helped start the emerging field of Cardio-Oncology, and is similar to the most frequent cardiovascular diagnosis noted by clinicians from several other leading centers (20–35%) [24, 25]. However, Cardio-Oncology has grown remarkably over the last 10–20 years, with a wide spectrum of cardiovascular diagnoses and indications for referral (Fig. 5b) [8, 14]. Accordingly, at some other leading centers, the most frequent cardiovascular diagnosis or indication for referral has been reported as hypertension [14], arrythmia [17], or comprehensive risk assessment prior to beginning of therapy to optimize cardioprotection [8] in the practice of Preventive Cardio-Oncology [21]. This illustrates an opportunity for growth in our Clinic, to increase the fraction of high-risk patients who undergo comprehensive cardiovascular risk evaluation and management of risk factors prior to administration of cardiotoxic therapy.
Our clinic cares for patients with a range of cancer types (Fig. 5d). Individuals with breast, lung, and hematologic cancers represent a substantial proportion of our patient population, similar to other Cardio-Oncology clinics [8, 14, 22, 26]. The most frequent cancer diagnosis, breast cancer (43%), is consistent with reports from other leading cardio-oncology clinics such as the Mayo Clinic (39.2%) [15] and the Cleveland Clinic in Florida (44.3%) [14]. While hematologic malignancies such as leukemia and lymphoma represented 29% of our patients and was the second most prevalent cancer within our cohort, they comprised the most frequent forms of cancer at other cardio-oncology clinics such as at the Moffitt Cancer Center (31%) [8] and at UCLA (32.70%) [25]. However, the absolute difference was relatively insignificant. Overall, similar to these established cardio-oncology clinics, we receive patients from across a variety of cancers.
A wide breadth of cancer therapeutics is associated with cardiotoxicity [21]. Anthracyclines associate with cardiomyopathy, especially when used with trastuzumab. Targeted therapies (e.g., TKIs) can cause new or worsening of pre-existing hypertension. ICIs are associated with an increased incidence of myocarditis. Some cytotoxic chemotherapeutics, such as cisplatin, increase the risk of venous thromboembolism, and antimetabolites such as fluoropyrimidines have long been associated with a broad range of cardiotoxicities. Radiation therapy is associated with ischemic heart disease, valve dysfunction, conduction abnormalities, pericardial disease, and cardiomyopathy. Patients with cancer who have developed cardiovascular toxicity or who may be at high risk for cardiovascular toxicity should be referred to the Cardio-Oncology clinic for close follow-up.
The most frequently used cancer medication used among our patients was trastuzumab (29%), with the second most frequent being anthracyclines (24%). This was similar to other institutions, with anthracyclines and trastuzumab among the most common cancer drugs in their Cardio-Oncology clinics. Yet, anthracyclines were typically noted more commonly than trastuzumab. The Cleveland Clinic in Florida saw patients most commonly treated with radiation (40%), followed by anthracyclines (26.8%) [14]. The Moffitt Cancer Center most frequently had patients who were treated with anthracyclines (52%), with HER2 targeted therapies representing 27% of the cancer drugs [8]. This difference may reflect a high frequency of patients with HER+ breast cancer in our population (diagnosed by a ratio of HER2 to chromosome 17 signals on dual probe fluorescent in situ hybridization ≥2 or ≥ 6 HER2 signals/cell [27]), as well as the keen attention to a substantial fall in left ventricular ejection fraction or global longitudinal strain as a potential prognostic factor in our patients, per American Society of Echocardiography (ASE) guidelines [28].
All of these patient data distributions were obtained in the context of the Virtual-Hybrid patient flow in our de novo Cardio-Oncology Clinic (Fig. 3), that can be modeled by other future Virtual-Hybrid Cardio-Oncology clinics initiated during the pandemic. Table 1 compares the first few weeks of our de novo C-O clinic setup model with two published manuscripts describing conversion of pre-existing in-person C-O clinics to providing telehealth visits as an option for patients. The table shows similar numbers of patients seen in the initial periods of the clinics, although the numbers in our new clinic went from 0 to 10 in the first 3 weeks, compared to going from up to 40 patients weekly to 11 patients in 2.5 weeks for a group that converted their in-person clinic to a virtual option. Overall, CV diagnoses and cancer types were comparable; distributions of cancer drugs were not reported by the other group. Important differences were noted. Most of our patients in the pandemic were new (90%), given the de novo status of the Cardio-Oncology Clinic, while the converted virtual clinic of another group initially focused on established patients for > 50% of their patient visits. While key personnel were also the same (e.g., physician, advanced practice provider, nurse or nurse coordinator), we also report virtual versions of supportive staffing patterns, including the virtual scheduling and rooming process and pharmacy and lifestyle modification visits. Additionally, trainees have been integrally involved in the establishment of our Cardio-Oncology Clinic, with residents training in program-building, and medical students and fellows training in ambulatory cardio-oncology clinical practice and cardio-oncology critical thinking, respectively. Finally, besides the patient flow (Fig. 3) and de novo nature of our Virtual-Hybrid clinic initiated in the pandemic, our unique contribution may be the virtual resources, compared to the essential “webside manner” [7] or an alternative algorithm [4] for triaging virtual or in-person visits to the physician or advanced practice provider (Table 1).
Table 1 Comparisons Among Clinic Models Described In The Pandemic
Virtual-Hybrid Clinic Telehealth Clinic (14) Triage Clinic (4)
Model Type De Novo Conversion Conversion
Time Frame Compared 3 weeks 2.5 weeks Not reported
Number of Patients 10 11 Not reported
New Visits (%) 90 45 Not reported
Variety of CV Diagnoses Yes Yes Not reported
Variety of CA Types Yes Yes Not reported
Variety of CA Drugs Yes Unknown Not reported
Referrals Yes Unknown Yes
Scheduling Yes Unknown Not reported
Rooming Process Yes Unknown Not Reported
Virtual AA Yes Unknown Not Reported
Virtual MA Yes Unknown Not Reported
Virtual Physician Yes Yes Yes
Virtual APP Yes Unknown Yes
Virtual Pharmacist Yes Unknown Not Reported
Virtual Nurse (Coordinator) Yes Unknown Yes
Unique Contribution Virtual Resources Webside Manner Triage Algorithm
Similar to the formation or conversion of Cardio-Oncology clinics, many protocols for treatment regimens and cancer patients are yet to be standardized. While no standard protocols have been widely adopted at Cardio-Oncology practices, various institutions and writing groups have proposed some approaches (e.g., ASE or ASCO guidelines). We have collaboratively developed institutional algorithms for various cardiovascular toxicities and medications based on existing scientific statements, society guidelines, expert consensus statements, and manuscripts from leading cardio-oncology research institutions. The goal is to adopt, adapt, develop, and continuously update these algorithms, as new literature arises in order to establish best practices and an institutional standard of care.
Conclusion
Starting a new Cardio-Oncology Clinic in the pandemic has its challenges, and yet for our patients can be invaluable. Appropriately competing priorities in the pandemic can limit the scheduling of meetings and gathering of people together in one virtual room to discuss a mutual vision. Gathering resources for patient and clinician education can also be formidable, as can social distancing and obtaining important imaging. However, multiple virtual one-on-one or small group meetings can be beneficial for building institutional relationships. Similarly, virtual visits have risen to the challenge to ensure maintenance of patient care throughout the pandemic. Modifications have also been made to enable safety and distancing during imaging. With the benefit of these adjustments to address the challenge, this report provides a foundation for initiating a cardio-oncology clinic in the pandemic, with virtual resources and tools to equip patients and clinicians.
In the future, we will also lay out a roadmap for initiation of comprehensive cardio-oncology programs with the five pillars of patient care, education, research, community engagement, and innovation in the era of digital transformation accelerated by the pandemic. Novel risk modifiers and risk attenuation methods, such as breast arterial calcification, clonal hematopoiesis of indeterminate potential, and Cardio-Oncology prehabilitation, habilitation, and rehabilitation will also be addressed. Future innovation to implement recommendations from clinical trials across the nation currently underway that utilize mobile health or web-based diet and physical activity interventions and/or seek to determine the impact of cardioprotective pharmacotherapy in Preventive Cardio-Oncology will also be assessed (ClinicalTrials.Gov: NCT01988571, NCT02943590, NCT02562716, NCT01968200, NCT03265574, NCT03760588, NCT03386383, NCT02244411, NCT03223753). Many of these studies incorporate virtual technologies that will be very helpful during and after the pandemic as we continue pursuit of digital transformation.
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Acknowledgements
We are grateful to the following individuals, as well as all of the departments and divisions at Froedtert & MCW that have rallied together to help us establish the hybrid Cardio-Oncology clinic or to see our patients needing subspecialty care, or to partner with us in referrals from the inpatient service, especially the following clinicians: Stacey Gardiner MD, Jason Rubenstein MD, David Ishizawar MD, Jalaj Garg MD, Andrew Rosenblum MD. We are also grateful to Nicole Lohr MD PhD and the clinical sections at the Zablocki Veterans Administration Medical Center that have also helped us establish an affiliate Cardio-Oncology Clinic in tandem at the VAMC in Milwaukee, WI.
Authors’ contributions
SAB conceived of the study, obtained, analyzed and interpreted the data, and made a substantial contribution to the writing of the manuscript; SP made a substantial contribution to the writing of the manuscript; DR made a substantial contribution to the writing of the manuscript; SZ obtained the data and made a substantial contribution to the writing of the manuscript; ML interpreted the data and made a substantial contribution to the writing of the manuscript; TN made a substantial contribution to the writing of the manuscript; BS analyzed the data and made a substantial contribution to the writing of the manuscript; RM made a substantial contribution to the writing of the manuscript; JMac made a substantial contribution to the writing of the manuscript; KD made a substantial contribution to the writing of the manuscript; JMes made a substantial contribution to the writing of the manuscript; DM made a substantial contribution to the writing of the manuscript; JS made a substantial contribution to the writing of the manuscript. All authors read and approved the final manuscript.
Funding
No funding was associated with this work.
Availability of data and materials
The datasets during and/or analyzed during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The study was approved by the Froedtert & MCW Institutional Review Board (ID PRO00038807); HIPAA informed consent was waived for this minimal risk study.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests. | TRASTUZUMAB | DrugsGivenReaction | CC BY | 33441188 | 18,793,759 | 2021-01-13 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Palpitations'. | A virtual-hybrid approach to launching a cardio-oncology clinic during a pandemic.
BACKGROUND
As cardiovascular disease is a leading cause of death in cancer survivors, the new subspecialty of Cardio-Oncology has emerged to address prevention, monitoring, and management of cardiovascular toxicities to cancer therapies. During the coronavirus disease of 2019 (COVID-19) pandemic, we developed a Virtual-Hybrid Approach to build a de novo Cardio-Oncology Clinic.
METHODS
We conceptualized a Virtual-Hybrid Approach including three arms: information seeking in locations with existing Cardio-Oncology clinics, information gathering at the location for a new clinic, and information sharing to report clinic-building outcomes. A retrospective review of outcomes included collection and synthesis of data from our first 3 months (at pandemic peak) on types of appointments, cancers, drugs, and cardiotoxicities. Data were presented using descriptive statistics.
RESULTS
A de-novo Cardio-Oncology clinic was developed structured from the ground up to integrate virtual and in-person care in a hybrid and innovative model, using the three arms of the Virtual-Hybrid Approach. First, we garnered in-person and virtual preparation through hands-on experiences, training, and discussions in existing Cardio-Oncology Clinics and conferences. Next, we gleaned information through virtual inquiry and niche-building. With partners throughout the institution, a virtual referral process was established for outpatient referrals and inpatient e-consult referrals to actualize a hybrid care spectrum for our patients administered by a multidisciplinary hybrid care team of clinicians, ancillary support staff, and clinical pharmacists. Among the multi-subspecialty clinic sessions, approximately 50% were in Cardio-Oncology, 20% in Preventive Cardiology, and 30% in General Cardiology. In the hybrid model, the Heart & Vascular Center had started to re-open, allowing for 65% of our visits to be in person. In additional analyses, the most frequent cardiovascular diagnosis was cardiomyopathy (34%), the most common cancer drug leading to referral was trastuzumab (29%), and the most prevalent cancer type was breast cancer (42%).
CONCLUSIONS
This Virtual-Hybrid Approach and retrospective review provides guidance and information regarding initiating a brand-new Cardio-Oncology Clinic during the pandemic for cancer patients/survivors. This report also furnishes virtual resources for patients, virtual tools for oncologists, cardiologists, and administrators tasked with starting new clinics during the pandemic, and innovative future directions for this digital pandemic to post-pandemic era.
Introduction
Cardio-Oncology care has been adjusted in the COVID-19 pandemic with limited in-person clinic or hospital visits, increased use of teleconsultation, less frequent imaging, increased reliance on biomarkers, and considerations of differential diagnoses involving COVID-19 when evaluating cancer patients or survivors for possible cardiovascular toxicity [1]. Monitoring and management algorithms have been developed to help guide virtual care [2–4]. In the pandemic, we have changed the way in which we provide healthcare services at our clinics and institutions. This has challenged us to restructure current systems for the safety of our patients.
Various forms of innovation have come to bear in the pandemic, including telemedicine, digital health, artificial intelligence, social media, informatics, big data, and precision medicine [5, 6]. Telemedicine is the primary form of innovation that has been most developed in the pandemic [2, 5, 7]. Social media has been very helpful for dissemination of information, as well as education, and has been integral for creating online groups for support and determining the best ways for proceeding in the pandemic and advocating for our patients and colleagues in this period [5, 6]. In addition, the Doximity social media application has been valuable to practices across the nation, due to its telehealth platform (Doximity Video and Phone; https://www.doximity.com/dialer-video).
Despite the growing need, and allowances made during the pandemic, many centers do not have formal Cardio-Oncology clinics. Starting a new clinic can be challenging. The COVID-19 pandemic has made the process significantly more difficult, with the need to minimize exposure and maximize patient safety.
Currently, limited information is available on how to start a Cardio-Oncology Clinic during a pandemic, albeit given the high risk of morbidity or mortality in COVID-19-positive patients who also have cancer or CVD [8–13]. Several institutions have published on their experiences with starting in-person Cardio-Oncology clinics prior to the pandemic [8, 14–17]. One group has reported on their conversion from existing in-person Cardio-Oncology visits to telemedicine consultations, seeing 11 patients virtually within a few weeks [7]. Many have considered implications of the pandemic on the practice and study of cardio-oncology [2, 4, 5, 18–20], and two groups have suggested models for clinics converting from existing in-person care to televisits [4, 5]. Yet, no groups have directly addressed steps for de novo virtual-hybrid clinic formation within the limitations of the pandemic and without conversion of a pre-existing Cardio-Oncology clinic.
Our report offers a template for other centers to develop their own new Cardio-Oncology clinics during the pandemic. We determined a Virtual-Hybrid Approach to clinic launch, with both virtual and in-person elements of three key arms: information seeking where there are existing Cardio-Oncology Clinics in place, information gathering where the clinic will be built, and information sharing to report on initial patient data demonstrating the success of the launch (Fig. 1). We then performed retrospective chart review to collect and synthesize data on the types of appointments (new versus established, virtual versus in-person), cancers (e.g., breast, prostate, leukemia, lung), cancer drugs, and cardiovascular toxicities (e.g., cardiomyopathy, hypertension) for patients seen virtually or in person in our new Cardio-Oncology clinic at Froedtert Hospital and Medical College of Wisconsin (F&MCW). Here, we will discuss our findings in the context of previous publications on launching Cardio-Oncology Clinics prior to the pandemic. Our results will present distributions of cancer drugs and types, and cardiovascular diagnoses, similar to previous publications on Cardio-Oncology clinic-building. However, we will differentiate and illuminate the techniques that leverage the virtual underpinnings of pandemic clinic-building. We submit that it is feasible to establish a new Cardio-Oncology Clinic for cancer patients or survivors with or at risk for cardiovascular toxicity from cancer therapy during a pandemic, providing optimal care for new patients in the midst of the need for safety and minimizing exposure. We also propose virtual resources for patients and clinicians and describe innovative future directions in the pandemic and post-pandemic period.
Fig. 1 The Virtual-Hybrid Approach to Cardio-Oncology Clinic-building in the pandemic
Methods
Virtual-hybrid approach
We pursued a Virtual-Hybrid Approach of information seeking, information gathering, and information sharing (Fig. 1). For information seeking, we focused on institutions that already had a Cardio-Oncology clinic in place. Prior to the COVID-19 pandemic, substantial experience was gained at an established in-person Cardio-Oncology clinic at a world-renowned leading hospital. Published manuscripts on pre-pandemic building and operations of Cardio-Oncology clinics at other institutions were reviewed. Extensive networking with leaders of Cardio-Oncology clinics around the United States and in the United Kingdom was accomplished at regional, national, and international meetings in person and on social media in a hybrid approach. These meetings were attended in person pre-COVID-19 and virtually during the pandemic. For information gathering, we addressed the location in which the new Cardio-Oncology clinic would be built. We learned about existing resources in the destination Heart & Vascular Center and existing needs and patients in the destination partner cancer center. We networked with physicians, advanced practice providers (APPs), nurses, service line leaders, and administrators in the Heart & Vascular Center and the cancer center, as well as in primary care and other supporting specialties. The subsequent Cardio-Oncology clinic sessions were intermingled with other subspecialty areas, to optimize availability for patient visits while filling clinic slots and tailoring spectrum of care to emerging patient needs. Cardio-Oncology patient visits were included in multi-subspecialty clinics.
Retrospective study design
For quantitative data, we pursued a retrospective observational study to determine the distribution of outpatient visits in the first 3 months of our virtual-hybrid Cardio-Oncology Clinic. We reviewed data from charts of patients (all were 18 years of age or older) who received outpatient care from the new Director of Cardio-Oncology at F&MCW between April 15, 2020 and July 17, 2020 to determine which of these patients were considered to be in Cardio-Oncology, Preventive Cardiology, or General Cardiology. We collated all three to determine the percentage of patients seen in Cardio-Oncology, compared to the other two specialties. Preventive Cardiology was collated as a partner clinic to help build the Preventive Cardio-Oncology component of the Cardio-Oncology Clinic, to help apply established principles for prevention. From among the multi-subspecialty clinic sessions, we determined the proportion of patients who were specifically cancer patients or survivors with or at risk for cardiovascular toxicity from cancer therapy and thereby seen in the Cardio-Oncology Clinic. Next, we identified the distribution of cardiovascular toxicities in cancer patients or survivors seen in the Cardio-Oncology Clinic. We also evaluated the spectrum of cancer drugs received by cancer patients or survivors seen in the Cardio-Oncology Clinic. In addition, we summarized the types of cancers in patients seen in the Cardio-Oncology Clinic. Finally, we assessed the frequency of virtual visits during the course of the pandemic over our first 3 months for patients seen in the Cardio-Oncology Clinic. This retrospective review was approved by the F&MCW IRB; HIPAA informed consent was waived for this minimal risk study, which did not involve any form of intervention and was conducted in compliance with good clinical and research practice. The team designed and carried out the study with reliance on virtual communication tools.
Data collection and analysis
Data gathering, management, and analysis were conducted at F&MCW. We collected patient-related, disease-related, treatment-related, and outcome-related data, particularly patient sex, type of appointment (new versus established, virtual versus in-person), type of cancer (e.g., breast, prostate, leukemia, lung), type of cancer drug, and type of cardiovascular toxicity (e.g., cardiomyopathy, hypertension). In order to minimize any risk of breaching patient confidentiality, all data collection occurred on institutional-based computing environments with de-identified data used for analyses. There were no alternative procedures for the subjects as this is a retrospective review of data that are not amenable to prospective collection and review. Descriptive graphs or tables of patient-, disease-, treatment-, and outcome-related variables distributions were prepared, with no comparisons made needing statistical tests.
Results
Virtual preparation
Preparation for starting the Cardio-Oncology clinic followed a Virtual-Hybrid Approach (Fig. 1, left). Five overarching factors employing virtual communication methods emerged to ensure the successful launching of the clinic. Team and individual experience and exposure to various areas of interest in Cardio-Oncology were achieved and assessed before and during the pandemic. Far-reaching connections to experts and potential collaborators in the field were developed and exercised. Close contact with the institution launching this clinic was important to determine the resources available; these resources dictated the strategy and potential outcomes of the clinic. Importantly, the expectations of others for the Cardio-Oncology clinic were determined and incorporated. Finally, recognition of the limitations that exist at the destination institution guided care and goal setting.
Virtual inquiry
Before initiating the Cardio-Oncology clinic in the destination institution, existing structures, patient base, and needs in the Heart & Vascular Center as well as the Cancer Center were evaluated, adhering to pandemic protocols (Fig. 1, middle). Pre-existing building blocks for the planned Cardio-Oncology clinic were assessed, and the partner Preventive Cardiology clinic was investigated. We also evaluated characteristics of the cancer center patient population to best position the clinic for success.
Virtual niche-building
Five main aspects of niche-building were pursued. Partnerships with Vascular and Cancer Center physicians, advanced practice providers, and service line leaders were developed to initiate and grow the clinic (Fig. 1, middle). The Cardio-Oncology team and clinic flexibility were demonstrated through openness to taking quicksteps. Presentations were made at Grand Rounds and rounds across the institution in Cardiology, Hematology/Oncology, Radiation Oncology, Surgical Oncology, Internal Medicine, and Family Medicine to promote the clinic capabilities. Collaborative solutions for problems facing fields complementing Cardio-Oncology developed trust and collaboration. Teamwork was developed by leveraging diversity of perspectives and virtual communication technologies, to establish effective patient care despite COVID-19 limitations.
Hybrid care Spectrum
The hybrid F&MCW Cardio-Oncology Clinic was initiated and established in the outpatient setting, in close partnership with the Preventive Cardiology Clinic, Cancer Center, and inpatient Cardiology Consult and Hematology/Oncology teams (Fig. 1, right).
Initial and subsequent visits have been completed in person or by video, with phone visits also available for virtual return visits if patients without adept and available smartphone use have limited ability to appear in person. Virtual patient visits over our first 3 months occurred with the use of telemedicine platforms integrated with Epic (via MyChart for patients and Haiku/Canto for clinicians), or using the Doximity video call function. Patients with in-person appointments are screened appropriately on arrival for signs or symptoms of COVID-19 or exposure, following institutional protocols. Wearing masks is required of all patients, and each patient can be accompanied by a family member; some choose to also wear gloves or face shields. There is sufficient room for maintaining social distancing in the clinic waiting room and hallways.
Innovation
Current innovation in the clinic also includes Virtual Clinician Tools and Virtual Patient Resources (Fig. 2). For clinicians, the links for an AHA CME course on Novel Concepts, Current Debates and Treatment Considerations in Cardio-Oncology, an online Cardio-Oncology Compendium hosting risk assessment clinical decision aids, Cardio-Oncology Drug Regimen and Acronym Databases, and UPTODATE access for reviewing Cardio-Oncology drug information are supplied. For patients, the video from the International Cardio-Oncology Society explaining the Cardio-Oncology subspecialty, American College of Cardiology (ACC) mobile health (mHealth) CardioSmart education app and website, Cancer Heart Talk mini-podcast series accessed via SoundCloud app and website, Cardio-Oncology Frequently Asked Questions, and ChemoCare website are provided for patient-facing Cardio-Oncology and heart anatomy and physiology education, engagement, and awareness. Virtual Resources for Preventive Cardio-Oncology are also made available to our patients. These include the American Heart Association (AHA) Physical Activity Recommendations, AHA Life’s Simple 7 Webpages, American Society For Preventive Cardiology Online Coaching Webpages in partnership with Intervent, and the Become An Ex Smoking Cessation Support Webpages in partnership with Mayo Clinic. The resources are provided in the Epic patient portal MyChart, and more ways to make the resources accessible to a broad and diverse patient population are in development. Future innovation in the clinic will explore contemporary initiatives connecting patients and their safely guarded data with their permission with wearable devices, health information technology, informatics, artificial intelligence, personalized medicine, and additional mobile health (mHealth) applications.
Fig. 2 Virtual patient and clinician education and resources. Available online as PDF with hot links in the CardioOnc Compendium (https://tinyurl.com/CardioOncCompendium)
Virtual visit infrastructure and timeline
There was no pre-existing Cardio-Oncology program at the time of launching our de novo Virtual/Hybrid Cardio-Oncology Clinic. The newly recruited Director of Cardio-Oncology was tasked with the responsibility of launching the new clinic, with support from the Heart & Vascular Center clinic administrators, medical director, and Cardiology Division and Department of Medicine leadership. Prior to opening the Cardio-Oncology Clinic, the Heart & Vascular Center initiated virtual conversion then additionally collaborated with Inception Health (MCW’s innovation lab company) over the course of 4 weeks to iteratively develop the clinical informatics infrastructure for virtual visits. The video visits were designed to function using clinician’s personal smartphones, iPads, and tablets, with direct web browser video links from the electronic health record mobile application. Direct video calls through the Doximity mobile application were also approved. Existing Inception Health personnel re-allocated their time in order to adopt and maintain responsibility for the virtual component of all ambulatory clinics across the health system, in partnership with medical and administrative directors of each clinic area, such as the Heart & Vascular Center. No additional costs or hires were pursued to facilitate the development of the virtual visit infrastructure and timeline. Existing resources and personnel were re-allocated to virtual visit design to enable building the virtual clinics in the Heart & Vascular Center. To assist clinicians and billing compliance colleagues, note templates were created for video and phone visits to indicate patient informed consent for virtual visits due to the pandemic, as well as to capture limited appropriate physical examinations, in addition to the amount of time spent on records review and real-time medical counseling.
Initial consults were electronically triaged by either a cardiologist or a cardiology fellow supervised by a cardiologist. Each triage team determined which consults would be appropriate as virtual video visits, versus in-person to occur once the Heart and Vascular Center started re-opening routine physical visits, or whether patients needed to be evaluated urgently in person. During the first week of operation, the brand-new Cardio-Oncology Clinic started entirely virtually with only video and phone visits. As the Heart and Vascular Center re-opened for physical patient visits the following week, from week 2 through the remainder of the first 3 months the Cardio-Oncology Clinic had both virtual and in-person visits integrated throughout each clinic session weekly, based on whether patients were new and whether they had smart device or computer functionality available.
Virtual referral network and process
Cardio-Oncology patient assessment begins within a referral network before the patient arrives at a Cardio-Oncology clinic. Consequently, forming a virtual referral network and enacting a user-friendly virtual referral process was a key component of building the Cardio-Oncology clinic during the pandemic. All referral patterns and networks for our de novo Cardio-Oncology Clinic were built from the ground up. Initial referrals were from within our health system; this quickly expanded to consults from outside of our health system encompassing the entire state. Patients were referred to our Clinic by clinicians or by self-referrals. Some of our local patients connected to us after being introduced to us by their clinicians in other states or through family members in other states who learned about us from their own clinicians or community-based Cardiology society outreach events.
Referrals across the institution and outside of our health system have come to us from the Divisions of Hematology and Oncology, Internal Medicine, Family Medicine, Surgical Oncology/Breast Clinic, and Survivorship Clinics. From the cancer center’s perspective, there may be many “triggers” that would warrant a Cardio-Oncology referral. For example, an abnormal ECG, an abnormal echocardiogram, cardiovascular symptoms, previous cardiovascular history (e.g., coronary artery disease, hypertension, cardiomyopathy) particularly in a patient who previously underwent treatment or is beginning new treatment with cardiotoxic neoplastic medications or radiation therapy and is at high risk of cardiovascular toxicity, or those in preparation for stem cell transplant, or oncologic surgery. Referral protocols were determined based on standard practice, discussions with colleagues in Medical and Radiation Oncology, Hematology, Bone Marrow Transplant, Surgical Oncology/Breast Clinic, Children’s Hospital, Radiation Oncology, Primary Care, and updated literature reviews.
Cancer survivors are at a higher risk than the general population for cardiovascular morbidity and mortality. If a cancer survivor needing to be evaluated is already under the care of a cardiologist, the referring provider can reach out to their cardiologist for guidance on the appropriate CV surveillance. If they do not already have a cardiologist, a Cardio-Oncology consult should be requested. The Cardio-Oncology consult can be placed using a direct Cardio-Oncology button within the universally available Cardiovascular Consult order panel. Referrers can also place a General Cardiology consult and mention the Cardio-Oncology physician by name as requested by the clinician or patient. An E-Consult functionality is also being implemented for those patients who need to be assessed sooner than the next available appointment, or for those patients who may not need a full Cardio-Oncology evaluation, or if referring providers are uncertain. The e-consult can also be placed as a second opinion requested by the inpatient Cardiology Consult team.
The inpatient Cardiology Consult service will continue to directly address inpatient consults from the inpatient hematology/oncology services. The inpatient Cardiology Consult service can collaborate with the Cardio-Oncology Clinic via formal Cardio-Oncology E-consults in the electronic health record Epic if a specific focused question arises regarding Cardio-Oncology relevant to the care of individual currently hospitalized patients that have already been formally evaluated by the inpatient Cardiology Consult service. After a patient has been formally evaluated by the inpatient Cardiology Consult service, if the patient is appropriate for outpatient follow up in the Cardiology clinic with Cardio-Oncology, this should be communicated to the primary Hematology/Oncology service. If appropriate at the time of consultation, the inpatient cardiology consult service can make the follow-up appointment. Oftentimes, this patient population remains in the inpatient setting for several weeks. If this is the case, the Cardiology clinic phone number and clinician information should be provided to the primary service to do so prior to the patient being discharged from the hospital.
Virtual-hybrid multidisciplinary team
It is important to develop a multidisciplinary team and initially focus on allocation of pre-existing resources. Accordingly, some roles among our Cardio-Oncology clinic personnel are shared with other subspecialties. Our virtual-hybrid multidisciplinary Cardio-Oncology Clinic personnel include physicians, a nurse practitioner (NP), a nurse, a research support specialist, medical assistants, pharmacists, administrative assistants, and administrators. All personnel with pre-existing in-person roles and practices re-allocated a portion of their time to the development and practice of virtual visits.
Our clinic and partners consist of board-certified Cardiologists with special training in various cardiac subspecialties (e.g., cardio-oncology, preventive cardiology, heart failure and transplant, electrophysiology, interventional cardiology), who collaborate closely with our cancer experts. Our physicians together specialize in the prevention, diagnosis, and treatment of heart and vascular disorders resulting from side effects of cancer therapy. Our comprehensive team of advanced practice providers, nurses, and pharmacists work alongside our physicians to care for patients from the moment of cancer diagnosis through life’s survivorship journey. The NP typically sees established patients when needed to follow up on imaging, intervention, or diagnostic and management plans, and may also see select new patients. In complex cases, the NP discusses the care of established patients with both the cardio-oncologist and the referring clinician. The nurse assists with patient triage and communications (including addressing patient requests and queries), liaises closely with the nurse practitioner and pharmacists, and educates patients on Cardio-Oncology using virtual materials. Our clinical pharmacists function at the highest level of their advanced training, similar to all clinic personnel, and assist with medication education, review, titration, discussion, and prescription, particularly for heart failure, hypertension, hyperlipidemia, and smoking cessation, as well as commenting on potential drug interactions.
For Preventive Cardio-Oncology, we additionally partner with our dietitians and exercise physiologists to help advise our patients on nutrition and exercise plans, as well as our colleagues in cardiopulmonary stress testing where applicable. Further, in the pandemic, we provide patients with free online coaching options for lifestyle modification (Fig. 2). We also direct patients to AHA webpages with guidance on pursuing ideal cardiovascular health.
Virtual-hybrid patient flow
Once a referral is placed by the designated order buttons in the electronic health record, central schedulers or the Cardio-Oncology Clinic administrative assistant schedule the new patient for a video or in-person visit (Fig. 3). The clinic administrative assistant works closely with our health professionals in our interdisciplinary advanced subspecialty clinic to gather relevant clinical reports and history pertinent to patient appointments. Virtual medical assistants contact patients a few days before their appointments to confirm and troubleshoot virtual connectivity. On the appointment day, medical assistants then ‘room’ patients for virtual or in-person visits by preparing patients for their medical visits (including reviewing medications and in-person or at-home virtual vital signs), and also rechecking virtual connectivity for video visits. The clinician then completes the visit virtually or in-person and introduces the patient to the range of electronic resources available. Following the visit, the clinical administrative assistant arranges follow-up testing and appointments.
Fig. 3 Virtual-Hybrid Patient Flow Chart. Admin = Administrative; MA = Medical Assistant; MD = Medical Doctor; NP = Nurse Practitioner
Virtual risk assessment
Baseline risk assessment and follow-up start with oncology and primary care [21]. Asymptomatic low risk patients with low-risk treatment plans can have continued assessment and follow-up by oncology and primary care in partnership. Patients who have symptoms, are at high risk based on their history, or are planned for high-risk treatment plans should be referred to Cardio-Oncology for prevention, monitoring, and management recommendations. Recommendations should adhere to society expert consensus, scientific statements, and guidelines for prevention, surveillance, and survivorship, and optimize CVD risk and medications [21]. A putative risk score based on medication-related and patient-related risk factors can be used to guide monitoring and management recommendations for most Cardio-Oncology patients [22], and can be used in a virtual clinical decision aid (https://tinyurl.com/CardioOncCDA) (Fig. 4). Specific risk scores are also available for adults treated with anthracyclines, trastuzumab, or other drugs, or for adult survivors of childhood cancers [9–13].
Fig. 4 Virtual Cardio-Oncology clinical decision aid (CDA). Risk assessment (https://tinyurl.com/CardioOncCDA) to guide monitoring and management recommendations regarding development of cardiomyopathy for most Cardio-Oncology patients; a CDA specifically for women with early breast cancer is also available in the CardioOnc Compendium (https://tinyurl.com/CardioOncCompendium)
Virtual management algorithms
Evidence-based management algorithms have been selected or developed as adjunctive resources for inpatient teams. They are available online in a virtual collection for use in the inpatient setting by the inpatient Cardiology Consult service or hematology/oncology teams to assist with diagnosis and treatment of cardiovascular toxicities from cancer therapies or cancer itself. The algorithms cover cardiomyopathy from anthracyclines or trastuzumab, planned chemotherapy with pre-existing cardiomyopathy, neurohormonal therapy or dexrazoxane for cardioprotection, myocarditis, persistent malignant pericardial effusion, hypertension, surveillance after radiation therapy or drugs that cause ischemia, malignant pericardial effusion, and other salient topics frequently encountered.
Virtual community engagement
The local, regional, national, and international community was virtually engaged via social media posts on Twitter (using #MCWCardioOnc on @DrBrownCares or @PrevCardioOnc), podcasts hosted by the MCW CTSI (available on iTunes, Google, and Apple podcast platforms), Heart Success podcast series, and Cancer Heart Talk brief 15-min mini-podcast series (available on SoundCloud). Perspectives were also published for international community engagement in the Women Heart Alliance newsletter, as well as on the AHA Early Career Blog, ACC Women in Cardiology Blog, CardioOncTrain.Com Blog, and PrevCardioOnc.Com Blog. Virtual continuing medical education (CME) presentations were also given at the Wisconsin state ACC annual conference meeting, Midwest ACC annual conference meeting, Southeast ACC annual conference meeting, Brazilian Cardio-Oncology Symposium, and the Ohio State Cardio-Oncology CME conference, then subsequently at the AHA and ACC annual national scientific sessions.
Distribution of patient data
In our multi-subspecialty clinic visits (virtual and in-person integrated and combined; n = 182; 136 new and 47 returns), approximately 50% of patient visits were in Cardio-Oncology, 20% were in Preventive Cardio-Oncology, and 30% were in General Cardiology (Fig. 5a). Overall among Cardio-Oncology visits, 65% were in person, consistent with early and safe clinic re-opening in a hybrid model, with 19% by video and 16% by phone, with the fraction by phone decreasing over time as patients and clinic personnel became more adept with troubleshooting video. Of new patients, 77% were in person, and the remainder by video. No Cardio-Oncology patients presenting in person developed any signs or symptoms concerning for COVID-19.
Fig. 5 Initial Clinic-Building Outcomes Using the Virtual-Hybrid Approach. a Distribution of Cardio-Oncology, Preventive Cardio-Oncology, and General Cardiology patients seen in our multi-subspecialty clinic visits. b Distribution of cardiovascular diagnosis or indication for referral. c Distribution of cancer drugs. d Distribution of cancer types
The most frequent cardiovascular diagnosis or indication for referral was cardiomyopathy (34%) (Fig. 5b). Other diagnoses included decrease in global longitudinal strain, diastolic congestive heart failure, hypertension, myocarditis, dyspnea, chest pain, palpitations, survivorship, risk assessment, and pre-bone marrow transplant, among other cardiovascular diagnoses or visit indications. The most frequent cancer drug was trastuzumab (29%) (Fig. 5c), managed according to a novel algorithm developed in our de novo Virtual-Hybrid Cardio-Oncology Clinic based on the recent publication indicating the safety of continuation of trastuzumab for left ventricular ejection fraction of 40% or greater [23] (Fig. 6). The second most frequent cancer drug was anthracycline (24%). Other drugs included, tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), endocrine therapies, and investigational therapeutics, among others. The most frequent cancer type in our clinic was breast cancer (42%) (Fig. 5d). These trends in cardiovascular diagnosis or indication and cancer drugs or types were similar in assessments of virtual visits alone, with the most frequent being cardiomyopathy (43%), trastuzumab (41%), and breast cancer (44%), respectively. The findings of similar cardiovascular and cancer distributions in virtual versus in-person visits indicated an optimal qualitative return on resource and personnel investment.
Fig. 6 Algorithm for Continuation of Trastuzumab Therapy with Mild LV Dysfunction
Imaging and medication titration
In our clinic, a distribution of cardiovascular diagnoses determines the imaging needed for each patient (Fig. 5b). Therefore, a number of imaging modalities are useful to our patients (e.g., echocardiography, computed tomography with or without angiography, magnetic resonance imaging, coronary angiography, myocardial perfusion imaging). Our most frequently used imaging modality is echocardiography. The frequency of obtaining echocardiograms has depended on each patient’s condition and cancer treatment. A substantial portion of patients coming to us on trastuzumab have needed an echocardiogram every 1–3 months, depending on the extent of adverse effects on left ventricular ejection fraction (LVEF) or strain In these patients, medication titration has occurred approximately every 2 weeks, and for very symptomatic patients with volume overload, they have often been seen weekly..
In our management algorithms, early referral prior to the onset of symptoms has been emphasized, especially in cancer patients or survivors with a history of cardiovascular disease, cardiotoxic neoplastic agents, or a high risk of cardiovascular toxicity. This has provided an opportunity for us to assess and discuss ways to optimize the benefit to risk ratio of continuing with the current cancer treatment plan, and more importantly how and when to put cardioprotective measures in place to facilitate safe cancer therapy. Such discussions have also resulted in closer monitoring. Some conditions have warranted proceeding to other modalities of non-invasive imaging, such as cardiac MRI if myocarditis is suspected. For cases in which coronary artery disease is suspected, our patients undergo functional assessment of their coronaries with a stress test or anatomical assessment with a coronary CT scan or invasive coronary angiography. In our practice, only exercise stress tests were halted due to the pandemic. Every other form of imaging including rest and stress echo, as well as MRI and nuclear medicine have remained readily available for those with cardiovascular toxicities or individuals considered to be at moderate or high risk. This allowed us to adhere to pre-pandemic imaging recommendations tailored during the pandemic to limit imaging if possible to those who are at higher risk for cardiovascular toxicities or who have already been diagnosed with these adverse effects [1–4] (e.g., Fig. 6).
Discussion
The COVID-19 pandemic has inevitably compelled leaders of healthcare clinics to rethink and restructure approaches to deliver optimal care for patients. Our brand-new Cardio-Oncology clinic has been built to thrive in this new pandemic landscape by utilizing virtual technology as one of the key components of our clinic-building and care model since its inception. While existing clinics have reinvented their operations through the uptake of technology, our clinic has been able to capitalize on this resource to deliver virtual-hybrid care from the start. Virtual communication has proved useful to coordinate referral networks and care among providers within a multidisciplinary team across different clinics and departments. We see a variety of cancer patients, types, and drugs (Fig. 5), and our distribution results are generally congruent with reports from other leading cardio-oncology clinics [8, 14, 15, 17, 22].
Various methods have been developed for risk assessment to help guide providers and patients in determining the appropriate guidelines for care. We offer the use of virtual risk assessment tools such as the computed risk scores based on medication- and patient-related risk factors [22] (Fig. 4) (https://tinyurl.com/CardioOncCompendium), as well as recommendations for establishing cross-provider partnerships to continuously evaluate risk [21]. Other online databases containing useful information and guidelines are readily accessible and can help guide clinical practices. We encourage use of these virtual tools, which can further facilitate collaborative Cardio-Oncology care in the pandemic. Our conversations with international colleagues have suggested additional utility of these virtual tools beyond the pandemic. The online resources can be very helpful in settings where clinical practitioners work alone without support from nurses, pharmacists, nutrition specialists, or exercise physiologists.
Virtual-hybrid care has extended the care team’s capabilities for delivering and maintaining patient education and follow-up. The internet continues to be a robust resource, containing a wealth of health information that is easily accessible to the general population. Various mobile applications and electronic devices have also been developed in recent years to educate, track, and manage patients’ health and lifestyles. While these tools provide patients with greater accessibility and independence, they also create a valuable opportunity for healthcare providers to further engage patients. In a virtual-hybrid model, this becomes increasingly important, as patients may frequently transition between virtual and in-person visits. Forming care partnerships with patients through these virtual information and health-tracking resources becomes crucial in the continuity of care and proper health maintenance as we move through the pandemic.
Our most frequent cardiovascular diagnosis was cardiomyopathy (34%), which is reflective of the management need that first helped start the emerging field of Cardio-Oncology, and is similar to the most frequent cardiovascular diagnosis noted by clinicians from several other leading centers (20–35%) [24, 25]. However, Cardio-Oncology has grown remarkably over the last 10–20 years, with a wide spectrum of cardiovascular diagnoses and indications for referral (Fig. 5b) [8, 14]. Accordingly, at some other leading centers, the most frequent cardiovascular diagnosis or indication for referral has been reported as hypertension [14], arrythmia [17], or comprehensive risk assessment prior to beginning of therapy to optimize cardioprotection [8] in the practice of Preventive Cardio-Oncology [21]. This illustrates an opportunity for growth in our Clinic, to increase the fraction of high-risk patients who undergo comprehensive cardiovascular risk evaluation and management of risk factors prior to administration of cardiotoxic therapy.
Our clinic cares for patients with a range of cancer types (Fig. 5d). Individuals with breast, lung, and hematologic cancers represent a substantial proportion of our patient population, similar to other Cardio-Oncology clinics [8, 14, 22, 26]. The most frequent cancer diagnosis, breast cancer (43%), is consistent with reports from other leading cardio-oncology clinics such as the Mayo Clinic (39.2%) [15] and the Cleveland Clinic in Florida (44.3%) [14]. While hematologic malignancies such as leukemia and lymphoma represented 29% of our patients and was the second most prevalent cancer within our cohort, they comprised the most frequent forms of cancer at other cardio-oncology clinics such as at the Moffitt Cancer Center (31%) [8] and at UCLA (32.70%) [25]. However, the absolute difference was relatively insignificant. Overall, similar to these established cardio-oncology clinics, we receive patients from across a variety of cancers.
A wide breadth of cancer therapeutics is associated with cardiotoxicity [21]. Anthracyclines associate with cardiomyopathy, especially when used with trastuzumab. Targeted therapies (e.g., TKIs) can cause new or worsening of pre-existing hypertension. ICIs are associated with an increased incidence of myocarditis. Some cytotoxic chemotherapeutics, such as cisplatin, increase the risk of venous thromboembolism, and antimetabolites such as fluoropyrimidines have long been associated with a broad range of cardiotoxicities. Radiation therapy is associated with ischemic heart disease, valve dysfunction, conduction abnormalities, pericardial disease, and cardiomyopathy. Patients with cancer who have developed cardiovascular toxicity or who may be at high risk for cardiovascular toxicity should be referred to the Cardio-Oncology clinic for close follow-up.
The most frequently used cancer medication used among our patients was trastuzumab (29%), with the second most frequent being anthracyclines (24%). This was similar to other institutions, with anthracyclines and trastuzumab among the most common cancer drugs in their Cardio-Oncology clinics. Yet, anthracyclines were typically noted more commonly than trastuzumab. The Cleveland Clinic in Florida saw patients most commonly treated with radiation (40%), followed by anthracyclines (26.8%) [14]. The Moffitt Cancer Center most frequently had patients who were treated with anthracyclines (52%), with HER2 targeted therapies representing 27% of the cancer drugs [8]. This difference may reflect a high frequency of patients with HER+ breast cancer in our population (diagnosed by a ratio of HER2 to chromosome 17 signals on dual probe fluorescent in situ hybridization ≥2 or ≥ 6 HER2 signals/cell [27]), as well as the keen attention to a substantial fall in left ventricular ejection fraction or global longitudinal strain as a potential prognostic factor in our patients, per American Society of Echocardiography (ASE) guidelines [28].
All of these patient data distributions were obtained in the context of the Virtual-Hybrid patient flow in our de novo Cardio-Oncology Clinic (Fig. 3), that can be modeled by other future Virtual-Hybrid Cardio-Oncology clinics initiated during the pandemic. Table 1 compares the first few weeks of our de novo C-O clinic setup model with two published manuscripts describing conversion of pre-existing in-person C-O clinics to providing telehealth visits as an option for patients. The table shows similar numbers of patients seen in the initial periods of the clinics, although the numbers in our new clinic went from 0 to 10 in the first 3 weeks, compared to going from up to 40 patients weekly to 11 patients in 2.5 weeks for a group that converted their in-person clinic to a virtual option. Overall, CV diagnoses and cancer types were comparable; distributions of cancer drugs were not reported by the other group. Important differences were noted. Most of our patients in the pandemic were new (90%), given the de novo status of the Cardio-Oncology Clinic, while the converted virtual clinic of another group initially focused on established patients for > 50% of their patient visits. While key personnel were also the same (e.g., physician, advanced practice provider, nurse or nurse coordinator), we also report virtual versions of supportive staffing patterns, including the virtual scheduling and rooming process and pharmacy and lifestyle modification visits. Additionally, trainees have been integrally involved in the establishment of our Cardio-Oncology Clinic, with residents training in program-building, and medical students and fellows training in ambulatory cardio-oncology clinical practice and cardio-oncology critical thinking, respectively. Finally, besides the patient flow (Fig. 3) and de novo nature of our Virtual-Hybrid clinic initiated in the pandemic, our unique contribution may be the virtual resources, compared to the essential “webside manner” [7] or an alternative algorithm [4] for triaging virtual or in-person visits to the physician or advanced practice provider (Table 1).
Table 1 Comparisons Among Clinic Models Described In The Pandemic
Virtual-Hybrid Clinic Telehealth Clinic (14) Triage Clinic (4)
Model Type De Novo Conversion Conversion
Time Frame Compared 3 weeks 2.5 weeks Not reported
Number of Patients 10 11 Not reported
New Visits (%) 90 45 Not reported
Variety of CV Diagnoses Yes Yes Not reported
Variety of CA Types Yes Yes Not reported
Variety of CA Drugs Yes Unknown Not reported
Referrals Yes Unknown Yes
Scheduling Yes Unknown Not reported
Rooming Process Yes Unknown Not Reported
Virtual AA Yes Unknown Not Reported
Virtual MA Yes Unknown Not Reported
Virtual Physician Yes Yes Yes
Virtual APP Yes Unknown Yes
Virtual Pharmacist Yes Unknown Not Reported
Virtual Nurse (Coordinator) Yes Unknown Yes
Unique Contribution Virtual Resources Webside Manner Triage Algorithm
Similar to the formation or conversion of Cardio-Oncology clinics, many protocols for treatment regimens and cancer patients are yet to be standardized. While no standard protocols have been widely adopted at Cardio-Oncology practices, various institutions and writing groups have proposed some approaches (e.g., ASE or ASCO guidelines). We have collaboratively developed institutional algorithms for various cardiovascular toxicities and medications based on existing scientific statements, society guidelines, expert consensus statements, and manuscripts from leading cardio-oncology research institutions. The goal is to adopt, adapt, develop, and continuously update these algorithms, as new literature arises in order to establish best practices and an institutional standard of care.
Conclusion
Starting a new Cardio-Oncology Clinic in the pandemic has its challenges, and yet for our patients can be invaluable. Appropriately competing priorities in the pandemic can limit the scheduling of meetings and gathering of people together in one virtual room to discuss a mutual vision. Gathering resources for patient and clinician education can also be formidable, as can social distancing and obtaining important imaging. However, multiple virtual one-on-one or small group meetings can be beneficial for building institutional relationships. Similarly, virtual visits have risen to the challenge to ensure maintenance of patient care throughout the pandemic. Modifications have also been made to enable safety and distancing during imaging. With the benefit of these adjustments to address the challenge, this report provides a foundation for initiating a cardio-oncology clinic in the pandemic, with virtual resources and tools to equip patients and clinicians.
In the future, we will also lay out a roadmap for initiation of comprehensive cardio-oncology programs with the five pillars of patient care, education, research, community engagement, and innovation in the era of digital transformation accelerated by the pandemic. Novel risk modifiers and risk attenuation methods, such as breast arterial calcification, clonal hematopoiesis of indeterminate potential, and Cardio-Oncology prehabilitation, habilitation, and rehabilitation will also be addressed. Future innovation to implement recommendations from clinical trials across the nation currently underway that utilize mobile health or web-based diet and physical activity interventions and/or seek to determine the impact of cardioprotective pharmacotherapy in Preventive Cardio-Oncology will also be assessed (ClinicalTrials.Gov: NCT01988571, NCT02943590, NCT02562716, NCT01968200, NCT03265574, NCT03760588, NCT03386383, NCT02244411, NCT03223753). Many of these studies incorporate virtual technologies that will be very helpful during and after the pandemic as we continue pursuit of digital transformation.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We are grateful to the following individuals, as well as all of the departments and divisions at Froedtert & MCW that have rallied together to help us establish the hybrid Cardio-Oncology clinic or to see our patients needing subspecialty care, or to partner with us in referrals from the inpatient service, especially the following clinicians: Stacey Gardiner MD, Jason Rubenstein MD, David Ishizawar MD, Jalaj Garg MD, Andrew Rosenblum MD. We are also grateful to Nicole Lohr MD PhD and the clinical sections at the Zablocki Veterans Administration Medical Center that have also helped us establish an affiliate Cardio-Oncology Clinic in tandem at the VAMC in Milwaukee, WI.
Authors’ contributions
SAB conceived of the study, obtained, analyzed and interpreted the data, and made a substantial contribution to the writing of the manuscript; SP made a substantial contribution to the writing of the manuscript; DR made a substantial contribution to the writing of the manuscript; SZ obtained the data and made a substantial contribution to the writing of the manuscript; ML interpreted the data and made a substantial contribution to the writing of the manuscript; TN made a substantial contribution to the writing of the manuscript; BS analyzed the data and made a substantial contribution to the writing of the manuscript; RM made a substantial contribution to the writing of the manuscript; JMac made a substantial contribution to the writing of the manuscript; KD made a substantial contribution to the writing of the manuscript; JMes made a substantial contribution to the writing of the manuscript; DM made a substantial contribution to the writing of the manuscript; JS made a substantial contribution to the writing of the manuscript. All authors read and approved the final manuscript.
Funding
No funding was associated with this work.
Availability of data and materials
The datasets during and/or analyzed during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The study was approved by the Froedtert & MCW Institutional Review Board (ID PRO00038807); HIPAA informed consent was waived for this minimal risk study.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests. | TRASTUZUMAB | DrugsGivenReaction | CC BY | 33441188 | 18,793,759 | 2021-01-13 |
What was the outcome of reaction 'Death'? | A virtual-hybrid approach to launching a cardio-oncology clinic during a pandemic.
BACKGROUND
As cardiovascular disease is a leading cause of death in cancer survivors, the new subspecialty of Cardio-Oncology has emerged to address prevention, monitoring, and management of cardiovascular toxicities to cancer therapies. During the coronavirus disease of 2019 (COVID-19) pandemic, we developed a Virtual-Hybrid Approach to build a de novo Cardio-Oncology Clinic.
METHODS
We conceptualized a Virtual-Hybrid Approach including three arms: information seeking in locations with existing Cardio-Oncology clinics, information gathering at the location for a new clinic, and information sharing to report clinic-building outcomes. A retrospective review of outcomes included collection and synthesis of data from our first 3 months (at pandemic peak) on types of appointments, cancers, drugs, and cardiotoxicities. Data were presented using descriptive statistics.
RESULTS
A de-novo Cardio-Oncology clinic was developed structured from the ground up to integrate virtual and in-person care in a hybrid and innovative model, using the three arms of the Virtual-Hybrid Approach. First, we garnered in-person and virtual preparation through hands-on experiences, training, and discussions in existing Cardio-Oncology Clinics and conferences. Next, we gleaned information through virtual inquiry and niche-building. With partners throughout the institution, a virtual referral process was established for outpatient referrals and inpatient e-consult referrals to actualize a hybrid care spectrum for our patients administered by a multidisciplinary hybrid care team of clinicians, ancillary support staff, and clinical pharmacists. Among the multi-subspecialty clinic sessions, approximately 50% were in Cardio-Oncology, 20% in Preventive Cardiology, and 30% in General Cardiology. In the hybrid model, the Heart & Vascular Center had started to re-open, allowing for 65% of our visits to be in person. In additional analyses, the most frequent cardiovascular diagnosis was cardiomyopathy (34%), the most common cancer drug leading to referral was trastuzumab (29%), and the most prevalent cancer type was breast cancer (42%).
CONCLUSIONS
This Virtual-Hybrid Approach and retrospective review provides guidance and information regarding initiating a brand-new Cardio-Oncology Clinic during the pandemic for cancer patients/survivors. This report also furnishes virtual resources for patients, virtual tools for oncologists, cardiologists, and administrators tasked with starting new clinics during the pandemic, and innovative future directions for this digital pandemic to post-pandemic era.
Introduction
Cardio-Oncology care has been adjusted in the COVID-19 pandemic with limited in-person clinic or hospital visits, increased use of teleconsultation, less frequent imaging, increased reliance on biomarkers, and considerations of differential diagnoses involving COVID-19 when evaluating cancer patients or survivors for possible cardiovascular toxicity [1]. Monitoring and management algorithms have been developed to help guide virtual care [2–4]. In the pandemic, we have changed the way in which we provide healthcare services at our clinics and institutions. This has challenged us to restructure current systems for the safety of our patients.
Various forms of innovation have come to bear in the pandemic, including telemedicine, digital health, artificial intelligence, social media, informatics, big data, and precision medicine [5, 6]. Telemedicine is the primary form of innovation that has been most developed in the pandemic [2, 5, 7]. Social media has been very helpful for dissemination of information, as well as education, and has been integral for creating online groups for support and determining the best ways for proceeding in the pandemic and advocating for our patients and colleagues in this period [5, 6]. In addition, the Doximity social media application has been valuable to practices across the nation, due to its telehealth platform (Doximity Video and Phone; https://www.doximity.com/dialer-video).
Despite the growing need, and allowances made during the pandemic, many centers do not have formal Cardio-Oncology clinics. Starting a new clinic can be challenging. The COVID-19 pandemic has made the process significantly more difficult, with the need to minimize exposure and maximize patient safety.
Currently, limited information is available on how to start a Cardio-Oncology Clinic during a pandemic, albeit given the high risk of morbidity or mortality in COVID-19-positive patients who also have cancer or CVD [8–13]. Several institutions have published on their experiences with starting in-person Cardio-Oncology clinics prior to the pandemic [8, 14–17]. One group has reported on their conversion from existing in-person Cardio-Oncology visits to telemedicine consultations, seeing 11 patients virtually within a few weeks [7]. Many have considered implications of the pandemic on the practice and study of cardio-oncology [2, 4, 5, 18–20], and two groups have suggested models for clinics converting from existing in-person care to televisits [4, 5]. Yet, no groups have directly addressed steps for de novo virtual-hybrid clinic formation within the limitations of the pandemic and without conversion of a pre-existing Cardio-Oncology clinic.
Our report offers a template for other centers to develop their own new Cardio-Oncology clinics during the pandemic. We determined a Virtual-Hybrid Approach to clinic launch, with both virtual and in-person elements of three key arms: information seeking where there are existing Cardio-Oncology Clinics in place, information gathering where the clinic will be built, and information sharing to report on initial patient data demonstrating the success of the launch (Fig. 1). We then performed retrospective chart review to collect and synthesize data on the types of appointments (new versus established, virtual versus in-person), cancers (e.g., breast, prostate, leukemia, lung), cancer drugs, and cardiovascular toxicities (e.g., cardiomyopathy, hypertension) for patients seen virtually or in person in our new Cardio-Oncology clinic at Froedtert Hospital and Medical College of Wisconsin (F&MCW). Here, we will discuss our findings in the context of previous publications on launching Cardio-Oncology Clinics prior to the pandemic. Our results will present distributions of cancer drugs and types, and cardiovascular diagnoses, similar to previous publications on Cardio-Oncology clinic-building. However, we will differentiate and illuminate the techniques that leverage the virtual underpinnings of pandemic clinic-building. We submit that it is feasible to establish a new Cardio-Oncology Clinic for cancer patients or survivors with or at risk for cardiovascular toxicity from cancer therapy during a pandemic, providing optimal care for new patients in the midst of the need for safety and minimizing exposure. We also propose virtual resources for patients and clinicians and describe innovative future directions in the pandemic and post-pandemic period.
Fig. 1 The Virtual-Hybrid Approach to Cardio-Oncology Clinic-building in the pandemic
Methods
Virtual-hybrid approach
We pursued a Virtual-Hybrid Approach of information seeking, information gathering, and information sharing (Fig. 1). For information seeking, we focused on institutions that already had a Cardio-Oncology clinic in place. Prior to the COVID-19 pandemic, substantial experience was gained at an established in-person Cardio-Oncology clinic at a world-renowned leading hospital. Published manuscripts on pre-pandemic building and operations of Cardio-Oncology clinics at other institutions were reviewed. Extensive networking with leaders of Cardio-Oncology clinics around the United States and in the United Kingdom was accomplished at regional, national, and international meetings in person and on social media in a hybrid approach. These meetings were attended in person pre-COVID-19 and virtually during the pandemic. For information gathering, we addressed the location in which the new Cardio-Oncology clinic would be built. We learned about existing resources in the destination Heart & Vascular Center and existing needs and patients in the destination partner cancer center. We networked with physicians, advanced practice providers (APPs), nurses, service line leaders, and administrators in the Heart & Vascular Center and the cancer center, as well as in primary care and other supporting specialties. The subsequent Cardio-Oncology clinic sessions were intermingled with other subspecialty areas, to optimize availability for patient visits while filling clinic slots and tailoring spectrum of care to emerging patient needs. Cardio-Oncology patient visits were included in multi-subspecialty clinics.
Retrospective study design
For quantitative data, we pursued a retrospective observational study to determine the distribution of outpatient visits in the first 3 months of our virtual-hybrid Cardio-Oncology Clinic. We reviewed data from charts of patients (all were 18 years of age or older) who received outpatient care from the new Director of Cardio-Oncology at F&MCW between April 15, 2020 and July 17, 2020 to determine which of these patients were considered to be in Cardio-Oncology, Preventive Cardiology, or General Cardiology. We collated all three to determine the percentage of patients seen in Cardio-Oncology, compared to the other two specialties. Preventive Cardiology was collated as a partner clinic to help build the Preventive Cardio-Oncology component of the Cardio-Oncology Clinic, to help apply established principles for prevention. From among the multi-subspecialty clinic sessions, we determined the proportion of patients who were specifically cancer patients or survivors with or at risk for cardiovascular toxicity from cancer therapy and thereby seen in the Cardio-Oncology Clinic. Next, we identified the distribution of cardiovascular toxicities in cancer patients or survivors seen in the Cardio-Oncology Clinic. We also evaluated the spectrum of cancer drugs received by cancer patients or survivors seen in the Cardio-Oncology Clinic. In addition, we summarized the types of cancers in patients seen in the Cardio-Oncology Clinic. Finally, we assessed the frequency of virtual visits during the course of the pandemic over our first 3 months for patients seen in the Cardio-Oncology Clinic. This retrospective review was approved by the F&MCW IRB; HIPAA informed consent was waived for this minimal risk study, which did not involve any form of intervention and was conducted in compliance with good clinical and research practice. The team designed and carried out the study with reliance on virtual communication tools.
Data collection and analysis
Data gathering, management, and analysis were conducted at F&MCW. We collected patient-related, disease-related, treatment-related, and outcome-related data, particularly patient sex, type of appointment (new versus established, virtual versus in-person), type of cancer (e.g., breast, prostate, leukemia, lung), type of cancer drug, and type of cardiovascular toxicity (e.g., cardiomyopathy, hypertension). In order to minimize any risk of breaching patient confidentiality, all data collection occurred on institutional-based computing environments with de-identified data used for analyses. There were no alternative procedures for the subjects as this is a retrospective review of data that are not amenable to prospective collection and review. Descriptive graphs or tables of patient-, disease-, treatment-, and outcome-related variables distributions were prepared, with no comparisons made needing statistical tests.
Results
Virtual preparation
Preparation for starting the Cardio-Oncology clinic followed a Virtual-Hybrid Approach (Fig. 1, left). Five overarching factors employing virtual communication methods emerged to ensure the successful launching of the clinic. Team and individual experience and exposure to various areas of interest in Cardio-Oncology were achieved and assessed before and during the pandemic. Far-reaching connections to experts and potential collaborators in the field were developed and exercised. Close contact with the institution launching this clinic was important to determine the resources available; these resources dictated the strategy and potential outcomes of the clinic. Importantly, the expectations of others for the Cardio-Oncology clinic were determined and incorporated. Finally, recognition of the limitations that exist at the destination institution guided care and goal setting.
Virtual inquiry
Before initiating the Cardio-Oncology clinic in the destination institution, existing structures, patient base, and needs in the Heart & Vascular Center as well as the Cancer Center were evaluated, adhering to pandemic protocols (Fig. 1, middle). Pre-existing building blocks for the planned Cardio-Oncology clinic were assessed, and the partner Preventive Cardiology clinic was investigated. We also evaluated characteristics of the cancer center patient population to best position the clinic for success.
Virtual niche-building
Five main aspects of niche-building were pursued. Partnerships with Vascular and Cancer Center physicians, advanced practice providers, and service line leaders were developed to initiate and grow the clinic (Fig. 1, middle). The Cardio-Oncology team and clinic flexibility were demonstrated through openness to taking quicksteps. Presentations were made at Grand Rounds and rounds across the institution in Cardiology, Hematology/Oncology, Radiation Oncology, Surgical Oncology, Internal Medicine, and Family Medicine to promote the clinic capabilities. Collaborative solutions for problems facing fields complementing Cardio-Oncology developed trust and collaboration. Teamwork was developed by leveraging diversity of perspectives and virtual communication technologies, to establish effective patient care despite COVID-19 limitations.
Hybrid care Spectrum
The hybrid F&MCW Cardio-Oncology Clinic was initiated and established in the outpatient setting, in close partnership with the Preventive Cardiology Clinic, Cancer Center, and inpatient Cardiology Consult and Hematology/Oncology teams (Fig. 1, right).
Initial and subsequent visits have been completed in person or by video, with phone visits also available for virtual return visits if patients without adept and available smartphone use have limited ability to appear in person. Virtual patient visits over our first 3 months occurred with the use of telemedicine platforms integrated with Epic (via MyChart for patients and Haiku/Canto for clinicians), or using the Doximity video call function. Patients with in-person appointments are screened appropriately on arrival for signs or symptoms of COVID-19 or exposure, following institutional protocols. Wearing masks is required of all patients, and each patient can be accompanied by a family member; some choose to also wear gloves or face shields. There is sufficient room for maintaining social distancing in the clinic waiting room and hallways.
Innovation
Current innovation in the clinic also includes Virtual Clinician Tools and Virtual Patient Resources (Fig. 2). For clinicians, the links for an AHA CME course on Novel Concepts, Current Debates and Treatment Considerations in Cardio-Oncology, an online Cardio-Oncology Compendium hosting risk assessment clinical decision aids, Cardio-Oncology Drug Regimen and Acronym Databases, and UPTODATE access for reviewing Cardio-Oncology drug information are supplied. For patients, the video from the International Cardio-Oncology Society explaining the Cardio-Oncology subspecialty, American College of Cardiology (ACC) mobile health (mHealth) CardioSmart education app and website, Cancer Heart Talk mini-podcast series accessed via SoundCloud app and website, Cardio-Oncology Frequently Asked Questions, and ChemoCare website are provided for patient-facing Cardio-Oncology and heart anatomy and physiology education, engagement, and awareness. Virtual Resources for Preventive Cardio-Oncology are also made available to our patients. These include the American Heart Association (AHA) Physical Activity Recommendations, AHA Life’s Simple 7 Webpages, American Society For Preventive Cardiology Online Coaching Webpages in partnership with Intervent, and the Become An Ex Smoking Cessation Support Webpages in partnership with Mayo Clinic. The resources are provided in the Epic patient portal MyChart, and more ways to make the resources accessible to a broad and diverse patient population are in development. Future innovation in the clinic will explore contemporary initiatives connecting patients and their safely guarded data with their permission with wearable devices, health information technology, informatics, artificial intelligence, personalized medicine, and additional mobile health (mHealth) applications.
Fig. 2 Virtual patient and clinician education and resources. Available online as PDF with hot links in the CardioOnc Compendium (https://tinyurl.com/CardioOncCompendium)
Virtual visit infrastructure and timeline
There was no pre-existing Cardio-Oncology program at the time of launching our de novo Virtual/Hybrid Cardio-Oncology Clinic. The newly recruited Director of Cardio-Oncology was tasked with the responsibility of launching the new clinic, with support from the Heart & Vascular Center clinic administrators, medical director, and Cardiology Division and Department of Medicine leadership. Prior to opening the Cardio-Oncology Clinic, the Heart & Vascular Center initiated virtual conversion then additionally collaborated with Inception Health (MCW’s innovation lab company) over the course of 4 weeks to iteratively develop the clinical informatics infrastructure for virtual visits. The video visits were designed to function using clinician’s personal smartphones, iPads, and tablets, with direct web browser video links from the electronic health record mobile application. Direct video calls through the Doximity mobile application were also approved. Existing Inception Health personnel re-allocated their time in order to adopt and maintain responsibility for the virtual component of all ambulatory clinics across the health system, in partnership with medical and administrative directors of each clinic area, such as the Heart & Vascular Center. No additional costs or hires were pursued to facilitate the development of the virtual visit infrastructure and timeline. Existing resources and personnel were re-allocated to virtual visit design to enable building the virtual clinics in the Heart & Vascular Center. To assist clinicians and billing compliance colleagues, note templates were created for video and phone visits to indicate patient informed consent for virtual visits due to the pandemic, as well as to capture limited appropriate physical examinations, in addition to the amount of time spent on records review and real-time medical counseling.
Initial consults were electronically triaged by either a cardiologist or a cardiology fellow supervised by a cardiologist. Each triage team determined which consults would be appropriate as virtual video visits, versus in-person to occur once the Heart and Vascular Center started re-opening routine physical visits, or whether patients needed to be evaluated urgently in person. During the first week of operation, the brand-new Cardio-Oncology Clinic started entirely virtually with only video and phone visits. As the Heart and Vascular Center re-opened for physical patient visits the following week, from week 2 through the remainder of the first 3 months the Cardio-Oncology Clinic had both virtual and in-person visits integrated throughout each clinic session weekly, based on whether patients were new and whether they had smart device or computer functionality available.
Virtual referral network and process
Cardio-Oncology patient assessment begins within a referral network before the patient arrives at a Cardio-Oncology clinic. Consequently, forming a virtual referral network and enacting a user-friendly virtual referral process was a key component of building the Cardio-Oncology clinic during the pandemic. All referral patterns and networks for our de novo Cardio-Oncology Clinic were built from the ground up. Initial referrals were from within our health system; this quickly expanded to consults from outside of our health system encompassing the entire state. Patients were referred to our Clinic by clinicians or by self-referrals. Some of our local patients connected to us after being introduced to us by their clinicians in other states or through family members in other states who learned about us from their own clinicians or community-based Cardiology society outreach events.
Referrals across the institution and outside of our health system have come to us from the Divisions of Hematology and Oncology, Internal Medicine, Family Medicine, Surgical Oncology/Breast Clinic, and Survivorship Clinics. From the cancer center’s perspective, there may be many “triggers” that would warrant a Cardio-Oncology referral. For example, an abnormal ECG, an abnormal echocardiogram, cardiovascular symptoms, previous cardiovascular history (e.g., coronary artery disease, hypertension, cardiomyopathy) particularly in a patient who previously underwent treatment or is beginning new treatment with cardiotoxic neoplastic medications or radiation therapy and is at high risk of cardiovascular toxicity, or those in preparation for stem cell transplant, or oncologic surgery. Referral protocols were determined based on standard practice, discussions with colleagues in Medical and Radiation Oncology, Hematology, Bone Marrow Transplant, Surgical Oncology/Breast Clinic, Children’s Hospital, Radiation Oncology, Primary Care, and updated literature reviews.
Cancer survivors are at a higher risk than the general population for cardiovascular morbidity and mortality. If a cancer survivor needing to be evaluated is already under the care of a cardiologist, the referring provider can reach out to their cardiologist for guidance on the appropriate CV surveillance. If they do not already have a cardiologist, a Cardio-Oncology consult should be requested. The Cardio-Oncology consult can be placed using a direct Cardio-Oncology button within the universally available Cardiovascular Consult order panel. Referrers can also place a General Cardiology consult and mention the Cardio-Oncology physician by name as requested by the clinician or patient. An E-Consult functionality is also being implemented for those patients who need to be assessed sooner than the next available appointment, or for those patients who may not need a full Cardio-Oncology evaluation, or if referring providers are uncertain. The e-consult can also be placed as a second opinion requested by the inpatient Cardiology Consult team.
The inpatient Cardiology Consult service will continue to directly address inpatient consults from the inpatient hematology/oncology services. The inpatient Cardiology Consult service can collaborate with the Cardio-Oncology Clinic via formal Cardio-Oncology E-consults in the electronic health record Epic if a specific focused question arises regarding Cardio-Oncology relevant to the care of individual currently hospitalized patients that have already been formally evaluated by the inpatient Cardiology Consult service. After a patient has been formally evaluated by the inpatient Cardiology Consult service, if the patient is appropriate for outpatient follow up in the Cardiology clinic with Cardio-Oncology, this should be communicated to the primary Hematology/Oncology service. If appropriate at the time of consultation, the inpatient cardiology consult service can make the follow-up appointment. Oftentimes, this patient population remains in the inpatient setting for several weeks. If this is the case, the Cardiology clinic phone number and clinician information should be provided to the primary service to do so prior to the patient being discharged from the hospital.
Virtual-hybrid multidisciplinary team
It is important to develop a multidisciplinary team and initially focus on allocation of pre-existing resources. Accordingly, some roles among our Cardio-Oncology clinic personnel are shared with other subspecialties. Our virtual-hybrid multidisciplinary Cardio-Oncology Clinic personnel include physicians, a nurse practitioner (NP), a nurse, a research support specialist, medical assistants, pharmacists, administrative assistants, and administrators. All personnel with pre-existing in-person roles and practices re-allocated a portion of their time to the development and practice of virtual visits.
Our clinic and partners consist of board-certified Cardiologists with special training in various cardiac subspecialties (e.g., cardio-oncology, preventive cardiology, heart failure and transplant, electrophysiology, interventional cardiology), who collaborate closely with our cancer experts. Our physicians together specialize in the prevention, diagnosis, and treatment of heart and vascular disorders resulting from side effects of cancer therapy. Our comprehensive team of advanced practice providers, nurses, and pharmacists work alongside our physicians to care for patients from the moment of cancer diagnosis through life’s survivorship journey. The NP typically sees established patients when needed to follow up on imaging, intervention, or diagnostic and management plans, and may also see select new patients. In complex cases, the NP discusses the care of established patients with both the cardio-oncologist and the referring clinician. The nurse assists with patient triage and communications (including addressing patient requests and queries), liaises closely with the nurse practitioner and pharmacists, and educates patients on Cardio-Oncology using virtual materials. Our clinical pharmacists function at the highest level of their advanced training, similar to all clinic personnel, and assist with medication education, review, titration, discussion, and prescription, particularly for heart failure, hypertension, hyperlipidemia, and smoking cessation, as well as commenting on potential drug interactions.
For Preventive Cardio-Oncology, we additionally partner with our dietitians and exercise physiologists to help advise our patients on nutrition and exercise plans, as well as our colleagues in cardiopulmonary stress testing where applicable. Further, in the pandemic, we provide patients with free online coaching options for lifestyle modification (Fig. 2). We also direct patients to AHA webpages with guidance on pursuing ideal cardiovascular health.
Virtual-hybrid patient flow
Once a referral is placed by the designated order buttons in the electronic health record, central schedulers or the Cardio-Oncology Clinic administrative assistant schedule the new patient for a video or in-person visit (Fig. 3). The clinic administrative assistant works closely with our health professionals in our interdisciplinary advanced subspecialty clinic to gather relevant clinical reports and history pertinent to patient appointments. Virtual medical assistants contact patients a few days before their appointments to confirm and troubleshoot virtual connectivity. On the appointment day, medical assistants then ‘room’ patients for virtual or in-person visits by preparing patients for their medical visits (including reviewing medications and in-person or at-home virtual vital signs), and also rechecking virtual connectivity for video visits. The clinician then completes the visit virtually or in-person and introduces the patient to the range of electronic resources available. Following the visit, the clinical administrative assistant arranges follow-up testing and appointments.
Fig. 3 Virtual-Hybrid Patient Flow Chart. Admin = Administrative; MA = Medical Assistant; MD = Medical Doctor; NP = Nurse Practitioner
Virtual risk assessment
Baseline risk assessment and follow-up start with oncology and primary care [21]. Asymptomatic low risk patients with low-risk treatment plans can have continued assessment and follow-up by oncology and primary care in partnership. Patients who have symptoms, are at high risk based on their history, or are planned for high-risk treatment plans should be referred to Cardio-Oncology for prevention, monitoring, and management recommendations. Recommendations should adhere to society expert consensus, scientific statements, and guidelines for prevention, surveillance, and survivorship, and optimize CVD risk and medications [21]. A putative risk score based on medication-related and patient-related risk factors can be used to guide monitoring and management recommendations for most Cardio-Oncology patients [22], and can be used in a virtual clinical decision aid (https://tinyurl.com/CardioOncCDA) (Fig. 4). Specific risk scores are also available for adults treated with anthracyclines, trastuzumab, or other drugs, or for adult survivors of childhood cancers [9–13].
Fig. 4 Virtual Cardio-Oncology clinical decision aid (CDA). Risk assessment (https://tinyurl.com/CardioOncCDA) to guide monitoring and management recommendations regarding development of cardiomyopathy for most Cardio-Oncology patients; a CDA specifically for women with early breast cancer is also available in the CardioOnc Compendium (https://tinyurl.com/CardioOncCompendium)
Virtual management algorithms
Evidence-based management algorithms have been selected or developed as adjunctive resources for inpatient teams. They are available online in a virtual collection for use in the inpatient setting by the inpatient Cardiology Consult service or hematology/oncology teams to assist with diagnosis and treatment of cardiovascular toxicities from cancer therapies or cancer itself. The algorithms cover cardiomyopathy from anthracyclines or trastuzumab, planned chemotherapy with pre-existing cardiomyopathy, neurohormonal therapy or dexrazoxane for cardioprotection, myocarditis, persistent malignant pericardial effusion, hypertension, surveillance after radiation therapy or drugs that cause ischemia, malignant pericardial effusion, and other salient topics frequently encountered.
Virtual community engagement
The local, regional, national, and international community was virtually engaged via social media posts on Twitter (using #MCWCardioOnc on @DrBrownCares or @PrevCardioOnc), podcasts hosted by the MCW CTSI (available on iTunes, Google, and Apple podcast platforms), Heart Success podcast series, and Cancer Heart Talk brief 15-min mini-podcast series (available on SoundCloud). Perspectives were also published for international community engagement in the Women Heart Alliance newsletter, as well as on the AHA Early Career Blog, ACC Women in Cardiology Blog, CardioOncTrain.Com Blog, and PrevCardioOnc.Com Blog. Virtual continuing medical education (CME) presentations were also given at the Wisconsin state ACC annual conference meeting, Midwest ACC annual conference meeting, Southeast ACC annual conference meeting, Brazilian Cardio-Oncology Symposium, and the Ohio State Cardio-Oncology CME conference, then subsequently at the AHA and ACC annual national scientific sessions.
Distribution of patient data
In our multi-subspecialty clinic visits (virtual and in-person integrated and combined; n = 182; 136 new and 47 returns), approximately 50% of patient visits were in Cardio-Oncology, 20% were in Preventive Cardio-Oncology, and 30% were in General Cardiology (Fig. 5a). Overall among Cardio-Oncology visits, 65% were in person, consistent with early and safe clinic re-opening in a hybrid model, with 19% by video and 16% by phone, with the fraction by phone decreasing over time as patients and clinic personnel became more adept with troubleshooting video. Of new patients, 77% were in person, and the remainder by video. No Cardio-Oncology patients presenting in person developed any signs or symptoms concerning for COVID-19.
Fig. 5 Initial Clinic-Building Outcomes Using the Virtual-Hybrid Approach. a Distribution of Cardio-Oncology, Preventive Cardio-Oncology, and General Cardiology patients seen in our multi-subspecialty clinic visits. b Distribution of cardiovascular diagnosis or indication for referral. c Distribution of cancer drugs. d Distribution of cancer types
The most frequent cardiovascular diagnosis or indication for referral was cardiomyopathy (34%) (Fig. 5b). Other diagnoses included decrease in global longitudinal strain, diastolic congestive heart failure, hypertension, myocarditis, dyspnea, chest pain, palpitations, survivorship, risk assessment, and pre-bone marrow transplant, among other cardiovascular diagnoses or visit indications. The most frequent cancer drug was trastuzumab (29%) (Fig. 5c), managed according to a novel algorithm developed in our de novo Virtual-Hybrid Cardio-Oncology Clinic based on the recent publication indicating the safety of continuation of trastuzumab for left ventricular ejection fraction of 40% or greater [23] (Fig. 6). The second most frequent cancer drug was anthracycline (24%). Other drugs included, tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), endocrine therapies, and investigational therapeutics, among others. The most frequent cancer type in our clinic was breast cancer (42%) (Fig. 5d). These trends in cardiovascular diagnosis or indication and cancer drugs or types were similar in assessments of virtual visits alone, with the most frequent being cardiomyopathy (43%), trastuzumab (41%), and breast cancer (44%), respectively. The findings of similar cardiovascular and cancer distributions in virtual versus in-person visits indicated an optimal qualitative return on resource and personnel investment.
Fig. 6 Algorithm for Continuation of Trastuzumab Therapy with Mild LV Dysfunction
Imaging and medication titration
In our clinic, a distribution of cardiovascular diagnoses determines the imaging needed for each patient (Fig. 5b). Therefore, a number of imaging modalities are useful to our patients (e.g., echocardiography, computed tomography with or without angiography, magnetic resonance imaging, coronary angiography, myocardial perfusion imaging). Our most frequently used imaging modality is echocardiography. The frequency of obtaining echocardiograms has depended on each patient’s condition and cancer treatment. A substantial portion of patients coming to us on trastuzumab have needed an echocardiogram every 1–3 months, depending on the extent of adverse effects on left ventricular ejection fraction (LVEF) or strain In these patients, medication titration has occurred approximately every 2 weeks, and for very symptomatic patients with volume overload, they have often been seen weekly..
In our management algorithms, early referral prior to the onset of symptoms has been emphasized, especially in cancer patients or survivors with a history of cardiovascular disease, cardiotoxic neoplastic agents, or a high risk of cardiovascular toxicity. This has provided an opportunity for us to assess and discuss ways to optimize the benefit to risk ratio of continuing with the current cancer treatment plan, and more importantly how and when to put cardioprotective measures in place to facilitate safe cancer therapy. Such discussions have also resulted in closer monitoring. Some conditions have warranted proceeding to other modalities of non-invasive imaging, such as cardiac MRI if myocarditis is suspected. For cases in which coronary artery disease is suspected, our patients undergo functional assessment of their coronaries with a stress test or anatomical assessment with a coronary CT scan or invasive coronary angiography. In our practice, only exercise stress tests were halted due to the pandemic. Every other form of imaging including rest and stress echo, as well as MRI and nuclear medicine have remained readily available for those with cardiovascular toxicities or individuals considered to be at moderate or high risk. This allowed us to adhere to pre-pandemic imaging recommendations tailored during the pandemic to limit imaging if possible to those who are at higher risk for cardiovascular toxicities or who have already been diagnosed with these adverse effects [1–4] (e.g., Fig. 6).
Discussion
The COVID-19 pandemic has inevitably compelled leaders of healthcare clinics to rethink and restructure approaches to deliver optimal care for patients. Our brand-new Cardio-Oncology clinic has been built to thrive in this new pandemic landscape by utilizing virtual technology as one of the key components of our clinic-building and care model since its inception. While existing clinics have reinvented their operations through the uptake of technology, our clinic has been able to capitalize on this resource to deliver virtual-hybrid care from the start. Virtual communication has proved useful to coordinate referral networks and care among providers within a multidisciplinary team across different clinics and departments. We see a variety of cancer patients, types, and drugs (Fig. 5), and our distribution results are generally congruent with reports from other leading cardio-oncology clinics [8, 14, 15, 17, 22].
Various methods have been developed for risk assessment to help guide providers and patients in determining the appropriate guidelines for care. We offer the use of virtual risk assessment tools such as the computed risk scores based on medication- and patient-related risk factors [22] (Fig. 4) (https://tinyurl.com/CardioOncCompendium), as well as recommendations for establishing cross-provider partnerships to continuously evaluate risk [21]. Other online databases containing useful information and guidelines are readily accessible and can help guide clinical practices. We encourage use of these virtual tools, which can further facilitate collaborative Cardio-Oncology care in the pandemic. Our conversations with international colleagues have suggested additional utility of these virtual tools beyond the pandemic. The online resources can be very helpful in settings where clinical practitioners work alone without support from nurses, pharmacists, nutrition specialists, or exercise physiologists.
Virtual-hybrid care has extended the care team’s capabilities for delivering and maintaining patient education and follow-up. The internet continues to be a robust resource, containing a wealth of health information that is easily accessible to the general population. Various mobile applications and electronic devices have also been developed in recent years to educate, track, and manage patients’ health and lifestyles. While these tools provide patients with greater accessibility and independence, they also create a valuable opportunity for healthcare providers to further engage patients. In a virtual-hybrid model, this becomes increasingly important, as patients may frequently transition between virtual and in-person visits. Forming care partnerships with patients through these virtual information and health-tracking resources becomes crucial in the continuity of care and proper health maintenance as we move through the pandemic.
Our most frequent cardiovascular diagnosis was cardiomyopathy (34%), which is reflective of the management need that first helped start the emerging field of Cardio-Oncology, and is similar to the most frequent cardiovascular diagnosis noted by clinicians from several other leading centers (20–35%) [24, 25]. However, Cardio-Oncology has grown remarkably over the last 10–20 years, with a wide spectrum of cardiovascular diagnoses and indications for referral (Fig. 5b) [8, 14]. Accordingly, at some other leading centers, the most frequent cardiovascular diagnosis or indication for referral has been reported as hypertension [14], arrythmia [17], or comprehensive risk assessment prior to beginning of therapy to optimize cardioprotection [8] in the practice of Preventive Cardio-Oncology [21]. This illustrates an opportunity for growth in our Clinic, to increase the fraction of high-risk patients who undergo comprehensive cardiovascular risk evaluation and management of risk factors prior to administration of cardiotoxic therapy.
Our clinic cares for patients with a range of cancer types (Fig. 5d). Individuals with breast, lung, and hematologic cancers represent a substantial proportion of our patient population, similar to other Cardio-Oncology clinics [8, 14, 22, 26]. The most frequent cancer diagnosis, breast cancer (43%), is consistent with reports from other leading cardio-oncology clinics such as the Mayo Clinic (39.2%) [15] and the Cleveland Clinic in Florida (44.3%) [14]. While hematologic malignancies such as leukemia and lymphoma represented 29% of our patients and was the second most prevalent cancer within our cohort, they comprised the most frequent forms of cancer at other cardio-oncology clinics such as at the Moffitt Cancer Center (31%) [8] and at UCLA (32.70%) [25]. However, the absolute difference was relatively insignificant. Overall, similar to these established cardio-oncology clinics, we receive patients from across a variety of cancers.
A wide breadth of cancer therapeutics is associated with cardiotoxicity [21]. Anthracyclines associate with cardiomyopathy, especially when used with trastuzumab. Targeted therapies (e.g., TKIs) can cause new or worsening of pre-existing hypertension. ICIs are associated with an increased incidence of myocarditis. Some cytotoxic chemotherapeutics, such as cisplatin, increase the risk of venous thromboembolism, and antimetabolites such as fluoropyrimidines have long been associated with a broad range of cardiotoxicities. Radiation therapy is associated with ischemic heart disease, valve dysfunction, conduction abnormalities, pericardial disease, and cardiomyopathy. Patients with cancer who have developed cardiovascular toxicity or who may be at high risk for cardiovascular toxicity should be referred to the Cardio-Oncology clinic for close follow-up.
The most frequently used cancer medication used among our patients was trastuzumab (29%), with the second most frequent being anthracyclines (24%). This was similar to other institutions, with anthracyclines and trastuzumab among the most common cancer drugs in their Cardio-Oncology clinics. Yet, anthracyclines were typically noted more commonly than trastuzumab. The Cleveland Clinic in Florida saw patients most commonly treated with radiation (40%), followed by anthracyclines (26.8%) [14]. The Moffitt Cancer Center most frequently had patients who were treated with anthracyclines (52%), with HER2 targeted therapies representing 27% of the cancer drugs [8]. This difference may reflect a high frequency of patients with HER+ breast cancer in our population (diagnosed by a ratio of HER2 to chromosome 17 signals on dual probe fluorescent in situ hybridization ≥2 or ≥ 6 HER2 signals/cell [27]), as well as the keen attention to a substantial fall in left ventricular ejection fraction or global longitudinal strain as a potential prognostic factor in our patients, per American Society of Echocardiography (ASE) guidelines [28].
All of these patient data distributions were obtained in the context of the Virtual-Hybrid patient flow in our de novo Cardio-Oncology Clinic (Fig. 3), that can be modeled by other future Virtual-Hybrid Cardio-Oncology clinics initiated during the pandemic. Table 1 compares the first few weeks of our de novo C-O clinic setup model with two published manuscripts describing conversion of pre-existing in-person C-O clinics to providing telehealth visits as an option for patients. The table shows similar numbers of patients seen in the initial periods of the clinics, although the numbers in our new clinic went from 0 to 10 in the first 3 weeks, compared to going from up to 40 patients weekly to 11 patients in 2.5 weeks for a group that converted their in-person clinic to a virtual option. Overall, CV diagnoses and cancer types were comparable; distributions of cancer drugs were not reported by the other group. Important differences were noted. Most of our patients in the pandemic were new (90%), given the de novo status of the Cardio-Oncology Clinic, while the converted virtual clinic of another group initially focused on established patients for > 50% of their patient visits. While key personnel were also the same (e.g., physician, advanced practice provider, nurse or nurse coordinator), we also report virtual versions of supportive staffing patterns, including the virtual scheduling and rooming process and pharmacy and lifestyle modification visits. Additionally, trainees have been integrally involved in the establishment of our Cardio-Oncology Clinic, with residents training in program-building, and medical students and fellows training in ambulatory cardio-oncology clinical practice and cardio-oncology critical thinking, respectively. Finally, besides the patient flow (Fig. 3) and de novo nature of our Virtual-Hybrid clinic initiated in the pandemic, our unique contribution may be the virtual resources, compared to the essential “webside manner” [7] or an alternative algorithm [4] for triaging virtual or in-person visits to the physician or advanced practice provider (Table 1).
Table 1 Comparisons Among Clinic Models Described In The Pandemic
Virtual-Hybrid Clinic Telehealth Clinic (14) Triage Clinic (4)
Model Type De Novo Conversion Conversion
Time Frame Compared 3 weeks 2.5 weeks Not reported
Number of Patients 10 11 Not reported
New Visits (%) 90 45 Not reported
Variety of CV Diagnoses Yes Yes Not reported
Variety of CA Types Yes Yes Not reported
Variety of CA Drugs Yes Unknown Not reported
Referrals Yes Unknown Yes
Scheduling Yes Unknown Not reported
Rooming Process Yes Unknown Not Reported
Virtual AA Yes Unknown Not Reported
Virtual MA Yes Unknown Not Reported
Virtual Physician Yes Yes Yes
Virtual APP Yes Unknown Yes
Virtual Pharmacist Yes Unknown Not Reported
Virtual Nurse (Coordinator) Yes Unknown Yes
Unique Contribution Virtual Resources Webside Manner Triage Algorithm
Similar to the formation or conversion of Cardio-Oncology clinics, many protocols for treatment regimens and cancer patients are yet to be standardized. While no standard protocols have been widely adopted at Cardio-Oncology practices, various institutions and writing groups have proposed some approaches (e.g., ASE or ASCO guidelines). We have collaboratively developed institutional algorithms for various cardiovascular toxicities and medications based on existing scientific statements, society guidelines, expert consensus statements, and manuscripts from leading cardio-oncology research institutions. The goal is to adopt, adapt, develop, and continuously update these algorithms, as new literature arises in order to establish best practices and an institutional standard of care.
Conclusion
Starting a new Cardio-Oncology Clinic in the pandemic has its challenges, and yet for our patients can be invaluable. Appropriately competing priorities in the pandemic can limit the scheduling of meetings and gathering of people together in one virtual room to discuss a mutual vision. Gathering resources for patient and clinician education can also be formidable, as can social distancing and obtaining important imaging. However, multiple virtual one-on-one or small group meetings can be beneficial for building institutional relationships. Similarly, virtual visits have risen to the challenge to ensure maintenance of patient care throughout the pandemic. Modifications have also been made to enable safety and distancing during imaging. With the benefit of these adjustments to address the challenge, this report provides a foundation for initiating a cardio-oncology clinic in the pandemic, with virtual resources and tools to equip patients and clinicians.
In the future, we will also lay out a roadmap for initiation of comprehensive cardio-oncology programs with the five pillars of patient care, education, research, community engagement, and innovation in the era of digital transformation accelerated by the pandemic. Novel risk modifiers and risk attenuation methods, such as breast arterial calcification, clonal hematopoiesis of indeterminate potential, and Cardio-Oncology prehabilitation, habilitation, and rehabilitation will also be addressed. Future innovation to implement recommendations from clinical trials across the nation currently underway that utilize mobile health or web-based diet and physical activity interventions and/or seek to determine the impact of cardioprotective pharmacotherapy in Preventive Cardio-Oncology will also be assessed (ClinicalTrials.Gov: NCT01988571, NCT02943590, NCT02562716, NCT01968200, NCT03265574, NCT03760588, NCT03386383, NCT02244411, NCT03223753). Many of these studies incorporate virtual technologies that will be very helpful during and after the pandemic as we continue pursuit of digital transformation.
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Acknowledgements
We are grateful to the following individuals, as well as all of the departments and divisions at Froedtert & MCW that have rallied together to help us establish the hybrid Cardio-Oncology clinic or to see our patients needing subspecialty care, or to partner with us in referrals from the inpatient service, especially the following clinicians: Stacey Gardiner MD, Jason Rubenstein MD, David Ishizawar MD, Jalaj Garg MD, Andrew Rosenblum MD. We are also grateful to Nicole Lohr MD PhD and the clinical sections at the Zablocki Veterans Administration Medical Center that have also helped us establish an affiliate Cardio-Oncology Clinic in tandem at the VAMC in Milwaukee, WI.
Authors’ contributions
SAB conceived of the study, obtained, analyzed and interpreted the data, and made a substantial contribution to the writing of the manuscript; SP made a substantial contribution to the writing of the manuscript; DR made a substantial contribution to the writing of the manuscript; SZ obtained the data and made a substantial contribution to the writing of the manuscript; ML interpreted the data and made a substantial contribution to the writing of the manuscript; TN made a substantial contribution to the writing of the manuscript; BS analyzed the data and made a substantial contribution to the writing of the manuscript; RM made a substantial contribution to the writing of the manuscript; JMac made a substantial contribution to the writing of the manuscript; KD made a substantial contribution to the writing of the manuscript; JMes made a substantial contribution to the writing of the manuscript; DM made a substantial contribution to the writing of the manuscript; JS made a substantial contribution to the writing of the manuscript. All authors read and approved the final manuscript.
Funding
No funding was associated with this work.
Availability of data and materials
The datasets during and/or analyzed during the current study available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The study was approved by the Froedtert & MCW Institutional Review Board (ID PRO00038807); HIPAA informed consent was waived for this minimal risk study.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests. | Fatal | ReactionOutcome | CC BY | 33441188 | 18,793,759 | 2021-01-13 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Angioedema'. | Tissue Plasminogen Activator-Induced Angioedema Involving a Posterior Cerebral Artery Infarct: A Case Presentation.
BACKGROUND Angioedema is characterized by localized swelling of subcutaneous or submucosal tissue resulting from fluid extravasation due to the loss of vascular integrity. It most commonly occurs with exposure to allergens and certain medications, namely nonsteroidal anti-inflammatory agents and angiotensin-converting enzyme inhibitors. There have been few incidences of angioedema following the administration of tissue plasminogen activator. CASE REPORT We describe an 84-year-old woman with a history of hypertension managed with lisinopril who presented with an acute onset of right-sided hemiparesis, slurred speech, and right-sided hemianopsia. Urgent computed tomography of the head revealed subacute infarct of the left pons without hemorrhage. Intravenous alteplase was administered and within 30 min our patient developed severe orolingual edema requiring emergent intubation. Subsequent imaging revealed acute to subacute infarct of the left occipital lobe in the posterior cerebral artery region, consistent with her initial presenting symptoms. CONCLUSIONS Angioedema induced by tissue plasminogen activator occurs in approximately 1-5% of patients receiving thrombolysis for ischemic stroke and can be life-threatening. The risk is increased in patients taking angiotensin-converting enzyme inhibitors, in patients with ischemic strokes of the middle cerebral artery, and in the presence of C1 esterase inhibitor deficiency. This phenomenon is usually self-limited and treatment is supportive, although evidence supports the use of antihistamines, steroids, epinephrine, and complement inhibitors. Due to the severity of angioedema and the potential progression to airway compromise, it is crucial to closely monitor patients receiving tissue plasminogen activator.
Background
It is becoming increasingly common to use tissue plasminogen activator (tPA) in the treatment of acute ischemic stroke, pulmonary embolism, and ST-elevation myocardial infarctions. Since tPA was approved in 1996, its utilization has illustrated marked improvement in stroke recovery and decreased hospital stay [1]. Major concerns with the administration of tPA are intracranial hemorrhage, edema, and possible brain herniation; however, other severe reactions such as hemopericardium, cardiac tamponade, angioedema, and anaphylaxis should not be forgotten.
Angioedema induced by tPA is an infrequent, but potentially fatal outcome of thrombolysis. The mechanisms behind such reactions are presumed to involve mast cells, bradykinin release, histamine, and the complement cascade. It primarily occurs with infarction of the middle cerebral artery and is more likely to occur in patients with concomitant use of angiotensin-converting enzyme inhibitors and in carriers of C1 esterase inhibitor deficiency. It is mostly self-limited and treatment is usually supportive. Some cases may require antihistamines, steroids, and epinephrine, with refractory cases needing complement inhibitors and severe cases leading to intubation or cricothyroidotomy. In this report, we present a case of an elderly woman who developed angioedema following tPA administration for treatment of a posterior cerebral artery stroke, which has only been documented in 2 other cases, as per our literature review.
Case Report
An 84-year-old woman presented to the Emergency Department for right-sided weakness, slurred speech, and right-sided hemianopsia after having collapsed onto the floor. She had a history of hypertension, which managed with lisinopril; chronic obstructive pulmonary disease; and lung cancer with subsequent left upper lobectomy. Her history also included atrial fibrillation, but she had not been on anticoagulation therapy for approximately 3 months due to gastrointestinal bleed. The patient did not experience loss of consciousness, convulsions, or any prodromal symptoms. Upon arrival to the Emergency Department, she was found to have 2/5 strength of her right-sided extremities and right-sided neglect. An urgent computed tomography (CT) scan of the head was performed and revealed a subacute infarct of the left pons with no acute hemorrhage (Figure 1). A CT angiography was obtained and confirmed these findings. She was given 0.9 mg/kg alteplase intravenously, 10% as a bolus followed by an intravenous infusion of the remaining dose. Within 30 min from the onset of infusion, she developed orolingual angioedema consisting of tongue swelling and bilateral lip swelling requiring emergent intubation for airway protection.
The infusion was stopped prematurely, and the patient was given intravenous methylprednisolone 125 mg, diphenhydramine 50 mg, and famotidine 20 mg to help treat her angioedema. The neurology and critical care teams aided in the management of her care. There was marked improvement of her angioedema within 24 h, and she was subsequently extubated the following morning. Repeat CT of the head revealed an acute to subacute infarct with encephalomalacia of the left occipital lobe, which was believed to be the cause of her initial deficits (Figure 2). Echocardiography did not reveal an atrial shunt or evidence of thrombi. Subsequent magnetic resonance imaging illustrated infarct involving the posterior cerebral artery circulation without hemorrhagic conversion (Figure 3). She was started on full-dose aspirin as well as fluoxetine 20 mg daily for stroke recovery. She began to work with physical therapy and had some improvement in her motor skills as well as her vision.
During her hospitalization, she experienced persistent nausea and vomiting, ultimately controlled with promethazine. Her anticoagulation was restarted 10 days after the onset of her stroke. Her strength did not improve as she or her family had hoped. Family discussions were held, and it was decided the best course of action would be to receive hospice care at home. She was ultimately discharged to home with hospice on morphine sulfate, lorazepam, fluoxetine, and promethazine. She died a week later.
Discussion
Tissue plasminogen activator is commonly used to treat ischemic stroke, myocardial infarction, and pulmonary embolism. It is generally well tolerated and can be life-saving; however, there are concerning adverse reactions to be mindful of, one of which is angioedema. Angioedema induced by tPA is an uncommon but potentially fatal occurrence. It is typically observed within 1 h of completing the tPA infusion [2]. It is postulated to occur in approximately 1–5% of patients receiving thrombolysis after an ischemic stroke, and it usually presents with hemifacial edema contralateral to the infarct zone [3]. An extensive study done by Myslimi et al. [4] evaluated 923 patients who received thrombolysis for stroke treatment. Of these patients, only 20 developed angioedema. A retrospective chart review performed by Sczepanski and Bozyk [5] reviewed 147 cases, with only 4 developing edema.
The mechanism behind this phenomenon is still unclear; however, several hypotheses have been proposed to explain this occurrence. One hypothesis suggests a bradykinin-mediated pathway, in which tPA hydrolyzes plasminogen into plasmin, which in turn activates the kinin pathway augmenting the production of bradykinin [5]. Bradykinin is a potent pro-inflammatory and pro-edematous peptide that increases vascular permeability and vasodilation, leading to angioedema. In addition, tPA can augment histamine, causing vasodilation [3]. Other hypotheses propose that both tPA and plasmin activate the complement pathway, increasing complement levels and in turn activating mast cells, histamine, and basophil degranulation, which contribute to angioedema [5,6]. An additional hypothesis focuses on a mutation of the plasminogen gene, drawing on the remarkable clinical similarity between tPA-induced orolingual angioedema and a recently described new subtype of hereditary angioedema with normal C1 inhibitor. This subtype is caused by a highly specific missense mutation of the plasminogen gene and the resulting presence of the aberrant plasminogen protein is hypothesized to lead to angioedema [7].
The risk of developing angioedema following thrombolytic administration is amplified in patients who take angiotensin-converting enzyme (ACE) inhibitors because these drugs increase the concentration of circulating bradykinin [8]. Additionally, neurokinins such as substance P are increased with ACE inhibition and are mediators in inflammation and angioedema [9]. The combination of tPA-related increase in bradykinin, ACE inhibitor-mediated decrease in bradykinin metabolism, and ACE inhibitor-related increase in neurokinin levels amplify the risk of angioedema. For instance, in the study by Myslimi et al. [4], among the 20 patients who developed angioedema after thrombolysis, 45% concomitantly took ACE inhibitors.
Lesion-mapping studies have been performed that concluded infarctions of the middle cerebral artery, especially the branch that supplies the right insular cortex, have the highest propensity of causing angioedema. Ninety percent of patients who developed angioedema in the study completed by Myslimi et al. [4] and 75% of those in the study done by Sczepanski and Bozyk [5] had infarcts of the middle cerebral artery. The lesion-mapping study by Frohlich et al. [3] illustrated an association with right-sided insular infarcts and the development on tPA-related angioedema. The authors postulated that insular infarcts augment sympathetic hyperactivity due to impaired autonomic function, which in turn intensifies proinflammatory cytokine production and vascular permeability thus causing orolingual edema [3]. It is also believed that the tissue damage itself could be a trigger for angioedema via the generation of bradykinin, which increases inflammation and edema [4,8]. Our patient, however, had a posterior cerebral artery infarct, which is not consistent with this hypothesis, making our case unusual. In the retrospective institutional study done by Sczepanski and Bozyk [5], only 1 out of 147 patients had an infarct involving the posterior cerebral artery, and only 1 out of 42 patients in the analysis by Hurford et al. [10] had involvement of the posterior circulation. None were detected in the lesion-mapping study by Frohlich et al. [3] or in the meta-analysis by Yayan [1], and no alternate explanation could be found to support angioedema following tPA treatment of a posterior circulation stroke. The Table 1 summarizes findings from multiple studies including stroke location, development of angioedema after thrombolysis, and concomitant ACE inhibition [11–13].
Angioedema mediated by tPA is a rare and potentially life-threatening occurrence. At the first signs of tPA-induced angioedema, hospital staff should be aware of the commonly used interventions and medications. It is critical to discontinue the tPA infusion when signs of angioedema occur. The 2018 guidelines for the management of tPA-induced angioedema recommend the administration of intravenous methylprednisolone 125 mg, oral diphenhydramine 50 mg, and oral ranitidine 50 mg or famotidine 20 mg with a class IIb recommendation and level C expert opinion [14,15]. If symptoms persist despite these measures, epinephrine can be administered; however, it should be administered cautiously because it may suddenly increase blood pressure and thus the risk of intracranial hemorrhage [14]. Epinephrine would have been a reasonable alternative in this case due to the extent of angioedema that developed. Other alternatives include fresh frozen plasma, ecallantide (a recombinant protein that inhibits kallikrein), and C1 esterase inhibitors, all of which have been primarily used in ACE inhibitor-triggered angioedema or C1 esterase inhibitor deficiency but could have a role in tPA-related angioedema given the role of bradykinin [2,14]. Pahs et al. [16] demonstrated the use of plasma-derived C1 esterase inhibitor in a case of tPA-mediated angioedema. They described a case of potential airway compromise following tPA administration refractory to steroids and H2 blockers that ultimately resolved with a C1 esterase inhibitor and avoided the need for an invasive airway maneuver [16]. One last alternate therapy involves icatibant, a selective bradykinin B2 receptor antagonist; however, this is contraindicated with concomitant use of ACE inhibitors because they exert their vasodilating effect via increased bradykinin concentrations [17]. In severe or refractory cases of angioedema, patients may require intubation or cricothyroidotomy.
Conclusions
Angioedema induced by tPA is an infrequent but potentially fatal outcome of thrombolysis occurring in 1 of 50 patients, which increases to 1 of 10 in insular infarcts and 1 of 6 in individuals who are concomitantly using ACE inhibitors at the time of thrombolysis [4]. Angioedema typically presents within the hour of tPA administration and can quickly compromise the airway. Due to its severity, close monitoring of these individuals is imperative and prompt treatment is essential. Though exposed to ACE inhibitors, our patient was found to have an infarct of her posterior cerebral artery and developed angioedema after thrombolysis. This combination has rarely been documented, making this case unusual.
Conflicts of interest
None.
Figure 1. Computed tomography at initial presentation showing subacute infarct of the left pons indicated by the yellow arrow.
Figure 2. Repeat computed tomography showing acute to subacute infarct with encephalomalacia involving the left occipital lobe indicated by the red arrow.
Figure 3. Magnetic resonance imaging revealing an area of ischemia supplied by the posterior cerebral artery indicated by the green arrow.
Table 1. Comparison of studies involving tissue plasminogen activator-associated angioedema, highlighting the location of stroke and concomitant angiotensin-converting enzyme (ACE) inhibition.
Study Number of tPA-treated stroke patients Angioedema post-thrombolysis Concomitant ACE-inhibition* Locations of Infarct (n)
Myslimi et al. [4] 923 20 9 MCA (18)
Lin et al. [11] 559 5 2 MCA (5)
Engelter et al. [9] 120 2 1 Insular
Frohlich et al. [3] 136 15 10 Primarily MCA
Correia et al. [12] 236 8 5 MCA (3); Frontal (1); Basal Ganglia (1); Others (3)
Hill et al. [13] 176 9 7 MCA/Insula (7); Brainstem (1)
Yayan [1] n.s. 41 24 MCA (18); Insular (3); Others (3); Not mentioned (17)
Sczepanski and Bozyk [5] 147 4 3 MCA (3); PCA (1)
Hurford et al. [10] 530 42 24 ACA (38); Lacunar (3); PCA (1)
ACA – anterior cerebral artery; MCA – middle cerebral artery; n – number of infarcts in listed location correlating to number of patients with angioedema after thrombolysis in a given study; n.s. – not specified; PCA – posterior cerebral artery.
* Number of patients using ACE inhibitors that developed angioedema after thrombolysis. | ALTEPLASE, LISINOPRIL | DrugsGivenReaction | CC BY-NC-ND | 33441533 | 18,915,688 | 2021-01-14 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cerebral infarction'. | Tissue Plasminogen Activator-Induced Angioedema Involving a Posterior Cerebral Artery Infarct: A Case Presentation.
BACKGROUND Angioedema is characterized by localized swelling of subcutaneous or submucosal tissue resulting from fluid extravasation due to the loss of vascular integrity. It most commonly occurs with exposure to allergens and certain medications, namely nonsteroidal anti-inflammatory agents and angiotensin-converting enzyme inhibitors. There have been few incidences of angioedema following the administration of tissue plasminogen activator. CASE REPORT We describe an 84-year-old woman with a history of hypertension managed with lisinopril who presented with an acute onset of right-sided hemiparesis, slurred speech, and right-sided hemianopsia. Urgent computed tomography of the head revealed subacute infarct of the left pons without hemorrhage. Intravenous alteplase was administered and within 30 min our patient developed severe orolingual edema requiring emergent intubation. Subsequent imaging revealed acute to subacute infarct of the left occipital lobe in the posterior cerebral artery region, consistent with her initial presenting symptoms. CONCLUSIONS Angioedema induced by tissue plasminogen activator occurs in approximately 1-5% of patients receiving thrombolysis for ischemic stroke and can be life-threatening. The risk is increased in patients taking angiotensin-converting enzyme inhibitors, in patients with ischemic strokes of the middle cerebral artery, and in the presence of C1 esterase inhibitor deficiency. This phenomenon is usually self-limited and treatment is supportive, although evidence supports the use of antihistamines, steroids, epinephrine, and complement inhibitors. Due to the severity of angioedema and the potential progression to airway compromise, it is crucial to closely monitor patients receiving tissue plasminogen activator.
Background
It is becoming increasingly common to use tissue plasminogen activator (tPA) in the treatment of acute ischemic stroke, pulmonary embolism, and ST-elevation myocardial infarctions. Since tPA was approved in 1996, its utilization has illustrated marked improvement in stroke recovery and decreased hospital stay [1]. Major concerns with the administration of tPA are intracranial hemorrhage, edema, and possible brain herniation; however, other severe reactions such as hemopericardium, cardiac tamponade, angioedema, and anaphylaxis should not be forgotten.
Angioedema induced by tPA is an infrequent, but potentially fatal outcome of thrombolysis. The mechanisms behind such reactions are presumed to involve mast cells, bradykinin release, histamine, and the complement cascade. It primarily occurs with infarction of the middle cerebral artery and is more likely to occur in patients with concomitant use of angiotensin-converting enzyme inhibitors and in carriers of C1 esterase inhibitor deficiency. It is mostly self-limited and treatment is usually supportive. Some cases may require antihistamines, steroids, and epinephrine, with refractory cases needing complement inhibitors and severe cases leading to intubation or cricothyroidotomy. In this report, we present a case of an elderly woman who developed angioedema following tPA administration for treatment of a posterior cerebral artery stroke, which has only been documented in 2 other cases, as per our literature review.
Case Report
An 84-year-old woman presented to the Emergency Department for right-sided weakness, slurred speech, and right-sided hemianopsia after having collapsed onto the floor. She had a history of hypertension, which managed with lisinopril; chronic obstructive pulmonary disease; and lung cancer with subsequent left upper lobectomy. Her history also included atrial fibrillation, but she had not been on anticoagulation therapy for approximately 3 months due to gastrointestinal bleed. The patient did not experience loss of consciousness, convulsions, or any prodromal symptoms. Upon arrival to the Emergency Department, she was found to have 2/5 strength of her right-sided extremities and right-sided neglect. An urgent computed tomography (CT) scan of the head was performed and revealed a subacute infarct of the left pons with no acute hemorrhage (Figure 1). A CT angiography was obtained and confirmed these findings. She was given 0.9 mg/kg alteplase intravenously, 10% as a bolus followed by an intravenous infusion of the remaining dose. Within 30 min from the onset of infusion, she developed orolingual angioedema consisting of tongue swelling and bilateral lip swelling requiring emergent intubation for airway protection.
The infusion was stopped prematurely, and the patient was given intravenous methylprednisolone 125 mg, diphenhydramine 50 mg, and famotidine 20 mg to help treat her angioedema. The neurology and critical care teams aided in the management of her care. There was marked improvement of her angioedema within 24 h, and she was subsequently extubated the following morning. Repeat CT of the head revealed an acute to subacute infarct with encephalomalacia of the left occipital lobe, which was believed to be the cause of her initial deficits (Figure 2). Echocardiography did not reveal an atrial shunt or evidence of thrombi. Subsequent magnetic resonance imaging illustrated infarct involving the posterior cerebral artery circulation without hemorrhagic conversion (Figure 3). She was started on full-dose aspirin as well as fluoxetine 20 mg daily for stroke recovery. She began to work with physical therapy and had some improvement in her motor skills as well as her vision.
During her hospitalization, she experienced persistent nausea and vomiting, ultimately controlled with promethazine. Her anticoagulation was restarted 10 days after the onset of her stroke. Her strength did not improve as she or her family had hoped. Family discussions were held, and it was decided the best course of action would be to receive hospice care at home. She was ultimately discharged to home with hospice on morphine sulfate, lorazepam, fluoxetine, and promethazine. She died a week later.
Discussion
Tissue plasminogen activator is commonly used to treat ischemic stroke, myocardial infarction, and pulmonary embolism. It is generally well tolerated and can be life-saving; however, there are concerning adverse reactions to be mindful of, one of which is angioedema. Angioedema induced by tPA is an uncommon but potentially fatal occurrence. It is typically observed within 1 h of completing the tPA infusion [2]. It is postulated to occur in approximately 1–5% of patients receiving thrombolysis after an ischemic stroke, and it usually presents with hemifacial edema contralateral to the infarct zone [3]. An extensive study done by Myslimi et al. [4] evaluated 923 patients who received thrombolysis for stroke treatment. Of these patients, only 20 developed angioedema. A retrospective chart review performed by Sczepanski and Bozyk [5] reviewed 147 cases, with only 4 developing edema.
The mechanism behind this phenomenon is still unclear; however, several hypotheses have been proposed to explain this occurrence. One hypothesis suggests a bradykinin-mediated pathway, in which tPA hydrolyzes plasminogen into plasmin, which in turn activates the kinin pathway augmenting the production of bradykinin [5]. Bradykinin is a potent pro-inflammatory and pro-edematous peptide that increases vascular permeability and vasodilation, leading to angioedema. In addition, tPA can augment histamine, causing vasodilation [3]. Other hypotheses propose that both tPA and plasmin activate the complement pathway, increasing complement levels and in turn activating mast cells, histamine, and basophil degranulation, which contribute to angioedema [5,6]. An additional hypothesis focuses on a mutation of the plasminogen gene, drawing on the remarkable clinical similarity between tPA-induced orolingual angioedema and a recently described new subtype of hereditary angioedema with normal C1 inhibitor. This subtype is caused by a highly specific missense mutation of the plasminogen gene and the resulting presence of the aberrant plasminogen protein is hypothesized to lead to angioedema [7].
The risk of developing angioedema following thrombolytic administration is amplified in patients who take angiotensin-converting enzyme (ACE) inhibitors because these drugs increase the concentration of circulating bradykinin [8]. Additionally, neurokinins such as substance P are increased with ACE inhibition and are mediators in inflammation and angioedema [9]. The combination of tPA-related increase in bradykinin, ACE inhibitor-mediated decrease in bradykinin metabolism, and ACE inhibitor-related increase in neurokinin levels amplify the risk of angioedema. For instance, in the study by Myslimi et al. [4], among the 20 patients who developed angioedema after thrombolysis, 45% concomitantly took ACE inhibitors.
Lesion-mapping studies have been performed that concluded infarctions of the middle cerebral artery, especially the branch that supplies the right insular cortex, have the highest propensity of causing angioedema. Ninety percent of patients who developed angioedema in the study completed by Myslimi et al. [4] and 75% of those in the study done by Sczepanski and Bozyk [5] had infarcts of the middle cerebral artery. The lesion-mapping study by Frohlich et al. [3] illustrated an association with right-sided insular infarcts and the development on tPA-related angioedema. The authors postulated that insular infarcts augment sympathetic hyperactivity due to impaired autonomic function, which in turn intensifies proinflammatory cytokine production and vascular permeability thus causing orolingual edema [3]. It is also believed that the tissue damage itself could be a trigger for angioedema via the generation of bradykinin, which increases inflammation and edema [4,8]. Our patient, however, had a posterior cerebral artery infarct, which is not consistent with this hypothesis, making our case unusual. In the retrospective institutional study done by Sczepanski and Bozyk [5], only 1 out of 147 patients had an infarct involving the posterior cerebral artery, and only 1 out of 42 patients in the analysis by Hurford et al. [10] had involvement of the posterior circulation. None were detected in the lesion-mapping study by Frohlich et al. [3] or in the meta-analysis by Yayan [1], and no alternate explanation could be found to support angioedema following tPA treatment of a posterior circulation stroke. The Table 1 summarizes findings from multiple studies including stroke location, development of angioedema after thrombolysis, and concomitant ACE inhibition [11–13].
Angioedema mediated by tPA is a rare and potentially life-threatening occurrence. At the first signs of tPA-induced angioedema, hospital staff should be aware of the commonly used interventions and medications. It is critical to discontinue the tPA infusion when signs of angioedema occur. The 2018 guidelines for the management of tPA-induced angioedema recommend the administration of intravenous methylprednisolone 125 mg, oral diphenhydramine 50 mg, and oral ranitidine 50 mg or famotidine 20 mg with a class IIb recommendation and level C expert opinion [14,15]. If symptoms persist despite these measures, epinephrine can be administered; however, it should be administered cautiously because it may suddenly increase blood pressure and thus the risk of intracranial hemorrhage [14]. Epinephrine would have been a reasonable alternative in this case due to the extent of angioedema that developed. Other alternatives include fresh frozen plasma, ecallantide (a recombinant protein that inhibits kallikrein), and C1 esterase inhibitors, all of which have been primarily used in ACE inhibitor-triggered angioedema or C1 esterase inhibitor deficiency but could have a role in tPA-related angioedema given the role of bradykinin [2,14]. Pahs et al. [16] demonstrated the use of plasma-derived C1 esterase inhibitor in a case of tPA-mediated angioedema. They described a case of potential airway compromise following tPA administration refractory to steroids and H2 blockers that ultimately resolved with a C1 esterase inhibitor and avoided the need for an invasive airway maneuver [16]. One last alternate therapy involves icatibant, a selective bradykinin B2 receptor antagonist; however, this is contraindicated with concomitant use of ACE inhibitors because they exert their vasodilating effect via increased bradykinin concentrations [17]. In severe or refractory cases of angioedema, patients may require intubation or cricothyroidotomy.
Conclusions
Angioedema induced by tPA is an infrequent but potentially fatal outcome of thrombolysis occurring in 1 of 50 patients, which increases to 1 of 10 in insular infarcts and 1 of 6 in individuals who are concomitantly using ACE inhibitors at the time of thrombolysis [4]. Angioedema typically presents within the hour of tPA administration and can quickly compromise the airway. Due to its severity, close monitoring of these individuals is imperative and prompt treatment is essential. Though exposed to ACE inhibitors, our patient was found to have an infarct of her posterior cerebral artery and developed angioedema after thrombolysis. This combination has rarely been documented, making this case unusual.
Conflicts of interest
None.
Figure 1. Computed tomography at initial presentation showing subacute infarct of the left pons indicated by the yellow arrow.
Figure 2. Repeat computed tomography showing acute to subacute infarct with encephalomalacia involving the left occipital lobe indicated by the red arrow.
Figure 3. Magnetic resonance imaging revealing an area of ischemia supplied by the posterior cerebral artery indicated by the green arrow.
Table 1. Comparison of studies involving tissue plasminogen activator-associated angioedema, highlighting the location of stroke and concomitant angiotensin-converting enzyme (ACE) inhibition.
Study Number of tPA-treated stroke patients Angioedema post-thrombolysis Concomitant ACE-inhibition* Locations of Infarct (n)
Myslimi et al. [4] 923 20 9 MCA (18)
Lin et al. [11] 559 5 2 MCA (5)
Engelter et al. [9] 120 2 1 Insular
Frohlich et al. [3] 136 15 10 Primarily MCA
Correia et al. [12] 236 8 5 MCA (3); Frontal (1); Basal Ganglia (1); Others (3)
Hill et al. [13] 176 9 7 MCA/Insula (7); Brainstem (1)
Yayan [1] n.s. 41 24 MCA (18); Insular (3); Others (3); Not mentioned (17)
Sczepanski and Bozyk [5] 147 4 3 MCA (3); PCA (1)
Hurford et al. [10] 530 42 24 ACA (38); Lacunar (3); PCA (1)
ACA – anterior cerebral artery; MCA – middle cerebral artery; n – number of infarcts in listed location correlating to number of patients with angioedema after thrombolysis in a given study; n.s. – not specified; PCA – posterior cerebral artery.
* Number of patients using ACE inhibitors that developed angioedema after thrombolysis. | ALTEPLASE, LISINOPRIL | DrugsGivenReaction | CC BY-NC-ND | 33441533 | 18,955,161 | 2021-01-14 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug interaction'. | Tissue Plasminogen Activator-Induced Angioedema Involving a Posterior Cerebral Artery Infarct: A Case Presentation.
BACKGROUND Angioedema is characterized by localized swelling of subcutaneous or submucosal tissue resulting from fluid extravasation due to the loss of vascular integrity. It most commonly occurs with exposure to allergens and certain medications, namely nonsteroidal anti-inflammatory agents and angiotensin-converting enzyme inhibitors. There have been few incidences of angioedema following the administration of tissue plasminogen activator. CASE REPORT We describe an 84-year-old woman with a history of hypertension managed with lisinopril who presented with an acute onset of right-sided hemiparesis, slurred speech, and right-sided hemianopsia. Urgent computed tomography of the head revealed subacute infarct of the left pons without hemorrhage. Intravenous alteplase was administered and within 30 min our patient developed severe orolingual edema requiring emergent intubation. Subsequent imaging revealed acute to subacute infarct of the left occipital lobe in the posterior cerebral artery region, consistent with her initial presenting symptoms. CONCLUSIONS Angioedema induced by tissue plasminogen activator occurs in approximately 1-5% of patients receiving thrombolysis for ischemic stroke and can be life-threatening. The risk is increased in patients taking angiotensin-converting enzyme inhibitors, in patients with ischemic strokes of the middle cerebral artery, and in the presence of C1 esterase inhibitor deficiency. This phenomenon is usually self-limited and treatment is supportive, although evidence supports the use of antihistamines, steroids, epinephrine, and complement inhibitors. Due to the severity of angioedema and the potential progression to airway compromise, it is crucial to closely monitor patients receiving tissue plasminogen activator.
Background
It is becoming increasingly common to use tissue plasminogen activator (tPA) in the treatment of acute ischemic stroke, pulmonary embolism, and ST-elevation myocardial infarctions. Since tPA was approved in 1996, its utilization has illustrated marked improvement in stroke recovery and decreased hospital stay [1]. Major concerns with the administration of tPA are intracranial hemorrhage, edema, and possible brain herniation; however, other severe reactions such as hemopericardium, cardiac tamponade, angioedema, and anaphylaxis should not be forgotten.
Angioedema induced by tPA is an infrequent, but potentially fatal outcome of thrombolysis. The mechanisms behind such reactions are presumed to involve mast cells, bradykinin release, histamine, and the complement cascade. It primarily occurs with infarction of the middle cerebral artery and is more likely to occur in patients with concomitant use of angiotensin-converting enzyme inhibitors and in carriers of C1 esterase inhibitor deficiency. It is mostly self-limited and treatment is usually supportive. Some cases may require antihistamines, steroids, and epinephrine, with refractory cases needing complement inhibitors and severe cases leading to intubation or cricothyroidotomy. In this report, we present a case of an elderly woman who developed angioedema following tPA administration for treatment of a posterior cerebral artery stroke, which has only been documented in 2 other cases, as per our literature review.
Case Report
An 84-year-old woman presented to the Emergency Department for right-sided weakness, slurred speech, and right-sided hemianopsia after having collapsed onto the floor. She had a history of hypertension, which managed with lisinopril; chronic obstructive pulmonary disease; and lung cancer with subsequent left upper lobectomy. Her history also included atrial fibrillation, but she had not been on anticoagulation therapy for approximately 3 months due to gastrointestinal bleed. The patient did not experience loss of consciousness, convulsions, or any prodromal symptoms. Upon arrival to the Emergency Department, she was found to have 2/5 strength of her right-sided extremities and right-sided neglect. An urgent computed tomography (CT) scan of the head was performed and revealed a subacute infarct of the left pons with no acute hemorrhage (Figure 1). A CT angiography was obtained and confirmed these findings. She was given 0.9 mg/kg alteplase intravenously, 10% as a bolus followed by an intravenous infusion of the remaining dose. Within 30 min from the onset of infusion, she developed orolingual angioedema consisting of tongue swelling and bilateral lip swelling requiring emergent intubation for airway protection.
The infusion was stopped prematurely, and the patient was given intravenous methylprednisolone 125 mg, diphenhydramine 50 mg, and famotidine 20 mg to help treat her angioedema. The neurology and critical care teams aided in the management of her care. There was marked improvement of her angioedema within 24 h, and she was subsequently extubated the following morning. Repeat CT of the head revealed an acute to subacute infarct with encephalomalacia of the left occipital lobe, which was believed to be the cause of her initial deficits (Figure 2). Echocardiography did not reveal an atrial shunt or evidence of thrombi. Subsequent magnetic resonance imaging illustrated infarct involving the posterior cerebral artery circulation without hemorrhagic conversion (Figure 3). She was started on full-dose aspirin as well as fluoxetine 20 mg daily for stroke recovery. She began to work with physical therapy and had some improvement in her motor skills as well as her vision.
During her hospitalization, she experienced persistent nausea and vomiting, ultimately controlled with promethazine. Her anticoagulation was restarted 10 days after the onset of her stroke. Her strength did not improve as she or her family had hoped. Family discussions were held, and it was decided the best course of action would be to receive hospice care at home. She was ultimately discharged to home with hospice on morphine sulfate, lorazepam, fluoxetine, and promethazine. She died a week later.
Discussion
Tissue plasminogen activator is commonly used to treat ischemic stroke, myocardial infarction, and pulmonary embolism. It is generally well tolerated and can be life-saving; however, there are concerning adverse reactions to be mindful of, one of which is angioedema. Angioedema induced by tPA is an uncommon but potentially fatal occurrence. It is typically observed within 1 h of completing the tPA infusion [2]. It is postulated to occur in approximately 1–5% of patients receiving thrombolysis after an ischemic stroke, and it usually presents with hemifacial edema contralateral to the infarct zone [3]. An extensive study done by Myslimi et al. [4] evaluated 923 patients who received thrombolysis for stroke treatment. Of these patients, only 20 developed angioedema. A retrospective chart review performed by Sczepanski and Bozyk [5] reviewed 147 cases, with only 4 developing edema.
The mechanism behind this phenomenon is still unclear; however, several hypotheses have been proposed to explain this occurrence. One hypothesis suggests a bradykinin-mediated pathway, in which tPA hydrolyzes plasminogen into plasmin, which in turn activates the kinin pathway augmenting the production of bradykinin [5]. Bradykinin is a potent pro-inflammatory and pro-edematous peptide that increases vascular permeability and vasodilation, leading to angioedema. In addition, tPA can augment histamine, causing vasodilation [3]. Other hypotheses propose that both tPA and plasmin activate the complement pathway, increasing complement levels and in turn activating mast cells, histamine, and basophil degranulation, which contribute to angioedema [5,6]. An additional hypothesis focuses on a mutation of the plasminogen gene, drawing on the remarkable clinical similarity between tPA-induced orolingual angioedema and a recently described new subtype of hereditary angioedema with normal C1 inhibitor. This subtype is caused by a highly specific missense mutation of the plasminogen gene and the resulting presence of the aberrant plasminogen protein is hypothesized to lead to angioedema [7].
The risk of developing angioedema following thrombolytic administration is amplified in patients who take angiotensin-converting enzyme (ACE) inhibitors because these drugs increase the concentration of circulating bradykinin [8]. Additionally, neurokinins such as substance P are increased with ACE inhibition and are mediators in inflammation and angioedema [9]. The combination of tPA-related increase in bradykinin, ACE inhibitor-mediated decrease in bradykinin metabolism, and ACE inhibitor-related increase in neurokinin levels amplify the risk of angioedema. For instance, in the study by Myslimi et al. [4], among the 20 patients who developed angioedema after thrombolysis, 45% concomitantly took ACE inhibitors.
Lesion-mapping studies have been performed that concluded infarctions of the middle cerebral artery, especially the branch that supplies the right insular cortex, have the highest propensity of causing angioedema. Ninety percent of patients who developed angioedema in the study completed by Myslimi et al. [4] and 75% of those in the study done by Sczepanski and Bozyk [5] had infarcts of the middle cerebral artery. The lesion-mapping study by Frohlich et al. [3] illustrated an association with right-sided insular infarcts and the development on tPA-related angioedema. The authors postulated that insular infarcts augment sympathetic hyperactivity due to impaired autonomic function, which in turn intensifies proinflammatory cytokine production and vascular permeability thus causing orolingual edema [3]. It is also believed that the tissue damage itself could be a trigger for angioedema via the generation of bradykinin, which increases inflammation and edema [4,8]. Our patient, however, had a posterior cerebral artery infarct, which is not consistent with this hypothesis, making our case unusual. In the retrospective institutional study done by Sczepanski and Bozyk [5], only 1 out of 147 patients had an infarct involving the posterior cerebral artery, and only 1 out of 42 patients in the analysis by Hurford et al. [10] had involvement of the posterior circulation. None were detected in the lesion-mapping study by Frohlich et al. [3] or in the meta-analysis by Yayan [1], and no alternate explanation could be found to support angioedema following tPA treatment of a posterior circulation stroke. The Table 1 summarizes findings from multiple studies including stroke location, development of angioedema after thrombolysis, and concomitant ACE inhibition [11–13].
Angioedema mediated by tPA is a rare and potentially life-threatening occurrence. At the first signs of tPA-induced angioedema, hospital staff should be aware of the commonly used interventions and medications. It is critical to discontinue the tPA infusion when signs of angioedema occur. The 2018 guidelines for the management of tPA-induced angioedema recommend the administration of intravenous methylprednisolone 125 mg, oral diphenhydramine 50 mg, and oral ranitidine 50 mg or famotidine 20 mg with a class IIb recommendation and level C expert opinion [14,15]. If symptoms persist despite these measures, epinephrine can be administered; however, it should be administered cautiously because it may suddenly increase blood pressure and thus the risk of intracranial hemorrhage [14]. Epinephrine would have been a reasonable alternative in this case due to the extent of angioedema that developed. Other alternatives include fresh frozen plasma, ecallantide (a recombinant protein that inhibits kallikrein), and C1 esterase inhibitors, all of which have been primarily used in ACE inhibitor-triggered angioedema or C1 esterase inhibitor deficiency but could have a role in tPA-related angioedema given the role of bradykinin [2,14]. Pahs et al. [16] demonstrated the use of plasma-derived C1 esterase inhibitor in a case of tPA-mediated angioedema. They described a case of potential airway compromise following tPA administration refractory to steroids and H2 blockers that ultimately resolved with a C1 esterase inhibitor and avoided the need for an invasive airway maneuver [16]. One last alternate therapy involves icatibant, a selective bradykinin B2 receptor antagonist; however, this is contraindicated with concomitant use of ACE inhibitors because they exert their vasodilating effect via increased bradykinin concentrations [17]. In severe or refractory cases of angioedema, patients may require intubation or cricothyroidotomy.
Conclusions
Angioedema induced by tPA is an infrequent but potentially fatal outcome of thrombolysis occurring in 1 of 50 patients, which increases to 1 of 10 in insular infarcts and 1 of 6 in individuals who are concomitantly using ACE inhibitors at the time of thrombolysis [4]. Angioedema typically presents within the hour of tPA administration and can quickly compromise the airway. Due to its severity, close monitoring of these individuals is imperative and prompt treatment is essential. Though exposed to ACE inhibitors, our patient was found to have an infarct of her posterior cerebral artery and developed angioedema after thrombolysis. This combination has rarely been documented, making this case unusual.
Conflicts of interest
None.
Figure 1. Computed tomography at initial presentation showing subacute infarct of the left pons indicated by the yellow arrow.
Figure 2. Repeat computed tomography showing acute to subacute infarct with encephalomalacia involving the left occipital lobe indicated by the red arrow.
Figure 3. Magnetic resonance imaging revealing an area of ischemia supplied by the posterior cerebral artery indicated by the green arrow.
Table 1. Comparison of studies involving tissue plasminogen activator-associated angioedema, highlighting the location of stroke and concomitant angiotensin-converting enzyme (ACE) inhibition.
Study Number of tPA-treated stroke patients Angioedema post-thrombolysis Concomitant ACE-inhibition* Locations of Infarct (n)
Myslimi et al. [4] 923 20 9 MCA (18)
Lin et al. [11] 559 5 2 MCA (5)
Engelter et al. [9] 120 2 1 Insular
Frohlich et al. [3] 136 15 10 Primarily MCA
Correia et al. [12] 236 8 5 MCA (3); Frontal (1); Basal Ganglia (1); Others (3)
Hill et al. [13] 176 9 7 MCA/Insula (7); Brainstem (1)
Yayan [1] n.s. 41 24 MCA (18); Insular (3); Others (3); Not mentioned (17)
Sczepanski and Bozyk [5] 147 4 3 MCA (3); PCA (1)
Hurford et al. [10] 530 42 24 ACA (38); Lacunar (3); PCA (1)
ACA – anterior cerebral artery; MCA – middle cerebral artery; n – number of infarcts in listed location correlating to number of patients with angioedema after thrombolysis in a given study; n.s. – not specified; PCA – posterior cerebral artery.
* Number of patients using ACE inhibitors that developed angioedema after thrombolysis. | ALTEPLASE, LISINOPRIL | DrugsGivenReaction | CC BY-NC-ND | 33441533 | 18,915,688 | 2021-01-14 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Swollen tongue'. | Tissue Plasminogen Activator-Induced Angioedema Involving a Posterior Cerebral Artery Infarct: A Case Presentation.
BACKGROUND Angioedema is characterized by localized swelling of subcutaneous or submucosal tissue resulting from fluid extravasation due to the loss of vascular integrity. It most commonly occurs with exposure to allergens and certain medications, namely nonsteroidal anti-inflammatory agents and angiotensin-converting enzyme inhibitors. There have been few incidences of angioedema following the administration of tissue plasminogen activator. CASE REPORT We describe an 84-year-old woman with a history of hypertension managed with lisinopril who presented with an acute onset of right-sided hemiparesis, slurred speech, and right-sided hemianopsia. Urgent computed tomography of the head revealed subacute infarct of the left pons without hemorrhage. Intravenous alteplase was administered and within 30 min our patient developed severe orolingual edema requiring emergent intubation. Subsequent imaging revealed acute to subacute infarct of the left occipital lobe in the posterior cerebral artery region, consistent with her initial presenting symptoms. CONCLUSIONS Angioedema induced by tissue plasminogen activator occurs in approximately 1-5% of patients receiving thrombolysis for ischemic stroke and can be life-threatening. The risk is increased in patients taking angiotensin-converting enzyme inhibitors, in patients with ischemic strokes of the middle cerebral artery, and in the presence of C1 esterase inhibitor deficiency. This phenomenon is usually self-limited and treatment is supportive, although evidence supports the use of antihistamines, steroids, epinephrine, and complement inhibitors. Due to the severity of angioedema and the potential progression to airway compromise, it is crucial to closely monitor patients receiving tissue plasminogen activator.
Background
It is becoming increasingly common to use tissue plasminogen activator (tPA) in the treatment of acute ischemic stroke, pulmonary embolism, and ST-elevation myocardial infarctions. Since tPA was approved in 1996, its utilization has illustrated marked improvement in stroke recovery and decreased hospital stay [1]. Major concerns with the administration of tPA are intracranial hemorrhage, edema, and possible brain herniation; however, other severe reactions such as hemopericardium, cardiac tamponade, angioedema, and anaphylaxis should not be forgotten.
Angioedema induced by tPA is an infrequent, but potentially fatal outcome of thrombolysis. The mechanisms behind such reactions are presumed to involve mast cells, bradykinin release, histamine, and the complement cascade. It primarily occurs with infarction of the middle cerebral artery and is more likely to occur in patients with concomitant use of angiotensin-converting enzyme inhibitors and in carriers of C1 esterase inhibitor deficiency. It is mostly self-limited and treatment is usually supportive. Some cases may require antihistamines, steroids, and epinephrine, with refractory cases needing complement inhibitors and severe cases leading to intubation or cricothyroidotomy. In this report, we present a case of an elderly woman who developed angioedema following tPA administration for treatment of a posterior cerebral artery stroke, which has only been documented in 2 other cases, as per our literature review.
Case Report
An 84-year-old woman presented to the Emergency Department for right-sided weakness, slurred speech, and right-sided hemianopsia after having collapsed onto the floor. She had a history of hypertension, which managed with lisinopril; chronic obstructive pulmonary disease; and lung cancer with subsequent left upper lobectomy. Her history also included atrial fibrillation, but she had not been on anticoagulation therapy for approximately 3 months due to gastrointestinal bleed. The patient did not experience loss of consciousness, convulsions, or any prodromal symptoms. Upon arrival to the Emergency Department, she was found to have 2/5 strength of her right-sided extremities and right-sided neglect. An urgent computed tomography (CT) scan of the head was performed and revealed a subacute infarct of the left pons with no acute hemorrhage (Figure 1). A CT angiography was obtained and confirmed these findings. She was given 0.9 mg/kg alteplase intravenously, 10% as a bolus followed by an intravenous infusion of the remaining dose. Within 30 min from the onset of infusion, she developed orolingual angioedema consisting of tongue swelling and bilateral lip swelling requiring emergent intubation for airway protection.
The infusion was stopped prematurely, and the patient was given intravenous methylprednisolone 125 mg, diphenhydramine 50 mg, and famotidine 20 mg to help treat her angioedema. The neurology and critical care teams aided in the management of her care. There was marked improvement of her angioedema within 24 h, and she was subsequently extubated the following morning. Repeat CT of the head revealed an acute to subacute infarct with encephalomalacia of the left occipital lobe, which was believed to be the cause of her initial deficits (Figure 2). Echocardiography did not reveal an atrial shunt or evidence of thrombi. Subsequent magnetic resonance imaging illustrated infarct involving the posterior cerebral artery circulation without hemorrhagic conversion (Figure 3). She was started on full-dose aspirin as well as fluoxetine 20 mg daily for stroke recovery. She began to work with physical therapy and had some improvement in her motor skills as well as her vision.
During her hospitalization, she experienced persistent nausea and vomiting, ultimately controlled with promethazine. Her anticoagulation was restarted 10 days after the onset of her stroke. Her strength did not improve as she or her family had hoped. Family discussions were held, and it was decided the best course of action would be to receive hospice care at home. She was ultimately discharged to home with hospice on morphine sulfate, lorazepam, fluoxetine, and promethazine. She died a week later.
Discussion
Tissue plasminogen activator is commonly used to treat ischemic stroke, myocardial infarction, and pulmonary embolism. It is generally well tolerated and can be life-saving; however, there are concerning adverse reactions to be mindful of, one of which is angioedema. Angioedema induced by tPA is an uncommon but potentially fatal occurrence. It is typically observed within 1 h of completing the tPA infusion [2]. It is postulated to occur in approximately 1–5% of patients receiving thrombolysis after an ischemic stroke, and it usually presents with hemifacial edema contralateral to the infarct zone [3]. An extensive study done by Myslimi et al. [4] evaluated 923 patients who received thrombolysis for stroke treatment. Of these patients, only 20 developed angioedema. A retrospective chart review performed by Sczepanski and Bozyk [5] reviewed 147 cases, with only 4 developing edema.
The mechanism behind this phenomenon is still unclear; however, several hypotheses have been proposed to explain this occurrence. One hypothesis suggests a bradykinin-mediated pathway, in which tPA hydrolyzes plasminogen into plasmin, which in turn activates the kinin pathway augmenting the production of bradykinin [5]. Bradykinin is a potent pro-inflammatory and pro-edematous peptide that increases vascular permeability and vasodilation, leading to angioedema. In addition, tPA can augment histamine, causing vasodilation [3]. Other hypotheses propose that both tPA and plasmin activate the complement pathway, increasing complement levels and in turn activating mast cells, histamine, and basophil degranulation, which contribute to angioedema [5,6]. An additional hypothesis focuses on a mutation of the plasminogen gene, drawing on the remarkable clinical similarity between tPA-induced orolingual angioedema and a recently described new subtype of hereditary angioedema with normal C1 inhibitor. This subtype is caused by a highly specific missense mutation of the plasminogen gene and the resulting presence of the aberrant plasminogen protein is hypothesized to lead to angioedema [7].
The risk of developing angioedema following thrombolytic administration is amplified in patients who take angiotensin-converting enzyme (ACE) inhibitors because these drugs increase the concentration of circulating bradykinin [8]. Additionally, neurokinins such as substance P are increased with ACE inhibition and are mediators in inflammation and angioedema [9]. The combination of tPA-related increase in bradykinin, ACE inhibitor-mediated decrease in bradykinin metabolism, and ACE inhibitor-related increase in neurokinin levels amplify the risk of angioedema. For instance, in the study by Myslimi et al. [4], among the 20 patients who developed angioedema after thrombolysis, 45% concomitantly took ACE inhibitors.
Lesion-mapping studies have been performed that concluded infarctions of the middle cerebral artery, especially the branch that supplies the right insular cortex, have the highest propensity of causing angioedema. Ninety percent of patients who developed angioedema in the study completed by Myslimi et al. [4] and 75% of those in the study done by Sczepanski and Bozyk [5] had infarcts of the middle cerebral artery. The lesion-mapping study by Frohlich et al. [3] illustrated an association with right-sided insular infarcts and the development on tPA-related angioedema. The authors postulated that insular infarcts augment sympathetic hyperactivity due to impaired autonomic function, which in turn intensifies proinflammatory cytokine production and vascular permeability thus causing orolingual edema [3]. It is also believed that the tissue damage itself could be a trigger for angioedema via the generation of bradykinin, which increases inflammation and edema [4,8]. Our patient, however, had a posterior cerebral artery infarct, which is not consistent with this hypothesis, making our case unusual. In the retrospective institutional study done by Sczepanski and Bozyk [5], only 1 out of 147 patients had an infarct involving the posterior cerebral artery, and only 1 out of 42 patients in the analysis by Hurford et al. [10] had involvement of the posterior circulation. None were detected in the lesion-mapping study by Frohlich et al. [3] or in the meta-analysis by Yayan [1], and no alternate explanation could be found to support angioedema following tPA treatment of a posterior circulation stroke. The Table 1 summarizes findings from multiple studies including stroke location, development of angioedema after thrombolysis, and concomitant ACE inhibition [11–13].
Angioedema mediated by tPA is a rare and potentially life-threatening occurrence. At the first signs of tPA-induced angioedema, hospital staff should be aware of the commonly used interventions and medications. It is critical to discontinue the tPA infusion when signs of angioedema occur. The 2018 guidelines for the management of tPA-induced angioedema recommend the administration of intravenous methylprednisolone 125 mg, oral diphenhydramine 50 mg, and oral ranitidine 50 mg or famotidine 20 mg with a class IIb recommendation and level C expert opinion [14,15]. If symptoms persist despite these measures, epinephrine can be administered; however, it should be administered cautiously because it may suddenly increase blood pressure and thus the risk of intracranial hemorrhage [14]. Epinephrine would have been a reasonable alternative in this case due to the extent of angioedema that developed. Other alternatives include fresh frozen plasma, ecallantide (a recombinant protein that inhibits kallikrein), and C1 esterase inhibitors, all of which have been primarily used in ACE inhibitor-triggered angioedema or C1 esterase inhibitor deficiency but could have a role in tPA-related angioedema given the role of bradykinin [2,14]. Pahs et al. [16] demonstrated the use of plasma-derived C1 esterase inhibitor in a case of tPA-mediated angioedema. They described a case of potential airway compromise following tPA administration refractory to steroids and H2 blockers that ultimately resolved with a C1 esterase inhibitor and avoided the need for an invasive airway maneuver [16]. One last alternate therapy involves icatibant, a selective bradykinin B2 receptor antagonist; however, this is contraindicated with concomitant use of ACE inhibitors because they exert their vasodilating effect via increased bradykinin concentrations [17]. In severe or refractory cases of angioedema, patients may require intubation or cricothyroidotomy.
Conclusions
Angioedema induced by tPA is an infrequent but potentially fatal outcome of thrombolysis occurring in 1 of 50 patients, which increases to 1 of 10 in insular infarcts and 1 of 6 in individuals who are concomitantly using ACE inhibitors at the time of thrombolysis [4]. Angioedema typically presents within the hour of tPA administration and can quickly compromise the airway. Due to its severity, close monitoring of these individuals is imperative and prompt treatment is essential. Though exposed to ACE inhibitors, our patient was found to have an infarct of her posterior cerebral artery and developed angioedema after thrombolysis. This combination has rarely been documented, making this case unusual.
Conflicts of interest
None.
Figure 1. Computed tomography at initial presentation showing subacute infarct of the left pons indicated by the yellow arrow.
Figure 2. Repeat computed tomography showing acute to subacute infarct with encephalomalacia involving the left occipital lobe indicated by the red arrow.
Figure 3. Magnetic resonance imaging revealing an area of ischemia supplied by the posterior cerebral artery indicated by the green arrow.
Table 1. Comparison of studies involving tissue plasminogen activator-associated angioedema, highlighting the location of stroke and concomitant angiotensin-converting enzyme (ACE) inhibition.
Study Number of tPA-treated stroke patients Angioedema post-thrombolysis Concomitant ACE-inhibition* Locations of Infarct (n)
Myslimi et al. [4] 923 20 9 MCA (18)
Lin et al. [11] 559 5 2 MCA (5)
Engelter et al. [9] 120 2 1 Insular
Frohlich et al. [3] 136 15 10 Primarily MCA
Correia et al. [12] 236 8 5 MCA (3); Frontal (1); Basal Ganglia (1); Others (3)
Hill et al. [13] 176 9 7 MCA/Insula (7); Brainstem (1)
Yayan [1] n.s. 41 24 MCA (18); Insular (3); Others (3); Not mentioned (17)
Sczepanski and Bozyk [5] 147 4 3 MCA (3); PCA (1)
Hurford et al. [10] 530 42 24 ACA (38); Lacunar (3); PCA (1)
ACA – anterior cerebral artery; MCA – middle cerebral artery; n – number of infarcts in listed location correlating to number of patients with angioedema after thrombolysis in a given study; n.s. – not specified; PCA – posterior cerebral artery.
* Number of patients using ACE inhibitors that developed angioedema after thrombolysis. | ALTEPLASE, LISINOPRIL | DrugsGivenReaction | CC BY-NC-ND | 33441533 | 18,980,846 | 2021-01-14 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapy partial responder'. | Tissue Plasminogen Activator-Induced Angioedema Involving a Posterior Cerebral Artery Infarct: A Case Presentation.
BACKGROUND Angioedema is characterized by localized swelling of subcutaneous or submucosal tissue resulting from fluid extravasation due to the loss of vascular integrity. It most commonly occurs with exposure to allergens and certain medications, namely nonsteroidal anti-inflammatory agents and angiotensin-converting enzyme inhibitors. There have been few incidences of angioedema following the administration of tissue plasminogen activator. CASE REPORT We describe an 84-year-old woman with a history of hypertension managed with lisinopril who presented with an acute onset of right-sided hemiparesis, slurred speech, and right-sided hemianopsia. Urgent computed tomography of the head revealed subacute infarct of the left pons without hemorrhage. Intravenous alteplase was administered and within 30 min our patient developed severe orolingual edema requiring emergent intubation. Subsequent imaging revealed acute to subacute infarct of the left occipital lobe in the posterior cerebral artery region, consistent with her initial presenting symptoms. CONCLUSIONS Angioedema induced by tissue plasminogen activator occurs in approximately 1-5% of patients receiving thrombolysis for ischemic stroke and can be life-threatening. The risk is increased in patients taking angiotensin-converting enzyme inhibitors, in patients with ischemic strokes of the middle cerebral artery, and in the presence of C1 esterase inhibitor deficiency. This phenomenon is usually self-limited and treatment is supportive, although evidence supports the use of antihistamines, steroids, epinephrine, and complement inhibitors. Due to the severity of angioedema and the potential progression to airway compromise, it is crucial to closely monitor patients receiving tissue plasminogen activator.
Background
It is becoming increasingly common to use tissue plasminogen activator (tPA) in the treatment of acute ischemic stroke, pulmonary embolism, and ST-elevation myocardial infarctions. Since tPA was approved in 1996, its utilization has illustrated marked improvement in stroke recovery and decreased hospital stay [1]. Major concerns with the administration of tPA are intracranial hemorrhage, edema, and possible brain herniation; however, other severe reactions such as hemopericardium, cardiac tamponade, angioedema, and anaphylaxis should not be forgotten.
Angioedema induced by tPA is an infrequent, but potentially fatal outcome of thrombolysis. The mechanisms behind such reactions are presumed to involve mast cells, bradykinin release, histamine, and the complement cascade. It primarily occurs with infarction of the middle cerebral artery and is more likely to occur in patients with concomitant use of angiotensin-converting enzyme inhibitors and in carriers of C1 esterase inhibitor deficiency. It is mostly self-limited and treatment is usually supportive. Some cases may require antihistamines, steroids, and epinephrine, with refractory cases needing complement inhibitors and severe cases leading to intubation or cricothyroidotomy. In this report, we present a case of an elderly woman who developed angioedema following tPA administration for treatment of a posterior cerebral artery stroke, which has only been documented in 2 other cases, as per our literature review.
Case Report
An 84-year-old woman presented to the Emergency Department for right-sided weakness, slurred speech, and right-sided hemianopsia after having collapsed onto the floor. She had a history of hypertension, which managed with lisinopril; chronic obstructive pulmonary disease; and lung cancer with subsequent left upper lobectomy. Her history also included atrial fibrillation, but she had not been on anticoagulation therapy for approximately 3 months due to gastrointestinal bleed. The patient did not experience loss of consciousness, convulsions, or any prodromal symptoms. Upon arrival to the Emergency Department, she was found to have 2/5 strength of her right-sided extremities and right-sided neglect. An urgent computed tomography (CT) scan of the head was performed and revealed a subacute infarct of the left pons with no acute hemorrhage (Figure 1). A CT angiography was obtained and confirmed these findings. She was given 0.9 mg/kg alteplase intravenously, 10% as a bolus followed by an intravenous infusion of the remaining dose. Within 30 min from the onset of infusion, she developed orolingual angioedema consisting of tongue swelling and bilateral lip swelling requiring emergent intubation for airway protection.
The infusion was stopped prematurely, and the patient was given intravenous methylprednisolone 125 mg, diphenhydramine 50 mg, and famotidine 20 mg to help treat her angioedema. The neurology and critical care teams aided in the management of her care. There was marked improvement of her angioedema within 24 h, and she was subsequently extubated the following morning. Repeat CT of the head revealed an acute to subacute infarct with encephalomalacia of the left occipital lobe, which was believed to be the cause of her initial deficits (Figure 2). Echocardiography did not reveal an atrial shunt or evidence of thrombi. Subsequent magnetic resonance imaging illustrated infarct involving the posterior cerebral artery circulation without hemorrhagic conversion (Figure 3). She was started on full-dose aspirin as well as fluoxetine 20 mg daily for stroke recovery. She began to work with physical therapy and had some improvement in her motor skills as well as her vision.
During her hospitalization, she experienced persistent nausea and vomiting, ultimately controlled with promethazine. Her anticoagulation was restarted 10 days after the onset of her stroke. Her strength did not improve as she or her family had hoped. Family discussions were held, and it was decided the best course of action would be to receive hospice care at home. She was ultimately discharged to home with hospice on morphine sulfate, lorazepam, fluoxetine, and promethazine. She died a week later.
Discussion
Tissue plasminogen activator is commonly used to treat ischemic stroke, myocardial infarction, and pulmonary embolism. It is generally well tolerated and can be life-saving; however, there are concerning adverse reactions to be mindful of, one of which is angioedema. Angioedema induced by tPA is an uncommon but potentially fatal occurrence. It is typically observed within 1 h of completing the tPA infusion [2]. It is postulated to occur in approximately 1–5% of patients receiving thrombolysis after an ischemic stroke, and it usually presents with hemifacial edema contralateral to the infarct zone [3]. An extensive study done by Myslimi et al. [4] evaluated 923 patients who received thrombolysis for stroke treatment. Of these patients, only 20 developed angioedema. A retrospective chart review performed by Sczepanski and Bozyk [5] reviewed 147 cases, with only 4 developing edema.
The mechanism behind this phenomenon is still unclear; however, several hypotheses have been proposed to explain this occurrence. One hypothesis suggests a bradykinin-mediated pathway, in which tPA hydrolyzes plasminogen into plasmin, which in turn activates the kinin pathway augmenting the production of bradykinin [5]. Bradykinin is a potent pro-inflammatory and pro-edematous peptide that increases vascular permeability and vasodilation, leading to angioedema. In addition, tPA can augment histamine, causing vasodilation [3]. Other hypotheses propose that both tPA and plasmin activate the complement pathway, increasing complement levels and in turn activating mast cells, histamine, and basophil degranulation, which contribute to angioedema [5,6]. An additional hypothesis focuses on a mutation of the plasminogen gene, drawing on the remarkable clinical similarity between tPA-induced orolingual angioedema and a recently described new subtype of hereditary angioedema with normal C1 inhibitor. This subtype is caused by a highly specific missense mutation of the plasminogen gene and the resulting presence of the aberrant plasminogen protein is hypothesized to lead to angioedema [7].
The risk of developing angioedema following thrombolytic administration is amplified in patients who take angiotensin-converting enzyme (ACE) inhibitors because these drugs increase the concentration of circulating bradykinin [8]. Additionally, neurokinins such as substance P are increased with ACE inhibition and are mediators in inflammation and angioedema [9]. The combination of tPA-related increase in bradykinin, ACE inhibitor-mediated decrease in bradykinin metabolism, and ACE inhibitor-related increase in neurokinin levels amplify the risk of angioedema. For instance, in the study by Myslimi et al. [4], among the 20 patients who developed angioedema after thrombolysis, 45% concomitantly took ACE inhibitors.
Lesion-mapping studies have been performed that concluded infarctions of the middle cerebral artery, especially the branch that supplies the right insular cortex, have the highest propensity of causing angioedema. Ninety percent of patients who developed angioedema in the study completed by Myslimi et al. [4] and 75% of those in the study done by Sczepanski and Bozyk [5] had infarcts of the middle cerebral artery. The lesion-mapping study by Frohlich et al. [3] illustrated an association with right-sided insular infarcts and the development on tPA-related angioedema. The authors postulated that insular infarcts augment sympathetic hyperactivity due to impaired autonomic function, which in turn intensifies proinflammatory cytokine production and vascular permeability thus causing orolingual edema [3]. It is also believed that the tissue damage itself could be a trigger for angioedema via the generation of bradykinin, which increases inflammation and edema [4,8]. Our patient, however, had a posterior cerebral artery infarct, which is not consistent with this hypothesis, making our case unusual. In the retrospective institutional study done by Sczepanski and Bozyk [5], only 1 out of 147 patients had an infarct involving the posterior cerebral artery, and only 1 out of 42 patients in the analysis by Hurford et al. [10] had involvement of the posterior circulation. None were detected in the lesion-mapping study by Frohlich et al. [3] or in the meta-analysis by Yayan [1], and no alternate explanation could be found to support angioedema following tPA treatment of a posterior circulation stroke. The Table 1 summarizes findings from multiple studies including stroke location, development of angioedema after thrombolysis, and concomitant ACE inhibition [11–13].
Angioedema mediated by tPA is a rare and potentially life-threatening occurrence. At the first signs of tPA-induced angioedema, hospital staff should be aware of the commonly used interventions and medications. It is critical to discontinue the tPA infusion when signs of angioedema occur. The 2018 guidelines for the management of tPA-induced angioedema recommend the administration of intravenous methylprednisolone 125 mg, oral diphenhydramine 50 mg, and oral ranitidine 50 mg or famotidine 20 mg with a class IIb recommendation and level C expert opinion [14,15]. If symptoms persist despite these measures, epinephrine can be administered; however, it should be administered cautiously because it may suddenly increase blood pressure and thus the risk of intracranial hemorrhage [14]. Epinephrine would have been a reasonable alternative in this case due to the extent of angioedema that developed. Other alternatives include fresh frozen plasma, ecallantide (a recombinant protein that inhibits kallikrein), and C1 esterase inhibitors, all of which have been primarily used in ACE inhibitor-triggered angioedema or C1 esterase inhibitor deficiency but could have a role in tPA-related angioedema given the role of bradykinin [2,14]. Pahs et al. [16] demonstrated the use of plasma-derived C1 esterase inhibitor in a case of tPA-mediated angioedema. They described a case of potential airway compromise following tPA administration refractory to steroids and H2 blockers that ultimately resolved with a C1 esterase inhibitor and avoided the need for an invasive airway maneuver [16]. One last alternate therapy involves icatibant, a selective bradykinin B2 receptor antagonist; however, this is contraindicated with concomitant use of ACE inhibitors because they exert their vasodilating effect via increased bradykinin concentrations [17]. In severe or refractory cases of angioedema, patients may require intubation or cricothyroidotomy.
Conclusions
Angioedema induced by tPA is an infrequent but potentially fatal outcome of thrombolysis occurring in 1 of 50 patients, which increases to 1 of 10 in insular infarcts and 1 of 6 in individuals who are concomitantly using ACE inhibitors at the time of thrombolysis [4]. Angioedema typically presents within the hour of tPA administration and can quickly compromise the airway. Due to its severity, close monitoring of these individuals is imperative and prompt treatment is essential. Though exposed to ACE inhibitors, our patient was found to have an infarct of her posterior cerebral artery and developed angioedema after thrombolysis. This combination has rarely been documented, making this case unusual.
Conflicts of interest
None.
Figure 1. Computed tomography at initial presentation showing subacute infarct of the left pons indicated by the yellow arrow.
Figure 2. Repeat computed tomography showing acute to subacute infarct with encephalomalacia involving the left occipital lobe indicated by the red arrow.
Figure 3. Magnetic resonance imaging revealing an area of ischemia supplied by the posterior cerebral artery indicated by the green arrow.
Table 1. Comparison of studies involving tissue plasminogen activator-associated angioedema, highlighting the location of stroke and concomitant angiotensin-converting enzyme (ACE) inhibition.
Study Number of tPA-treated stroke patients Angioedema post-thrombolysis Concomitant ACE-inhibition* Locations of Infarct (n)
Myslimi et al. [4] 923 20 9 MCA (18)
Lin et al. [11] 559 5 2 MCA (5)
Engelter et al. [9] 120 2 1 Insular
Frohlich et al. [3] 136 15 10 Primarily MCA
Correia et al. [12] 236 8 5 MCA (3); Frontal (1); Basal Ganglia (1); Others (3)
Hill et al. [13] 176 9 7 MCA/Insula (7); Brainstem (1)
Yayan [1] n.s. 41 24 MCA (18); Insular (3); Others (3); Not mentioned (17)
Sczepanski and Bozyk [5] 147 4 3 MCA (3); PCA (1)
Hurford et al. [10] 530 42 24 ACA (38); Lacunar (3); PCA (1)
ACA – anterior cerebral artery; MCA – middle cerebral artery; n – number of infarcts in listed location correlating to number of patients with angioedema after thrombolysis in a given study; n.s. – not specified; PCA – posterior cerebral artery.
* Number of patients using ACE inhibitors that developed angioedema after thrombolysis. | ASPIRIN, FLUOXETINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33441533 | 18,936,733 | 2021-01-14 |
What was the administration route of drug 'LISINOPRIL'? | Tissue Plasminogen Activator-Induced Angioedema Involving a Posterior Cerebral Artery Infarct: A Case Presentation.
BACKGROUND Angioedema is characterized by localized swelling of subcutaneous or submucosal tissue resulting from fluid extravasation due to the loss of vascular integrity. It most commonly occurs with exposure to allergens and certain medications, namely nonsteroidal anti-inflammatory agents and angiotensin-converting enzyme inhibitors. There have been few incidences of angioedema following the administration of tissue plasminogen activator. CASE REPORT We describe an 84-year-old woman with a history of hypertension managed with lisinopril who presented with an acute onset of right-sided hemiparesis, slurred speech, and right-sided hemianopsia. Urgent computed tomography of the head revealed subacute infarct of the left pons without hemorrhage. Intravenous alteplase was administered and within 30 min our patient developed severe orolingual edema requiring emergent intubation. Subsequent imaging revealed acute to subacute infarct of the left occipital lobe in the posterior cerebral artery region, consistent with her initial presenting symptoms. CONCLUSIONS Angioedema induced by tissue plasminogen activator occurs in approximately 1-5% of patients receiving thrombolysis for ischemic stroke and can be life-threatening. The risk is increased in patients taking angiotensin-converting enzyme inhibitors, in patients with ischemic strokes of the middle cerebral artery, and in the presence of C1 esterase inhibitor deficiency. This phenomenon is usually self-limited and treatment is supportive, although evidence supports the use of antihistamines, steroids, epinephrine, and complement inhibitors. Due to the severity of angioedema and the potential progression to airway compromise, it is crucial to closely monitor patients receiving tissue plasminogen activator.
Background
It is becoming increasingly common to use tissue plasminogen activator (tPA) in the treatment of acute ischemic stroke, pulmonary embolism, and ST-elevation myocardial infarctions. Since tPA was approved in 1996, its utilization has illustrated marked improvement in stroke recovery and decreased hospital stay [1]. Major concerns with the administration of tPA are intracranial hemorrhage, edema, and possible brain herniation; however, other severe reactions such as hemopericardium, cardiac tamponade, angioedema, and anaphylaxis should not be forgotten.
Angioedema induced by tPA is an infrequent, but potentially fatal outcome of thrombolysis. The mechanisms behind such reactions are presumed to involve mast cells, bradykinin release, histamine, and the complement cascade. It primarily occurs with infarction of the middle cerebral artery and is more likely to occur in patients with concomitant use of angiotensin-converting enzyme inhibitors and in carriers of C1 esterase inhibitor deficiency. It is mostly self-limited and treatment is usually supportive. Some cases may require antihistamines, steroids, and epinephrine, with refractory cases needing complement inhibitors and severe cases leading to intubation or cricothyroidotomy. In this report, we present a case of an elderly woman who developed angioedema following tPA administration for treatment of a posterior cerebral artery stroke, which has only been documented in 2 other cases, as per our literature review.
Case Report
An 84-year-old woman presented to the Emergency Department for right-sided weakness, slurred speech, and right-sided hemianopsia after having collapsed onto the floor. She had a history of hypertension, which managed with lisinopril; chronic obstructive pulmonary disease; and lung cancer with subsequent left upper lobectomy. Her history also included atrial fibrillation, but she had not been on anticoagulation therapy for approximately 3 months due to gastrointestinal bleed. The patient did not experience loss of consciousness, convulsions, or any prodromal symptoms. Upon arrival to the Emergency Department, she was found to have 2/5 strength of her right-sided extremities and right-sided neglect. An urgent computed tomography (CT) scan of the head was performed and revealed a subacute infarct of the left pons with no acute hemorrhage (Figure 1). A CT angiography was obtained and confirmed these findings. She was given 0.9 mg/kg alteplase intravenously, 10% as a bolus followed by an intravenous infusion of the remaining dose. Within 30 min from the onset of infusion, she developed orolingual angioedema consisting of tongue swelling and bilateral lip swelling requiring emergent intubation for airway protection.
The infusion was stopped prematurely, and the patient was given intravenous methylprednisolone 125 mg, diphenhydramine 50 mg, and famotidine 20 mg to help treat her angioedema. The neurology and critical care teams aided in the management of her care. There was marked improvement of her angioedema within 24 h, and she was subsequently extubated the following morning. Repeat CT of the head revealed an acute to subacute infarct with encephalomalacia of the left occipital lobe, which was believed to be the cause of her initial deficits (Figure 2). Echocardiography did not reveal an atrial shunt or evidence of thrombi. Subsequent magnetic resonance imaging illustrated infarct involving the posterior cerebral artery circulation without hemorrhagic conversion (Figure 3). She was started on full-dose aspirin as well as fluoxetine 20 mg daily for stroke recovery. She began to work with physical therapy and had some improvement in her motor skills as well as her vision.
During her hospitalization, she experienced persistent nausea and vomiting, ultimately controlled with promethazine. Her anticoagulation was restarted 10 days after the onset of her stroke. Her strength did not improve as she or her family had hoped. Family discussions were held, and it was decided the best course of action would be to receive hospice care at home. She was ultimately discharged to home with hospice on morphine sulfate, lorazepam, fluoxetine, and promethazine. She died a week later.
Discussion
Tissue plasminogen activator is commonly used to treat ischemic stroke, myocardial infarction, and pulmonary embolism. It is generally well tolerated and can be life-saving; however, there are concerning adverse reactions to be mindful of, one of which is angioedema. Angioedema induced by tPA is an uncommon but potentially fatal occurrence. It is typically observed within 1 h of completing the tPA infusion [2]. It is postulated to occur in approximately 1–5% of patients receiving thrombolysis after an ischemic stroke, and it usually presents with hemifacial edema contralateral to the infarct zone [3]. An extensive study done by Myslimi et al. [4] evaluated 923 patients who received thrombolysis for stroke treatment. Of these patients, only 20 developed angioedema. A retrospective chart review performed by Sczepanski and Bozyk [5] reviewed 147 cases, with only 4 developing edema.
The mechanism behind this phenomenon is still unclear; however, several hypotheses have been proposed to explain this occurrence. One hypothesis suggests a bradykinin-mediated pathway, in which tPA hydrolyzes plasminogen into plasmin, which in turn activates the kinin pathway augmenting the production of bradykinin [5]. Bradykinin is a potent pro-inflammatory and pro-edematous peptide that increases vascular permeability and vasodilation, leading to angioedema. In addition, tPA can augment histamine, causing vasodilation [3]. Other hypotheses propose that both tPA and plasmin activate the complement pathway, increasing complement levels and in turn activating mast cells, histamine, and basophil degranulation, which contribute to angioedema [5,6]. An additional hypothesis focuses on a mutation of the plasminogen gene, drawing on the remarkable clinical similarity between tPA-induced orolingual angioedema and a recently described new subtype of hereditary angioedema with normal C1 inhibitor. This subtype is caused by a highly specific missense mutation of the plasminogen gene and the resulting presence of the aberrant plasminogen protein is hypothesized to lead to angioedema [7].
The risk of developing angioedema following thrombolytic administration is amplified in patients who take angiotensin-converting enzyme (ACE) inhibitors because these drugs increase the concentration of circulating bradykinin [8]. Additionally, neurokinins such as substance P are increased with ACE inhibition and are mediators in inflammation and angioedema [9]. The combination of tPA-related increase in bradykinin, ACE inhibitor-mediated decrease in bradykinin metabolism, and ACE inhibitor-related increase in neurokinin levels amplify the risk of angioedema. For instance, in the study by Myslimi et al. [4], among the 20 patients who developed angioedema after thrombolysis, 45% concomitantly took ACE inhibitors.
Lesion-mapping studies have been performed that concluded infarctions of the middle cerebral artery, especially the branch that supplies the right insular cortex, have the highest propensity of causing angioedema. Ninety percent of patients who developed angioedema in the study completed by Myslimi et al. [4] and 75% of those in the study done by Sczepanski and Bozyk [5] had infarcts of the middle cerebral artery. The lesion-mapping study by Frohlich et al. [3] illustrated an association with right-sided insular infarcts and the development on tPA-related angioedema. The authors postulated that insular infarcts augment sympathetic hyperactivity due to impaired autonomic function, which in turn intensifies proinflammatory cytokine production and vascular permeability thus causing orolingual edema [3]. It is also believed that the tissue damage itself could be a trigger for angioedema via the generation of bradykinin, which increases inflammation and edema [4,8]. Our patient, however, had a posterior cerebral artery infarct, which is not consistent with this hypothesis, making our case unusual. In the retrospective institutional study done by Sczepanski and Bozyk [5], only 1 out of 147 patients had an infarct involving the posterior cerebral artery, and only 1 out of 42 patients in the analysis by Hurford et al. [10] had involvement of the posterior circulation. None were detected in the lesion-mapping study by Frohlich et al. [3] or in the meta-analysis by Yayan [1], and no alternate explanation could be found to support angioedema following tPA treatment of a posterior circulation stroke. The Table 1 summarizes findings from multiple studies including stroke location, development of angioedema after thrombolysis, and concomitant ACE inhibition [11–13].
Angioedema mediated by tPA is a rare and potentially life-threatening occurrence. At the first signs of tPA-induced angioedema, hospital staff should be aware of the commonly used interventions and medications. It is critical to discontinue the tPA infusion when signs of angioedema occur. The 2018 guidelines for the management of tPA-induced angioedema recommend the administration of intravenous methylprednisolone 125 mg, oral diphenhydramine 50 mg, and oral ranitidine 50 mg or famotidine 20 mg with a class IIb recommendation and level C expert opinion [14,15]. If symptoms persist despite these measures, epinephrine can be administered; however, it should be administered cautiously because it may suddenly increase blood pressure and thus the risk of intracranial hemorrhage [14]. Epinephrine would have been a reasonable alternative in this case due to the extent of angioedema that developed. Other alternatives include fresh frozen plasma, ecallantide (a recombinant protein that inhibits kallikrein), and C1 esterase inhibitors, all of which have been primarily used in ACE inhibitor-triggered angioedema or C1 esterase inhibitor deficiency but could have a role in tPA-related angioedema given the role of bradykinin [2,14]. Pahs et al. [16] demonstrated the use of plasma-derived C1 esterase inhibitor in a case of tPA-mediated angioedema. They described a case of potential airway compromise following tPA administration refractory to steroids and H2 blockers that ultimately resolved with a C1 esterase inhibitor and avoided the need for an invasive airway maneuver [16]. One last alternate therapy involves icatibant, a selective bradykinin B2 receptor antagonist; however, this is contraindicated with concomitant use of ACE inhibitors because they exert their vasodilating effect via increased bradykinin concentrations [17]. In severe or refractory cases of angioedema, patients may require intubation or cricothyroidotomy.
Conclusions
Angioedema induced by tPA is an infrequent but potentially fatal outcome of thrombolysis occurring in 1 of 50 patients, which increases to 1 of 10 in insular infarcts and 1 of 6 in individuals who are concomitantly using ACE inhibitors at the time of thrombolysis [4]. Angioedema typically presents within the hour of tPA administration and can quickly compromise the airway. Due to its severity, close monitoring of these individuals is imperative and prompt treatment is essential. Though exposed to ACE inhibitors, our patient was found to have an infarct of her posterior cerebral artery and developed angioedema after thrombolysis. This combination has rarely been documented, making this case unusual.
Conflicts of interest
None.
Figure 1. Computed tomography at initial presentation showing subacute infarct of the left pons indicated by the yellow arrow.
Figure 2. Repeat computed tomography showing acute to subacute infarct with encephalomalacia involving the left occipital lobe indicated by the red arrow.
Figure 3. Magnetic resonance imaging revealing an area of ischemia supplied by the posterior cerebral artery indicated by the green arrow.
Table 1. Comparison of studies involving tissue plasminogen activator-associated angioedema, highlighting the location of stroke and concomitant angiotensin-converting enzyme (ACE) inhibition.
Study Number of tPA-treated stroke patients Angioedema post-thrombolysis Concomitant ACE-inhibition* Locations of Infarct (n)
Myslimi et al. [4] 923 20 9 MCA (18)
Lin et al. [11] 559 5 2 MCA (5)
Engelter et al. [9] 120 2 1 Insular
Frohlich et al. [3] 136 15 10 Primarily MCA
Correia et al. [12] 236 8 5 MCA (3); Frontal (1); Basal Ganglia (1); Others (3)
Hill et al. [13] 176 9 7 MCA/Insula (7); Brainstem (1)
Yayan [1] n.s. 41 24 MCA (18); Insular (3); Others (3); Not mentioned (17)
Sczepanski and Bozyk [5] 147 4 3 MCA (3); PCA (1)
Hurford et al. [10] 530 42 24 ACA (38); Lacunar (3); PCA (1)
ACA – anterior cerebral artery; MCA – middle cerebral artery; n – number of infarcts in listed location correlating to number of patients with angioedema after thrombolysis in a given study; n.s. – not specified; PCA – posterior cerebral artery.
* Number of patients using ACE inhibitors that developed angioedema after thrombolysis. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33441533 | 18,932,205 | 2021-01-14 |
What was the dosage of drug 'LISINOPRIL'? | Tissue Plasminogen Activator-Induced Angioedema Involving a Posterior Cerebral Artery Infarct: A Case Presentation.
BACKGROUND Angioedema is characterized by localized swelling of subcutaneous or submucosal tissue resulting from fluid extravasation due to the loss of vascular integrity. It most commonly occurs with exposure to allergens and certain medications, namely nonsteroidal anti-inflammatory agents and angiotensin-converting enzyme inhibitors. There have been few incidences of angioedema following the administration of tissue plasminogen activator. CASE REPORT We describe an 84-year-old woman with a history of hypertension managed with lisinopril who presented with an acute onset of right-sided hemiparesis, slurred speech, and right-sided hemianopsia. Urgent computed tomography of the head revealed subacute infarct of the left pons without hemorrhage. Intravenous alteplase was administered and within 30 min our patient developed severe orolingual edema requiring emergent intubation. Subsequent imaging revealed acute to subacute infarct of the left occipital lobe in the posterior cerebral artery region, consistent with her initial presenting symptoms. CONCLUSIONS Angioedema induced by tissue plasminogen activator occurs in approximately 1-5% of patients receiving thrombolysis for ischemic stroke and can be life-threatening. The risk is increased in patients taking angiotensin-converting enzyme inhibitors, in patients with ischemic strokes of the middle cerebral artery, and in the presence of C1 esterase inhibitor deficiency. This phenomenon is usually self-limited and treatment is supportive, although evidence supports the use of antihistamines, steroids, epinephrine, and complement inhibitors. Due to the severity of angioedema and the potential progression to airway compromise, it is crucial to closely monitor patients receiving tissue plasminogen activator.
Background
It is becoming increasingly common to use tissue plasminogen activator (tPA) in the treatment of acute ischemic stroke, pulmonary embolism, and ST-elevation myocardial infarctions. Since tPA was approved in 1996, its utilization has illustrated marked improvement in stroke recovery and decreased hospital stay [1]. Major concerns with the administration of tPA are intracranial hemorrhage, edema, and possible brain herniation; however, other severe reactions such as hemopericardium, cardiac tamponade, angioedema, and anaphylaxis should not be forgotten.
Angioedema induced by tPA is an infrequent, but potentially fatal outcome of thrombolysis. The mechanisms behind such reactions are presumed to involve mast cells, bradykinin release, histamine, and the complement cascade. It primarily occurs with infarction of the middle cerebral artery and is more likely to occur in patients with concomitant use of angiotensin-converting enzyme inhibitors and in carriers of C1 esterase inhibitor deficiency. It is mostly self-limited and treatment is usually supportive. Some cases may require antihistamines, steroids, and epinephrine, with refractory cases needing complement inhibitors and severe cases leading to intubation or cricothyroidotomy. In this report, we present a case of an elderly woman who developed angioedema following tPA administration for treatment of a posterior cerebral artery stroke, which has only been documented in 2 other cases, as per our literature review.
Case Report
An 84-year-old woman presented to the Emergency Department for right-sided weakness, slurred speech, and right-sided hemianopsia after having collapsed onto the floor. She had a history of hypertension, which managed with lisinopril; chronic obstructive pulmonary disease; and lung cancer with subsequent left upper lobectomy. Her history also included atrial fibrillation, but she had not been on anticoagulation therapy for approximately 3 months due to gastrointestinal bleed. The patient did not experience loss of consciousness, convulsions, or any prodromal symptoms. Upon arrival to the Emergency Department, she was found to have 2/5 strength of her right-sided extremities and right-sided neglect. An urgent computed tomography (CT) scan of the head was performed and revealed a subacute infarct of the left pons with no acute hemorrhage (Figure 1). A CT angiography was obtained and confirmed these findings. She was given 0.9 mg/kg alteplase intravenously, 10% as a bolus followed by an intravenous infusion of the remaining dose. Within 30 min from the onset of infusion, she developed orolingual angioedema consisting of tongue swelling and bilateral lip swelling requiring emergent intubation for airway protection.
The infusion was stopped prematurely, and the patient was given intravenous methylprednisolone 125 mg, diphenhydramine 50 mg, and famotidine 20 mg to help treat her angioedema. The neurology and critical care teams aided in the management of her care. There was marked improvement of her angioedema within 24 h, and she was subsequently extubated the following morning. Repeat CT of the head revealed an acute to subacute infarct with encephalomalacia of the left occipital lobe, which was believed to be the cause of her initial deficits (Figure 2). Echocardiography did not reveal an atrial shunt or evidence of thrombi. Subsequent magnetic resonance imaging illustrated infarct involving the posterior cerebral artery circulation without hemorrhagic conversion (Figure 3). She was started on full-dose aspirin as well as fluoxetine 20 mg daily for stroke recovery. She began to work with physical therapy and had some improvement in her motor skills as well as her vision.
During her hospitalization, she experienced persistent nausea and vomiting, ultimately controlled with promethazine. Her anticoagulation was restarted 10 days after the onset of her stroke. Her strength did not improve as she or her family had hoped. Family discussions were held, and it was decided the best course of action would be to receive hospice care at home. She was ultimately discharged to home with hospice on morphine sulfate, lorazepam, fluoxetine, and promethazine. She died a week later.
Discussion
Tissue plasminogen activator is commonly used to treat ischemic stroke, myocardial infarction, and pulmonary embolism. It is generally well tolerated and can be life-saving; however, there are concerning adverse reactions to be mindful of, one of which is angioedema. Angioedema induced by tPA is an uncommon but potentially fatal occurrence. It is typically observed within 1 h of completing the tPA infusion [2]. It is postulated to occur in approximately 1–5% of patients receiving thrombolysis after an ischemic stroke, and it usually presents with hemifacial edema contralateral to the infarct zone [3]. An extensive study done by Myslimi et al. [4] evaluated 923 patients who received thrombolysis for stroke treatment. Of these patients, only 20 developed angioedema. A retrospective chart review performed by Sczepanski and Bozyk [5] reviewed 147 cases, with only 4 developing edema.
The mechanism behind this phenomenon is still unclear; however, several hypotheses have been proposed to explain this occurrence. One hypothesis suggests a bradykinin-mediated pathway, in which tPA hydrolyzes plasminogen into plasmin, which in turn activates the kinin pathway augmenting the production of bradykinin [5]. Bradykinin is a potent pro-inflammatory and pro-edematous peptide that increases vascular permeability and vasodilation, leading to angioedema. In addition, tPA can augment histamine, causing vasodilation [3]. Other hypotheses propose that both tPA and plasmin activate the complement pathway, increasing complement levels and in turn activating mast cells, histamine, and basophil degranulation, which contribute to angioedema [5,6]. An additional hypothesis focuses on a mutation of the plasminogen gene, drawing on the remarkable clinical similarity between tPA-induced orolingual angioedema and a recently described new subtype of hereditary angioedema with normal C1 inhibitor. This subtype is caused by a highly specific missense mutation of the plasminogen gene and the resulting presence of the aberrant plasminogen protein is hypothesized to lead to angioedema [7].
The risk of developing angioedema following thrombolytic administration is amplified in patients who take angiotensin-converting enzyme (ACE) inhibitors because these drugs increase the concentration of circulating bradykinin [8]. Additionally, neurokinins such as substance P are increased with ACE inhibition and are mediators in inflammation and angioedema [9]. The combination of tPA-related increase in bradykinin, ACE inhibitor-mediated decrease in bradykinin metabolism, and ACE inhibitor-related increase in neurokinin levels amplify the risk of angioedema. For instance, in the study by Myslimi et al. [4], among the 20 patients who developed angioedema after thrombolysis, 45% concomitantly took ACE inhibitors.
Lesion-mapping studies have been performed that concluded infarctions of the middle cerebral artery, especially the branch that supplies the right insular cortex, have the highest propensity of causing angioedema. Ninety percent of patients who developed angioedema in the study completed by Myslimi et al. [4] and 75% of those in the study done by Sczepanski and Bozyk [5] had infarcts of the middle cerebral artery. The lesion-mapping study by Frohlich et al. [3] illustrated an association with right-sided insular infarcts and the development on tPA-related angioedema. The authors postulated that insular infarcts augment sympathetic hyperactivity due to impaired autonomic function, which in turn intensifies proinflammatory cytokine production and vascular permeability thus causing orolingual edema [3]. It is also believed that the tissue damage itself could be a trigger for angioedema via the generation of bradykinin, which increases inflammation and edema [4,8]. Our patient, however, had a posterior cerebral artery infarct, which is not consistent with this hypothesis, making our case unusual. In the retrospective institutional study done by Sczepanski and Bozyk [5], only 1 out of 147 patients had an infarct involving the posterior cerebral artery, and only 1 out of 42 patients in the analysis by Hurford et al. [10] had involvement of the posterior circulation. None were detected in the lesion-mapping study by Frohlich et al. [3] or in the meta-analysis by Yayan [1], and no alternate explanation could be found to support angioedema following tPA treatment of a posterior circulation stroke. The Table 1 summarizes findings from multiple studies including stroke location, development of angioedema after thrombolysis, and concomitant ACE inhibition [11–13].
Angioedema mediated by tPA is a rare and potentially life-threatening occurrence. At the first signs of tPA-induced angioedema, hospital staff should be aware of the commonly used interventions and medications. It is critical to discontinue the tPA infusion when signs of angioedema occur. The 2018 guidelines for the management of tPA-induced angioedema recommend the administration of intravenous methylprednisolone 125 mg, oral diphenhydramine 50 mg, and oral ranitidine 50 mg or famotidine 20 mg with a class IIb recommendation and level C expert opinion [14,15]. If symptoms persist despite these measures, epinephrine can be administered; however, it should be administered cautiously because it may suddenly increase blood pressure and thus the risk of intracranial hemorrhage [14]. Epinephrine would have been a reasonable alternative in this case due to the extent of angioedema that developed. Other alternatives include fresh frozen plasma, ecallantide (a recombinant protein that inhibits kallikrein), and C1 esterase inhibitors, all of which have been primarily used in ACE inhibitor-triggered angioedema or C1 esterase inhibitor deficiency but could have a role in tPA-related angioedema given the role of bradykinin [2,14]. Pahs et al. [16] demonstrated the use of plasma-derived C1 esterase inhibitor in a case of tPA-mediated angioedema. They described a case of potential airway compromise following tPA administration refractory to steroids and H2 blockers that ultimately resolved with a C1 esterase inhibitor and avoided the need for an invasive airway maneuver [16]. One last alternate therapy involves icatibant, a selective bradykinin B2 receptor antagonist; however, this is contraindicated with concomitant use of ACE inhibitors because they exert their vasodilating effect via increased bradykinin concentrations [17]. In severe or refractory cases of angioedema, patients may require intubation or cricothyroidotomy.
Conclusions
Angioedema induced by tPA is an infrequent but potentially fatal outcome of thrombolysis occurring in 1 of 50 patients, which increases to 1 of 10 in insular infarcts and 1 of 6 in individuals who are concomitantly using ACE inhibitors at the time of thrombolysis [4]. Angioedema typically presents within the hour of tPA administration and can quickly compromise the airway. Due to its severity, close monitoring of these individuals is imperative and prompt treatment is essential. Though exposed to ACE inhibitors, our patient was found to have an infarct of her posterior cerebral artery and developed angioedema after thrombolysis. This combination has rarely been documented, making this case unusual.
Conflicts of interest
None.
Figure 1. Computed tomography at initial presentation showing subacute infarct of the left pons indicated by the yellow arrow.
Figure 2. Repeat computed tomography showing acute to subacute infarct with encephalomalacia involving the left occipital lobe indicated by the red arrow.
Figure 3. Magnetic resonance imaging revealing an area of ischemia supplied by the posterior cerebral artery indicated by the green arrow.
Table 1. Comparison of studies involving tissue plasminogen activator-associated angioedema, highlighting the location of stroke and concomitant angiotensin-converting enzyme (ACE) inhibition.
Study Number of tPA-treated stroke patients Angioedema post-thrombolysis Concomitant ACE-inhibition* Locations of Infarct (n)
Myslimi et al. [4] 923 20 9 MCA (18)
Lin et al. [11] 559 5 2 MCA (5)
Engelter et al. [9] 120 2 1 Insular
Frohlich et al. [3] 136 15 10 Primarily MCA
Correia et al. [12] 236 8 5 MCA (3); Frontal (1); Basal Ganglia (1); Others (3)
Hill et al. [13] 176 9 7 MCA/Insula (7); Brainstem (1)
Yayan [1] n.s. 41 24 MCA (18); Insular (3); Others (3); Not mentioned (17)
Sczepanski and Bozyk [5] 147 4 3 MCA (3); PCA (1)
Hurford et al. [10] 530 42 24 ACA (38); Lacunar (3); PCA (1)
ACA – anterior cerebral artery; MCA – middle cerebral artery; n – number of infarcts in listed location correlating to number of patients with angioedema after thrombolysis in a given study; n.s. – not specified; PCA – posterior cerebral artery.
* Number of patients using ACE inhibitors that developed angioedema after thrombolysis. | UNKNOWN | DrugDosageText | CC BY-NC-ND | 33441533 | 18,915,192 | 2021-01-14 |
What was the outcome of reaction 'Angioedema'? | Tissue Plasminogen Activator-Induced Angioedema Involving a Posterior Cerebral Artery Infarct: A Case Presentation.
BACKGROUND Angioedema is characterized by localized swelling of subcutaneous or submucosal tissue resulting from fluid extravasation due to the loss of vascular integrity. It most commonly occurs with exposure to allergens and certain medications, namely nonsteroidal anti-inflammatory agents and angiotensin-converting enzyme inhibitors. There have been few incidences of angioedema following the administration of tissue plasminogen activator. CASE REPORT We describe an 84-year-old woman with a history of hypertension managed with lisinopril who presented with an acute onset of right-sided hemiparesis, slurred speech, and right-sided hemianopsia. Urgent computed tomography of the head revealed subacute infarct of the left pons without hemorrhage. Intravenous alteplase was administered and within 30 min our patient developed severe orolingual edema requiring emergent intubation. Subsequent imaging revealed acute to subacute infarct of the left occipital lobe in the posterior cerebral artery region, consistent with her initial presenting symptoms. CONCLUSIONS Angioedema induced by tissue plasminogen activator occurs in approximately 1-5% of patients receiving thrombolysis for ischemic stroke and can be life-threatening. The risk is increased in patients taking angiotensin-converting enzyme inhibitors, in patients with ischemic strokes of the middle cerebral artery, and in the presence of C1 esterase inhibitor deficiency. This phenomenon is usually self-limited and treatment is supportive, although evidence supports the use of antihistamines, steroids, epinephrine, and complement inhibitors. Due to the severity of angioedema and the potential progression to airway compromise, it is crucial to closely monitor patients receiving tissue plasminogen activator.
Background
It is becoming increasingly common to use tissue plasminogen activator (tPA) in the treatment of acute ischemic stroke, pulmonary embolism, and ST-elevation myocardial infarctions. Since tPA was approved in 1996, its utilization has illustrated marked improvement in stroke recovery and decreased hospital stay [1]. Major concerns with the administration of tPA are intracranial hemorrhage, edema, and possible brain herniation; however, other severe reactions such as hemopericardium, cardiac tamponade, angioedema, and anaphylaxis should not be forgotten.
Angioedema induced by tPA is an infrequent, but potentially fatal outcome of thrombolysis. The mechanisms behind such reactions are presumed to involve mast cells, bradykinin release, histamine, and the complement cascade. It primarily occurs with infarction of the middle cerebral artery and is more likely to occur in patients with concomitant use of angiotensin-converting enzyme inhibitors and in carriers of C1 esterase inhibitor deficiency. It is mostly self-limited and treatment is usually supportive. Some cases may require antihistamines, steroids, and epinephrine, with refractory cases needing complement inhibitors and severe cases leading to intubation or cricothyroidotomy. In this report, we present a case of an elderly woman who developed angioedema following tPA administration for treatment of a posterior cerebral artery stroke, which has only been documented in 2 other cases, as per our literature review.
Case Report
An 84-year-old woman presented to the Emergency Department for right-sided weakness, slurred speech, and right-sided hemianopsia after having collapsed onto the floor. She had a history of hypertension, which managed with lisinopril; chronic obstructive pulmonary disease; and lung cancer with subsequent left upper lobectomy. Her history also included atrial fibrillation, but she had not been on anticoagulation therapy for approximately 3 months due to gastrointestinal bleed. The patient did not experience loss of consciousness, convulsions, or any prodromal symptoms. Upon arrival to the Emergency Department, she was found to have 2/5 strength of her right-sided extremities and right-sided neglect. An urgent computed tomography (CT) scan of the head was performed and revealed a subacute infarct of the left pons with no acute hemorrhage (Figure 1). A CT angiography was obtained and confirmed these findings. She was given 0.9 mg/kg alteplase intravenously, 10% as a bolus followed by an intravenous infusion of the remaining dose. Within 30 min from the onset of infusion, she developed orolingual angioedema consisting of tongue swelling and bilateral lip swelling requiring emergent intubation for airway protection.
The infusion was stopped prematurely, and the patient was given intravenous methylprednisolone 125 mg, diphenhydramine 50 mg, and famotidine 20 mg to help treat her angioedema. The neurology and critical care teams aided in the management of her care. There was marked improvement of her angioedema within 24 h, and she was subsequently extubated the following morning. Repeat CT of the head revealed an acute to subacute infarct with encephalomalacia of the left occipital lobe, which was believed to be the cause of her initial deficits (Figure 2). Echocardiography did not reveal an atrial shunt or evidence of thrombi. Subsequent magnetic resonance imaging illustrated infarct involving the posterior cerebral artery circulation without hemorrhagic conversion (Figure 3). She was started on full-dose aspirin as well as fluoxetine 20 mg daily for stroke recovery. She began to work with physical therapy and had some improvement in her motor skills as well as her vision.
During her hospitalization, she experienced persistent nausea and vomiting, ultimately controlled with promethazine. Her anticoagulation was restarted 10 days after the onset of her stroke. Her strength did not improve as she or her family had hoped. Family discussions were held, and it was decided the best course of action would be to receive hospice care at home. She was ultimately discharged to home with hospice on morphine sulfate, lorazepam, fluoxetine, and promethazine. She died a week later.
Discussion
Tissue plasminogen activator is commonly used to treat ischemic stroke, myocardial infarction, and pulmonary embolism. It is generally well tolerated and can be life-saving; however, there are concerning adverse reactions to be mindful of, one of which is angioedema. Angioedema induced by tPA is an uncommon but potentially fatal occurrence. It is typically observed within 1 h of completing the tPA infusion [2]. It is postulated to occur in approximately 1–5% of patients receiving thrombolysis after an ischemic stroke, and it usually presents with hemifacial edema contralateral to the infarct zone [3]. An extensive study done by Myslimi et al. [4] evaluated 923 patients who received thrombolysis for stroke treatment. Of these patients, only 20 developed angioedema. A retrospective chart review performed by Sczepanski and Bozyk [5] reviewed 147 cases, with only 4 developing edema.
The mechanism behind this phenomenon is still unclear; however, several hypotheses have been proposed to explain this occurrence. One hypothesis suggests a bradykinin-mediated pathway, in which tPA hydrolyzes plasminogen into plasmin, which in turn activates the kinin pathway augmenting the production of bradykinin [5]. Bradykinin is a potent pro-inflammatory and pro-edematous peptide that increases vascular permeability and vasodilation, leading to angioedema. In addition, tPA can augment histamine, causing vasodilation [3]. Other hypotheses propose that both tPA and plasmin activate the complement pathway, increasing complement levels and in turn activating mast cells, histamine, and basophil degranulation, which contribute to angioedema [5,6]. An additional hypothesis focuses on a mutation of the plasminogen gene, drawing on the remarkable clinical similarity between tPA-induced orolingual angioedema and a recently described new subtype of hereditary angioedema with normal C1 inhibitor. This subtype is caused by a highly specific missense mutation of the plasminogen gene and the resulting presence of the aberrant plasminogen protein is hypothesized to lead to angioedema [7].
The risk of developing angioedema following thrombolytic administration is amplified in patients who take angiotensin-converting enzyme (ACE) inhibitors because these drugs increase the concentration of circulating bradykinin [8]. Additionally, neurokinins such as substance P are increased with ACE inhibition and are mediators in inflammation and angioedema [9]. The combination of tPA-related increase in bradykinin, ACE inhibitor-mediated decrease in bradykinin metabolism, and ACE inhibitor-related increase in neurokinin levels amplify the risk of angioedema. For instance, in the study by Myslimi et al. [4], among the 20 patients who developed angioedema after thrombolysis, 45% concomitantly took ACE inhibitors.
Lesion-mapping studies have been performed that concluded infarctions of the middle cerebral artery, especially the branch that supplies the right insular cortex, have the highest propensity of causing angioedema. Ninety percent of patients who developed angioedema in the study completed by Myslimi et al. [4] and 75% of those in the study done by Sczepanski and Bozyk [5] had infarcts of the middle cerebral artery. The lesion-mapping study by Frohlich et al. [3] illustrated an association with right-sided insular infarcts and the development on tPA-related angioedema. The authors postulated that insular infarcts augment sympathetic hyperactivity due to impaired autonomic function, which in turn intensifies proinflammatory cytokine production and vascular permeability thus causing orolingual edema [3]. It is also believed that the tissue damage itself could be a trigger for angioedema via the generation of bradykinin, which increases inflammation and edema [4,8]. Our patient, however, had a posterior cerebral artery infarct, which is not consistent with this hypothesis, making our case unusual. In the retrospective institutional study done by Sczepanski and Bozyk [5], only 1 out of 147 patients had an infarct involving the posterior cerebral artery, and only 1 out of 42 patients in the analysis by Hurford et al. [10] had involvement of the posterior circulation. None were detected in the lesion-mapping study by Frohlich et al. [3] or in the meta-analysis by Yayan [1], and no alternate explanation could be found to support angioedema following tPA treatment of a posterior circulation stroke. The Table 1 summarizes findings from multiple studies including stroke location, development of angioedema after thrombolysis, and concomitant ACE inhibition [11–13].
Angioedema mediated by tPA is a rare and potentially life-threatening occurrence. At the first signs of tPA-induced angioedema, hospital staff should be aware of the commonly used interventions and medications. It is critical to discontinue the tPA infusion when signs of angioedema occur. The 2018 guidelines for the management of tPA-induced angioedema recommend the administration of intravenous methylprednisolone 125 mg, oral diphenhydramine 50 mg, and oral ranitidine 50 mg or famotidine 20 mg with a class IIb recommendation and level C expert opinion [14,15]. If symptoms persist despite these measures, epinephrine can be administered; however, it should be administered cautiously because it may suddenly increase blood pressure and thus the risk of intracranial hemorrhage [14]. Epinephrine would have been a reasonable alternative in this case due to the extent of angioedema that developed. Other alternatives include fresh frozen plasma, ecallantide (a recombinant protein that inhibits kallikrein), and C1 esterase inhibitors, all of which have been primarily used in ACE inhibitor-triggered angioedema or C1 esterase inhibitor deficiency but could have a role in tPA-related angioedema given the role of bradykinin [2,14]. Pahs et al. [16] demonstrated the use of plasma-derived C1 esterase inhibitor in a case of tPA-mediated angioedema. They described a case of potential airway compromise following tPA administration refractory to steroids and H2 blockers that ultimately resolved with a C1 esterase inhibitor and avoided the need for an invasive airway maneuver [16]. One last alternate therapy involves icatibant, a selective bradykinin B2 receptor antagonist; however, this is contraindicated with concomitant use of ACE inhibitors because they exert their vasodilating effect via increased bradykinin concentrations [17]. In severe or refractory cases of angioedema, patients may require intubation or cricothyroidotomy.
Conclusions
Angioedema induced by tPA is an infrequent but potentially fatal outcome of thrombolysis occurring in 1 of 50 patients, which increases to 1 of 10 in insular infarcts and 1 of 6 in individuals who are concomitantly using ACE inhibitors at the time of thrombolysis [4]. Angioedema typically presents within the hour of tPA administration and can quickly compromise the airway. Due to its severity, close monitoring of these individuals is imperative and prompt treatment is essential. Though exposed to ACE inhibitors, our patient was found to have an infarct of her posterior cerebral artery and developed angioedema after thrombolysis. This combination has rarely been documented, making this case unusual.
Conflicts of interest
None.
Figure 1. Computed tomography at initial presentation showing subacute infarct of the left pons indicated by the yellow arrow.
Figure 2. Repeat computed tomography showing acute to subacute infarct with encephalomalacia involving the left occipital lobe indicated by the red arrow.
Figure 3. Magnetic resonance imaging revealing an area of ischemia supplied by the posterior cerebral artery indicated by the green arrow.
Table 1. Comparison of studies involving tissue plasminogen activator-associated angioedema, highlighting the location of stroke and concomitant angiotensin-converting enzyme (ACE) inhibition.
Study Number of tPA-treated stroke patients Angioedema post-thrombolysis Concomitant ACE-inhibition* Locations of Infarct (n)
Myslimi et al. [4] 923 20 9 MCA (18)
Lin et al. [11] 559 5 2 MCA (5)
Engelter et al. [9] 120 2 1 Insular
Frohlich et al. [3] 136 15 10 Primarily MCA
Correia et al. [12] 236 8 5 MCA (3); Frontal (1); Basal Ganglia (1); Others (3)
Hill et al. [13] 176 9 7 MCA/Insula (7); Brainstem (1)
Yayan [1] n.s. 41 24 MCA (18); Insular (3); Others (3); Not mentioned (17)
Sczepanski and Bozyk [5] 147 4 3 MCA (3); PCA (1)
Hurford et al. [10] 530 42 24 ACA (38); Lacunar (3); PCA (1)
ACA – anterior cerebral artery; MCA – middle cerebral artery; n – number of infarcts in listed location correlating to number of patients with angioedema after thrombolysis in a given study; n.s. – not specified; PCA – posterior cerebral artery.
* Number of patients using ACE inhibitors that developed angioedema after thrombolysis. | Recovering | ReactionOutcome | CC BY-NC-ND | 33441533 | 18,915,688 | 2021-01-14 |
What was the outcome of reaction 'Drug interaction'? | Tissue Plasminogen Activator-Induced Angioedema Involving a Posterior Cerebral Artery Infarct: A Case Presentation.
BACKGROUND Angioedema is characterized by localized swelling of subcutaneous or submucosal tissue resulting from fluid extravasation due to the loss of vascular integrity. It most commonly occurs with exposure to allergens and certain medications, namely nonsteroidal anti-inflammatory agents and angiotensin-converting enzyme inhibitors. There have been few incidences of angioedema following the administration of tissue plasminogen activator. CASE REPORT We describe an 84-year-old woman with a history of hypertension managed with lisinopril who presented with an acute onset of right-sided hemiparesis, slurred speech, and right-sided hemianopsia. Urgent computed tomography of the head revealed subacute infarct of the left pons without hemorrhage. Intravenous alteplase was administered and within 30 min our patient developed severe orolingual edema requiring emergent intubation. Subsequent imaging revealed acute to subacute infarct of the left occipital lobe in the posterior cerebral artery region, consistent with her initial presenting symptoms. CONCLUSIONS Angioedema induced by tissue plasminogen activator occurs in approximately 1-5% of patients receiving thrombolysis for ischemic stroke and can be life-threatening. The risk is increased in patients taking angiotensin-converting enzyme inhibitors, in patients with ischemic strokes of the middle cerebral artery, and in the presence of C1 esterase inhibitor deficiency. This phenomenon is usually self-limited and treatment is supportive, although evidence supports the use of antihistamines, steroids, epinephrine, and complement inhibitors. Due to the severity of angioedema and the potential progression to airway compromise, it is crucial to closely monitor patients receiving tissue plasminogen activator.
Background
It is becoming increasingly common to use tissue plasminogen activator (tPA) in the treatment of acute ischemic stroke, pulmonary embolism, and ST-elevation myocardial infarctions. Since tPA was approved in 1996, its utilization has illustrated marked improvement in stroke recovery and decreased hospital stay [1]. Major concerns with the administration of tPA are intracranial hemorrhage, edema, and possible brain herniation; however, other severe reactions such as hemopericardium, cardiac tamponade, angioedema, and anaphylaxis should not be forgotten.
Angioedema induced by tPA is an infrequent, but potentially fatal outcome of thrombolysis. The mechanisms behind such reactions are presumed to involve mast cells, bradykinin release, histamine, and the complement cascade. It primarily occurs with infarction of the middle cerebral artery and is more likely to occur in patients with concomitant use of angiotensin-converting enzyme inhibitors and in carriers of C1 esterase inhibitor deficiency. It is mostly self-limited and treatment is usually supportive. Some cases may require antihistamines, steroids, and epinephrine, with refractory cases needing complement inhibitors and severe cases leading to intubation or cricothyroidotomy. In this report, we present a case of an elderly woman who developed angioedema following tPA administration for treatment of a posterior cerebral artery stroke, which has only been documented in 2 other cases, as per our literature review.
Case Report
An 84-year-old woman presented to the Emergency Department for right-sided weakness, slurred speech, and right-sided hemianopsia after having collapsed onto the floor. She had a history of hypertension, which managed with lisinopril; chronic obstructive pulmonary disease; and lung cancer with subsequent left upper lobectomy. Her history also included atrial fibrillation, but she had not been on anticoagulation therapy for approximately 3 months due to gastrointestinal bleed. The patient did not experience loss of consciousness, convulsions, or any prodromal symptoms. Upon arrival to the Emergency Department, she was found to have 2/5 strength of her right-sided extremities and right-sided neglect. An urgent computed tomography (CT) scan of the head was performed and revealed a subacute infarct of the left pons with no acute hemorrhage (Figure 1). A CT angiography was obtained and confirmed these findings. She was given 0.9 mg/kg alteplase intravenously, 10% as a bolus followed by an intravenous infusion of the remaining dose. Within 30 min from the onset of infusion, she developed orolingual angioedema consisting of tongue swelling and bilateral lip swelling requiring emergent intubation for airway protection.
The infusion was stopped prematurely, and the patient was given intravenous methylprednisolone 125 mg, diphenhydramine 50 mg, and famotidine 20 mg to help treat her angioedema. The neurology and critical care teams aided in the management of her care. There was marked improvement of her angioedema within 24 h, and she was subsequently extubated the following morning. Repeat CT of the head revealed an acute to subacute infarct with encephalomalacia of the left occipital lobe, which was believed to be the cause of her initial deficits (Figure 2). Echocardiography did not reveal an atrial shunt or evidence of thrombi. Subsequent magnetic resonance imaging illustrated infarct involving the posterior cerebral artery circulation without hemorrhagic conversion (Figure 3). She was started on full-dose aspirin as well as fluoxetine 20 mg daily for stroke recovery. She began to work with physical therapy and had some improvement in her motor skills as well as her vision.
During her hospitalization, she experienced persistent nausea and vomiting, ultimately controlled with promethazine. Her anticoagulation was restarted 10 days after the onset of her stroke. Her strength did not improve as she or her family had hoped. Family discussions were held, and it was decided the best course of action would be to receive hospice care at home. She was ultimately discharged to home with hospice on morphine sulfate, lorazepam, fluoxetine, and promethazine. She died a week later.
Discussion
Tissue plasminogen activator is commonly used to treat ischemic stroke, myocardial infarction, and pulmonary embolism. It is generally well tolerated and can be life-saving; however, there are concerning adverse reactions to be mindful of, one of which is angioedema. Angioedema induced by tPA is an uncommon but potentially fatal occurrence. It is typically observed within 1 h of completing the tPA infusion [2]. It is postulated to occur in approximately 1–5% of patients receiving thrombolysis after an ischemic stroke, and it usually presents with hemifacial edema contralateral to the infarct zone [3]. An extensive study done by Myslimi et al. [4] evaluated 923 patients who received thrombolysis for stroke treatment. Of these patients, only 20 developed angioedema. A retrospective chart review performed by Sczepanski and Bozyk [5] reviewed 147 cases, with only 4 developing edema.
The mechanism behind this phenomenon is still unclear; however, several hypotheses have been proposed to explain this occurrence. One hypothesis suggests a bradykinin-mediated pathway, in which tPA hydrolyzes plasminogen into plasmin, which in turn activates the kinin pathway augmenting the production of bradykinin [5]. Bradykinin is a potent pro-inflammatory and pro-edematous peptide that increases vascular permeability and vasodilation, leading to angioedema. In addition, tPA can augment histamine, causing vasodilation [3]. Other hypotheses propose that both tPA and plasmin activate the complement pathway, increasing complement levels and in turn activating mast cells, histamine, and basophil degranulation, which contribute to angioedema [5,6]. An additional hypothesis focuses on a mutation of the plasminogen gene, drawing on the remarkable clinical similarity between tPA-induced orolingual angioedema and a recently described new subtype of hereditary angioedema with normal C1 inhibitor. This subtype is caused by a highly specific missense mutation of the plasminogen gene and the resulting presence of the aberrant plasminogen protein is hypothesized to lead to angioedema [7].
The risk of developing angioedema following thrombolytic administration is amplified in patients who take angiotensin-converting enzyme (ACE) inhibitors because these drugs increase the concentration of circulating bradykinin [8]. Additionally, neurokinins such as substance P are increased with ACE inhibition and are mediators in inflammation and angioedema [9]. The combination of tPA-related increase in bradykinin, ACE inhibitor-mediated decrease in bradykinin metabolism, and ACE inhibitor-related increase in neurokinin levels amplify the risk of angioedema. For instance, in the study by Myslimi et al. [4], among the 20 patients who developed angioedema after thrombolysis, 45% concomitantly took ACE inhibitors.
Lesion-mapping studies have been performed that concluded infarctions of the middle cerebral artery, especially the branch that supplies the right insular cortex, have the highest propensity of causing angioedema. Ninety percent of patients who developed angioedema in the study completed by Myslimi et al. [4] and 75% of those in the study done by Sczepanski and Bozyk [5] had infarcts of the middle cerebral artery. The lesion-mapping study by Frohlich et al. [3] illustrated an association with right-sided insular infarcts and the development on tPA-related angioedema. The authors postulated that insular infarcts augment sympathetic hyperactivity due to impaired autonomic function, which in turn intensifies proinflammatory cytokine production and vascular permeability thus causing orolingual edema [3]. It is also believed that the tissue damage itself could be a trigger for angioedema via the generation of bradykinin, which increases inflammation and edema [4,8]. Our patient, however, had a posterior cerebral artery infarct, which is not consistent with this hypothesis, making our case unusual. In the retrospective institutional study done by Sczepanski and Bozyk [5], only 1 out of 147 patients had an infarct involving the posterior cerebral artery, and only 1 out of 42 patients in the analysis by Hurford et al. [10] had involvement of the posterior circulation. None were detected in the lesion-mapping study by Frohlich et al. [3] or in the meta-analysis by Yayan [1], and no alternate explanation could be found to support angioedema following tPA treatment of a posterior circulation stroke. The Table 1 summarizes findings from multiple studies including stroke location, development of angioedema after thrombolysis, and concomitant ACE inhibition [11–13].
Angioedema mediated by tPA is a rare and potentially life-threatening occurrence. At the first signs of tPA-induced angioedema, hospital staff should be aware of the commonly used interventions and medications. It is critical to discontinue the tPA infusion when signs of angioedema occur. The 2018 guidelines for the management of tPA-induced angioedema recommend the administration of intravenous methylprednisolone 125 mg, oral diphenhydramine 50 mg, and oral ranitidine 50 mg or famotidine 20 mg with a class IIb recommendation and level C expert opinion [14,15]. If symptoms persist despite these measures, epinephrine can be administered; however, it should be administered cautiously because it may suddenly increase blood pressure and thus the risk of intracranial hemorrhage [14]. Epinephrine would have been a reasonable alternative in this case due to the extent of angioedema that developed. Other alternatives include fresh frozen plasma, ecallantide (a recombinant protein that inhibits kallikrein), and C1 esterase inhibitors, all of which have been primarily used in ACE inhibitor-triggered angioedema or C1 esterase inhibitor deficiency but could have a role in tPA-related angioedema given the role of bradykinin [2,14]. Pahs et al. [16] demonstrated the use of plasma-derived C1 esterase inhibitor in a case of tPA-mediated angioedema. They described a case of potential airway compromise following tPA administration refractory to steroids and H2 blockers that ultimately resolved with a C1 esterase inhibitor and avoided the need for an invasive airway maneuver [16]. One last alternate therapy involves icatibant, a selective bradykinin B2 receptor antagonist; however, this is contraindicated with concomitant use of ACE inhibitors because they exert their vasodilating effect via increased bradykinin concentrations [17]. In severe or refractory cases of angioedema, patients may require intubation or cricothyroidotomy.
Conclusions
Angioedema induced by tPA is an infrequent but potentially fatal outcome of thrombolysis occurring in 1 of 50 patients, which increases to 1 of 10 in insular infarcts and 1 of 6 in individuals who are concomitantly using ACE inhibitors at the time of thrombolysis [4]. Angioedema typically presents within the hour of tPA administration and can quickly compromise the airway. Due to its severity, close monitoring of these individuals is imperative and prompt treatment is essential. Though exposed to ACE inhibitors, our patient was found to have an infarct of her posterior cerebral artery and developed angioedema after thrombolysis. This combination has rarely been documented, making this case unusual.
Conflicts of interest
None.
Figure 1. Computed tomography at initial presentation showing subacute infarct of the left pons indicated by the yellow arrow.
Figure 2. Repeat computed tomography showing acute to subacute infarct with encephalomalacia involving the left occipital lobe indicated by the red arrow.
Figure 3. Magnetic resonance imaging revealing an area of ischemia supplied by the posterior cerebral artery indicated by the green arrow.
Table 1. Comparison of studies involving tissue plasminogen activator-associated angioedema, highlighting the location of stroke and concomitant angiotensin-converting enzyme (ACE) inhibition.
Study Number of tPA-treated stroke patients Angioedema post-thrombolysis Concomitant ACE-inhibition* Locations of Infarct (n)
Myslimi et al. [4] 923 20 9 MCA (18)
Lin et al. [11] 559 5 2 MCA (5)
Engelter et al. [9] 120 2 1 Insular
Frohlich et al. [3] 136 15 10 Primarily MCA
Correia et al. [12] 236 8 5 MCA (3); Frontal (1); Basal Ganglia (1); Others (3)
Hill et al. [13] 176 9 7 MCA/Insula (7); Brainstem (1)
Yayan [1] n.s. 41 24 MCA (18); Insular (3); Others (3); Not mentioned (17)
Sczepanski and Bozyk [5] 147 4 3 MCA (3); PCA (1)
Hurford et al. [10] 530 42 24 ACA (38); Lacunar (3); PCA (1)
ACA – anterior cerebral artery; MCA – middle cerebral artery; n – number of infarcts in listed location correlating to number of patients with angioedema after thrombolysis in a given study; n.s. – not specified; PCA – posterior cerebral artery.
* Number of patients using ACE inhibitors that developed angioedema after thrombolysis. | Recovering | ReactionOutcome | CC BY-NC-ND | 33441533 | 18,915,688 | 2021-01-14 |
What was the outcome of reaction 'Swollen tongue'? | Tissue Plasminogen Activator-Induced Angioedema Involving a Posterior Cerebral Artery Infarct: A Case Presentation.
BACKGROUND Angioedema is characterized by localized swelling of subcutaneous or submucosal tissue resulting from fluid extravasation due to the loss of vascular integrity. It most commonly occurs with exposure to allergens and certain medications, namely nonsteroidal anti-inflammatory agents and angiotensin-converting enzyme inhibitors. There have been few incidences of angioedema following the administration of tissue plasminogen activator. CASE REPORT We describe an 84-year-old woman with a history of hypertension managed with lisinopril who presented with an acute onset of right-sided hemiparesis, slurred speech, and right-sided hemianopsia. Urgent computed tomography of the head revealed subacute infarct of the left pons without hemorrhage. Intravenous alteplase was administered and within 30 min our patient developed severe orolingual edema requiring emergent intubation. Subsequent imaging revealed acute to subacute infarct of the left occipital lobe in the posterior cerebral artery region, consistent with her initial presenting symptoms. CONCLUSIONS Angioedema induced by tissue plasminogen activator occurs in approximately 1-5% of patients receiving thrombolysis for ischemic stroke and can be life-threatening. The risk is increased in patients taking angiotensin-converting enzyme inhibitors, in patients with ischemic strokes of the middle cerebral artery, and in the presence of C1 esterase inhibitor deficiency. This phenomenon is usually self-limited and treatment is supportive, although evidence supports the use of antihistamines, steroids, epinephrine, and complement inhibitors. Due to the severity of angioedema and the potential progression to airway compromise, it is crucial to closely monitor patients receiving tissue plasminogen activator.
Background
It is becoming increasingly common to use tissue plasminogen activator (tPA) in the treatment of acute ischemic stroke, pulmonary embolism, and ST-elevation myocardial infarctions. Since tPA was approved in 1996, its utilization has illustrated marked improvement in stroke recovery and decreased hospital stay [1]. Major concerns with the administration of tPA are intracranial hemorrhage, edema, and possible brain herniation; however, other severe reactions such as hemopericardium, cardiac tamponade, angioedema, and anaphylaxis should not be forgotten.
Angioedema induced by tPA is an infrequent, but potentially fatal outcome of thrombolysis. The mechanisms behind such reactions are presumed to involve mast cells, bradykinin release, histamine, and the complement cascade. It primarily occurs with infarction of the middle cerebral artery and is more likely to occur in patients with concomitant use of angiotensin-converting enzyme inhibitors and in carriers of C1 esterase inhibitor deficiency. It is mostly self-limited and treatment is usually supportive. Some cases may require antihistamines, steroids, and epinephrine, with refractory cases needing complement inhibitors and severe cases leading to intubation or cricothyroidotomy. In this report, we present a case of an elderly woman who developed angioedema following tPA administration for treatment of a posterior cerebral artery stroke, which has only been documented in 2 other cases, as per our literature review.
Case Report
An 84-year-old woman presented to the Emergency Department for right-sided weakness, slurred speech, and right-sided hemianopsia after having collapsed onto the floor. She had a history of hypertension, which managed with lisinopril; chronic obstructive pulmonary disease; and lung cancer with subsequent left upper lobectomy. Her history also included atrial fibrillation, but she had not been on anticoagulation therapy for approximately 3 months due to gastrointestinal bleed. The patient did not experience loss of consciousness, convulsions, or any prodromal symptoms. Upon arrival to the Emergency Department, she was found to have 2/5 strength of her right-sided extremities and right-sided neglect. An urgent computed tomography (CT) scan of the head was performed and revealed a subacute infarct of the left pons with no acute hemorrhage (Figure 1). A CT angiography was obtained and confirmed these findings. She was given 0.9 mg/kg alteplase intravenously, 10% as a bolus followed by an intravenous infusion of the remaining dose. Within 30 min from the onset of infusion, she developed orolingual angioedema consisting of tongue swelling and bilateral lip swelling requiring emergent intubation for airway protection.
The infusion was stopped prematurely, and the patient was given intravenous methylprednisolone 125 mg, diphenhydramine 50 mg, and famotidine 20 mg to help treat her angioedema. The neurology and critical care teams aided in the management of her care. There was marked improvement of her angioedema within 24 h, and she was subsequently extubated the following morning. Repeat CT of the head revealed an acute to subacute infarct with encephalomalacia of the left occipital lobe, which was believed to be the cause of her initial deficits (Figure 2). Echocardiography did not reveal an atrial shunt or evidence of thrombi. Subsequent magnetic resonance imaging illustrated infarct involving the posterior cerebral artery circulation without hemorrhagic conversion (Figure 3). She was started on full-dose aspirin as well as fluoxetine 20 mg daily for stroke recovery. She began to work with physical therapy and had some improvement in her motor skills as well as her vision.
During her hospitalization, she experienced persistent nausea and vomiting, ultimately controlled with promethazine. Her anticoagulation was restarted 10 days after the onset of her stroke. Her strength did not improve as she or her family had hoped. Family discussions were held, and it was decided the best course of action would be to receive hospice care at home. She was ultimately discharged to home with hospice on morphine sulfate, lorazepam, fluoxetine, and promethazine. She died a week later.
Discussion
Tissue plasminogen activator is commonly used to treat ischemic stroke, myocardial infarction, and pulmonary embolism. It is generally well tolerated and can be life-saving; however, there are concerning adverse reactions to be mindful of, one of which is angioedema. Angioedema induced by tPA is an uncommon but potentially fatal occurrence. It is typically observed within 1 h of completing the tPA infusion [2]. It is postulated to occur in approximately 1–5% of patients receiving thrombolysis after an ischemic stroke, and it usually presents with hemifacial edema contralateral to the infarct zone [3]. An extensive study done by Myslimi et al. [4] evaluated 923 patients who received thrombolysis for stroke treatment. Of these patients, only 20 developed angioedema. A retrospective chart review performed by Sczepanski and Bozyk [5] reviewed 147 cases, with only 4 developing edema.
The mechanism behind this phenomenon is still unclear; however, several hypotheses have been proposed to explain this occurrence. One hypothesis suggests a bradykinin-mediated pathway, in which tPA hydrolyzes plasminogen into plasmin, which in turn activates the kinin pathway augmenting the production of bradykinin [5]. Bradykinin is a potent pro-inflammatory and pro-edematous peptide that increases vascular permeability and vasodilation, leading to angioedema. In addition, tPA can augment histamine, causing vasodilation [3]. Other hypotheses propose that both tPA and plasmin activate the complement pathway, increasing complement levels and in turn activating mast cells, histamine, and basophil degranulation, which contribute to angioedema [5,6]. An additional hypothesis focuses on a mutation of the plasminogen gene, drawing on the remarkable clinical similarity between tPA-induced orolingual angioedema and a recently described new subtype of hereditary angioedema with normal C1 inhibitor. This subtype is caused by a highly specific missense mutation of the plasminogen gene and the resulting presence of the aberrant plasminogen protein is hypothesized to lead to angioedema [7].
The risk of developing angioedema following thrombolytic administration is amplified in patients who take angiotensin-converting enzyme (ACE) inhibitors because these drugs increase the concentration of circulating bradykinin [8]. Additionally, neurokinins such as substance P are increased with ACE inhibition and are mediators in inflammation and angioedema [9]. The combination of tPA-related increase in bradykinin, ACE inhibitor-mediated decrease in bradykinin metabolism, and ACE inhibitor-related increase in neurokinin levels amplify the risk of angioedema. For instance, in the study by Myslimi et al. [4], among the 20 patients who developed angioedema after thrombolysis, 45% concomitantly took ACE inhibitors.
Lesion-mapping studies have been performed that concluded infarctions of the middle cerebral artery, especially the branch that supplies the right insular cortex, have the highest propensity of causing angioedema. Ninety percent of patients who developed angioedema in the study completed by Myslimi et al. [4] and 75% of those in the study done by Sczepanski and Bozyk [5] had infarcts of the middle cerebral artery. The lesion-mapping study by Frohlich et al. [3] illustrated an association with right-sided insular infarcts and the development on tPA-related angioedema. The authors postulated that insular infarcts augment sympathetic hyperactivity due to impaired autonomic function, which in turn intensifies proinflammatory cytokine production and vascular permeability thus causing orolingual edema [3]. It is also believed that the tissue damage itself could be a trigger for angioedema via the generation of bradykinin, which increases inflammation and edema [4,8]. Our patient, however, had a posterior cerebral artery infarct, which is not consistent with this hypothesis, making our case unusual. In the retrospective institutional study done by Sczepanski and Bozyk [5], only 1 out of 147 patients had an infarct involving the posterior cerebral artery, and only 1 out of 42 patients in the analysis by Hurford et al. [10] had involvement of the posterior circulation. None were detected in the lesion-mapping study by Frohlich et al. [3] or in the meta-analysis by Yayan [1], and no alternate explanation could be found to support angioedema following tPA treatment of a posterior circulation stroke. The Table 1 summarizes findings from multiple studies including stroke location, development of angioedema after thrombolysis, and concomitant ACE inhibition [11–13].
Angioedema mediated by tPA is a rare and potentially life-threatening occurrence. At the first signs of tPA-induced angioedema, hospital staff should be aware of the commonly used interventions and medications. It is critical to discontinue the tPA infusion when signs of angioedema occur. The 2018 guidelines for the management of tPA-induced angioedema recommend the administration of intravenous methylprednisolone 125 mg, oral diphenhydramine 50 mg, and oral ranitidine 50 mg or famotidine 20 mg with a class IIb recommendation and level C expert opinion [14,15]. If symptoms persist despite these measures, epinephrine can be administered; however, it should be administered cautiously because it may suddenly increase blood pressure and thus the risk of intracranial hemorrhage [14]. Epinephrine would have been a reasonable alternative in this case due to the extent of angioedema that developed. Other alternatives include fresh frozen plasma, ecallantide (a recombinant protein that inhibits kallikrein), and C1 esterase inhibitors, all of which have been primarily used in ACE inhibitor-triggered angioedema or C1 esterase inhibitor deficiency but could have a role in tPA-related angioedema given the role of bradykinin [2,14]. Pahs et al. [16] demonstrated the use of plasma-derived C1 esterase inhibitor in a case of tPA-mediated angioedema. They described a case of potential airway compromise following tPA administration refractory to steroids and H2 blockers that ultimately resolved with a C1 esterase inhibitor and avoided the need for an invasive airway maneuver [16]. One last alternate therapy involves icatibant, a selective bradykinin B2 receptor antagonist; however, this is contraindicated with concomitant use of ACE inhibitors because they exert their vasodilating effect via increased bradykinin concentrations [17]. In severe or refractory cases of angioedema, patients may require intubation or cricothyroidotomy.
Conclusions
Angioedema induced by tPA is an infrequent but potentially fatal outcome of thrombolysis occurring in 1 of 50 patients, which increases to 1 of 10 in insular infarcts and 1 of 6 in individuals who are concomitantly using ACE inhibitors at the time of thrombolysis [4]. Angioedema typically presents within the hour of tPA administration and can quickly compromise the airway. Due to its severity, close monitoring of these individuals is imperative and prompt treatment is essential. Though exposed to ACE inhibitors, our patient was found to have an infarct of her posterior cerebral artery and developed angioedema after thrombolysis. This combination has rarely been documented, making this case unusual.
Conflicts of interest
None.
Figure 1. Computed tomography at initial presentation showing subacute infarct of the left pons indicated by the yellow arrow.
Figure 2. Repeat computed tomography showing acute to subacute infarct with encephalomalacia involving the left occipital lobe indicated by the red arrow.
Figure 3. Magnetic resonance imaging revealing an area of ischemia supplied by the posterior cerebral artery indicated by the green arrow.
Table 1. Comparison of studies involving tissue plasminogen activator-associated angioedema, highlighting the location of stroke and concomitant angiotensin-converting enzyme (ACE) inhibition.
Study Number of tPA-treated stroke patients Angioedema post-thrombolysis Concomitant ACE-inhibition* Locations of Infarct (n)
Myslimi et al. [4] 923 20 9 MCA (18)
Lin et al. [11] 559 5 2 MCA (5)
Engelter et al. [9] 120 2 1 Insular
Frohlich et al. [3] 136 15 10 Primarily MCA
Correia et al. [12] 236 8 5 MCA (3); Frontal (1); Basal Ganglia (1); Others (3)
Hill et al. [13] 176 9 7 MCA/Insula (7); Brainstem (1)
Yayan [1] n.s. 41 24 MCA (18); Insular (3); Others (3); Not mentioned (17)
Sczepanski and Bozyk [5] 147 4 3 MCA (3); PCA (1)
Hurford et al. [10] 530 42 24 ACA (38); Lacunar (3); PCA (1)
ACA – anterior cerebral artery; MCA – middle cerebral artery; n – number of infarcts in listed location correlating to number of patients with angioedema after thrombolysis in a given study; n.s. – not specified; PCA – posterior cerebral artery.
* Number of patients using ACE inhibitors that developed angioedema after thrombolysis. | Recovering | ReactionOutcome | CC BY-NC-ND | 33441533 | 18,980,846 | 2021-01-14 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lens dislocation'. | Three-year outcomes of vitrectomy combined with intraoperative dexamethasone implantation for non-tractional refractory diabetic macular edema.
This retrospective, consecutive interventional study investigated the long-term clinical outcomes of combined vitrectomy with intraoperative dexamethasone implants for non-tractional refractory diabetic macular edema (DME). The study included 43 eyes from 39 participants with DME that had continued for more than 6 months despite repeated non-surgical treatment. Postoperative changes in best-corrected visual acuity (BCVA) and central macular thickness (CMT) were evaluated over 3 years. A Kaplan-Meier curve was obtained for any additional non-surgical treatment, and the average number of non-surgical treatments required for DME before and after surgery was compared. Other postsurgical complications were also investigated. The logMAR BCVA improved from 0.526 ± 0.417 (20/67) preoperatively to 0.294 ± 0.374 (20/39) 3 years postoperatively (p < 0.001, generalized estimating equation). The CMT improved from 478 ± 122 μm preoperatively to 314 ± 90 μm 3 years postoperatively (p < 0.001, generalized estimating equation). Additional non-surgical treatment was not required for 29 (67%) eyes. The average number of annual non-surgical treatments decreased from 5.04 times preoperatively to 0.34 times postoperatively. Seventeen (40%) eyes developed temporary ocular hypertension after surgery, which normalized after antihypertensive eye drop instillation. In conclusion, vitrectomy combined with intraoperative dexamethasone implantation provides satisfactory long-term clinical outcomes for non-tractional refractory DME while reducing the number of intraocular injections for DME.
Introduction
Diabetic macular edema (DME) is a major cause of visual impairment in patients with diabetes1. It is characterized by the accumulation of fluid and/or protein within the retinal layer of the macula caused by microvascular compromise, Muller cell dysfunction, and blood-retinal barrier breakdown2. Non-surgical treatments, including macular laser photocoagulation3, intravitreal injections of either anti-vascular endothelial growth factor (VEGF) agents4,5 or corticosteroids6,7, and posterior sub-tenon injection of corticosteroids8,9, are considered the main treatment methods for DME. However, in cases where DME does not respond successfully to these non-surgical treatments, vitrectomy can be considered an alternative therapeutic approach10–12.
Conventionally, intravitreal triamcinolone has been used in combination with vitrectomy since it has proven to be effective in preventing various postsurgical complications, such as macular edema13. However, a limitation of this intervention is the increased clearance of triamcinolone in vitrectomized eyes, approximately six times faster than that in non-vitrectomized eyes14.
Ozurdex (Allergan, Irvine, CA, USA), a dexamethasone intravitreal implant, is a biodegradable device that releases dexamethasone for up to 6 months in both vitrectomized and non-vitrectomized eyes15,16. Numerous studies have reported that Ozurdex is a safe and effective management modality for DME7,17,18 and can delay the progression of diabetic retinopathy19–21. Considering the clearance issue of triamcinolone in vitrectomized eyes, Ozurdex is a good alternative for intravitreal triamcinolone in combination with vitrectomy for DME resistant to other treatments.
Previously, there have been a few studies assessing the clinical outcomes of vitrectomy combined with intraoperative dexamethasone implantation for DME22–24. However, these studies only reported short-term clinical results of up to a maximum of 1 year. Therefore, we investigated the long-term clinical outcomes of vitrectomy combined with intravitreal dexamethasone implantation for non-tractional refractory DME.
Methods
Setting
This was a retrospective interventional study of consecutive patients with non-tractional refractory DME who were treated with vitrectomy combined with intravitreal dexamethasone implantation and were followed up for at least 3 years after surgery. The study adhered to the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of Samsung Medical Center, Seoul, Republic of Korea (IRB number 2020-02-124). The board waived the requirement for informed consent owing to the retrospective design of the study.
Subjects
The electronic medical records of all consecutive patients who were diagnosed with non-tractional refractory DME with central macular thickness (CMT) greater than 300 μm at Samsung Medical Center between January 2015 and March 2017 were retrospectively reviewed. Non-tractional refractory DME was defined as biomicroscopically, angiographically, and tomographically confirmed DME that had continued for more than 6 months despite repeated non-surgical treatments (including macular laser photocoagulation, posterior sub-tenon corticosteroid injection, intravitreal corticosteroid injection, and intravitreal injection of anti-VEGF agents) in the absence of any evidence of traction force (e.g., vitreomacular traction or epiretinal membrane) on optical coherence tomography (OCT). Subjects with active proliferative diabetic retinopathy requiring surgical management, those with prior history of vitreoretinal surgery, those with evidence of any other past or concomitant retinal diseases that might affect visual acuity or macular microstructure, and those who were lost to follow-up before 3 years postoperatively were excluded from the study. Among the 52 eyes with non-tractional refractory DME that met the study inclusion criteria, 9 eyes were excluded owing to the following reasons: active vitreous hemorrhage at the time of surgery (2 eyes), history of vitreoretinal surgery (1 eye), follow-up period of less than 3 years (6 eyes). Finally, 43 eyes of 39 patients were included in the study.
Preoperative examination
All subjects underwent thorough preoperative ocular examination, including best-corrected visual acuity (BCVA) measurement using a Snellen chart, manifest refraction, applanation tonometry, slit-lamp biomicroscopy, and dilated fundus examination. Wide-field fluorescein angiography was routinely performed preoperatively to evaluate the severity of diabetic retinopathy and the extent of the non-perfusion area, and spectral domain OCT (Spectralis HRA-OCT; Heidelberg Engineering, Heidelberg, Germany) was performed to evaluate any vitreomacular interface abnormalities and measure the CMT.
Surgical technique
Standard transconjunctival sutureless pars plana vitrectomy was performed by a single surgeon (SWK) using a Constellation (Alcon Laboratories, Fort Worth, TX, USA) or Associate (Dutch Ophthalmic Research Center, Zuidland, the Netherlands) 23-gauge vitrectomy system under retrobulbar anesthesia. The internal limiting membrane (ILM) was removed with a radius of around 2-disc diameters from the fovea using intraocular forceps with the assistance of indocyanine green staining in some cases. Panretinal endolaser photocoagulation was performed concomitantly for patients with extensive retinal capillary dropout or with apparent high-risk characteristics. At the end of the operation, a dexamethasone implant was placed into the vitreous cavity through the 23-gauge vitrectomy port. Patients were advised to maintain a sitting position for a few hours to position the dexamethasone implant at the inferior periphery. Combined cataract surgery was performed in patients aged over 50 years to pretreat post-vitrectomy lens opacity.
Postoperative examination and management
Patients were routinely followed up at 1, 3, 6, 12, 24, and 36 months postoperatively in cases in which DME resolved and stabilized without further treatment. At every visit, patients underwent BCVA measurement, slit-lamp biomicroscopy, applanation tonometry, dilated fundus examination, and OCT. If macular edema did not respond to the surgery until postoperative 3 months or recurred/aggravated after resolution, non-surgical treatments were restarted and followed up according to an individual’s ocular condition. Patients who had intraocular pressure (IOP) greater than 21 mmHg were prescribed IOP-lowering eye drops, as recommended by glaucoma specialists, and managed accordingly.
Statistical analyses
We collected clinical data on BCVA, CMT, IOP, glaucoma medication usage, additional non-surgical treatment for DME after surgery, and other unexpected ocular complications from the preoperative period to 3 years after surgery. Improvement of BCVA (converted to a logarithm of the minimal angle of resolution [logMAR] scale) and CMT were assessed at postoperative 3, 6, 12, 24, and 36 months using a generalized estimating equation accounting for the correlation of paired eyes. We obtained a Kaplan–Meier curve of additional treatment requirement for DME after surgery and compared the average number of non-surgical treatments required for DME before and after surgery using a generalized estimating equation model. All statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) software version 23.0 (SPSS, Inc., Chicago, IL, USA). p values were two sided and considered statistically significant for values less than 0.05.
Results
Baseline demographics
The baseline characteristics of 43 eyes from 39 patients with non-tractional refractory DME are presented in Table 1. The mean (± standard deviation) age, number of prior injections of anti-VEGF for DME, and time period of non-surgical treatment before surgery were 57.8 ± 8.2 years, 6.25 ± 7.12, and 17.0 ± 14.2 months, respectively. Twelve eyes had a history of cataract surgery, and 24 eyes underwent cataract surgery combined with vitrectomy. Four eyes were treated with IOP-lowering medication before surgery.Table 1 Baseline demographics and clinical characteristics of subjects with diabetic macular edema refractory to prior treatments.
Variables Values
Number of patients (eyes) 39 (43)
Age, years, mean ± SD 57.8 ± 8.2
Sex, male: female 26:13
Type of DM, type 1:type 2 0:39
Duration of diabetes, years, mean ± SD 13.3 ± 8.6
Presence of hypertension, No. (%) 19/39 (48.7)
Presence of dyslipidemia, No. (%) 7/39 (17.9)
Severity of diabetic retinopathy, NPDR:PDR 11:32
Lens type, phakic:pseudophakic 31:12
Combined cataract surgery with vitrectomy, No. (%) 24/31 (77.4)
Treatment modalities used prior to the surgery
Intravitreal anti-VEGF, No. (%) 42/43 (97.7)
Number of treatment session, mean ± SD (range) 6.5 ± 7.1 (1–32)
Intravitreal dexamethasone, No. (%) 5/43 (11.6)
Number of treatment session, mean ± SD (range) 1.6 ± 0.9 (1–3)
Intravitreal triamcinolone, No. (%) 9/43 (20.9)
Number of treatment session, mean ± SD (range) 2.7 ± 2.8 (1–10)
Posterior sub-tenon triamcinolone, No. (%) 4/43 (9.3)
Number of treatment session, mean ± SD (range) 3.3 ± 4.5 (1–10)
Macular laser photocoagulation, No. (%) 9/43 (20.9)
Number of treatment session, mean ± SD (range) 1.9 ± 1.5 (1–5)
Duration of prior treatment for DME, months, mean ± SD 17.0 ± 14.2
Time between the last treatment and surgery, months, mean ± SD 2.83 ± 1.43
Preoperative BCVA, logMAR, mean ± SD 0.526 ± 0.417
Preoperative CMT, μm, mean ± SD 478 ± 122
Preoperative IOP, mmHg, mean ± SD 17.0 ± 2.8
On glaucoma medication (preoperatively), No. (%) 4/43
SD, standard deviation; DM, diabetes mellitus; NPDR, non-proliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy; DME, diabetic macular edema; VEGF, vascular endothelial growth factor; BCVA, best-corrected visual acuity; logMAR, logarithm of the minimal angle of resolution; CMT, central macular thickness; IOP, intraocular pressure.
Clinical outcomes
The logMAR BCVA was 0.526 ± 0.417 preoperatively, which gradually improved to 0.294 ± 0.374 at postoperative 3 years (p < 0.001). The CMT was 478 ± 122 μm before the surgery, which improved to 314 ± 90 μm 3 years after surgery (p < 0.001). The improvements were significant throughout the follow-up period. Figure 1 demonstrates the improvement in BCVA and CMT after surgery.Figure 1 Changes in the mean and standard deviation of the logarithm of the minimal angle of resolution (logMAR) best-corrected visual acuity (BCVA) and central macular thickness (CMT) at 3, 6, 12, 24, and 36 months after vitrectomy combined with intraoperative dexamethasone implantation for non-tractional refractory diabetic macular edema. Statistical significance was determined using a generalized estimating equation model accounting for the correlation structure of paired eyes. (A) The logMAR BCVA significantly improved postoperatively compared to the baseline during follow-up. (B) The CMT was significantly thinner postoperatively than preoperatively. The average CMT at 6 months was slightly thicker than that at 3 months, but the difference was not statistically significant (p = 0.258).
Twenty-nine of the 43 (67%) eyes responded well to the surgery and maintained the resolved state for 3 years. Fourteen (33%) eyes required additional non-surgical treatment for DME during the study period; 13 eyes required additional treatment within 1 year, and one eye received additional treatment at 32 months postoperatively. Figure 2 shows the Kaplan–Meier curve of additional treatment requirements for DME.Figure 2 The Kaplan–Meier curve for additional nonsurgical treatment requirement after vitrectomy combined with intraoperative dexamethasone implantation for non-tractional refractory diabetic macular edema. Twenty-nine of 43 (67%) eyes maintained the resolved state for 3 years, and 14 of 43 (33%) eyes required further treatment for diabetic macular edema. Ten of 43 (23%) eyes experienced temporary resolution of macular edema between 1 and 6 months postoperatively, but the macular edema recurred during the follow-up period and underwent additional treatment. Four (9%) subjects did not achieve resolution of macular edema and underwent additional treatment after 3 months postoperatively.
Table 2 presents the average annual number of non-surgical treatments performed before and after surgery. The number of intravitreal injection significantly decreased after surgery (p < 0.001), even in the subgroup analysis performed with patients who required additional treatment for more than once after surgery (p = 0.001).Table 2 Number of treatments for diabetic macular edema per year before and after vitrectomy combined with intraoperative dexamethasone implantation.
First visit to operation Operation to postoperative 3 years p value*
All subjects (43 eyes)
Overall intravitreal injection 4.99 ± 1.82 (2.0–9.0) 0.20 ± 0.48 (0.0–2.7) < 0.001
Anti-VEGF 4.42 ± 1.92 (0.0–9.0) 0.09 ± 0.43 (0.0–2.7) < 0.001
Dexamethasone 0.25 ± 0.89 (0.0–4.5) 0.10 ± 0.20 (0.0–0.7) 0.280
Triamcinolone 0.33 ± 0.87 (0.0–5.1) 0.01 ± 0.05 (0.0–0.3) 0.042
Posterior sub-tenon triamcinolone 0.14 ± 0.50 (0.0–2.8) 0.04 ± 0.11 (0.0–0.3) 0.224
Laser photocoagulation 0.29 ± 0.69 (0.0–2.8) 0.17 ± 0.34 (0.0–1.3) 0.299
Subjects who required additional treatment after surgery (14 eyes)
Overall intravitreal injection 5.12 ± 1.92 (2.0–8.3) 0.57 ± 0.68 (0.0–2.7) 0.001
Anti-VEGF 4.49 ± 2.17 (0.0–7.8) 0.26 ± 0.71 (0.0–2.7) 0.001
Dexamethasone 0.47 ± 1.40 (0.0–5.1) 0.29 ± 0.26 (0.0–0.7) 0.624
Triamcinolone 0.15 ± 0.32 (0.0–1.0) 0.02 ± 0.09 (0.0–0.3) 0.053
Posterior sub-tenon triamcinolone 0.13 ± 0.34 (0.0–1.1) 0.12 ± 0.17 (0.0–0.3) 0.880
Laser photocoagulation 0.56 ± 0.71 (0.0–2.3) 0.45 ± 0.45 (0.0–1.3) 0.654
VEGF, vascular endothelial growth factor.
Variables are described as mean ± standard deviation (range).
*p values were calculated using a generalized estimating equation accounting correlation structure for paired eyes.
Adverse events
Cases of postoperative leakage/hypotony, new retinal tears/breaks, anterior migration of the dexamethasone implant, or endophthalmitis were not observed. Seventeen (40%) eyes experienced a temporary increase in IOP (> 21 mmHg) after surgery, but the IOP normalized after using IOP-lowering eye drops. None of the subjects required filtering surgery within 3 years of vitrectomy. Of the seven eyes remaining phakic after vitrectomy, five eyes eventually underwent cataract surgery 16.4 ± 11.5 months after vitrectomy. One eye developed intraocular lens dislocation at 26 months postoperatively and underwent intraocular lens scleral fixation. No other complications were observed during the follow-up period.
Discussion
The present study elucidated that vitrectomy combined with intraoperative dexamethasone implantation can be an effective treatment for non-tractional refractory DME. The strong point of the current study is the confirmation of the long-term stability and efficacy of vitrectomy combined with intraoperative dexamethasone implantation for refractory DME. Additionally, the study also suggested that surgery may reduce the number of intravitreal injections required for managing DME.
Currently, the standard treatment method for DME is an intravitreal anti-VEGF injection or corticosteroid injection4–7. Some studies have suggested good long-term functional and anatomical outcomes of primary vitrectomy for treatment-naïve DME25, but most clinicians do not perform vitrectomy initially unless there is significant vitreomacular traction26. Anti-VEGF injections and corticosteroid injections often require frequent and continuous treatment sessions and not all patients respond successfully to the treatment27. This is a commonly encountered dilemma for ophthalmologists in clinical practice. In this situation, vitrectomy can be an alternative treatment. Several previous studies have reported the efficacy of vitrectomy for treatment-refractory DME10–12,28–30. The studies agree that vitrectomy helps reduce macular thickness in refractory DME, but improvement of visual acuity after vitrectomy has been controversial. Several long-term studies have suggested that vitrectomy for refractory DME is beneficial in both reducing CMT and improving visual acuity10–12,29–31. In contrast, in a large prospective study from the Diabetic Retinopathy Clinical Research Network (DRCR.net), vitrectomy was beneficial for reducing CMT; however, its efficacy for improving visual acuity was limited28. In addition to what has been investigated thus far, our study provides additional data on both anatomically and functionally favorable long-term results of vitrectomy combined with dexamethasone implantation for refractory DME. The more favorable visual acuity outcome of our study compared to that of DRCR.net may be attributable to the baseline characteristics of the patients28. Compared to DRCR.net, our study comprised only patients with type 2 diabetes who were significantly younger at the time of surgery and in whom the mean duration of diabetes was approximately 7 years shorter28. Additionally, all patients underwent ILM peeling and Ozurdex injection during surgery in our study, whereas only 64% underwent ILM peeling and no patient received a corticosteroid injection in DRCR.net28. Considering that ILM peeling may produce a more favorable visual outcome and the intraoperative use of corticosteroids plays a beneficial role after vitrectomy11,13,32, the difference in the detailed method of surgery (ILM peeling and intraoperative Ozurdex implant) may have produced better visual outcomes in our study than in DRCR.net.
Vitrectomy is known to treat macular edema, possibly through the following mechanisms: elimination of possible sources of traction on the macular area26, improvement of transvitreal oxygen delivery to the retina33, and removal of condensed chemical mediators that worsen the retinal vascular permeability34. In addition to vitrectomy, concurrent ILM peeling could also completely remove the source of traction and may facilitate the penetration of drugs into the retinal tissue24. In contrast, dexamethasone relieves DME in different ways. Dexamethasone blocks the production of VEGF and inflammatory mediators in the retina, inhibits macrophage and leukocyte adhesion/transmigration, and enhances the tight junctions of the blood-retinal barrier35,36. Combining these different mechanisms, vitrectomy with intraoperative dexamethasone implants is expected to produce a synergistic effect, provide more effective treatment, and yield favorable clinical outcomes.
There have been some reports regarding vitrectomy combined with intraoperative dexamethasone implantation for refractory DME. Lee et al.22 and Jung et al.24 reported the 1-year clinical outcomes in 18 eyes and 22 eyes, respectively. Both studies showed significant improvement in BCVA and CMT without ocular complications other than temporary IOP increase. Moreover, Pang et al. recently reported the 1-year outcome of vitrectomy combined with Ozurdex implantation for refractory macular edema secondary to diabetic retinopathy, retinal vein occlusion, and non-infectious posterior uveitis37. The subjects with DME in their study showed the most prominent improvement in BCVA and CMT and the longest macular edema-free period. However, the previous studies were limited by a relatively short follow-up period of 1 year or less. Therefore, they were not able to present sufficient information about the long-term efficacy, stability, and safety of vitrectomy combined with intraoperative Ozurdex implantation. Furthermore, they included both tractional and non-tractional DME in the analysis. Tractional and non-tractional DME may respond differently to vitrectomy. DME with a tractional component has better clinical outcomes than DME without a tractional component after vitrectomy26,28, and this is intuitively comprehensible. Therefore, it would have been better to report these two different entities separately. In contrast to the aforementioned studies, we were able to provide long-term clinical data and proved that BCVA and CMT of refractory DME improved after surgery and remained stable for 3 years. Furthermore, the present study did not include subjects with tractional components and verified favorable long-term clinical results even in non-tractional refractory DME. These are the strong points of our study.
In the present study, improvements in BCVA and CMT after surgery were significant throughout the follow-up period. However, although the mean BCVA gradually improved during follow-up, the mean CMT showed a temporary deterioration between 3 and 6 months postoperatively. The temporary increase of CMT a few months after surgery was also shown in previous studies22–24,37. This is consistent with the fact that the Ozurdex implant releases high concentrations of dexamethasone for approximately 2 months and subsequently releases relatively lower concentrations of dexamethasone afterward, extending the therapeutic period to 6 months38. A decrease in the dexamethasone concentration in the retina and vitreous fluid a few months after surgery may have caused a recurrence of macular edema in some patients and led to an increase in the average CMT. Subjects with recurring macular edema were treated accordingly, and the mean CMT improved thereafter and remained stable.
The proportion of subjects who required retreatment after surgery in the present study was similar to that reported in previous studies. Lee et al.22 and Jung et al.24 reported that 27% and 28% subjects, respectively, required additional treatment within 1 year. In our study, 33% subjects (14 eyes) required additional treatment during the study period. Most of the additional treatment resulting from the recurrence of macular edema after surgery occurs within 1 year after surgery. Among the 14 eyes that received additional treatment, 13 eyes required additional treatment within 12 months postoperatively, and only one eye required additional treatment at 32 months postoperatively. This means that eyes with DME that are successfully treated by vitrectomy combined with dexamethasone implantation and remain stable for a year are less likely to develop macular edema afterward. Additionally, the average number of intraocular injections also significantly decreased after surgery. Even the retreated subjects required fewer additional intraocular injections compared to the preoperative period. This may reduce the risk of ocular complications associated with frequent intraocular injections and may be more beneficial in terms of patient convenience and financial costs. Furthermore, prolonged treatment with anti-VEGF injections for DME can also increase the risk of cerebrovascular accidents and death39. Therefore, even in this anti-VEGF era, we believe that vitrectomy combined with intraoperative dexamethasone implantation could be a viable and useful option for non-tractional DME refractory to prolonged multiple injections of anti-VEGF.
Cataract formation and increase in IOP are the main concerns of both vitrectomy and intravitreal dexamethasone implantation. In our study, seven eyes were phakic after vitrectomy combined with intraoperative dexamethasone implantation. They did not undergo cataract surgery because of young age (< 50 years) at the time of vitrectomy. Five of the seven (71%) eyes later underwent cataract surgery because of the significant visual impairment caused by progression of lens opacity, and only two eyes were phakic at the end of the study period.
A temporary elevation of IOP after surgery was observed in some subjects, but it was well controlled with the use of IOP-lowering eye drops during the study period. However, a relatively large proportion of subjects (17 eyes, 40%) experienced an increase in IOP, and some of them (11 eyes, 25%) continued to use IOP-lowering eye drops until 36 months postoperatively. Additionally, one eye underwent filtering surgery for neovascular glaucoma after the study period (postoperative 47 months). Although it was reported that Ozurdex induces less IOP increase and cataract formation compared to triamcinolone40,41, they should not be taken lightly, and surgeons should take constant care of these complications.
This study has some strengths. It comprised a larger number of subjects than previous studies. To our knowledge, this is the first study reporting the long-term clinical outcomes of vitrectomy combined with intraoperative dexamethasone implantation for non-tractional refractory DME. However, this study has some limitations. First, due to the retrospective nature of this study, there could have been a bias in patient selection, and the preoperative and postoperative management for each individual was heterogeneous and not standardized. However, we believe that this reflects the real-world situation because different clinicians may have different treatment strategies for DME and that clinicians would try several different methods for refractory disease. Second, the results of the current study are limited by the lack of a control group. It would have been a more significant study if we were able to compare the efficacy of vitrectomy combined with intraoperative dexamethasone implantation with that of vitrectomy alone without intravitreal dexamethasone implantation or continued conventional treatment. Third, this study could not provide additional information on the predictors of postoperative clinical outcomes and when to switch from non-surgical treatment to surgical treatment for DME. Further studies addressing these issues may provide a better understanding of the benefits of vitrectomy combined with intraoperative dexamethasone implantation for non-tractional refractory DME.
In conclusion, vitrectomy combined with intravitreal dexamethasone implantation showed satisfactory long-term clinical outcomes in non-tractional refractory DME. This treatment may reduce the number of intraocular injections required for managing DME, thereby reducing ocular and systemic side effects and increasing patient comfort. Vitrectomy combined with intraoperative dexamethasone implantation could be an effective alternative treatment modality for non-tractional refractory DME.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author contributions
S.W.K. designed the study. S.H., K.T.K., and H.N. analyzed and interpreted the data. S.H. wrote the final paper. S.W.K. and S.J.K. reviewed the design, results, and final paper. All authors have read and approved the final manuscript.
Data availability
The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
Competing interests
The authors declare no competing interests. | DEXAMETHASONE | DrugsGivenReaction | CC BY | 33446712 | 19,233,686 | 2021-01-14 |
What was the administration route of drug 'DEXAMETHASONE'? | Three-year outcomes of vitrectomy combined with intraoperative dexamethasone implantation for non-tractional refractory diabetic macular edema.
This retrospective, consecutive interventional study investigated the long-term clinical outcomes of combined vitrectomy with intraoperative dexamethasone implants for non-tractional refractory diabetic macular edema (DME). The study included 43 eyes from 39 participants with DME that had continued for more than 6 months despite repeated non-surgical treatment. Postoperative changes in best-corrected visual acuity (BCVA) and central macular thickness (CMT) were evaluated over 3 years. A Kaplan-Meier curve was obtained for any additional non-surgical treatment, and the average number of non-surgical treatments required for DME before and after surgery was compared. Other postsurgical complications were also investigated. The logMAR BCVA improved from 0.526 ± 0.417 (20/67) preoperatively to 0.294 ± 0.374 (20/39) 3 years postoperatively (p < 0.001, generalized estimating equation). The CMT improved from 478 ± 122 μm preoperatively to 314 ± 90 μm 3 years postoperatively (p < 0.001, generalized estimating equation). Additional non-surgical treatment was not required for 29 (67%) eyes. The average number of annual non-surgical treatments decreased from 5.04 times preoperatively to 0.34 times postoperatively. Seventeen (40%) eyes developed temporary ocular hypertension after surgery, which normalized after antihypertensive eye drop instillation. In conclusion, vitrectomy combined with intraoperative dexamethasone implantation provides satisfactory long-term clinical outcomes for non-tractional refractory DME while reducing the number of intraocular injections for DME.
Introduction
Diabetic macular edema (DME) is a major cause of visual impairment in patients with diabetes1. It is characterized by the accumulation of fluid and/or protein within the retinal layer of the macula caused by microvascular compromise, Muller cell dysfunction, and blood-retinal barrier breakdown2. Non-surgical treatments, including macular laser photocoagulation3, intravitreal injections of either anti-vascular endothelial growth factor (VEGF) agents4,5 or corticosteroids6,7, and posterior sub-tenon injection of corticosteroids8,9, are considered the main treatment methods for DME. However, in cases where DME does not respond successfully to these non-surgical treatments, vitrectomy can be considered an alternative therapeutic approach10–12.
Conventionally, intravitreal triamcinolone has been used in combination with vitrectomy since it has proven to be effective in preventing various postsurgical complications, such as macular edema13. However, a limitation of this intervention is the increased clearance of triamcinolone in vitrectomized eyes, approximately six times faster than that in non-vitrectomized eyes14.
Ozurdex (Allergan, Irvine, CA, USA), a dexamethasone intravitreal implant, is a biodegradable device that releases dexamethasone for up to 6 months in both vitrectomized and non-vitrectomized eyes15,16. Numerous studies have reported that Ozurdex is a safe and effective management modality for DME7,17,18 and can delay the progression of diabetic retinopathy19–21. Considering the clearance issue of triamcinolone in vitrectomized eyes, Ozurdex is a good alternative for intravitreal triamcinolone in combination with vitrectomy for DME resistant to other treatments.
Previously, there have been a few studies assessing the clinical outcomes of vitrectomy combined with intraoperative dexamethasone implantation for DME22–24. However, these studies only reported short-term clinical results of up to a maximum of 1 year. Therefore, we investigated the long-term clinical outcomes of vitrectomy combined with intravitreal dexamethasone implantation for non-tractional refractory DME.
Methods
Setting
This was a retrospective interventional study of consecutive patients with non-tractional refractory DME who were treated with vitrectomy combined with intravitreal dexamethasone implantation and were followed up for at least 3 years after surgery. The study adhered to the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of Samsung Medical Center, Seoul, Republic of Korea (IRB number 2020-02-124). The board waived the requirement for informed consent owing to the retrospective design of the study.
Subjects
The electronic medical records of all consecutive patients who were diagnosed with non-tractional refractory DME with central macular thickness (CMT) greater than 300 μm at Samsung Medical Center between January 2015 and March 2017 were retrospectively reviewed. Non-tractional refractory DME was defined as biomicroscopically, angiographically, and tomographically confirmed DME that had continued for more than 6 months despite repeated non-surgical treatments (including macular laser photocoagulation, posterior sub-tenon corticosteroid injection, intravitreal corticosteroid injection, and intravitreal injection of anti-VEGF agents) in the absence of any evidence of traction force (e.g., vitreomacular traction or epiretinal membrane) on optical coherence tomography (OCT). Subjects with active proliferative diabetic retinopathy requiring surgical management, those with prior history of vitreoretinal surgery, those with evidence of any other past or concomitant retinal diseases that might affect visual acuity or macular microstructure, and those who were lost to follow-up before 3 years postoperatively were excluded from the study. Among the 52 eyes with non-tractional refractory DME that met the study inclusion criteria, 9 eyes were excluded owing to the following reasons: active vitreous hemorrhage at the time of surgery (2 eyes), history of vitreoretinal surgery (1 eye), follow-up period of less than 3 years (6 eyes). Finally, 43 eyes of 39 patients were included in the study.
Preoperative examination
All subjects underwent thorough preoperative ocular examination, including best-corrected visual acuity (BCVA) measurement using a Snellen chart, manifest refraction, applanation tonometry, slit-lamp biomicroscopy, and dilated fundus examination. Wide-field fluorescein angiography was routinely performed preoperatively to evaluate the severity of diabetic retinopathy and the extent of the non-perfusion area, and spectral domain OCT (Spectralis HRA-OCT; Heidelberg Engineering, Heidelberg, Germany) was performed to evaluate any vitreomacular interface abnormalities and measure the CMT.
Surgical technique
Standard transconjunctival sutureless pars plana vitrectomy was performed by a single surgeon (SWK) using a Constellation (Alcon Laboratories, Fort Worth, TX, USA) or Associate (Dutch Ophthalmic Research Center, Zuidland, the Netherlands) 23-gauge vitrectomy system under retrobulbar anesthesia. The internal limiting membrane (ILM) was removed with a radius of around 2-disc diameters from the fovea using intraocular forceps with the assistance of indocyanine green staining in some cases. Panretinal endolaser photocoagulation was performed concomitantly for patients with extensive retinal capillary dropout or with apparent high-risk characteristics. At the end of the operation, a dexamethasone implant was placed into the vitreous cavity through the 23-gauge vitrectomy port. Patients were advised to maintain a sitting position for a few hours to position the dexamethasone implant at the inferior periphery. Combined cataract surgery was performed in patients aged over 50 years to pretreat post-vitrectomy lens opacity.
Postoperative examination and management
Patients were routinely followed up at 1, 3, 6, 12, 24, and 36 months postoperatively in cases in which DME resolved and stabilized without further treatment. At every visit, patients underwent BCVA measurement, slit-lamp biomicroscopy, applanation tonometry, dilated fundus examination, and OCT. If macular edema did not respond to the surgery until postoperative 3 months or recurred/aggravated after resolution, non-surgical treatments were restarted and followed up according to an individual’s ocular condition. Patients who had intraocular pressure (IOP) greater than 21 mmHg were prescribed IOP-lowering eye drops, as recommended by glaucoma specialists, and managed accordingly.
Statistical analyses
We collected clinical data on BCVA, CMT, IOP, glaucoma medication usage, additional non-surgical treatment for DME after surgery, and other unexpected ocular complications from the preoperative period to 3 years after surgery. Improvement of BCVA (converted to a logarithm of the minimal angle of resolution [logMAR] scale) and CMT were assessed at postoperative 3, 6, 12, 24, and 36 months using a generalized estimating equation accounting for the correlation of paired eyes. We obtained a Kaplan–Meier curve of additional treatment requirement for DME after surgery and compared the average number of non-surgical treatments required for DME before and after surgery using a generalized estimating equation model. All statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) software version 23.0 (SPSS, Inc., Chicago, IL, USA). p values were two sided and considered statistically significant for values less than 0.05.
Results
Baseline demographics
The baseline characteristics of 43 eyes from 39 patients with non-tractional refractory DME are presented in Table 1. The mean (± standard deviation) age, number of prior injections of anti-VEGF for DME, and time period of non-surgical treatment before surgery were 57.8 ± 8.2 years, 6.25 ± 7.12, and 17.0 ± 14.2 months, respectively. Twelve eyes had a history of cataract surgery, and 24 eyes underwent cataract surgery combined with vitrectomy. Four eyes were treated with IOP-lowering medication before surgery.Table 1 Baseline demographics and clinical characteristics of subjects with diabetic macular edema refractory to prior treatments.
Variables Values
Number of patients (eyes) 39 (43)
Age, years, mean ± SD 57.8 ± 8.2
Sex, male: female 26:13
Type of DM, type 1:type 2 0:39
Duration of diabetes, years, mean ± SD 13.3 ± 8.6
Presence of hypertension, No. (%) 19/39 (48.7)
Presence of dyslipidemia, No. (%) 7/39 (17.9)
Severity of diabetic retinopathy, NPDR:PDR 11:32
Lens type, phakic:pseudophakic 31:12
Combined cataract surgery with vitrectomy, No. (%) 24/31 (77.4)
Treatment modalities used prior to the surgery
Intravitreal anti-VEGF, No. (%) 42/43 (97.7)
Number of treatment session, mean ± SD (range) 6.5 ± 7.1 (1–32)
Intravitreal dexamethasone, No. (%) 5/43 (11.6)
Number of treatment session, mean ± SD (range) 1.6 ± 0.9 (1–3)
Intravitreal triamcinolone, No. (%) 9/43 (20.9)
Number of treatment session, mean ± SD (range) 2.7 ± 2.8 (1–10)
Posterior sub-tenon triamcinolone, No. (%) 4/43 (9.3)
Number of treatment session, mean ± SD (range) 3.3 ± 4.5 (1–10)
Macular laser photocoagulation, No. (%) 9/43 (20.9)
Number of treatment session, mean ± SD (range) 1.9 ± 1.5 (1–5)
Duration of prior treatment for DME, months, mean ± SD 17.0 ± 14.2
Time between the last treatment and surgery, months, mean ± SD 2.83 ± 1.43
Preoperative BCVA, logMAR, mean ± SD 0.526 ± 0.417
Preoperative CMT, μm, mean ± SD 478 ± 122
Preoperative IOP, mmHg, mean ± SD 17.0 ± 2.8
On glaucoma medication (preoperatively), No. (%) 4/43
SD, standard deviation; DM, diabetes mellitus; NPDR, non-proliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy; DME, diabetic macular edema; VEGF, vascular endothelial growth factor; BCVA, best-corrected visual acuity; logMAR, logarithm of the minimal angle of resolution; CMT, central macular thickness; IOP, intraocular pressure.
Clinical outcomes
The logMAR BCVA was 0.526 ± 0.417 preoperatively, which gradually improved to 0.294 ± 0.374 at postoperative 3 years (p < 0.001). The CMT was 478 ± 122 μm before the surgery, which improved to 314 ± 90 μm 3 years after surgery (p < 0.001). The improvements were significant throughout the follow-up period. Figure 1 demonstrates the improvement in BCVA and CMT after surgery.Figure 1 Changes in the mean and standard deviation of the logarithm of the minimal angle of resolution (logMAR) best-corrected visual acuity (BCVA) and central macular thickness (CMT) at 3, 6, 12, 24, and 36 months after vitrectomy combined with intraoperative dexamethasone implantation for non-tractional refractory diabetic macular edema. Statistical significance was determined using a generalized estimating equation model accounting for the correlation structure of paired eyes. (A) The logMAR BCVA significantly improved postoperatively compared to the baseline during follow-up. (B) The CMT was significantly thinner postoperatively than preoperatively. The average CMT at 6 months was slightly thicker than that at 3 months, but the difference was not statistically significant (p = 0.258).
Twenty-nine of the 43 (67%) eyes responded well to the surgery and maintained the resolved state for 3 years. Fourteen (33%) eyes required additional non-surgical treatment for DME during the study period; 13 eyes required additional treatment within 1 year, and one eye received additional treatment at 32 months postoperatively. Figure 2 shows the Kaplan–Meier curve of additional treatment requirements for DME.Figure 2 The Kaplan–Meier curve for additional nonsurgical treatment requirement after vitrectomy combined with intraoperative dexamethasone implantation for non-tractional refractory diabetic macular edema. Twenty-nine of 43 (67%) eyes maintained the resolved state for 3 years, and 14 of 43 (33%) eyes required further treatment for diabetic macular edema. Ten of 43 (23%) eyes experienced temporary resolution of macular edema between 1 and 6 months postoperatively, but the macular edema recurred during the follow-up period and underwent additional treatment. Four (9%) subjects did not achieve resolution of macular edema and underwent additional treatment after 3 months postoperatively.
Table 2 presents the average annual number of non-surgical treatments performed before and after surgery. The number of intravitreal injection significantly decreased after surgery (p < 0.001), even in the subgroup analysis performed with patients who required additional treatment for more than once after surgery (p = 0.001).Table 2 Number of treatments for diabetic macular edema per year before and after vitrectomy combined with intraoperative dexamethasone implantation.
First visit to operation Operation to postoperative 3 years p value*
All subjects (43 eyes)
Overall intravitreal injection 4.99 ± 1.82 (2.0–9.0) 0.20 ± 0.48 (0.0–2.7) < 0.001
Anti-VEGF 4.42 ± 1.92 (0.0–9.0) 0.09 ± 0.43 (0.0–2.7) < 0.001
Dexamethasone 0.25 ± 0.89 (0.0–4.5) 0.10 ± 0.20 (0.0–0.7) 0.280
Triamcinolone 0.33 ± 0.87 (0.0–5.1) 0.01 ± 0.05 (0.0–0.3) 0.042
Posterior sub-tenon triamcinolone 0.14 ± 0.50 (0.0–2.8) 0.04 ± 0.11 (0.0–0.3) 0.224
Laser photocoagulation 0.29 ± 0.69 (0.0–2.8) 0.17 ± 0.34 (0.0–1.3) 0.299
Subjects who required additional treatment after surgery (14 eyes)
Overall intravitreal injection 5.12 ± 1.92 (2.0–8.3) 0.57 ± 0.68 (0.0–2.7) 0.001
Anti-VEGF 4.49 ± 2.17 (0.0–7.8) 0.26 ± 0.71 (0.0–2.7) 0.001
Dexamethasone 0.47 ± 1.40 (0.0–5.1) 0.29 ± 0.26 (0.0–0.7) 0.624
Triamcinolone 0.15 ± 0.32 (0.0–1.0) 0.02 ± 0.09 (0.0–0.3) 0.053
Posterior sub-tenon triamcinolone 0.13 ± 0.34 (0.0–1.1) 0.12 ± 0.17 (0.0–0.3) 0.880
Laser photocoagulation 0.56 ± 0.71 (0.0–2.3) 0.45 ± 0.45 (0.0–1.3) 0.654
VEGF, vascular endothelial growth factor.
Variables are described as mean ± standard deviation (range).
*p values were calculated using a generalized estimating equation accounting correlation structure for paired eyes.
Adverse events
Cases of postoperative leakage/hypotony, new retinal tears/breaks, anterior migration of the dexamethasone implant, or endophthalmitis were not observed. Seventeen (40%) eyes experienced a temporary increase in IOP (> 21 mmHg) after surgery, but the IOP normalized after using IOP-lowering eye drops. None of the subjects required filtering surgery within 3 years of vitrectomy. Of the seven eyes remaining phakic after vitrectomy, five eyes eventually underwent cataract surgery 16.4 ± 11.5 months after vitrectomy. One eye developed intraocular lens dislocation at 26 months postoperatively and underwent intraocular lens scleral fixation. No other complications were observed during the follow-up period.
Discussion
The present study elucidated that vitrectomy combined with intraoperative dexamethasone implantation can be an effective treatment for non-tractional refractory DME. The strong point of the current study is the confirmation of the long-term stability and efficacy of vitrectomy combined with intraoperative dexamethasone implantation for refractory DME. Additionally, the study also suggested that surgery may reduce the number of intravitreal injections required for managing DME.
Currently, the standard treatment method for DME is an intravitreal anti-VEGF injection or corticosteroid injection4–7. Some studies have suggested good long-term functional and anatomical outcomes of primary vitrectomy for treatment-naïve DME25, but most clinicians do not perform vitrectomy initially unless there is significant vitreomacular traction26. Anti-VEGF injections and corticosteroid injections often require frequent and continuous treatment sessions and not all patients respond successfully to the treatment27. This is a commonly encountered dilemma for ophthalmologists in clinical practice. In this situation, vitrectomy can be an alternative treatment. Several previous studies have reported the efficacy of vitrectomy for treatment-refractory DME10–12,28–30. The studies agree that vitrectomy helps reduce macular thickness in refractory DME, but improvement of visual acuity after vitrectomy has been controversial. Several long-term studies have suggested that vitrectomy for refractory DME is beneficial in both reducing CMT and improving visual acuity10–12,29–31. In contrast, in a large prospective study from the Diabetic Retinopathy Clinical Research Network (DRCR.net), vitrectomy was beneficial for reducing CMT; however, its efficacy for improving visual acuity was limited28. In addition to what has been investigated thus far, our study provides additional data on both anatomically and functionally favorable long-term results of vitrectomy combined with dexamethasone implantation for refractory DME. The more favorable visual acuity outcome of our study compared to that of DRCR.net may be attributable to the baseline characteristics of the patients28. Compared to DRCR.net, our study comprised only patients with type 2 diabetes who were significantly younger at the time of surgery and in whom the mean duration of diabetes was approximately 7 years shorter28. Additionally, all patients underwent ILM peeling and Ozurdex injection during surgery in our study, whereas only 64% underwent ILM peeling and no patient received a corticosteroid injection in DRCR.net28. Considering that ILM peeling may produce a more favorable visual outcome and the intraoperative use of corticosteroids plays a beneficial role after vitrectomy11,13,32, the difference in the detailed method of surgery (ILM peeling and intraoperative Ozurdex implant) may have produced better visual outcomes in our study than in DRCR.net.
Vitrectomy is known to treat macular edema, possibly through the following mechanisms: elimination of possible sources of traction on the macular area26, improvement of transvitreal oxygen delivery to the retina33, and removal of condensed chemical mediators that worsen the retinal vascular permeability34. In addition to vitrectomy, concurrent ILM peeling could also completely remove the source of traction and may facilitate the penetration of drugs into the retinal tissue24. In contrast, dexamethasone relieves DME in different ways. Dexamethasone blocks the production of VEGF and inflammatory mediators in the retina, inhibits macrophage and leukocyte adhesion/transmigration, and enhances the tight junctions of the blood-retinal barrier35,36. Combining these different mechanisms, vitrectomy with intraoperative dexamethasone implants is expected to produce a synergistic effect, provide more effective treatment, and yield favorable clinical outcomes.
There have been some reports regarding vitrectomy combined with intraoperative dexamethasone implantation for refractory DME. Lee et al.22 and Jung et al.24 reported the 1-year clinical outcomes in 18 eyes and 22 eyes, respectively. Both studies showed significant improvement in BCVA and CMT without ocular complications other than temporary IOP increase. Moreover, Pang et al. recently reported the 1-year outcome of vitrectomy combined with Ozurdex implantation for refractory macular edema secondary to diabetic retinopathy, retinal vein occlusion, and non-infectious posterior uveitis37. The subjects with DME in their study showed the most prominent improvement in BCVA and CMT and the longest macular edema-free period. However, the previous studies were limited by a relatively short follow-up period of 1 year or less. Therefore, they were not able to present sufficient information about the long-term efficacy, stability, and safety of vitrectomy combined with intraoperative Ozurdex implantation. Furthermore, they included both tractional and non-tractional DME in the analysis. Tractional and non-tractional DME may respond differently to vitrectomy. DME with a tractional component has better clinical outcomes than DME without a tractional component after vitrectomy26,28, and this is intuitively comprehensible. Therefore, it would have been better to report these two different entities separately. In contrast to the aforementioned studies, we were able to provide long-term clinical data and proved that BCVA and CMT of refractory DME improved after surgery and remained stable for 3 years. Furthermore, the present study did not include subjects with tractional components and verified favorable long-term clinical results even in non-tractional refractory DME. These are the strong points of our study.
In the present study, improvements in BCVA and CMT after surgery were significant throughout the follow-up period. However, although the mean BCVA gradually improved during follow-up, the mean CMT showed a temporary deterioration between 3 and 6 months postoperatively. The temporary increase of CMT a few months after surgery was also shown in previous studies22–24,37. This is consistent with the fact that the Ozurdex implant releases high concentrations of dexamethasone for approximately 2 months and subsequently releases relatively lower concentrations of dexamethasone afterward, extending the therapeutic period to 6 months38. A decrease in the dexamethasone concentration in the retina and vitreous fluid a few months after surgery may have caused a recurrence of macular edema in some patients and led to an increase in the average CMT. Subjects with recurring macular edema were treated accordingly, and the mean CMT improved thereafter and remained stable.
The proportion of subjects who required retreatment after surgery in the present study was similar to that reported in previous studies. Lee et al.22 and Jung et al.24 reported that 27% and 28% subjects, respectively, required additional treatment within 1 year. In our study, 33% subjects (14 eyes) required additional treatment during the study period. Most of the additional treatment resulting from the recurrence of macular edema after surgery occurs within 1 year after surgery. Among the 14 eyes that received additional treatment, 13 eyes required additional treatment within 12 months postoperatively, and only one eye required additional treatment at 32 months postoperatively. This means that eyes with DME that are successfully treated by vitrectomy combined with dexamethasone implantation and remain stable for a year are less likely to develop macular edema afterward. Additionally, the average number of intraocular injections also significantly decreased after surgery. Even the retreated subjects required fewer additional intraocular injections compared to the preoperative period. This may reduce the risk of ocular complications associated with frequent intraocular injections and may be more beneficial in terms of patient convenience and financial costs. Furthermore, prolonged treatment with anti-VEGF injections for DME can also increase the risk of cerebrovascular accidents and death39. Therefore, even in this anti-VEGF era, we believe that vitrectomy combined with intraoperative dexamethasone implantation could be a viable and useful option for non-tractional DME refractory to prolonged multiple injections of anti-VEGF.
Cataract formation and increase in IOP are the main concerns of both vitrectomy and intravitreal dexamethasone implantation. In our study, seven eyes were phakic after vitrectomy combined with intraoperative dexamethasone implantation. They did not undergo cataract surgery because of young age (< 50 years) at the time of vitrectomy. Five of the seven (71%) eyes later underwent cataract surgery because of the significant visual impairment caused by progression of lens opacity, and only two eyes were phakic at the end of the study period.
A temporary elevation of IOP after surgery was observed in some subjects, but it was well controlled with the use of IOP-lowering eye drops during the study period. However, a relatively large proportion of subjects (17 eyes, 40%) experienced an increase in IOP, and some of them (11 eyes, 25%) continued to use IOP-lowering eye drops until 36 months postoperatively. Additionally, one eye underwent filtering surgery for neovascular glaucoma after the study period (postoperative 47 months). Although it was reported that Ozurdex induces less IOP increase and cataract formation compared to triamcinolone40,41, they should not be taken lightly, and surgeons should take constant care of these complications.
This study has some strengths. It comprised a larger number of subjects than previous studies. To our knowledge, this is the first study reporting the long-term clinical outcomes of vitrectomy combined with intraoperative dexamethasone implantation for non-tractional refractory DME. However, this study has some limitations. First, due to the retrospective nature of this study, there could have been a bias in patient selection, and the preoperative and postoperative management for each individual was heterogeneous and not standardized. However, we believe that this reflects the real-world situation because different clinicians may have different treatment strategies for DME and that clinicians would try several different methods for refractory disease. Second, the results of the current study are limited by the lack of a control group. It would have been a more significant study if we were able to compare the efficacy of vitrectomy combined with intraoperative dexamethasone implantation with that of vitrectomy alone without intravitreal dexamethasone implantation or continued conventional treatment. Third, this study could not provide additional information on the predictors of postoperative clinical outcomes and when to switch from non-surgical treatment to surgical treatment for DME. Further studies addressing these issues may provide a better understanding of the benefits of vitrectomy combined with intraoperative dexamethasone implantation for non-tractional refractory DME.
In conclusion, vitrectomy combined with intravitreal dexamethasone implantation showed satisfactory long-term clinical outcomes in non-tractional refractory DME. This treatment may reduce the number of intraocular injections required for managing DME, thereby reducing ocular and systemic side effects and increasing patient comfort. Vitrectomy combined with intraoperative dexamethasone implantation could be an effective alternative treatment modality for non-tractional refractory DME.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author contributions
S.W.K. designed the study. S.H., K.T.K., and H.N. analyzed and interpreted the data. S.H. wrote the final paper. S.W.K. and S.J.K. reviewed the design, results, and final paper. All authors have read and approved the final manuscript.
Data availability
The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
Competing interests
The authors declare no competing interests. | Intraocular | DrugAdministrationRoute | CC BY | 33446712 | 19,233,686 | 2021-01-14 |
What was the outcome of reaction 'Lens dislocation'? | Three-year outcomes of vitrectomy combined with intraoperative dexamethasone implantation for non-tractional refractory diabetic macular edema.
This retrospective, consecutive interventional study investigated the long-term clinical outcomes of combined vitrectomy with intraoperative dexamethasone implants for non-tractional refractory diabetic macular edema (DME). The study included 43 eyes from 39 participants with DME that had continued for more than 6 months despite repeated non-surgical treatment. Postoperative changes in best-corrected visual acuity (BCVA) and central macular thickness (CMT) were evaluated over 3 years. A Kaplan-Meier curve was obtained for any additional non-surgical treatment, and the average number of non-surgical treatments required for DME before and after surgery was compared. Other postsurgical complications were also investigated. The logMAR BCVA improved from 0.526 ± 0.417 (20/67) preoperatively to 0.294 ± 0.374 (20/39) 3 years postoperatively (p < 0.001, generalized estimating equation). The CMT improved from 478 ± 122 μm preoperatively to 314 ± 90 μm 3 years postoperatively (p < 0.001, generalized estimating equation). Additional non-surgical treatment was not required for 29 (67%) eyes. The average number of annual non-surgical treatments decreased from 5.04 times preoperatively to 0.34 times postoperatively. Seventeen (40%) eyes developed temporary ocular hypertension after surgery, which normalized after antihypertensive eye drop instillation. In conclusion, vitrectomy combined with intraoperative dexamethasone implantation provides satisfactory long-term clinical outcomes for non-tractional refractory DME while reducing the number of intraocular injections for DME.
Introduction
Diabetic macular edema (DME) is a major cause of visual impairment in patients with diabetes1. It is characterized by the accumulation of fluid and/or protein within the retinal layer of the macula caused by microvascular compromise, Muller cell dysfunction, and blood-retinal barrier breakdown2. Non-surgical treatments, including macular laser photocoagulation3, intravitreal injections of either anti-vascular endothelial growth factor (VEGF) agents4,5 or corticosteroids6,7, and posterior sub-tenon injection of corticosteroids8,9, are considered the main treatment methods for DME. However, in cases where DME does not respond successfully to these non-surgical treatments, vitrectomy can be considered an alternative therapeutic approach10–12.
Conventionally, intravitreal triamcinolone has been used in combination with vitrectomy since it has proven to be effective in preventing various postsurgical complications, such as macular edema13. However, a limitation of this intervention is the increased clearance of triamcinolone in vitrectomized eyes, approximately six times faster than that in non-vitrectomized eyes14.
Ozurdex (Allergan, Irvine, CA, USA), a dexamethasone intravitreal implant, is a biodegradable device that releases dexamethasone for up to 6 months in both vitrectomized and non-vitrectomized eyes15,16. Numerous studies have reported that Ozurdex is a safe and effective management modality for DME7,17,18 and can delay the progression of diabetic retinopathy19–21. Considering the clearance issue of triamcinolone in vitrectomized eyes, Ozurdex is a good alternative for intravitreal triamcinolone in combination with vitrectomy for DME resistant to other treatments.
Previously, there have been a few studies assessing the clinical outcomes of vitrectomy combined with intraoperative dexamethasone implantation for DME22–24. However, these studies only reported short-term clinical results of up to a maximum of 1 year. Therefore, we investigated the long-term clinical outcomes of vitrectomy combined with intravitreal dexamethasone implantation for non-tractional refractory DME.
Methods
Setting
This was a retrospective interventional study of consecutive patients with non-tractional refractory DME who were treated with vitrectomy combined with intravitreal dexamethasone implantation and were followed up for at least 3 years after surgery. The study adhered to the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of Samsung Medical Center, Seoul, Republic of Korea (IRB number 2020-02-124). The board waived the requirement for informed consent owing to the retrospective design of the study.
Subjects
The electronic medical records of all consecutive patients who were diagnosed with non-tractional refractory DME with central macular thickness (CMT) greater than 300 μm at Samsung Medical Center between January 2015 and March 2017 were retrospectively reviewed. Non-tractional refractory DME was defined as biomicroscopically, angiographically, and tomographically confirmed DME that had continued for more than 6 months despite repeated non-surgical treatments (including macular laser photocoagulation, posterior sub-tenon corticosteroid injection, intravitreal corticosteroid injection, and intravitreal injection of anti-VEGF agents) in the absence of any evidence of traction force (e.g., vitreomacular traction or epiretinal membrane) on optical coherence tomography (OCT). Subjects with active proliferative diabetic retinopathy requiring surgical management, those with prior history of vitreoretinal surgery, those with evidence of any other past or concomitant retinal diseases that might affect visual acuity or macular microstructure, and those who were lost to follow-up before 3 years postoperatively were excluded from the study. Among the 52 eyes with non-tractional refractory DME that met the study inclusion criteria, 9 eyes were excluded owing to the following reasons: active vitreous hemorrhage at the time of surgery (2 eyes), history of vitreoretinal surgery (1 eye), follow-up period of less than 3 years (6 eyes). Finally, 43 eyes of 39 patients were included in the study.
Preoperative examination
All subjects underwent thorough preoperative ocular examination, including best-corrected visual acuity (BCVA) measurement using a Snellen chart, manifest refraction, applanation tonometry, slit-lamp biomicroscopy, and dilated fundus examination. Wide-field fluorescein angiography was routinely performed preoperatively to evaluate the severity of diabetic retinopathy and the extent of the non-perfusion area, and spectral domain OCT (Spectralis HRA-OCT; Heidelberg Engineering, Heidelberg, Germany) was performed to evaluate any vitreomacular interface abnormalities and measure the CMT.
Surgical technique
Standard transconjunctival sutureless pars plana vitrectomy was performed by a single surgeon (SWK) using a Constellation (Alcon Laboratories, Fort Worth, TX, USA) or Associate (Dutch Ophthalmic Research Center, Zuidland, the Netherlands) 23-gauge vitrectomy system under retrobulbar anesthesia. The internal limiting membrane (ILM) was removed with a radius of around 2-disc diameters from the fovea using intraocular forceps with the assistance of indocyanine green staining in some cases. Panretinal endolaser photocoagulation was performed concomitantly for patients with extensive retinal capillary dropout or with apparent high-risk characteristics. At the end of the operation, a dexamethasone implant was placed into the vitreous cavity through the 23-gauge vitrectomy port. Patients were advised to maintain a sitting position for a few hours to position the dexamethasone implant at the inferior periphery. Combined cataract surgery was performed in patients aged over 50 years to pretreat post-vitrectomy lens opacity.
Postoperative examination and management
Patients were routinely followed up at 1, 3, 6, 12, 24, and 36 months postoperatively in cases in which DME resolved and stabilized without further treatment. At every visit, patients underwent BCVA measurement, slit-lamp biomicroscopy, applanation tonometry, dilated fundus examination, and OCT. If macular edema did not respond to the surgery until postoperative 3 months or recurred/aggravated after resolution, non-surgical treatments were restarted and followed up according to an individual’s ocular condition. Patients who had intraocular pressure (IOP) greater than 21 mmHg were prescribed IOP-lowering eye drops, as recommended by glaucoma specialists, and managed accordingly.
Statistical analyses
We collected clinical data on BCVA, CMT, IOP, glaucoma medication usage, additional non-surgical treatment for DME after surgery, and other unexpected ocular complications from the preoperative period to 3 years after surgery. Improvement of BCVA (converted to a logarithm of the minimal angle of resolution [logMAR] scale) and CMT were assessed at postoperative 3, 6, 12, 24, and 36 months using a generalized estimating equation accounting for the correlation of paired eyes. We obtained a Kaplan–Meier curve of additional treatment requirement for DME after surgery and compared the average number of non-surgical treatments required for DME before and after surgery using a generalized estimating equation model. All statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) software version 23.0 (SPSS, Inc., Chicago, IL, USA). p values were two sided and considered statistically significant for values less than 0.05.
Results
Baseline demographics
The baseline characteristics of 43 eyes from 39 patients with non-tractional refractory DME are presented in Table 1. The mean (± standard deviation) age, number of prior injections of anti-VEGF for DME, and time period of non-surgical treatment before surgery were 57.8 ± 8.2 years, 6.25 ± 7.12, and 17.0 ± 14.2 months, respectively. Twelve eyes had a history of cataract surgery, and 24 eyes underwent cataract surgery combined with vitrectomy. Four eyes were treated with IOP-lowering medication before surgery.Table 1 Baseline demographics and clinical characteristics of subjects with diabetic macular edema refractory to prior treatments.
Variables Values
Number of patients (eyes) 39 (43)
Age, years, mean ± SD 57.8 ± 8.2
Sex, male: female 26:13
Type of DM, type 1:type 2 0:39
Duration of diabetes, years, mean ± SD 13.3 ± 8.6
Presence of hypertension, No. (%) 19/39 (48.7)
Presence of dyslipidemia, No. (%) 7/39 (17.9)
Severity of diabetic retinopathy, NPDR:PDR 11:32
Lens type, phakic:pseudophakic 31:12
Combined cataract surgery with vitrectomy, No. (%) 24/31 (77.4)
Treatment modalities used prior to the surgery
Intravitreal anti-VEGF, No. (%) 42/43 (97.7)
Number of treatment session, mean ± SD (range) 6.5 ± 7.1 (1–32)
Intravitreal dexamethasone, No. (%) 5/43 (11.6)
Number of treatment session, mean ± SD (range) 1.6 ± 0.9 (1–3)
Intravitreal triamcinolone, No. (%) 9/43 (20.9)
Number of treatment session, mean ± SD (range) 2.7 ± 2.8 (1–10)
Posterior sub-tenon triamcinolone, No. (%) 4/43 (9.3)
Number of treatment session, mean ± SD (range) 3.3 ± 4.5 (1–10)
Macular laser photocoagulation, No. (%) 9/43 (20.9)
Number of treatment session, mean ± SD (range) 1.9 ± 1.5 (1–5)
Duration of prior treatment for DME, months, mean ± SD 17.0 ± 14.2
Time between the last treatment and surgery, months, mean ± SD 2.83 ± 1.43
Preoperative BCVA, logMAR, mean ± SD 0.526 ± 0.417
Preoperative CMT, μm, mean ± SD 478 ± 122
Preoperative IOP, mmHg, mean ± SD 17.0 ± 2.8
On glaucoma medication (preoperatively), No. (%) 4/43
SD, standard deviation; DM, diabetes mellitus; NPDR, non-proliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy; DME, diabetic macular edema; VEGF, vascular endothelial growth factor; BCVA, best-corrected visual acuity; logMAR, logarithm of the minimal angle of resolution; CMT, central macular thickness; IOP, intraocular pressure.
Clinical outcomes
The logMAR BCVA was 0.526 ± 0.417 preoperatively, which gradually improved to 0.294 ± 0.374 at postoperative 3 years (p < 0.001). The CMT was 478 ± 122 μm before the surgery, which improved to 314 ± 90 μm 3 years after surgery (p < 0.001). The improvements were significant throughout the follow-up period. Figure 1 demonstrates the improvement in BCVA and CMT after surgery.Figure 1 Changes in the mean and standard deviation of the logarithm of the minimal angle of resolution (logMAR) best-corrected visual acuity (BCVA) and central macular thickness (CMT) at 3, 6, 12, 24, and 36 months after vitrectomy combined with intraoperative dexamethasone implantation for non-tractional refractory diabetic macular edema. Statistical significance was determined using a generalized estimating equation model accounting for the correlation structure of paired eyes. (A) The logMAR BCVA significantly improved postoperatively compared to the baseline during follow-up. (B) The CMT was significantly thinner postoperatively than preoperatively. The average CMT at 6 months was slightly thicker than that at 3 months, but the difference was not statistically significant (p = 0.258).
Twenty-nine of the 43 (67%) eyes responded well to the surgery and maintained the resolved state for 3 years. Fourteen (33%) eyes required additional non-surgical treatment for DME during the study period; 13 eyes required additional treatment within 1 year, and one eye received additional treatment at 32 months postoperatively. Figure 2 shows the Kaplan–Meier curve of additional treatment requirements for DME.Figure 2 The Kaplan–Meier curve for additional nonsurgical treatment requirement after vitrectomy combined with intraoperative dexamethasone implantation for non-tractional refractory diabetic macular edema. Twenty-nine of 43 (67%) eyes maintained the resolved state for 3 years, and 14 of 43 (33%) eyes required further treatment for diabetic macular edema. Ten of 43 (23%) eyes experienced temporary resolution of macular edema between 1 and 6 months postoperatively, but the macular edema recurred during the follow-up period and underwent additional treatment. Four (9%) subjects did not achieve resolution of macular edema and underwent additional treatment after 3 months postoperatively.
Table 2 presents the average annual number of non-surgical treatments performed before and after surgery. The number of intravitreal injection significantly decreased after surgery (p < 0.001), even in the subgroup analysis performed with patients who required additional treatment for more than once after surgery (p = 0.001).Table 2 Number of treatments for diabetic macular edema per year before and after vitrectomy combined with intraoperative dexamethasone implantation.
First visit to operation Operation to postoperative 3 years p value*
All subjects (43 eyes)
Overall intravitreal injection 4.99 ± 1.82 (2.0–9.0) 0.20 ± 0.48 (0.0–2.7) < 0.001
Anti-VEGF 4.42 ± 1.92 (0.0–9.0) 0.09 ± 0.43 (0.0–2.7) < 0.001
Dexamethasone 0.25 ± 0.89 (0.0–4.5) 0.10 ± 0.20 (0.0–0.7) 0.280
Triamcinolone 0.33 ± 0.87 (0.0–5.1) 0.01 ± 0.05 (0.0–0.3) 0.042
Posterior sub-tenon triamcinolone 0.14 ± 0.50 (0.0–2.8) 0.04 ± 0.11 (0.0–0.3) 0.224
Laser photocoagulation 0.29 ± 0.69 (0.0–2.8) 0.17 ± 0.34 (0.0–1.3) 0.299
Subjects who required additional treatment after surgery (14 eyes)
Overall intravitreal injection 5.12 ± 1.92 (2.0–8.3) 0.57 ± 0.68 (0.0–2.7) 0.001
Anti-VEGF 4.49 ± 2.17 (0.0–7.8) 0.26 ± 0.71 (0.0–2.7) 0.001
Dexamethasone 0.47 ± 1.40 (0.0–5.1) 0.29 ± 0.26 (0.0–0.7) 0.624
Triamcinolone 0.15 ± 0.32 (0.0–1.0) 0.02 ± 0.09 (0.0–0.3) 0.053
Posterior sub-tenon triamcinolone 0.13 ± 0.34 (0.0–1.1) 0.12 ± 0.17 (0.0–0.3) 0.880
Laser photocoagulation 0.56 ± 0.71 (0.0–2.3) 0.45 ± 0.45 (0.0–1.3) 0.654
VEGF, vascular endothelial growth factor.
Variables are described as mean ± standard deviation (range).
*p values were calculated using a generalized estimating equation accounting correlation structure for paired eyes.
Adverse events
Cases of postoperative leakage/hypotony, new retinal tears/breaks, anterior migration of the dexamethasone implant, or endophthalmitis were not observed. Seventeen (40%) eyes experienced a temporary increase in IOP (> 21 mmHg) after surgery, but the IOP normalized after using IOP-lowering eye drops. None of the subjects required filtering surgery within 3 years of vitrectomy. Of the seven eyes remaining phakic after vitrectomy, five eyes eventually underwent cataract surgery 16.4 ± 11.5 months after vitrectomy. One eye developed intraocular lens dislocation at 26 months postoperatively and underwent intraocular lens scleral fixation. No other complications were observed during the follow-up period.
Discussion
The present study elucidated that vitrectomy combined with intraoperative dexamethasone implantation can be an effective treatment for non-tractional refractory DME. The strong point of the current study is the confirmation of the long-term stability and efficacy of vitrectomy combined with intraoperative dexamethasone implantation for refractory DME. Additionally, the study also suggested that surgery may reduce the number of intravitreal injections required for managing DME.
Currently, the standard treatment method for DME is an intravitreal anti-VEGF injection or corticosteroid injection4–7. Some studies have suggested good long-term functional and anatomical outcomes of primary vitrectomy for treatment-naïve DME25, but most clinicians do not perform vitrectomy initially unless there is significant vitreomacular traction26. Anti-VEGF injections and corticosteroid injections often require frequent and continuous treatment sessions and not all patients respond successfully to the treatment27. This is a commonly encountered dilemma for ophthalmologists in clinical practice. In this situation, vitrectomy can be an alternative treatment. Several previous studies have reported the efficacy of vitrectomy for treatment-refractory DME10–12,28–30. The studies agree that vitrectomy helps reduce macular thickness in refractory DME, but improvement of visual acuity after vitrectomy has been controversial. Several long-term studies have suggested that vitrectomy for refractory DME is beneficial in both reducing CMT and improving visual acuity10–12,29–31. In contrast, in a large prospective study from the Diabetic Retinopathy Clinical Research Network (DRCR.net), vitrectomy was beneficial for reducing CMT; however, its efficacy for improving visual acuity was limited28. In addition to what has been investigated thus far, our study provides additional data on both anatomically and functionally favorable long-term results of vitrectomy combined with dexamethasone implantation for refractory DME. The more favorable visual acuity outcome of our study compared to that of DRCR.net may be attributable to the baseline characteristics of the patients28. Compared to DRCR.net, our study comprised only patients with type 2 diabetes who were significantly younger at the time of surgery and in whom the mean duration of diabetes was approximately 7 years shorter28. Additionally, all patients underwent ILM peeling and Ozurdex injection during surgery in our study, whereas only 64% underwent ILM peeling and no patient received a corticosteroid injection in DRCR.net28. Considering that ILM peeling may produce a more favorable visual outcome and the intraoperative use of corticosteroids plays a beneficial role after vitrectomy11,13,32, the difference in the detailed method of surgery (ILM peeling and intraoperative Ozurdex implant) may have produced better visual outcomes in our study than in DRCR.net.
Vitrectomy is known to treat macular edema, possibly through the following mechanisms: elimination of possible sources of traction on the macular area26, improvement of transvitreal oxygen delivery to the retina33, and removal of condensed chemical mediators that worsen the retinal vascular permeability34. In addition to vitrectomy, concurrent ILM peeling could also completely remove the source of traction and may facilitate the penetration of drugs into the retinal tissue24. In contrast, dexamethasone relieves DME in different ways. Dexamethasone blocks the production of VEGF and inflammatory mediators in the retina, inhibits macrophage and leukocyte adhesion/transmigration, and enhances the tight junctions of the blood-retinal barrier35,36. Combining these different mechanisms, vitrectomy with intraoperative dexamethasone implants is expected to produce a synergistic effect, provide more effective treatment, and yield favorable clinical outcomes.
There have been some reports regarding vitrectomy combined with intraoperative dexamethasone implantation for refractory DME. Lee et al.22 and Jung et al.24 reported the 1-year clinical outcomes in 18 eyes and 22 eyes, respectively. Both studies showed significant improvement in BCVA and CMT without ocular complications other than temporary IOP increase. Moreover, Pang et al. recently reported the 1-year outcome of vitrectomy combined with Ozurdex implantation for refractory macular edema secondary to diabetic retinopathy, retinal vein occlusion, and non-infectious posterior uveitis37. The subjects with DME in their study showed the most prominent improvement in BCVA and CMT and the longest macular edema-free period. However, the previous studies were limited by a relatively short follow-up period of 1 year or less. Therefore, they were not able to present sufficient information about the long-term efficacy, stability, and safety of vitrectomy combined with intraoperative Ozurdex implantation. Furthermore, they included both tractional and non-tractional DME in the analysis. Tractional and non-tractional DME may respond differently to vitrectomy. DME with a tractional component has better clinical outcomes than DME without a tractional component after vitrectomy26,28, and this is intuitively comprehensible. Therefore, it would have been better to report these two different entities separately. In contrast to the aforementioned studies, we were able to provide long-term clinical data and proved that BCVA and CMT of refractory DME improved after surgery and remained stable for 3 years. Furthermore, the present study did not include subjects with tractional components and verified favorable long-term clinical results even in non-tractional refractory DME. These are the strong points of our study.
In the present study, improvements in BCVA and CMT after surgery were significant throughout the follow-up period. However, although the mean BCVA gradually improved during follow-up, the mean CMT showed a temporary deterioration between 3 and 6 months postoperatively. The temporary increase of CMT a few months after surgery was also shown in previous studies22–24,37. This is consistent with the fact that the Ozurdex implant releases high concentrations of dexamethasone for approximately 2 months and subsequently releases relatively lower concentrations of dexamethasone afterward, extending the therapeutic period to 6 months38. A decrease in the dexamethasone concentration in the retina and vitreous fluid a few months after surgery may have caused a recurrence of macular edema in some patients and led to an increase in the average CMT. Subjects with recurring macular edema were treated accordingly, and the mean CMT improved thereafter and remained stable.
The proportion of subjects who required retreatment after surgery in the present study was similar to that reported in previous studies. Lee et al.22 and Jung et al.24 reported that 27% and 28% subjects, respectively, required additional treatment within 1 year. In our study, 33% subjects (14 eyes) required additional treatment during the study period. Most of the additional treatment resulting from the recurrence of macular edema after surgery occurs within 1 year after surgery. Among the 14 eyes that received additional treatment, 13 eyes required additional treatment within 12 months postoperatively, and only one eye required additional treatment at 32 months postoperatively. This means that eyes with DME that are successfully treated by vitrectomy combined with dexamethasone implantation and remain stable for a year are less likely to develop macular edema afterward. Additionally, the average number of intraocular injections also significantly decreased after surgery. Even the retreated subjects required fewer additional intraocular injections compared to the preoperative period. This may reduce the risk of ocular complications associated with frequent intraocular injections and may be more beneficial in terms of patient convenience and financial costs. Furthermore, prolonged treatment with anti-VEGF injections for DME can also increase the risk of cerebrovascular accidents and death39. Therefore, even in this anti-VEGF era, we believe that vitrectomy combined with intraoperative dexamethasone implantation could be a viable and useful option for non-tractional DME refractory to prolonged multiple injections of anti-VEGF.
Cataract formation and increase in IOP are the main concerns of both vitrectomy and intravitreal dexamethasone implantation. In our study, seven eyes were phakic after vitrectomy combined with intraoperative dexamethasone implantation. They did not undergo cataract surgery because of young age (< 50 years) at the time of vitrectomy. Five of the seven (71%) eyes later underwent cataract surgery because of the significant visual impairment caused by progression of lens opacity, and only two eyes were phakic at the end of the study period.
A temporary elevation of IOP after surgery was observed in some subjects, but it was well controlled with the use of IOP-lowering eye drops during the study period. However, a relatively large proportion of subjects (17 eyes, 40%) experienced an increase in IOP, and some of them (11 eyes, 25%) continued to use IOP-lowering eye drops until 36 months postoperatively. Additionally, one eye underwent filtering surgery for neovascular glaucoma after the study period (postoperative 47 months). Although it was reported that Ozurdex induces less IOP increase and cataract formation compared to triamcinolone40,41, they should not be taken lightly, and surgeons should take constant care of these complications.
This study has some strengths. It comprised a larger number of subjects than previous studies. To our knowledge, this is the first study reporting the long-term clinical outcomes of vitrectomy combined with intraoperative dexamethasone implantation for non-tractional refractory DME. However, this study has some limitations. First, due to the retrospective nature of this study, there could have been a bias in patient selection, and the preoperative and postoperative management for each individual was heterogeneous and not standardized. However, we believe that this reflects the real-world situation because different clinicians may have different treatment strategies for DME and that clinicians would try several different methods for refractory disease. Second, the results of the current study are limited by the lack of a control group. It would have been a more significant study if we were able to compare the efficacy of vitrectomy combined with intraoperative dexamethasone implantation with that of vitrectomy alone without intravitreal dexamethasone implantation or continued conventional treatment. Third, this study could not provide additional information on the predictors of postoperative clinical outcomes and when to switch from non-surgical treatment to surgical treatment for DME. Further studies addressing these issues may provide a better understanding of the benefits of vitrectomy combined with intraoperative dexamethasone implantation for non-tractional refractory DME.
In conclusion, vitrectomy combined with intravitreal dexamethasone implantation showed satisfactory long-term clinical outcomes in non-tractional refractory DME. This treatment may reduce the number of intraocular injections required for managing DME, thereby reducing ocular and systemic side effects and increasing patient comfort. Vitrectomy combined with intraoperative dexamethasone implantation could be an effective alternative treatment modality for non-tractional refractory DME.
Publisher's note
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Author contributions
S.W.K. designed the study. S.H., K.T.K., and H.N. analyzed and interpreted the data. S.H. wrote the final paper. S.W.K. and S.J.K. reviewed the design, results, and final paper. All authors have read and approved the final manuscript.
Data availability
The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
Competing interests
The authors declare no competing interests. | Recovered | ReactionOutcome | CC BY | 33446712 | 19,233,686 | 2021-01-14 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ventricular tachycardia'. | Evaluation of Index of Cardio-Electrophysiological Balance in Patients With Atrial Fibrillation on Antiarrhythmic-Drug Therapy.
Index of cardio-electrophysiological balance (iCEB) has been described as a novel risk marker for predicting malignant ventricular arrhythmia. There remains limited evidence on the effects of amiodarone and propafenone used for sinus rhythm maintenance on iCEB in patients with atrial fibrillation (AF). The aim of this study was to evaluate iCEB in patients with AF on antiarrhythmic-drug therapy.
A total of 108 patients with AF (68 patients using amiodarone and 40 patients using propafenone) and 50 healthy subjects were included in the study. All groups underwent a standard 12-lead surface electrocardiogram. QRS duration, QT, T wave peak-to-end (Tp-e) intervals, iCEB (QT/QRS) and iCEBc (heart rate-corrected QT (QTc)/QRS) rates were calculated from the electrocardiogram and compared between groups.
QT, Tp-e intervals and Tp-e/QT ratio were significantly longer in the amiodarone group than the propafenone and control groups (P < 0.001, for all). iCEB was similar in the amiodarone and control groups (4.4 ± 0.6 and 4.2 ± 0.4; P > 0.05), while iCEB values in the propafenone group were significantly lower than the amiodarone group and control groups (3.9 ± 0.5; P < 0.001). There was a significantly difference in iCEBc values among the amiodarone, control and propafenone groups (4.8 ± 0.6, 4.6 ± 0.4 and 4.3 ± 0.6; P < 0.001, respectively).
In this study, higher iCEBc parameters were observed in patients using amiodarone, while iCEBc values were lowest among patients with AF using propafenone. Further studies are needed to determine whether these electrophysiological changes are associated with ventricular arrhythmias for patients with AF on antiarrhythmic-drug therapy.
Introduction
Atrial fibrillation (AF) is the most common heart rhythm disorder in clinical practice and is a significant risk factor for stroke and heart failure [1]. The prevalence of AF in the general population is 1-2%, and its incidence and prevalence increase with age. In older adults aged 65 years and older, the prevalence of AF increases to over 10% [2]. In AF treatment, the goal is to reduce cardiovascular mortality and morbidity. The two basic principles of AF treatment are preventing thromboembolic events and ensuring rhythm control or controlling the ventricular rate [3]. The use of antiarrhythmic drugs (AADs) or catheter ablation is often required to maintain sinus rhythm in patients with recurrent paroxysmal AF and in patients with persistent AF to maintain sinus rhythm following cardioversion. The primary concerns associated with the use of AADs are proarrhythmia and consequent ventricular tachyarrhythmia as well as bradycardia [3]. Regular 12-lead electrocardiogram (ECG) monitoring is required to assess the risk for proarrhythmia in patients taking AADs. Current guidelines recommend careful evaluation of the heart rhythm, heart rate, QRS duration, QT interval (i.e., the period of ventricular depolarization and repolarization) and QTc interval (i.e., QT interval corrected for heart rate) in ECG [4]. Despite their poor predictive value, QT interval and QRS duration are widely used in the clinical practice to assess the risk for drug-induced ventricular arrhythmia and sudden cardiac death (SCD).
Many ECG parameters have been developed in an effort to predict ventricular arrhythmias. One example is transmural dispersion of repolarization (TDR), which is measured using the T wave peak-to-end (Tp-e) interval and Tp-e/QT ratio. TDR is a potential marker for ventricular arrhythmias and SCD in patients with acquired long QT syndrome, congenital long QT syndrome, Brugada syndrome, acute myocardial infarction and heart failure [5-7]. Recently, the index of the cardio-electrophysiological balance (iCEB), which is calculated as QT interval divided by QRS duration (QT/QRS), was identified as a potential marker for predicting drug-induced ventricular arrhythmias in an animal model [8]. iCEB is equivalent to the cardiac wavelength λ, which plays an important role in ventricular arrhythmias and is measured via invasive electrophysiology (EP). Previous studies have suggested that iCEB may offer a non-invasive and readily measurable marker to detect increased arrhythmic risk in patients [9]. To date, there remains limited evidence on the effects of amiodarone and propafenone used for sinus rhythm maintenance on iCEB in patients with AF. This study assessed the iCEB and TDR values in AF patients on amiodarone and propafenone therapy.
Materials and Methods
Study population
The study included patients who attended the cardiology outpatient clinic of two different centers between January 2019 and December 2019. Eligible patients included those who were using propafenone (150 mg three times daily) or amiodarone (200 mg once a day) for paroxysmal or persistent AF with sinus rhythm detected in ECG. The control group included healthy individuals with sinus rhythm assessed using ECGs. Volunteers were recruited from hospital staffs. The healthy controls who had diagnosed cardiac or other organic disease, or who were using medications, were excluded.
Paroxysmal AF was defined as AF that developed suddenly and ended spontaneously within 7 days, whereas persistent AF was defined as AF with medicated or electrical cardioversion lasting more than 7 days [10]. Hypertension (HT) was defined as blood pressure ≥ 140/90 mm Hg or receiving antihypertensive treatment. Diabetes mellitus (DM) was defined as fasting blood glucose level ≥ 126 mg/dL or known DM diagnosis. Coronary artery disease (CAD) was defined as the presence of an angiographic lesion occupying ≥ 50% of the coronary artery, a history of coronary bypass surgery, or percutaneous coronary intervention. Stroke was diagnosed on the identification of ischemia or bleeding in the brain through clinical assessments and imaging methods in patients presenting with neurological dysfunction whose symptoms lasted more than 24 h. Transient ischemic attack was defined as temporary neurological dysfunction that lasted less than 24 h, which caused symptoms but did not result in death or disability [11]. Vascular disease diagnoses included CAD, peripheral artery disease, or aortic plaque. The CHA2DS2-VASc (congestive heart failure/left ventricular dysfunction, HT, aged ≥ 75 years, DM, stroke/transient ischemic attack/systemic embolism, vascular disease, aged 65 - 74 years, sex category) scores of patients were recorded [4].
We excluded patients with the following cardiac conditions: permanent AF, long-standing persistent AF, atrial flutter, previous AF ablation, acute decompensated heart failure and hereditary long QT syndrome. Also excluded were patients who were using medications that could affect the QRS, QT and Tp-e interval, including antibiotics, tricyclic antidepressants, antihistamines, or antipsychotics; patients with implantable cardioverter-defibrillators; those with previously known branch block and atrioventricular nodal block; and those with negative and/or biphasic T wave on their ECGs. Non-cardiac exclusion criteria were the presence of any severe non-cardiac illness limiting life expectancy, pregnancy, breast-feeding, a calculated glomerular filtration rate of < 60 mL/min at baseline, patients with liver failure and patients with thyroid gland disease. Patients who developed liver and/or thyroid disease due to amiodarone use were included in the study. The study methodology complied with the Declaration of Helsinki and the study protocol was approved by the Institutional Ethics Committee of Adiyaman University (26/06/2019, 2019/5-12).
ECG and echocardiographic examination
All participants underwent a 12-lead ECG (CardioFax S; Nihon Kohden, Tokyo, Japan) while at rest in the supine position. The ECG was set to the paper speed of 50 mm/s and calibrated such that 10 mm equals 1 mV. During the ECG recordings, all of the participants were in sinus rhythm. Resting heart rate was measured using the ECG data. ECG measurements of QRS duration, QT intervals and Tp-e intervals were manually calculated by two cardiologists who were blinded to patient data using calipers and a magnifying glass to decrease measurement errors. The measurements were performed on lead II and lead V5, and the longest QT interval and QRS complex duration were used for the analyses. The QT interval was measured from the beginning of the QRS complex to the end of the T wave, and the QT interval was corrected for heart rate using the Bazett formula: QTc = QT√(R-R interval). Using these measurements, Tp-e/QT, Tp-e/QTc, QT/QRS (iCEB) and QTc/QRS (iCEBc) ratios were calculated. The interobserver and intraobserver variation coefficients were 2.3% and 2.4%, respectively.
All echocardiographic examinations were performed using a Vivid 5 Pro device (General Electric, Horten, Norway) with a 2.5 MHz transducer. The measurements were performed in the left lateral decubitus position as recommended by the current American Society of Echocardiography guidelines [12], and three consecutive cycles were averaged for each parameter. Ejection fraction (EF) was calculated using the modified Simpson method. Left ventricular systolic dysfunction was defined as a left ventricular EF of < 50%. Left atrium (LA) anteroposterior diameter, diastolic interventricular septum (IVS) thickness and diastolic posterior wall thickness (PWT) were measured from parasternal long-axis views using M-mode.
Laboratory findings were collected from the hospital database. Following a 12 h fasting period, blood samples were collected for complete blood count analyses. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine, potassium and calcium levels were analyzed using the Architect c8000 Chemistry System (Abbott Diagnostics, USA) commercial kits. Thyroid-stimulating hormone (TSH) was measured using the UniCel DxI 800 Access Immunoassay System (Beckman Coulter, USA).
Statistical analyses
Continuous variables are reported as means ± standard deviations or medians. Categorical variables are expressed as counts and percentages. Kolmogorov-Smirnov tests and histograms were used to test for normality and to assess the distribution of the numerical variables, respectively. Demographic and clinical features, including ECG and echocardiography parameters, comorbidities, medications, risk scores and laboratory parameters, were compared between groups. One-way analysis of variance (ANOVA) and Kruskal-Wallis tests were used for intergroup comparisons when variables were normally and non-normally distributed, respectively. Intergroup differences were evaluated using parametric and non-parametric tests including the Tukey test and the Dwass-Steel-Critchlow-Fligner test, respectively. Differences in categorical variables were assessed using the Pearson Chi-square, Fisher exact, or Fisher-Freeman-Halton tests, depending on the sample size. The analyses compared patients with and without AF. For variables that showed a normal distribution, independent samples t-tests were used, whereas Mann-Whitney U tests were used to compare variables with non-normally distributed data. For categorical variables, the Pearson Chi-square and Fisher exact tests were used. All statistical analyses were performed using the Jamovi (Version 1.0.7) and JASP (Version 0.11.1) software programs. P values ≤ 0.05 were considered statistically significant.
Results
A total of 173 patients were eligible for study inclusion. Patients with unanalyzable ECG (n = 6) were excluded. In addition, patients who were taking sotalol (n = 9) were excluded due to their small sample size. After exclusions, 158 participants were included in the study. Demographic characteristics, comorbid conditions and laboratory parameters are shown in Table 1. The study groups included patients with persistent AF (n = 17), patients with paroxysmal AF (n = 91) and healthy individuals without AF (n = 50). Among the patients with AF, 68 (63%) were using amiodarone treatment and 40 (37%) were using propafenone treatment at baseline. There were no differences between the groups in terms of age and sex (P > 0.05). The amiodarone treatment group included 57 (83.8%) patients with paroxysmal AF and 11 (16.2%) with persistent AF, whereas the propafenone treatment group included 34 (85.0%) with paroxysmal AF and six (15.0%) with persistent AF. More than half (51.5%) of the patients in the amiodarone group had heart failure compared to only 2.5% in the propafenone group. The prevalence of CAD and stroke were significantly higher in patients using amiodarone compared to those using propafenone (both P < 0.05).
Table 1 Demographic Features, Comorbidities, Drug Use and Some Laboratory Parameters of the Amiodarone, Propafenone and Control Groups
Amiodarone (n = 68) Propafenone (n = 40) Control (n = 50) P value
Sex (%)
Female, n (%) 30 (44.1) 21 (52.5) 26 (52.0) 0.600a
Male, n (%) 38 (55.9) 19 (47.5) 24 (48.0)
Age (years) 65.3 ± 7.3 62.9 ± 5.5 62.7 ± 4.4 0.051b
Smoking (%) 16 (23.5) 6 (15.0) 8 (16.0) 0.445a
Duration of drug use (median (IQR)) 20.5 (16.0 - 29.0) 19.0 (13.8 - 23.0) - 0.034c
Type of atrial fibrillation
Paroxysmal 57 (83.8) 34 (85) - 0.087a
Persistent 11 (16.2) 6 (15) - 0.088a
Comorbidities
Heart failure (%)
Ischemic heart failure 25 (36.8) 0 (0.0) - < 0.001a
Non-ischemic heart failure 10 (14.7) 1 (2.5) - 0.043a
Hypertension (%) 48 (70.6) 20 (50.0) - 0.053a
Coronary artery disease (%) 38 (55.9) 8 (20.0) - 0.001a
Stroke (%) 12 (17.6) 1 (2.5) - 0.029a
Diabetes mellitus (%) 23 (33.8) 15 (37.5) - 0.859a
Concurrent medication use
Beta-blocker (%) 55 (80.9) 37 (92.5) - 0.174a
Calcium channel blocker (%) 7 (10.3) 3 (7.5) - 0.742a
ACE inhibitor/ARB (%) 59 (86.8) 22 (55.0) - 0.001a
Spironolactone (%) 13 (19.1) 0 (0.0) - 0.002a
NOAC (%) 30 (44.1) 16 (40) - 0.676a
Warfarin (%) 14 (20) 5 (12) - 0.286a
Aspirin (%) 20 (29) 9 (22.0) - 0.434a
Clopidogrel (%) 6 (8.8) 2 (5) - 0.707a
Laboratory parameters
Serum calcium (mg/dL) 9.5 ± 0.6 9.8 ± 0.5 9.7 ± 0.5 0.158b
Serum potassium (mEq/L) 4.2 ± 0.3 4.2 ± 0.3 4.2 ± 0.3 0.783b
Aspartate aminotransferase (U/L) 22.2 ± 5.3 24.7 ± 5.8 23.9 ± 6.6 0.068b
Alanine aminotransferase (U/L) 23.3 ± 6.2 25.0 ± 5.9 24.0 ± 7.2 0.374b
TSH (µU/mL) (median (IQR)) 2.4 (1.6 - 3.5) 2.5 (1.9 - 3.5) 2.3 (1.7 - 3.1) 0.493
Risk score
CHA2DS2-VASc score (median (IQR)) 3.0 (2.8 - 4.0) 2.0 (1.0 - 3.0) - < 0.001c
aDepending on the expected count, Pearson Chi-square, Fisher exact or Fisher-Freeman-Halton test was used. Descriptive statistics were presented as number (%). bOne-way ANOVA was used. Descriptive statistics were presented as mean ± standard deviation. cMann-Whitney U test was used. Descriptive statistics were presented as median (IQR). ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker; NOAC: new oral anticoagulants; TSH: thyroid-stimulating hormone; IQR: interquartile range.
Echocardiographic measurements, CHA2DS2-VASc scores and ECG parameters
Echocardiographic measurements, CHA2DS2-VASc scores and ECG parameters are shown in Table 2. The amiodarone group had a significantly lower median left ventricular EF (LVEF) and higher LA diameter compared to the propafenone group. The median CHA2DS2-VASc score of the amiodarone group was significantly higher than that of the propafenone group (P < 0.001). There were no significant differences in IVS thickness and PWT between the amiodarone and propafenone groups; however, the IVS thickness and PWT values were significantly higher in both treatment groups than in the control group (P < 0.001).
Table 2 Echocardiographic and Electrocardiographic Parameters of Amiodarone, Propafenone and Control Groups
Amiodarone (n = 68) Propafenone (n = 40) Control (n = 50) P value
Echocardiographic parameters
Heart rate (beat per minute) 72.1 ± 10.8 73.0 ± 11.4 75.8 ± 13.3 0.278
QRS (ms) 94.8 ± 13.0a 100.5 ± 13.2b 90.7 ± 6.7a < 0.001
QT interval (ms) 412.1 ± 37.0a 384.1 ± 30.7b 377.5 ± 26.8b < 0.001
QTc interval (ms) 450.1 ± 27.5a 421.8 ± 25.3b 412.1 ± 23.6b < 0.001
Tp-e interval (ms) 85.2 ± 18.9a 69.9 ± 10.3b 66.5 ± 10.6b < 0.001
Tp-e/QT ratio 0.20 (0.18 - 0.22)a 0.18 (0.16 - 0.20)b 0.17 (0.15 - 0.20)b < 0.001
cTp-e interval (ms) 93.8 ± 20.3a 78.6 ± 13.7b 75.1 ± 11.8b < 0.001
Tp-e/QTc ratio 0.18 (0.16 - 0.20)a 0.16 (0.15 - 0.19)b 0.16 (0.14 - 0.18)b < 0.001
iCEB 4.4 ± 0.6a 3.9 ± 0.5b 4.2 ± 0.4a < 0.001
iCEBc 4.8 ± 0.6a 4.3 ± 0.6b 4.6 ± 0.4c < 0.001
Echocardiography parameters
LVEF (median (IQR)) (%) 50.0 (35.0 - 55.0)a 55.0 (53.0 - 55.0)b 56.0 (55.0 - 60.0)b < 0.001
LA diameter (cm) 4.6 ± 0.6a 4.0 ± 0.3b 3.7 ± 0.3c < 0.001
IVS thickness (mm) 11.7 ± 1.1a 11.0 ± 0.8a 10.1 ± 1.0b < 0.001
PW thickness (mm) 10.6 ± 1.1a 10.1 ± 1.0a 9.0 ± 1.0b < 0.001
Advers events
TdP (%) 1 (1.5) 0 (0.0) - 0.999*
Non-sustained VT (%) 0 (0.0) 1 (2.5) - 0.370*
*Depending on the expected count, Pearson Chi-square, Fisher exact or Fisher-Freeman-Halton test was used. Descriptive statistics were presented as number (%). Multiple comparisons were marked with superscript letters in the table. As same letters notify no significant difference between the groups, different letters mean a significant difference between the groups. Tp-e: T wave peak-to-end; iCEB: index of cardio-electrophysiological balance; iCEBc: corrected iCEB; LVEF: left ventricular ejection fraction; LA: left atrial; IVS: interventricular septum; PW: posterior wall; VT: ventricular tachycardia; TdP: torsades de pointes; Tp-e: transmural dispersion of repolarisation; cTp-e: corrected Tp-e.
QT, QTc, Tp-e and cTp-e intervals were significantly increased in the amiodarone group compared to the propafenone and control groups (all P < 0.001) (Fig. 1). The intervals were similar among the propafenone and control groups (Table 2). Moreover, QRS duration was higher in the propafenone group compared to the amiodarone and control groups (P < 0.001).
Figure 1 Tp-e and cTp-e intervals in drug and control groups. Tp-e: T wave peak-to-end; cTp-e: corrected Tp-e.
The Tp-e/QT ratio was increased in patients with AF using amiodarone compared to the propafenone and control groups. It was similar between the propafenone and control groups. The findings were similar when Tp-e/QT ratio was corrected for heart rate (Fig. 2). One (1.5%) patient using amiodarone presented with torsades de pointes (TdP), while one (2.5%) patient using propafenone presented with ventricular tachycardia (VT) (Table 2).
Figure 2 Tp-e/QT and Tp-e/QTc rates in drug and control groups. Tp-e: T wave peak-to-end; Tp-e/QTc: corrected Tp-e/QT.
iCEB was similar among the amiodarone and control groups (4.4 ± 0.6 and 4.2 ± 0.4, respectively; P > 0.05) but was significantly lower in the propafenone group than in the amiodarone and control groups (4.4 ± 0.6, 4.2 ± 0.4 and 3.9 ± 0.5; P < 0.001). There was a significant difference in iCEBc values between amiodarone, control and propafenone groups (4.8 ± 0.6, 4.6 ± 0.4 and 4.3 ± 0.6, respectively; P < 0.001), with the amiodarone group having the highest value and the propafenone group having the lowest (Fig. 3).
Figure 3 iCEB and iCEBc values in drug and control groups. iCEB: index of cardio-electrophysiological balance; iCEBc: corrected iCEB.
The median Tp-e interval and Tp-e/QT ratio were higher in patients with AF (n = 108) than in controls (P < 0.001 and P = 0.001, respectively). However, there were no differences in iCEB and iCEBc values between patients with AF and the healthy controls (P = 0.74 and P = 0.60, respectively) (Table 3).
Table 3 Demographic Features, Electrocardiographic and Echocardiographic Parameters of the Whole Atrial Fibrillation and Control Subjects
Atrial fibrillation (n = 108) Control (n = 50) P value
Sex (%) 0.698
Female, n (%) 51 (47.2) 26 (52.0)
Male, n (%) 57 (52.8) 24 (48.0)
Age (years) 64.4 ± 6.7 62.7 ± 4.4 0.112
Smoking (%) 22 (20.4) 8 (16.0) 0.515
Electrocardiographic parameters
Heart rate (beats per minute) 72.4 ± 10.9 75.8 ± 13.3 0.121
QRS (ms) 96.9 ± 13.3 90.7 ± 6.7 < 0.001
QT interval (ms) 401.7 ± 37.2 377.5 ± 26.8 < 0.001
QTc interval (ms) 439.6 ± 29.9 412.1 ± 23.6 < 0.001
Tp-e interval (ms) 79.5 ± 17.8 66.5 ± 10.6 < 0.001
cTp-e interval (ms) 88.2 ± 19.5 75.1 ± 11.8 < 0.001
Tp-e/QT ratio 0.20 (0.17 - 0.22) 0.17 (0.15 - 0.20) 0.001
Tp-e/QTc ratio 0.18 (0.15 - 0.19) 0.16 (0.14 - 0.18) 0.001
iCEB 4.2 ± 0.6 4.2 ± 0.4 0.740
iCEBc 4.6 ± 0.7 4.6 ± 0.4 0.602
Echocardiography parameters
LVEF (median (IQR)) (%) 54.0 (44.5 - 55.0) 56.0 (55.0 - 60.0) < 0.001
LA diameter (cm) 4.4 ± 0.6 3.7 ± 0.3 < 0.001
iCEB: index of cardio-electrophysiological balance; iCEBc: corrected iCEB; LVEF: left ventricular ejection fraction; LA: left atrial; Tp-e: T wave peak-to-end; cTp-e: corrected Tp-e.
Discussion
The study included patients with persistent and paroxysmal AF and who were taking amiodarone or propafenone therapy. To assess the effects of amiodarone and propafenone treatment on ECG parameters, resting ECGs were obtained and compared inter se and with healthy controls. Significant prolongation of TRD markers such as Tp-e interval, cTp-e interval, Tp-e/QT and cTp-e/QT ratios was observed in patients using amiodarone, compared to those in the propafenone and control groups. Among patients taking amiodarone, the iCEBc values were significantly higher than those in the propafenone and control groups. iCEB and iCEBc values were significantly lower in the propafenone group than in the amiodarone and control groups. To our knowledge, the present study is the first in the literature that evaluates the iCEB and iCEBc in patients with AF using amiodarone or propafenone for the maintenance of sinus rhythm.
In several large-scale and randomized studies, rhythm control and rate control strategies have been evaluated in patients with AF [13-15]. These studies have found no differences in the stroke or mortality outcomes between the two strategies. Moreover, the two strategies have shown similar results in terms of quality of life and heart failure-related hospitalizations. Although sinus rhythm is the natural heart rhythm, in these studies, no significant benefit was observed among patients who underwent a rhythm control strategy. This finding may be attributed to failing to maintain the sinus rhythm in patients after cardioversion. In addition, AADs can cause adverse cardiac and extracardiac effects, thus close clinical follow-up is recommended to monitor the risk for proarrhythmia.
In clinical practice, Na+ channel blockers (class IC) such as flecainide and propafenone, and K+ channel blockers (class III) such as amiodarone, dronedarone, dofetilide and sotalol are often used as part of a rhythm control strategy in patients with AF. A recent European survey found that beta-blockers, propafenone, flecainide and amiodarone were most often used as first-line AADs for the prevention of AF in several patient groups [16]. Amiodarone is a broad-spectrum antiarrhythmic medication that acts on K+ ion channels throughout the heart. The medication acts on the rapidly delayed rectifier potassium current (IKr), thereby delaying repolarization. Accordingly, action potential and refractory period are elongated, which results in an increased QT interval and slightly increased QRS duration in ECGs. As a class IC antiarrhythmic agent, propafenone blocks the fast Na+ channels in Purkinje fibers and ventricular myocardium. Moreover, it has been shown to slightly block the IKr and beta-adrenergic receptors. As a result, propafenone increases the QRS duration without affecting the QT interval in ECGs [17].
All AADs used to maintain sinus rhythm have the potential to induce proarrhythmia, including monomorphic VT, TdP, or ventricular fibrillation (VF). Several strategies are used to identify the risk for proarrhythmia [18]. For class III agents, if the QTc interval is > 500 ms or if the patient experiences an increase in the QTc interval of > 60 ms after medication administration, discontinuation of the drug is recommended. For class IC drugs, when patients experience an increase of 25% in QRS interval from baseline, there is an increased risk for malignant ventricular arrhythmia, and medication discontinuation is recommended [19, 20]. Nevertheless, risk stratification for SCD from drug-induced proarrhythmia remains challenging. In the majority of drug-induced TdP cases, the QT interval was observed to be > 500 ms. However, the predictive value of the QT interval in predicting the TdP risk is low [21]. Amiodarone is the most effective AAD for rhythm control according to several clinical studies. Although it offers the lowest risk for causing TdP among class III agents, its extracardiac adverse effects limit its long-term use [18]. Several drugs that block the INa current have shown a propensity to induce proarrhythmia [22, 23]. In general, propafenone use can result in non-TdP-mediated ventricular arrhythmias, whereas amiodarone use can cause TdP-associated malignant ventricular arrhythmias [17]. In cases with amiodarone-induced TdP, hypokalemia or hypomagnesemia usually accompanies.
T waves show ventricular repolarization in ECGs. Given the limited sensitivity of QT dispersion (QTmax - QTmin), the Tp-e interval, Tp-e/QT and Tp-e/QTc ratio have been explored as novel parameters for assessing ventricular repolarization dispersion. Yamaguchi et al [5] demonstrated that the Tp-e interval was a better predictor of TdP than QT dispersion and QTc interval in patients with drug-induced long QT syndrome. Moreover, Liu et al [24] showed that increased QT intervals and Tp-e/QT ratios were associated with drug-induced TdP. In our study, the Tp-e interval, cTp-e interval, Tp-e/QT and Tp-e/QTc ratio parameters were observed to be higher in the amiodarone group than in the propafenone and control groups. These findings may be attributed to the effects of amiodarone on the repolarization phase. No difference was observed in the Tp-e interval, cTp-e interval, Tp-e/QT and Tp-e/QTc ratio parameters between the propafenone and control groups. This indicates that transmural dispersion of the T wave and variation in the QT interval encompass changes in the repolarization of the action potential. Therefore, these ECG markers may not be adequate to detect all types of drug-induced cardiac arrhythmias [8]. The 2016 AF guidelines published by the European Heart Association state that safety should be prioritized in patients requiring prolonged use of AADs [4]. Moreover, some AADs, such as propafenone, which do not prolong the QT interval, can still increase the risk for proarrhythmia [25]. Therefore, new parameters that do not depend solely on the QT interval are needed to help identify the risk for malignant ventricular arrhythmias.
The iCEB is a non-invasive parameter for assessing the risk for drug-induced ventricular proarrhythmia. It accounts for the repolarization and depolarization phases of the action potential and can help identify repolarization dispersion and conduction velocity abnormalities, which are important markers in the pathogenesis of arrhythmia. Several studies have demonstrated the relationship between the cardiac wavelength λ (λ = effective refractory period (ERP) × conduction velocity) and malignant ventricular arrhythmias. Aidonidis et al [26] used the cardiac wavelength λ as a parameter to study ventricular reentrant tachycardia and AF in an animal model. Another animal study demonstrated that QT interval was associated with ERP and that changes in QRS duration coincided with changes in conduction velocity [8]. More recently, Robyns et al [9] showed that the ERP measured invasively during electrophysiological study correlated with the QT interval. The study reported that iCEB (QT/QRS) and cardiac wavelength λ ((ERP) × conduction velocity) are equal, as each assess the repolarization and depolarization of the action potentials.
Previous studies have suggested that changes in iCEB values may predict an increased susceptibility to malignant ventricular arrhythmias. Lu et al [8] showed that the administration of dofetilide, an IKr blocker, resulted in increased QT, Tp-e intervals and iCEB, causing TdP in rabbit ventricular wedge samples. In addition, the study showed that encainide, an INA blocker, had no effect on QT and Tp-e intervals, reduced the iCEB values and resulted in non-TdP-like VT. Given these findings, the authors suggested that iCEB may be a better biomarker that Tp-e and QT intervals for identifying the risk for drug-induced non-TdP, such as ventricular arrhythmia. Robyns et al [9] showed that sotalol administration increases iCEB, whereas flecainide usage decreases iCEB in patients with paroxysmal supraventricular arrhythmias. Additionally, the authors compared iCEB values of 70 genotype positive congenital long QT syndrome (LQTS) patients, 57 genotype positive brugada syndrome (BrS) patients and 65 genotype negative family members in the same study. Their data showed that iCEB and iCEBc are significantly increased in LQTS and significantly reduced in BrS versus genotype negative family members. They attributed the higher iCEB to QT prolongation in LQTS patients. The probable reason for this is that class III agents increase phase 3 of the action potential and ERP by blocking IKr [18]. Furthermore, QT interval is prolonged either due to loss of function of the slow (IKs) or the rapid (IKr) in LQTS [27]. The possible mechanism of reduction of iCEB (QT/QRS) in treatment with class IC drugs is due to the blockage of fast Na+ channels. The mechanism of reduction of iCEB in BrS, which causes a loss of function of the cardiac sodium channel, is reduced sodium current. Accordingly, upstroke velocity of phase 0 of the action potential decreases [28]. This is seen as an increase in QRS duration on the surface ECG [9].
In this study, Tp-e and iCEBc values were highest in the amiodarone group and both iCEB and iCEBc values were the lowest in the propafenone group. In addition, the iCEBc value of the patient who presented with TdP was 5.2, while the iCEBc value of the patient who presented with non-TdP mediated VT was 3.58. Further studies are needed to determine whether these electrophysiological changes are associated with ventricular arrhythmias. In addition, iCEB values in patients using amiodarone were similar to those in health controls. Because amiodarone is a multiple ion-channel blocker, the QT/QRS ratio may be unaffected as it prolongs both the QT interval and QRS duration. Given that iCEB is equal to cardiac wavelength (λ), iCEB may be used as an indicator for malign arrhythmias. While AADs that prolong the QT interval cause increased iCEB and iCEBc durations, AADs that prolong the QRS duration result in decreased iCEB and iCEBc durations. Therefore, iCEBc prolongation and shortening may be an indicator for increased risk for malign arrhythmias.
Study limitations
This study had several limitations. First, a relatively small sample size was used and only patients receiving amiodarone and propafenone were included. Second, the cross-sectional design precluded our ability to assess causality. Patients were not followed longitudinally to assess the onset clinical events such as malignant ventricular arrhythmia and SCD. Third, ECGs were performed in patients in the cardiology outpatient clinic to assess the potential risk for cardiac arrhythmia; however, 24 h Holter monitoring may have been more appropriate for drug-related arrhythmia screening. Moreover, comorbidity and heart failure were more common in the amiodarone group. QRS duration, QT and Tp-e intervals may change due to left ventricular remodeling in heart failure as well as comorbidity. These confounding factors limited the evaluation of the pure effect of amiodarone. Finally, the validity of the observed iCEB values was not assessed given the invasive nature of the cardiac wavelength λ measurement.
Conclusions
To the best of our knowledge, this was the first study to investigate iCEB and iCEBc parameters in patients with AF. In this study, higher cTp-e intervals, Tp-e/QTc ratios and iCEBc parameters were observed in patients using amiodarone, while iCEB and iCEBc values were lowest among patients with AF using propafenone. Because iCEB and iCEBc represent the balance between the depolarization and repolarization of the cardiac action potential, these parameters may serve as a non-invasive, simple, and novel biomarker for detecting increased proarrhythmia risk in patients with AF on antiarrhythmic-drug therapy. Further studies are needed to determine whether these electrophysiological changes are associated with ventricular arrhythmias for patients with AF on antiarrhythmic-drug therapy.
None to declare.
Financial Disclosure
This study received no grant funding from any agency in the public, commercial or not-for-profit sectors.
Conflict of Interest
The authors declare that they have no conflict of interest.
Informed Consent
A signed informed written consent form was obtained from all participants.
Author Contributions
AA, RA and AS performed the research and analysed data. MK, RA, AA, EA and AS provided clinical data. AA, RA and MK wrote the paper and all authors critically reviewed and edited the paper. All authors read and approved the manuscript.
Data Availability
The data used to support the findings of this study are available from the corresponding author upon request. | PROPAFENONE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33447324 | 19,125,121 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abscess'. | Mycobacterium Mucogenicum Bacteremia and Nodular Soft Tissue Infection in a Person Who Uses Tap Water to Inject Drugs.
The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. In this study, we report a case of Mycobacterium mucogenicum bacteremia and associated nodular soft tissue infection in a person who uses tap water to inject drugs.
CASE
A 50-year-old female presented to a community hospital with a 24-hour history of fever and a right forearm abscess at the site of drug injection. The forearm abscess was incised and drained, and a sample was obtained for bacterial culture. Two peripheral blood cultures were collected before treatment with meropenem. The patient’s forearms demonstrated subcutaneous nodules that she maintained had increased in size slowly during the 2 years preceding her current hospital presentation.
The patient has psychiatric illness, of which intergenerational trauma is a probable factor [1, 2]; her parents attended Canada’s Indian Residential School system. She had been diagnosed with bipolar disorder, borderline personality disorder, and polysubstance use disorder. Her home medications included risperidone, quetiapine, fluoxetine, amitriptyline, and hydromorphone. Our patient injects cocaine on a daily basis and methamphetamine and opioids when cocaine is difficult to obtain. The patient injects her drugs using unfiltered tap water as sterile water ampules and filters are rarely accessible; she has a history of bacteremia from environmental organisms, including Sphingomonas spp, Microbacterium spp, Chryseobacterium indologenes, and Sphingobacterium spiritivorum. She denied sharing her injection paraphernalia and reusing her needles. At baseline, our patient is on home oxygen (2 L/minute) due to chronic obstructive pulmonary disease and pulmonary talcosis. Additional medical history includes inactive hepatitis C and fibromyalgia; she is human immunodeficiency virus negative. She lives in an apartment with her son in Winnipeg, Manitoba, Canada.
Her temperature was 38.2oC, her pulse 121 beats-per-minute, her blood pressure 92/59 mmHg, and her oxygen saturation was 94% while receiving 2 L/minute oxygen via nasal prongs. Physical examination revealed bilateral nodular lesions extending from the dorsum of her hands to her elbows (Figure 1). The nodules were firm and nontender with no overlying erythema. No epitrochlear or axillary lymphadenopathy was present, inconsistent with lymphangitic spread and more suggestive of distinct inoculation of different sites on the hands and forearms. A grade 2 systolic ejection murmur was heard at the right-upper-sternal border with no radiation. Other than clubbing, no peripheral signs of endocarditis were present.
Figure 1. Nodular lesions along the patient’s dorsum of her hand and along her forearm. The largest nodule is on the dorsum of her hand, reflecting the oldest nodule in the location of her earlier injection sites. The absence of lymphadenopathy and the presence of nodules in many locations beyond a single lymphatic drainage reflect separate inoculation events rather than lymphangitic spread.
The plastic surgery service was consulted to perform an excisional biopsy of one of the patient’s forearm nodules, which revealed necrotizing granulomas (Figure 2). Blood cultures were positive.
Figure 2. Suppurative granuloma with central necrosis and neutrophilic infiltration.
One of 2 original sets of blood cultures grew Mycobacterium mucogenicum and Stenotrophomonas maltophilia, identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF; Bruker Biotyper, Bruker Daltonics). Stenotrophomonas maltophilia was reported 2 days after blood draw and was susceptible to levofloxacin, trimethoprim-sulfamethoxazole, minocycline, and ceftazidime as determined by broth microdilution method and interpreted according to current Clinical and Laboratory Standards Institute (CLSI). Mycobacterium mucogenicum was reported 5 days after initial blood draw. Pathology from the patient’s excised forearm nodule demonstrated suppurative necrotizing granulomas associated with acid-fast bacilli on Fite’s stain, a peanut oil/xylene modification of Ziehl-Neelsen (see Figure 3). Within the nodule, foreign crystalline material was identified under examination with polarized light. Gram stain from the nodule revealed scant Gram-positive cocci and Gram-negative bacilli, but no organism grew on aerobic, anaerobic, or mycobacterial culture. Culture of fluid from her forearm abscess grew S maltophilia and Streptococcus pneumoniae. Transthoracic echocardiogram did not reveal any valvular vegetations or regurgitation.
Figure 3. Acid-fast bacilli (Fite’s stain) in the upper central part of the image. Crystalline material is seen in the lower left of the frame.
Although M mucogenicum susceptibilities were pending, the patient was treated with trimethoprim-sulfamethoxazole ([TMP-SMX] 4.5 mg/kg of the TMP component twice a day) and clarithromycin (500 milligrams orally twice a day), a regimen intended to treat S maltophilia as well as M mucogenicum. Treatment became complicated by a prolonged QTc on electrocardiogram after clarithromycin initiation; clarithromycin was changed to doxycycline (100 mg PO BID). Psychiatry was consulted to wean QTc-prolonging medications.
Antimicrobial susceptibility testing of the M mucogenicum isolate susceptibility testing demonstrated susceptibility to TMP-SMX, amikacin, cefoxitin, ciprofloxacin, clarithromycin, imipenem, linezolid, and moxifloxacin but resistance to doxycycline. Antimicrobial susceptibility was determined by broth microdilution and interpreted according to CLSI breakpoints. The patient’s prolonged QTc and psychiatric medications precluded the use of 2 oral agents with in vitro activity, and thus the patient was maintained on her existing regimen with a plan to change doxycycline to clarithromycin once QTc normalized. Multiple repeated blood cultures and mycobacterial blood culture were negative. Over the course of 12 weeks of therapy, the patient clinically improved and her nodules decreased in size and eventually disappeared altogether. Although the patient’s M mucogenicum bacteremia and nodular soft tissue infection resolved, she was subsequently diagnosed with endocarditis from other environmental organisms, including S maltophilia, and she was hospitalized for 6 weeks before being discharged home. During her admission for endocarditis, she was treated with TMP-SMX in addition to meropenem that would likely have therapeutic effect on residual M mucogenicum. Her most recent blood cultures 6 weeks after discharge are negative.
Patient Consent Statement
Written informed consent was obtained from the patient to describe her case and include pictures of her arms and nodule pathology. The design and publication of this work has been approved by the University of Manitoba Bannatyne Research Ethics Board (HS23928:H2020:227, approved May 4, 2020) and conforms to standards currently applied in Canada.
DISCUSSION
Mycobacterium mucogenicum is a rapidly growing nontuberculous mycobacterium (RGM) that routinely inhabits tap water [3, 4]. Mycobacterium mucogenicum’s ability to form biofilms and reproduce in environmental amoeba enables it to tolerate various forms of sanitization including mild chlorination [3]. Due to this fitness advantage in disinfected aqueous ecosystems, M mucogenicum is the most commonly identified RGM in tap water [5].
Mycobacterium mucogenicum infection has diverse clinical manifestations in both immunocompetent as well as immunocompromised hosts, although it is notorious for causing outbreaks of catheter-related blood stream infections among hemodialysis and oncology patients [3, 4, 6]. The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. To our knowledge, this is the second reported case of M mucogenicum infection associated with the injection of drugs [7]. Our patient’s polymicrobial bacteremia was due to injection of tap water from the same contaminated source that caused the granulomatous nodular inflammation in her forearms.
The concurrence of M mucogenicum and S maltophilia in the blood culture as well as the nodule may reflect a novel manifestation of mycobacterial coinfection with a Gram-negative bacillus. This phenomenon has been commonly described in patients with cystic fibrosis where horizontal gene transfer from pseudomonads contributes to the virulence of Mycobacterium abscessus [8]. Although polymicrobial culture positivity often suggests contamination, here the coexistence of RGM and Gram-negative bacillus may suggest the simultaneous inoculation of environmental symbionts.
Optimal treatment for M mucogenicum bacteremia and soft tissue infection remains unclear. If a single skin lesion is present, surgical excision should be considered. A combination of 2 agents, to which the isolate demonstrates in vitro susceptibility, is recommended to prevent the development of drug resistance [9, 10]. Mycobacterium mucogenicum is commonly susceptible to many antimicrobials including amikacin, cefoxitin, clarithromycin, imipenem, and TMP-SMX [3]. However, like other RGM, it remains resistant to first-line antituberculous medications.
CONCLUSIONS
As our case illustrates, among persons who inject drugs, bacteremia with RGM should not be considered a contaminant and may in fact point to other sites of infection. People who inject drugs often experience physical, psychiatric, and socioeconomic difficulties that limit their access to sterile injection equipment. Expanding harm reduction programs to increase accessibility of sterile paraphernalia could mitigate infectious complications of injection drug use and subsequent hospital admission. Antimicrobial options were significantly limited by our patient’s polypharmacy. This case further emphasizes the need for coordinated infectious disease, psychiatric, and addictions care. It is essential for infectious diseases specialists to incorporate harm reduction strategies into their patient interaction to prevent further infectious complications from intravenous drug use.
Acknowledgments
We thank our patient for her good sense of humor, her willingness to participate in this project, and her resilience in the face of difficult circumstances.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | AMITRIPTYLINE, CLARITHROMYCIN, FLUOXETINE HYDROCHLORIDE, HYDROMORPHONE, METHAMPHETAMINE, QUETIAPINE, RISPERIDONE, SULFAMETHOXAZOLE\TRIMETHOPRIM | DrugsGivenReaction | CC BY-NC-ND | 33447641 | 19,093,962 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Bacteraemia'. | Mycobacterium Mucogenicum Bacteremia and Nodular Soft Tissue Infection in a Person Who Uses Tap Water to Inject Drugs.
The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. In this study, we report a case of Mycobacterium mucogenicum bacteremia and associated nodular soft tissue infection in a person who uses tap water to inject drugs.
CASE
A 50-year-old female presented to a community hospital with a 24-hour history of fever and a right forearm abscess at the site of drug injection. The forearm abscess was incised and drained, and a sample was obtained for bacterial culture. Two peripheral blood cultures were collected before treatment with meropenem. The patient’s forearms demonstrated subcutaneous nodules that she maintained had increased in size slowly during the 2 years preceding her current hospital presentation.
The patient has psychiatric illness, of which intergenerational trauma is a probable factor [1, 2]; her parents attended Canada’s Indian Residential School system. She had been diagnosed with bipolar disorder, borderline personality disorder, and polysubstance use disorder. Her home medications included risperidone, quetiapine, fluoxetine, amitriptyline, and hydromorphone. Our patient injects cocaine on a daily basis and methamphetamine and opioids when cocaine is difficult to obtain. The patient injects her drugs using unfiltered tap water as sterile water ampules and filters are rarely accessible; she has a history of bacteremia from environmental organisms, including Sphingomonas spp, Microbacterium spp, Chryseobacterium indologenes, and Sphingobacterium spiritivorum. She denied sharing her injection paraphernalia and reusing her needles. At baseline, our patient is on home oxygen (2 L/minute) due to chronic obstructive pulmonary disease and pulmonary talcosis. Additional medical history includes inactive hepatitis C and fibromyalgia; she is human immunodeficiency virus negative. She lives in an apartment with her son in Winnipeg, Manitoba, Canada.
Her temperature was 38.2oC, her pulse 121 beats-per-minute, her blood pressure 92/59 mmHg, and her oxygen saturation was 94% while receiving 2 L/minute oxygen via nasal prongs. Physical examination revealed bilateral nodular lesions extending from the dorsum of her hands to her elbows (Figure 1). The nodules were firm and nontender with no overlying erythema. No epitrochlear or axillary lymphadenopathy was present, inconsistent with lymphangitic spread and more suggestive of distinct inoculation of different sites on the hands and forearms. A grade 2 systolic ejection murmur was heard at the right-upper-sternal border with no radiation. Other than clubbing, no peripheral signs of endocarditis were present.
Figure 1. Nodular lesions along the patient’s dorsum of her hand and along her forearm. The largest nodule is on the dorsum of her hand, reflecting the oldest nodule in the location of her earlier injection sites. The absence of lymphadenopathy and the presence of nodules in many locations beyond a single lymphatic drainage reflect separate inoculation events rather than lymphangitic spread.
The plastic surgery service was consulted to perform an excisional biopsy of one of the patient’s forearm nodules, which revealed necrotizing granulomas (Figure 2). Blood cultures were positive.
Figure 2. Suppurative granuloma with central necrosis and neutrophilic infiltration.
One of 2 original sets of blood cultures grew Mycobacterium mucogenicum and Stenotrophomonas maltophilia, identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF; Bruker Biotyper, Bruker Daltonics). Stenotrophomonas maltophilia was reported 2 days after blood draw and was susceptible to levofloxacin, trimethoprim-sulfamethoxazole, minocycline, and ceftazidime as determined by broth microdilution method and interpreted according to current Clinical and Laboratory Standards Institute (CLSI). Mycobacterium mucogenicum was reported 5 days after initial blood draw. Pathology from the patient’s excised forearm nodule demonstrated suppurative necrotizing granulomas associated with acid-fast bacilli on Fite’s stain, a peanut oil/xylene modification of Ziehl-Neelsen (see Figure 3). Within the nodule, foreign crystalline material was identified under examination with polarized light. Gram stain from the nodule revealed scant Gram-positive cocci and Gram-negative bacilli, but no organism grew on aerobic, anaerobic, or mycobacterial culture. Culture of fluid from her forearm abscess grew S maltophilia and Streptococcus pneumoniae. Transthoracic echocardiogram did not reveal any valvular vegetations or regurgitation.
Figure 3. Acid-fast bacilli (Fite’s stain) in the upper central part of the image. Crystalline material is seen in the lower left of the frame.
Although M mucogenicum susceptibilities were pending, the patient was treated with trimethoprim-sulfamethoxazole ([TMP-SMX] 4.5 mg/kg of the TMP component twice a day) and clarithromycin (500 milligrams orally twice a day), a regimen intended to treat S maltophilia as well as M mucogenicum. Treatment became complicated by a prolonged QTc on electrocardiogram after clarithromycin initiation; clarithromycin was changed to doxycycline (100 mg PO BID). Psychiatry was consulted to wean QTc-prolonging medications.
Antimicrobial susceptibility testing of the M mucogenicum isolate susceptibility testing demonstrated susceptibility to TMP-SMX, amikacin, cefoxitin, ciprofloxacin, clarithromycin, imipenem, linezolid, and moxifloxacin but resistance to doxycycline. Antimicrobial susceptibility was determined by broth microdilution and interpreted according to CLSI breakpoints. The patient’s prolonged QTc and psychiatric medications precluded the use of 2 oral agents with in vitro activity, and thus the patient was maintained on her existing regimen with a plan to change doxycycline to clarithromycin once QTc normalized. Multiple repeated blood cultures and mycobacterial blood culture were negative. Over the course of 12 weeks of therapy, the patient clinically improved and her nodules decreased in size and eventually disappeared altogether. Although the patient’s M mucogenicum bacteremia and nodular soft tissue infection resolved, she was subsequently diagnosed with endocarditis from other environmental organisms, including S maltophilia, and she was hospitalized for 6 weeks before being discharged home. During her admission for endocarditis, she was treated with TMP-SMX in addition to meropenem that would likely have therapeutic effect on residual M mucogenicum. Her most recent blood cultures 6 weeks after discharge are negative.
Patient Consent Statement
Written informed consent was obtained from the patient to describe her case and include pictures of her arms and nodule pathology. The design and publication of this work has been approved by the University of Manitoba Bannatyne Research Ethics Board (HS23928:H2020:227, approved May 4, 2020) and conforms to standards currently applied in Canada.
DISCUSSION
Mycobacterium mucogenicum is a rapidly growing nontuberculous mycobacterium (RGM) that routinely inhabits tap water [3, 4]. Mycobacterium mucogenicum’s ability to form biofilms and reproduce in environmental amoeba enables it to tolerate various forms of sanitization including mild chlorination [3]. Due to this fitness advantage in disinfected aqueous ecosystems, M mucogenicum is the most commonly identified RGM in tap water [5].
Mycobacterium mucogenicum infection has diverse clinical manifestations in both immunocompetent as well as immunocompromised hosts, although it is notorious for causing outbreaks of catheter-related blood stream infections among hemodialysis and oncology patients [3, 4, 6]. The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. To our knowledge, this is the second reported case of M mucogenicum infection associated with the injection of drugs [7]. Our patient’s polymicrobial bacteremia was due to injection of tap water from the same contaminated source that caused the granulomatous nodular inflammation in her forearms.
The concurrence of M mucogenicum and S maltophilia in the blood culture as well as the nodule may reflect a novel manifestation of mycobacterial coinfection with a Gram-negative bacillus. This phenomenon has been commonly described in patients with cystic fibrosis where horizontal gene transfer from pseudomonads contributes to the virulence of Mycobacterium abscessus [8]. Although polymicrobial culture positivity often suggests contamination, here the coexistence of RGM and Gram-negative bacillus may suggest the simultaneous inoculation of environmental symbionts.
Optimal treatment for M mucogenicum bacteremia and soft tissue infection remains unclear. If a single skin lesion is present, surgical excision should be considered. A combination of 2 agents, to which the isolate demonstrates in vitro susceptibility, is recommended to prevent the development of drug resistance [9, 10]. Mycobacterium mucogenicum is commonly susceptible to many antimicrobials including amikacin, cefoxitin, clarithromycin, imipenem, and TMP-SMX [3]. However, like other RGM, it remains resistant to first-line antituberculous medications.
CONCLUSIONS
As our case illustrates, among persons who inject drugs, bacteremia with RGM should not be considered a contaminant and may in fact point to other sites of infection. People who inject drugs often experience physical, psychiatric, and socioeconomic difficulties that limit their access to sterile injection equipment. Expanding harm reduction programs to increase accessibility of sterile paraphernalia could mitigate infectious complications of injection drug use and subsequent hospital admission. Antimicrobial options were significantly limited by our patient’s polypharmacy. This case further emphasizes the need for coordinated infectious disease, psychiatric, and addictions care. It is essential for infectious diseases specialists to incorporate harm reduction strategies into their patient interaction to prevent further infectious complications from intravenous drug use.
Acknowledgments
We thank our patient for her good sense of humor, her willingness to participate in this project, and her resilience in the face of difficult circumstances.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | AMITRIPTYLINE, CLARITHROMYCIN, FLUOXETINE HYDROCHLORIDE, HYDROMORPHONE, METHAMPHETAMINE, QUETIAPINE, RISPERIDONE, SULFAMETHOXAZOLE\TRIMETHOPRIM | DrugsGivenReaction | CC BY-NC-ND | 33447641 | 19,093,962 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Chronic obstructive pulmonary disease'. | Mycobacterium Mucogenicum Bacteremia and Nodular Soft Tissue Infection in a Person Who Uses Tap Water to Inject Drugs.
The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. In this study, we report a case of Mycobacterium mucogenicum bacteremia and associated nodular soft tissue infection in a person who uses tap water to inject drugs.
CASE
A 50-year-old female presented to a community hospital with a 24-hour history of fever and a right forearm abscess at the site of drug injection. The forearm abscess was incised and drained, and a sample was obtained for bacterial culture. Two peripheral blood cultures were collected before treatment with meropenem. The patient’s forearms demonstrated subcutaneous nodules that she maintained had increased in size slowly during the 2 years preceding her current hospital presentation.
The patient has psychiatric illness, of which intergenerational trauma is a probable factor [1, 2]; her parents attended Canada’s Indian Residential School system. She had been diagnosed with bipolar disorder, borderline personality disorder, and polysubstance use disorder. Her home medications included risperidone, quetiapine, fluoxetine, amitriptyline, and hydromorphone. Our patient injects cocaine on a daily basis and methamphetamine and opioids when cocaine is difficult to obtain. The patient injects her drugs using unfiltered tap water as sterile water ampules and filters are rarely accessible; she has a history of bacteremia from environmental organisms, including Sphingomonas spp, Microbacterium spp, Chryseobacterium indologenes, and Sphingobacterium spiritivorum. She denied sharing her injection paraphernalia and reusing her needles. At baseline, our patient is on home oxygen (2 L/minute) due to chronic obstructive pulmonary disease and pulmonary talcosis. Additional medical history includes inactive hepatitis C and fibromyalgia; she is human immunodeficiency virus negative. She lives in an apartment with her son in Winnipeg, Manitoba, Canada.
Her temperature was 38.2oC, her pulse 121 beats-per-minute, her blood pressure 92/59 mmHg, and her oxygen saturation was 94% while receiving 2 L/minute oxygen via nasal prongs. Physical examination revealed bilateral nodular lesions extending from the dorsum of her hands to her elbows (Figure 1). The nodules were firm and nontender with no overlying erythema. No epitrochlear or axillary lymphadenopathy was present, inconsistent with lymphangitic spread and more suggestive of distinct inoculation of different sites on the hands and forearms. A grade 2 systolic ejection murmur was heard at the right-upper-sternal border with no radiation. Other than clubbing, no peripheral signs of endocarditis were present.
Figure 1. Nodular lesions along the patient’s dorsum of her hand and along her forearm. The largest nodule is on the dorsum of her hand, reflecting the oldest nodule in the location of her earlier injection sites. The absence of lymphadenopathy and the presence of nodules in many locations beyond a single lymphatic drainage reflect separate inoculation events rather than lymphangitic spread.
The plastic surgery service was consulted to perform an excisional biopsy of one of the patient’s forearm nodules, which revealed necrotizing granulomas (Figure 2). Blood cultures were positive.
Figure 2. Suppurative granuloma with central necrosis and neutrophilic infiltration.
One of 2 original sets of blood cultures grew Mycobacterium mucogenicum and Stenotrophomonas maltophilia, identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF; Bruker Biotyper, Bruker Daltonics). Stenotrophomonas maltophilia was reported 2 days after blood draw and was susceptible to levofloxacin, trimethoprim-sulfamethoxazole, minocycline, and ceftazidime as determined by broth microdilution method and interpreted according to current Clinical and Laboratory Standards Institute (CLSI). Mycobacterium mucogenicum was reported 5 days after initial blood draw. Pathology from the patient’s excised forearm nodule demonstrated suppurative necrotizing granulomas associated with acid-fast bacilli on Fite’s stain, a peanut oil/xylene modification of Ziehl-Neelsen (see Figure 3). Within the nodule, foreign crystalline material was identified under examination with polarized light. Gram stain from the nodule revealed scant Gram-positive cocci and Gram-negative bacilli, but no organism grew on aerobic, anaerobic, or mycobacterial culture. Culture of fluid from her forearm abscess grew S maltophilia and Streptococcus pneumoniae. Transthoracic echocardiogram did not reveal any valvular vegetations or regurgitation.
Figure 3. Acid-fast bacilli (Fite’s stain) in the upper central part of the image. Crystalline material is seen in the lower left of the frame.
Although M mucogenicum susceptibilities were pending, the patient was treated with trimethoprim-sulfamethoxazole ([TMP-SMX] 4.5 mg/kg of the TMP component twice a day) and clarithromycin (500 milligrams orally twice a day), a regimen intended to treat S maltophilia as well as M mucogenicum. Treatment became complicated by a prolonged QTc on electrocardiogram after clarithromycin initiation; clarithromycin was changed to doxycycline (100 mg PO BID). Psychiatry was consulted to wean QTc-prolonging medications.
Antimicrobial susceptibility testing of the M mucogenicum isolate susceptibility testing demonstrated susceptibility to TMP-SMX, amikacin, cefoxitin, ciprofloxacin, clarithromycin, imipenem, linezolid, and moxifloxacin but resistance to doxycycline. Antimicrobial susceptibility was determined by broth microdilution and interpreted according to CLSI breakpoints. The patient’s prolonged QTc and psychiatric medications precluded the use of 2 oral agents with in vitro activity, and thus the patient was maintained on her existing regimen with a plan to change doxycycline to clarithromycin once QTc normalized. Multiple repeated blood cultures and mycobacterial blood culture were negative. Over the course of 12 weeks of therapy, the patient clinically improved and her nodules decreased in size and eventually disappeared altogether. Although the patient’s M mucogenicum bacteremia and nodular soft tissue infection resolved, she was subsequently diagnosed with endocarditis from other environmental organisms, including S maltophilia, and she was hospitalized for 6 weeks before being discharged home. During her admission for endocarditis, she was treated with TMP-SMX in addition to meropenem that would likely have therapeutic effect on residual M mucogenicum. Her most recent blood cultures 6 weeks after discharge are negative.
Patient Consent Statement
Written informed consent was obtained from the patient to describe her case and include pictures of her arms and nodule pathology. The design and publication of this work has been approved by the University of Manitoba Bannatyne Research Ethics Board (HS23928:H2020:227, approved May 4, 2020) and conforms to standards currently applied in Canada.
DISCUSSION
Mycobacterium mucogenicum is a rapidly growing nontuberculous mycobacterium (RGM) that routinely inhabits tap water [3, 4]. Mycobacterium mucogenicum’s ability to form biofilms and reproduce in environmental amoeba enables it to tolerate various forms of sanitization including mild chlorination [3]. Due to this fitness advantage in disinfected aqueous ecosystems, M mucogenicum is the most commonly identified RGM in tap water [5].
Mycobacterium mucogenicum infection has diverse clinical manifestations in both immunocompetent as well as immunocompromised hosts, although it is notorious for causing outbreaks of catheter-related blood stream infections among hemodialysis and oncology patients [3, 4, 6]. The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. To our knowledge, this is the second reported case of M mucogenicum infection associated with the injection of drugs [7]. Our patient’s polymicrobial bacteremia was due to injection of tap water from the same contaminated source that caused the granulomatous nodular inflammation in her forearms.
The concurrence of M mucogenicum and S maltophilia in the blood culture as well as the nodule may reflect a novel manifestation of mycobacterial coinfection with a Gram-negative bacillus. This phenomenon has been commonly described in patients with cystic fibrosis where horizontal gene transfer from pseudomonads contributes to the virulence of Mycobacterium abscessus [8]. Although polymicrobial culture positivity often suggests contamination, here the coexistence of RGM and Gram-negative bacillus may suggest the simultaneous inoculation of environmental symbionts.
Optimal treatment for M mucogenicum bacteremia and soft tissue infection remains unclear. If a single skin lesion is present, surgical excision should be considered. A combination of 2 agents, to which the isolate demonstrates in vitro susceptibility, is recommended to prevent the development of drug resistance [9, 10]. Mycobacterium mucogenicum is commonly susceptible to many antimicrobials including amikacin, cefoxitin, clarithromycin, imipenem, and TMP-SMX [3]. However, like other RGM, it remains resistant to first-line antituberculous medications.
CONCLUSIONS
As our case illustrates, among persons who inject drugs, bacteremia with RGM should not be considered a contaminant and may in fact point to other sites of infection. People who inject drugs often experience physical, psychiatric, and socioeconomic difficulties that limit their access to sterile injection equipment. Expanding harm reduction programs to increase accessibility of sterile paraphernalia could mitigate infectious complications of injection drug use and subsequent hospital admission. Antimicrobial options were significantly limited by our patient’s polypharmacy. This case further emphasizes the need for coordinated infectious disease, psychiatric, and addictions care. It is essential for infectious diseases specialists to incorporate harm reduction strategies into their patient interaction to prevent further infectious complications from intravenous drug use.
Acknowledgments
We thank our patient for her good sense of humor, her willingness to participate in this project, and her resilience in the face of difficult circumstances.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | AMITRIPTYLINE, CLARITHROMYCIN, FLUOXETINE HYDROCHLORIDE, HYDROMORPHONE, METHAMPHETAMINE, QUETIAPINE, RISPERIDONE, SULFAMETHOXAZOLE\TRIMETHOPRIM | DrugsGivenReaction | CC BY-NC-ND | 33447641 | 19,093,962 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug abuse'. | Mycobacterium Mucogenicum Bacteremia and Nodular Soft Tissue Infection in a Person Who Uses Tap Water to Inject Drugs.
The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. In this study, we report a case of Mycobacterium mucogenicum bacteremia and associated nodular soft tissue infection in a person who uses tap water to inject drugs.
CASE
A 50-year-old female presented to a community hospital with a 24-hour history of fever and a right forearm abscess at the site of drug injection. The forearm abscess was incised and drained, and a sample was obtained for bacterial culture. Two peripheral blood cultures were collected before treatment with meropenem. The patient’s forearms demonstrated subcutaneous nodules that she maintained had increased in size slowly during the 2 years preceding her current hospital presentation.
The patient has psychiatric illness, of which intergenerational trauma is a probable factor [1, 2]; her parents attended Canada’s Indian Residential School system. She had been diagnosed with bipolar disorder, borderline personality disorder, and polysubstance use disorder. Her home medications included risperidone, quetiapine, fluoxetine, amitriptyline, and hydromorphone. Our patient injects cocaine on a daily basis and methamphetamine and opioids when cocaine is difficult to obtain. The patient injects her drugs using unfiltered tap water as sterile water ampules and filters are rarely accessible; she has a history of bacteremia from environmental organisms, including Sphingomonas spp, Microbacterium spp, Chryseobacterium indologenes, and Sphingobacterium spiritivorum. She denied sharing her injection paraphernalia and reusing her needles. At baseline, our patient is on home oxygen (2 L/minute) due to chronic obstructive pulmonary disease and pulmonary talcosis. Additional medical history includes inactive hepatitis C and fibromyalgia; she is human immunodeficiency virus negative. She lives in an apartment with her son in Winnipeg, Manitoba, Canada.
Her temperature was 38.2oC, her pulse 121 beats-per-minute, her blood pressure 92/59 mmHg, and her oxygen saturation was 94% while receiving 2 L/minute oxygen via nasal prongs. Physical examination revealed bilateral nodular lesions extending from the dorsum of her hands to her elbows (Figure 1). The nodules were firm and nontender with no overlying erythema. No epitrochlear or axillary lymphadenopathy was present, inconsistent with lymphangitic spread and more suggestive of distinct inoculation of different sites on the hands and forearms. A grade 2 systolic ejection murmur was heard at the right-upper-sternal border with no radiation. Other than clubbing, no peripheral signs of endocarditis were present.
Figure 1. Nodular lesions along the patient’s dorsum of her hand and along her forearm. The largest nodule is on the dorsum of her hand, reflecting the oldest nodule in the location of her earlier injection sites. The absence of lymphadenopathy and the presence of nodules in many locations beyond a single lymphatic drainage reflect separate inoculation events rather than lymphangitic spread.
The plastic surgery service was consulted to perform an excisional biopsy of one of the patient’s forearm nodules, which revealed necrotizing granulomas (Figure 2). Blood cultures were positive.
Figure 2. Suppurative granuloma with central necrosis and neutrophilic infiltration.
One of 2 original sets of blood cultures grew Mycobacterium mucogenicum and Stenotrophomonas maltophilia, identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF; Bruker Biotyper, Bruker Daltonics). Stenotrophomonas maltophilia was reported 2 days after blood draw and was susceptible to levofloxacin, trimethoprim-sulfamethoxazole, minocycline, and ceftazidime as determined by broth microdilution method and interpreted according to current Clinical and Laboratory Standards Institute (CLSI). Mycobacterium mucogenicum was reported 5 days after initial blood draw. Pathology from the patient’s excised forearm nodule demonstrated suppurative necrotizing granulomas associated with acid-fast bacilli on Fite’s stain, a peanut oil/xylene modification of Ziehl-Neelsen (see Figure 3). Within the nodule, foreign crystalline material was identified under examination with polarized light. Gram stain from the nodule revealed scant Gram-positive cocci and Gram-negative bacilli, but no organism grew on aerobic, anaerobic, or mycobacterial culture. Culture of fluid from her forearm abscess grew S maltophilia and Streptococcus pneumoniae. Transthoracic echocardiogram did not reveal any valvular vegetations or regurgitation.
Figure 3. Acid-fast bacilli (Fite’s stain) in the upper central part of the image. Crystalline material is seen in the lower left of the frame.
Although M mucogenicum susceptibilities were pending, the patient was treated with trimethoprim-sulfamethoxazole ([TMP-SMX] 4.5 mg/kg of the TMP component twice a day) and clarithromycin (500 milligrams orally twice a day), a regimen intended to treat S maltophilia as well as M mucogenicum. Treatment became complicated by a prolonged QTc on electrocardiogram after clarithromycin initiation; clarithromycin was changed to doxycycline (100 mg PO BID). Psychiatry was consulted to wean QTc-prolonging medications.
Antimicrobial susceptibility testing of the M mucogenicum isolate susceptibility testing demonstrated susceptibility to TMP-SMX, amikacin, cefoxitin, ciprofloxacin, clarithromycin, imipenem, linezolid, and moxifloxacin but resistance to doxycycline. Antimicrobial susceptibility was determined by broth microdilution and interpreted according to CLSI breakpoints. The patient’s prolonged QTc and psychiatric medications precluded the use of 2 oral agents with in vitro activity, and thus the patient was maintained on her existing regimen with a plan to change doxycycline to clarithromycin once QTc normalized. Multiple repeated blood cultures and mycobacterial blood culture were negative. Over the course of 12 weeks of therapy, the patient clinically improved and her nodules decreased in size and eventually disappeared altogether. Although the patient’s M mucogenicum bacteremia and nodular soft tissue infection resolved, she was subsequently diagnosed with endocarditis from other environmental organisms, including S maltophilia, and she was hospitalized for 6 weeks before being discharged home. During her admission for endocarditis, she was treated with TMP-SMX in addition to meropenem that would likely have therapeutic effect on residual M mucogenicum. Her most recent blood cultures 6 weeks after discharge are negative.
Patient Consent Statement
Written informed consent was obtained from the patient to describe her case and include pictures of her arms and nodule pathology. The design and publication of this work has been approved by the University of Manitoba Bannatyne Research Ethics Board (HS23928:H2020:227, approved May 4, 2020) and conforms to standards currently applied in Canada.
DISCUSSION
Mycobacterium mucogenicum is a rapidly growing nontuberculous mycobacterium (RGM) that routinely inhabits tap water [3, 4]. Mycobacterium mucogenicum’s ability to form biofilms and reproduce in environmental amoeba enables it to tolerate various forms of sanitization including mild chlorination [3]. Due to this fitness advantage in disinfected aqueous ecosystems, M mucogenicum is the most commonly identified RGM in tap water [5].
Mycobacterium mucogenicum infection has diverse clinical manifestations in both immunocompetent as well as immunocompromised hosts, although it is notorious for causing outbreaks of catheter-related blood stream infections among hemodialysis and oncology patients [3, 4, 6]. The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. To our knowledge, this is the second reported case of M mucogenicum infection associated with the injection of drugs [7]. Our patient’s polymicrobial bacteremia was due to injection of tap water from the same contaminated source that caused the granulomatous nodular inflammation in her forearms.
The concurrence of M mucogenicum and S maltophilia in the blood culture as well as the nodule may reflect a novel manifestation of mycobacterial coinfection with a Gram-negative bacillus. This phenomenon has been commonly described in patients with cystic fibrosis where horizontal gene transfer from pseudomonads contributes to the virulence of Mycobacterium abscessus [8]. Although polymicrobial culture positivity often suggests contamination, here the coexistence of RGM and Gram-negative bacillus may suggest the simultaneous inoculation of environmental symbionts.
Optimal treatment for M mucogenicum bacteremia and soft tissue infection remains unclear. If a single skin lesion is present, surgical excision should be considered. A combination of 2 agents, to which the isolate demonstrates in vitro susceptibility, is recommended to prevent the development of drug resistance [9, 10]. Mycobacterium mucogenicum is commonly susceptible to many antimicrobials including amikacin, cefoxitin, clarithromycin, imipenem, and TMP-SMX [3]. However, like other RGM, it remains resistant to first-line antituberculous medications.
CONCLUSIONS
As our case illustrates, among persons who inject drugs, bacteremia with RGM should not be considered a contaminant and may in fact point to other sites of infection. People who inject drugs often experience physical, psychiatric, and socioeconomic difficulties that limit their access to sterile injection equipment. Expanding harm reduction programs to increase accessibility of sterile paraphernalia could mitigate infectious complications of injection drug use and subsequent hospital admission. Antimicrobial options were significantly limited by our patient’s polypharmacy. This case further emphasizes the need for coordinated infectious disease, psychiatric, and addictions care. It is essential for infectious diseases specialists to incorporate harm reduction strategies into their patient interaction to prevent further infectious complications from intravenous drug use.
Acknowledgments
We thank our patient for her good sense of humor, her willingness to participate in this project, and her resilience in the face of difficult circumstances.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | AMITRIPTYLINE, CLARITHROMYCIN, FLUOXETINE HYDROCHLORIDE, HYDROMORPHONE, METHAMPHETAMINE, QUETIAPINE, RISPERIDONE, SULFAMETHOXAZOLE\TRIMETHOPRIM | DrugsGivenReaction | CC BY-NC-ND | 33447641 | 19,093,962 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Electrocardiogram QT prolonged'. | Mycobacterium Mucogenicum Bacteremia and Nodular Soft Tissue Infection in a Person Who Uses Tap Water to Inject Drugs.
The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. In this study, we report a case of Mycobacterium mucogenicum bacteremia and associated nodular soft tissue infection in a person who uses tap water to inject drugs.
CASE
A 50-year-old female presented to a community hospital with a 24-hour history of fever and a right forearm abscess at the site of drug injection. The forearm abscess was incised and drained, and a sample was obtained for bacterial culture. Two peripheral blood cultures were collected before treatment with meropenem. The patient’s forearms demonstrated subcutaneous nodules that she maintained had increased in size slowly during the 2 years preceding her current hospital presentation.
The patient has psychiatric illness, of which intergenerational trauma is a probable factor [1, 2]; her parents attended Canada’s Indian Residential School system. She had been diagnosed with bipolar disorder, borderline personality disorder, and polysubstance use disorder. Her home medications included risperidone, quetiapine, fluoxetine, amitriptyline, and hydromorphone. Our patient injects cocaine on a daily basis and methamphetamine and opioids when cocaine is difficult to obtain. The patient injects her drugs using unfiltered tap water as sterile water ampules and filters are rarely accessible; she has a history of bacteremia from environmental organisms, including Sphingomonas spp, Microbacterium spp, Chryseobacterium indologenes, and Sphingobacterium spiritivorum. She denied sharing her injection paraphernalia and reusing her needles. At baseline, our patient is on home oxygen (2 L/minute) due to chronic obstructive pulmonary disease and pulmonary talcosis. Additional medical history includes inactive hepatitis C and fibromyalgia; she is human immunodeficiency virus negative. She lives in an apartment with her son in Winnipeg, Manitoba, Canada.
Her temperature was 38.2oC, her pulse 121 beats-per-minute, her blood pressure 92/59 mmHg, and her oxygen saturation was 94% while receiving 2 L/minute oxygen via nasal prongs. Physical examination revealed bilateral nodular lesions extending from the dorsum of her hands to her elbows (Figure 1). The nodules were firm and nontender with no overlying erythema. No epitrochlear or axillary lymphadenopathy was present, inconsistent with lymphangitic spread and more suggestive of distinct inoculation of different sites on the hands and forearms. A grade 2 systolic ejection murmur was heard at the right-upper-sternal border with no radiation. Other than clubbing, no peripheral signs of endocarditis were present.
Figure 1. Nodular lesions along the patient’s dorsum of her hand and along her forearm. The largest nodule is on the dorsum of her hand, reflecting the oldest nodule in the location of her earlier injection sites. The absence of lymphadenopathy and the presence of nodules in many locations beyond a single lymphatic drainage reflect separate inoculation events rather than lymphangitic spread.
The plastic surgery service was consulted to perform an excisional biopsy of one of the patient’s forearm nodules, which revealed necrotizing granulomas (Figure 2). Blood cultures were positive.
Figure 2. Suppurative granuloma with central necrosis and neutrophilic infiltration.
One of 2 original sets of blood cultures grew Mycobacterium mucogenicum and Stenotrophomonas maltophilia, identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF; Bruker Biotyper, Bruker Daltonics). Stenotrophomonas maltophilia was reported 2 days after blood draw and was susceptible to levofloxacin, trimethoprim-sulfamethoxazole, minocycline, and ceftazidime as determined by broth microdilution method and interpreted according to current Clinical and Laboratory Standards Institute (CLSI). Mycobacterium mucogenicum was reported 5 days after initial blood draw. Pathology from the patient’s excised forearm nodule demonstrated suppurative necrotizing granulomas associated with acid-fast bacilli on Fite’s stain, a peanut oil/xylene modification of Ziehl-Neelsen (see Figure 3). Within the nodule, foreign crystalline material was identified under examination with polarized light. Gram stain from the nodule revealed scant Gram-positive cocci and Gram-negative bacilli, but no organism grew on aerobic, anaerobic, or mycobacterial culture. Culture of fluid from her forearm abscess grew S maltophilia and Streptococcus pneumoniae. Transthoracic echocardiogram did not reveal any valvular vegetations or regurgitation.
Figure 3. Acid-fast bacilli (Fite’s stain) in the upper central part of the image. Crystalline material is seen in the lower left of the frame.
Although M mucogenicum susceptibilities were pending, the patient was treated with trimethoprim-sulfamethoxazole ([TMP-SMX] 4.5 mg/kg of the TMP component twice a day) and clarithromycin (500 milligrams orally twice a day), a regimen intended to treat S maltophilia as well as M mucogenicum. Treatment became complicated by a prolonged QTc on electrocardiogram after clarithromycin initiation; clarithromycin was changed to doxycycline (100 mg PO BID). Psychiatry was consulted to wean QTc-prolonging medications.
Antimicrobial susceptibility testing of the M mucogenicum isolate susceptibility testing demonstrated susceptibility to TMP-SMX, amikacin, cefoxitin, ciprofloxacin, clarithromycin, imipenem, linezolid, and moxifloxacin but resistance to doxycycline. Antimicrobial susceptibility was determined by broth microdilution and interpreted according to CLSI breakpoints. The patient’s prolonged QTc and psychiatric medications precluded the use of 2 oral agents with in vitro activity, and thus the patient was maintained on her existing regimen with a plan to change doxycycline to clarithromycin once QTc normalized. Multiple repeated blood cultures and mycobacterial blood culture were negative. Over the course of 12 weeks of therapy, the patient clinically improved and her nodules decreased in size and eventually disappeared altogether. Although the patient’s M mucogenicum bacteremia and nodular soft tissue infection resolved, she was subsequently diagnosed with endocarditis from other environmental organisms, including S maltophilia, and she was hospitalized for 6 weeks before being discharged home. During her admission for endocarditis, she was treated with TMP-SMX in addition to meropenem that would likely have therapeutic effect on residual M mucogenicum. Her most recent blood cultures 6 weeks after discharge are negative.
Patient Consent Statement
Written informed consent was obtained from the patient to describe her case and include pictures of her arms and nodule pathology. The design and publication of this work has been approved by the University of Manitoba Bannatyne Research Ethics Board (HS23928:H2020:227, approved May 4, 2020) and conforms to standards currently applied in Canada.
DISCUSSION
Mycobacterium mucogenicum is a rapidly growing nontuberculous mycobacterium (RGM) that routinely inhabits tap water [3, 4]. Mycobacterium mucogenicum’s ability to form biofilms and reproduce in environmental amoeba enables it to tolerate various forms of sanitization including mild chlorination [3]. Due to this fitness advantage in disinfected aqueous ecosystems, M mucogenicum is the most commonly identified RGM in tap water [5].
Mycobacterium mucogenicum infection has diverse clinical manifestations in both immunocompetent as well as immunocompromised hosts, although it is notorious for causing outbreaks of catheter-related blood stream infections among hemodialysis and oncology patients [3, 4, 6]. The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. To our knowledge, this is the second reported case of M mucogenicum infection associated with the injection of drugs [7]. Our patient’s polymicrobial bacteremia was due to injection of tap water from the same contaminated source that caused the granulomatous nodular inflammation in her forearms.
The concurrence of M mucogenicum and S maltophilia in the blood culture as well as the nodule may reflect a novel manifestation of mycobacterial coinfection with a Gram-negative bacillus. This phenomenon has been commonly described in patients with cystic fibrosis where horizontal gene transfer from pseudomonads contributes to the virulence of Mycobacterium abscessus [8]. Although polymicrobial culture positivity often suggests contamination, here the coexistence of RGM and Gram-negative bacillus may suggest the simultaneous inoculation of environmental symbionts.
Optimal treatment for M mucogenicum bacteremia and soft tissue infection remains unclear. If a single skin lesion is present, surgical excision should be considered. A combination of 2 agents, to which the isolate demonstrates in vitro susceptibility, is recommended to prevent the development of drug resistance [9, 10]. Mycobacterium mucogenicum is commonly susceptible to many antimicrobials including amikacin, cefoxitin, clarithromycin, imipenem, and TMP-SMX [3]. However, like other RGM, it remains resistant to first-line antituberculous medications.
CONCLUSIONS
As our case illustrates, among persons who inject drugs, bacteremia with RGM should not be considered a contaminant and may in fact point to other sites of infection. People who inject drugs often experience physical, psychiatric, and socioeconomic difficulties that limit their access to sterile injection equipment. Expanding harm reduction programs to increase accessibility of sterile paraphernalia could mitigate infectious complications of injection drug use and subsequent hospital admission. Antimicrobial options were significantly limited by our patient’s polypharmacy. This case further emphasizes the need for coordinated infectious disease, psychiatric, and addictions care. It is essential for infectious diseases specialists to incorporate harm reduction strategies into their patient interaction to prevent further infectious complications from intravenous drug use.
Acknowledgments
We thank our patient for her good sense of humor, her willingness to participate in this project, and her resilience in the face of difficult circumstances.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | AMITRIPTYLINE, CLARITHROMYCIN, FLUOXETINE HYDROCHLORIDE, HYDROMORPHONE, METHAMPHETAMINE, QUETIAPINE, RISPERIDONE, SULFAMETHOXAZOLE\TRIMETHOPRIM | DrugsGivenReaction | CC BY-NC-ND | 33447641 | 19,093,962 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Endocarditis'. | Mycobacterium Mucogenicum Bacteremia and Nodular Soft Tissue Infection in a Person Who Uses Tap Water to Inject Drugs.
The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. In this study, we report a case of Mycobacterium mucogenicum bacteremia and associated nodular soft tissue infection in a person who uses tap water to inject drugs.
CASE
A 50-year-old female presented to a community hospital with a 24-hour history of fever and a right forearm abscess at the site of drug injection. The forearm abscess was incised and drained, and a sample was obtained for bacterial culture. Two peripheral blood cultures were collected before treatment with meropenem. The patient’s forearms demonstrated subcutaneous nodules that she maintained had increased in size slowly during the 2 years preceding her current hospital presentation.
The patient has psychiatric illness, of which intergenerational trauma is a probable factor [1, 2]; her parents attended Canada’s Indian Residential School system. She had been diagnosed with bipolar disorder, borderline personality disorder, and polysubstance use disorder. Her home medications included risperidone, quetiapine, fluoxetine, amitriptyline, and hydromorphone. Our patient injects cocaine on a daily basis and methamphetamine and opioids when cocaine is difficult to obtain. The patient injects her drugs using unfiltered tap water as sterile water ampules and filters are rarely accessible; she has a history of bacteremia from environmental organisms, including Sphingomonas spp, Microbacterium spp, Chryseobacterium indologenes, and Sphingobacterium spiritivorum. She denied sharing her injection paraphernalia and reusing her needles. At baseline, our patient is on home oxygen (2 L/minute) due to chronic obstructive pulmonary disease and pulmonary talcosis. Additional medical history includes inactive hepatitis C and fibromyalgia; she is human immunodeficiency virus negative. She lives in an apartment with her son in Winnipeg, Manitoba, Canada.
Her temperature was 38.2oC, her pulse 121 beats-per-minute, her blood pressure 92/59 mmHg, and her oxygen saturation was 94% while receiving 2 L/minute oxygen via nasal prongs. Physical examination revealed bilateral nodular lesions extending from the dorsum of her hands to her elbows (Figure 1). The nodules were firm and nontender with no overlying erythema. No epitrochlear or axillary lymphadenopathy was present, inconsistent with lymphangitic spread and more suggestive of distinct inoculation of different sites on the hands and forearms. A grade 2 systolic ejection murmur was heard at the right-upper-sternal border with no radiation. Other than clubbing, no peripheral signs of endocarditis were present.
Figure 1. Nodular lesions along the patient’s dorsum of her hand and along her forearm. The largest nodule is on the dorsum of her hand, reflecting the oldest nodule in the location of her earlier injection sites. The absence of lymphadenopathy and the presence of nodules in many locations beyond a single lymphatic drainage reflect separate inoculation events rather than lymphangitic spread.
The plastic surgery service was consulted to perform an excisional biopsy of one of the patient’s forearm nodules, which revealed necrotizing granulomas (Figure 2). Blood cultures were positive.
Figure 2. Suppurative granuloma with central necrosis and neutrophilic infiltration.
One of 2 original sets of blood cultures grew Mycobacterium mucogenicum and Stenotrophomonas maltophilia, identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF; Bruker Biotyper, Bruker Daltonics). Stenotrophomonas maltophilia was reported 2 days after blood draw and was susceptible to levofloxacin, trimethoprim-sulfamethoxazole, minocycline, and ceftazidime as determined by broth microdilution method and interpreted according to current Clinical and Laboratory Standards Institute (CLSI). Mycobacterium mucogenicum was reported 5 days after initial blood draw. Pathology from the patient’s excised forearm nodule demonstrated suppurative necrotizing granulomas associated with acid-fast bacilli on Fite’s stain, a peanut oil/xylene modification of Ziehl-Neelsen (see Figure 3). Within the nodule, foreign crystalline material was identified under examination with polarized light. Gram stain from the nodule revealed scant Gram-positive cocci and Gram-negative bacilli, but no organism grew on aerobic, anaerobic, or mycobacterial culture. Culture of fluid from her forearm abscess grew S maltophilia and Streptococcus pneumoniae. Transthoracic echocardiogram did not reveal any valvular vegetations or regurgitation.
Figure 3. Acid-fast bacilli (Fite’s stain) in the upper central part of the image. Crystalline material is seen in the lower left of the frame.
Although M mucogenicum susceptibilities were pending, the patient was treated with trimethoprim-sulfamethoxazole ([TMP-SMX] 4.5 mg/kg of the TMP component twice a day) and clarithromycin (500 milligrams orally twice a day), a regimen intended to treat S maltophilia as well as M mucogenicum. Treatment became complicated by a prolonged QTc on electrocardiogram after clarithromycin initiation; clarithromycin was changed to doxycycline (100 mg PO BID). Psychiatry was consulted to wean QTc-prolonging medications.
Antimicrobial susceptibility testing of the M mucogenicum isolate susceptibility testing demonstrated susceptibility to TMP-SMX, amikacin, cefoxitin, ciprofloxacin, clarithromycin, imipenem, linezolid, and moxifloxacin but resistance to doxycycline. Antimicrobial susceptibility was determined by broth microdilution and interpreted according to CLSI breakpoints. The patient’s prolonged QTc and psychiatric medications precluded the use of 2 oral agents with in vitro activity, and thus the patient was maintained on her existing regimen with a plan to change doxycycline to clarithromycin once QTc normalized. Multiple repeated blood cultures and mycobacterial blood culture were negative. Over the course of 12 weeks of therapy, the patient clinically improved and her nodules decreased in size and eventually disappeared altogether. Although the patient’s M mucogenicum bacteremia and nodular soft tissue infection resolved, she was subsequently diagnosed with endocarditis from other environmental organisms, including S maltophilia, and she was hospitalized for 6 weeks before being discharged home. During her admission for endocarditis, she was treated with TMP-SMX in addition to meropenem that would likely have therapeutic effect on residual M mucogenicum. Her most recent blood cultures 6 weeks after discharge are negative.
Patient Consent Statement
Written informed consent was obtained from the patient to describe her case and include pictures of her arms and nodule pathology. The design and publication of this work has been approved by the University of Manitoba Bannatyne Research Ethics Board (HS23928:H2020:227, approved May 4, 2020) and conforms to standards currently applied in Canada.
DISCUSSION
Mycobacterium mucogenicum is a rapidly growing nontuberculous mycobacterium (RGM) that routinely inhabits tap water [3, 4]. Mycobacterium mucogenicum’s ability to form biofilms and reproduce in environmental amoeba enables it to tolerate various forms of sanitization including mild chlorination [3]. Due to this fitness advantage in disinfected aqueous ecosystems, M mucogenicum is the most commonly identified RGM in tap water [5].
Mycobacterium mucogenicum infection has diverse clinical manifestations in both immunocompetent as well as immunocompromised hosts, although it is notorious for causing outbreaks of catheter-related blood stream infections among hemodialysis and oncology patients [3, 4, 6]. The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. To our knowledge, this is the second reported case of M mucogenicum infection associated with the injection of drugs [7]. Our patient’s polymicrobial bacteremia was due to injection of tap water from the same contaminated source that caused the granulomatous nodular inflammation in her forearms.
The concurrence of M mucogenicum and S maltophilia in the blood culture as well as the nodule may reflect a novel manifestation of mycobacterial coinfection with a Gram-negative bacillus. This phenomenon has been commonly described in patients with cystic fibrosis where horizontal gene transfer from pseudomonads contributes to the virulence of Mycobacterium abscessus [8]. Although polymicrobial culture positivity often suggests contamination, here the coexistence of RGM and Gram-negative bacillus may suggest the simultaneous inoculation of environmental symbionts.
Optimal treatment for M mucogenicum bacteremia and soft tissue infection remains unclear. If a single skin lesion is present, surgical excision should be considered. A combination of 2 agents, to which the isolate demonstrates in vitro susceptibility, is recommended to prevent the development of drug resistance [9, 10]. Mycobacterium mucogenicum is commonly susceptible to many antimicrobials including amikacin, cefoxitin, clarithromycin, imipenem, and TMP-SMX [3]. However, like other RGM, it remains resistant to first-line antituberculous medications.
CONCLUSIONS
As our case illustrates, among persons who inject drugs, bacteremia with RGM should not be considered a contaminant and may in fact point to other sites of infection. People who inject drugs often experience physical, psychiatric, and socioeconomic difficulties that limit their access to sterile injection equipment. Expanding harm reduction programs to increase accessibility of sterile paraphernalia could mitigate infectious complications of injection drug use and subsequent hospital admission. Antimicrobial options were significantly limited by our patient’s polypharmacy. This case further emphasizes the need for coordinated infectious disease, psychiatric, and addictions care. It is essential for infectious diseases specialists to incorporate harm reduction strategies into their patient interaction to prevent further infectious complications from intravenous drug use.
Acknowledgments
We thank our patient for her good sense of humor, her willingness to participate in this project, and her resilience in the face of difficult circumstances.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | AMITRIPTYLINE, CLARITHROMYCIN, FLUOXETINE HYDROCHLORIDE, HYDROMORPHONE, METHAMPHETAMINE, QUETIAPINE, RISPERIDONE, SULFAMETHOXAZOLE\TRIMETHOPRIM | DrugsGivenReaction | CC BY-NC-ND | 33447641 | 19,093,962 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lung disorder'. | Mycobacterium Mucogenicum Bacteremia and Nodular Soft Tissue Infection in a Person Who Uses Tap Water to Inject Drugs.
The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. In this study, we report a case of Mycobacterium mucogenicum bacteremia and associated nodular soft tissue infection in a person who uses tap water to inject drugs.
CASE
A 50-year-old female presented to a community hospital with a 24-hour history of fever and a right forearm abscess at the site of drug injection. The forearm abscess was incised and drained, and a sample was obtained for bacterial culture. Two peripheral blood cultures were collected before treatment with meropenem. The patient’s forearms demonstrated subcutaneous nodules that she maintained had increased in size slowly during the 2 years preceding her current hospital presentation.
The patient has psychiatric illness, of which intergenerational trauma is a probable factor [1, 2]; her parents attended Canada’s Indian Residential School system. She had been diagnosed with bipolar disorder, borderline personality disorder, and polysubstance use disorder. Her home medications included risperidone, quetiapine, fluoxetine, amitriptyline, and hydromorphone. Our patient injects cocaine on a daily basis and methamphetamine and opioids when cocaine is difficult to obtain. The patient injects her drugs using unfiltered tap water as sterile water ampules and filters are rarely accessible; she has a history of bacteremia from environmental organisms, including Sphingomonas spp, Microbacterium spp, Chryseobacterium indologenes, and Sphingobacterium spiritivorum. She denied sharing her injection paraphernalia and reusing her needles. At baseline, our patient is on home oxygen (2 L/minute) due to chronic obstructive pulmonary disease and pulmonary talcosis. Additional medical history includes inactive hepatitis C and fibromyalgia; she is human immunodeficiency virus negative. She lives in an apartment with her son in Winnipeg, Manitoba, Canada.
Her temperature was 38.2oC, her pulse 121 beats-per-minute, her blood pressure 92/59 mmHg, and her oxygen saturation was 94% while receiving 2 L/minute oxygen via nasal prongs. Physical examination revealed bilateral nodular lesions extending from the dorsum of her hands to her elbows (Figure 1). The nodules were firm and nontender with no overlying erythema. No epitrochlear or axillary lymphadenopathy was present, inconsistent with lymphangitic spread and more suggestive of distinct inoculation of different sites on the hands and forearms. A grade 2 systolic ejection murmur was heard at the right-upper-sternal border with no radiation. Other than clubbing, no peripheral signs of endocarditis were present.
Figure 1. Nodular lesions along the patient’s dorsum of her hand and along her forearm. The largest nodule is on the dorsum of her hand, reflecting the oldest nodule in the location of her earlier injection sites. The absence of lymphadenopathy and the presence of nodules in many locations beyond a single lymphatic drainage reflect separate inoculation events rather than lymphangitic spread.
The plastic surgery service was consulted to perform an excisional biopsy of one of the patient’s forearm nodules, which revealed necrotizing granulomas (Figure 2). Blood cultures were positive.
Figure 2. Suppurative granuloma with central necrosis and neutrophilic infiltration.
One of 2 original sets of blood cultures grew Mycobacterium mucogenicum and Stenotrophomonas maltophilia, identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF; Bruker Biotyper, Bruker Daltonics). Stenotrophomonas maltophilia was reported 2 days after blood draw and was susceptible to levofloxacin, trimethoprim-sulfamethoxazole, minocycline, and ceftazidime as determined by broth microdilution method and interpreted according to current Clinical and Laboratory Standards Institute (CLSI). Mycobacterium mucogenicum was reported 5 days after initial blood draw. Pathology from the patient’s excised forearm nodule demonstrated suppurative necrotizing granulomas associated with acid-fast bacilli on Fite’s stain, a peanut oil/xylene modification of Ziehl-Neelsen (see Figure 3). Within the nodule, foreign crystalline material was identified under examination with polarized light. Gram stain from the nodule revealed scant Gram-positive cocci and Gram-negative bacilli, but no organism grew on aerobic, anaerobic, or mycobacterial culture. Culture of fluid from her forearm abscess grew S maltophilia and Streptococcus pneumoniae. Transthoracic echocardiogram did not reveal any valvular vegetations or regurgitation.
Figure 3. Acid-fast bacilli (Fite’s stain) in the upper central part of the image. Crystalline material is seen in the lower left of the frame.
Although M mucogenicum susceptibilities were pending, the patient was treated with trimethoprim-sulfamethoxazole ([TMP-SMX] 4.5 mg/kg of the TMP component twice a day) and clarithromycin (500 milligrams orally twice a day), a regimen intended to treat S maltophilia as well as M mucogenicum. Treatment became complicated by a prolonged QTc on electrocardiogram after clarithromycin initiation; clarithromycin was changed to doxycycline (100 mg PO BID). Psychiatry was consulted to wean QTc-prolonging medications.
Antimicrobial susceptibility testing of the M mucogenicum isolate susceptibility testing demonstrated susceptibility to TMP-SMX, amikacin, cefoxitin, ciprofloxacin, clarithromycin, imipenem, linezolid, and moxifloxacin but resistance to doxycycline. Antimicrobial susceptibility was determined by broth microdilution and interpreted according to CLSI breakpoints. The patient’s prolonged QTc and psychiatric medications precluded the use of 2 oral agents with in vitro activity, and thus the patient was maintained on her existing regimen with a plan to change doxycycline to clarithromycin once QTc normalized. Multiple repeated blood cultures and mycobacterial blood culture were negative. Over the course of 12 weeks of therapy, the patient clinically improved and her nodules decreased in size and eventually disappeared altogether. Although the patient’s M mucogenicum bacteremia and nodular soft tissue infection resolved, she was subsequently diagnosed with endocarditis from other environmental organisms, including S maltophilia, and she was hospitalized for 6 weeks before being discharged home. During her admission for endocarditis, she was treated with TMP-SMX in addition to meropenem that would likely have therapeutic effect on residual M mucogenicum. Her most recent blood cultures 6 weeks after discharge are negative.
Patient Consent Statement
Written informed consent was obtained from the patient to describe her case and include pictures of her arms and nodule pathology. The design and publication of this work has been approved by the University of Manitoba Bannatyne Research Ethics Board (HS23928:H2020:227, approved May 4, 2020) and conforms to standards currently applied in Canada.
DISCUSSION
Mycobacterium mucogenicum is a rapidly growing nontuberculous mycobacterium (RGM) that routinely inhabits tap water [3, 4]. Mycobacterium mucogenicum’s ability to form biofilms and reproduce in environmental amoeba enables it to tolerate various forms of sanitization including mild chlorination [3]. Due to this fitness advantage in disinfected aqueous ecosystems, M mucogenicum is the most commonly identified RGM in tap water [5].
Mycobacterium mucogenicum infection has diverse clinical manifestations in both immunocompetent as well as immunocompromised hosts, although it is notorious for causing outbreaks of catheter-related blood stream infections among hemodialysis and oncology patients [3, 4, 6]. The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. To our knowledge, this is the second reported case of M mucogenicum infection associated with the injection of drugs [7]. Our patient’s polymicrobial bacteremia was due to injection of tap water from the same contaminated source that caused the granulomatous nodular inflammation in her forearms.
The concurrence of M mucogenicum and S maltophilia in the blood culture as well as the nodule may reflect a novel manifestation of mycobacterial coinfection with a Gram-negative bacillus. This phenomenon has been commonly described in patients with cystic fibrosis where horizontal gene transfer from pseudomonads contributes to the virulence of Mycobacterium abscessus [8]. Although polymicrobial culture positivity often suggests contamination, here the coexistence of RGM and Gram-negative bacillus may suggest the simultaneous inoculation of environmental symbionts.
Optimal treatment for M mucogenicum bacteremia and soft tissue infection remains unclear. If a single skin lesion is present, surgical excision should be considered. A combination of 2 agents, to which the isolate demonstrates in vitro susceptibility, is recommended to prevent the development of drug resistance [9, 10]. Mycobacterium mucogenicum is commonly susceptible to many antimicrobials including amikacin, cefoxitin, clarithromycin, imipenem, and TMP-SMX [3]. However, like other RGM, it remains resistant to first-line antituberculous medications.
CONCLUSIONS
As our case illustrates, among persons who inject drugs, bacteremia with RGM should not be considered a contaminant and may in fact point to other sites of infection. People who inject drugs often experience physical, psychiatric, and socioeconomic difficulties that limit their access to sterile injection equipment. Expanding harm reduction programs to increase accessibility of sterile paraphernalia could mitigate infectious complications of injection drug use and subsequent hospital admission. Antimicrobial options were significantly limited by our patient’s polypharmacy. This case further emphasizes the need for coordinated infectious disease, psychiatric, and addictions care. It is essential for infectious diseases specialists to incorporate harm reduction strategies into their patient interaction to prevent further infectious complications from intravenous drug use.
Acknowledgments
We thank our patient for her good sense of humor, her willingness to participate in this project, and her resilience in the face of difficult circumstances.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | AMITRIPTYLINE, CLARITHROMYCIN, FLUOXETINE HYDROCHLORIDE, HYDROMORPHONE, METHAMPHETAMINE, QUETIAPINE, RISPERIDONE, SULFAMETHOXAZOLE\TRIMETHOPRIM | DrugsGivenReaction | CC BY-NC-ND | 33447641 | 19,093,962 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Mycobacterial infection'. | Mycobacterium Mucogenicum Bacteremia and Nodular Soft Tissue Infection in a Person Who Uses Tap Water to Inject Drugs.
The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. In this study, we report a case of Mycobacterium mucogenicum bacteremia and associated nodular soft tissue infection in a person who uses tap water to inject drugs.
CASE
A 50-year-old female presented to a community hospital with a 24-hour history of fever and a right forearm abscess at the site of drug injection. The forearm abscess was incised and drained, and a sample was obtained for bacterial culture. Two peripheral blood cultures were collected before treatment with meropenem. The patient’s forearms demonstrated subcutaneous nodules that she maintained had increased in size slowly during the 2 years preceding her current hospital presentation.
The patient has psychiatric illness, of which intergenerational trauma is a probable factor [1, 2]; her parents attended Canada’s Indian Residential School system. She had been diagnosed with bipolar disorder, borderline personality disorder, and polysubstance use disorder. Her home medications included risperidone, quetiapine, fluoxetine, amitriptyline, and hydromorphone. Our patient injects cocaine on a daily basis and methamphetamine and opioids when cocaine is difficult to obtain. The patient injects her drugs using unfiltered tap water as sterile water ampules and filters are rarely accessible; she has a history of bacteremia from environmental organisms, including Sphingomonas spp, Microbacterium spp, Chryseobacterium indologenes, and Sphingobacterium spiritivorum. She denied sharing her injection paraphernalia and reusing her needles. At baseline, our patient is on home oxygen (2 L/minute) due to chronic obstructive pulmonary disease and pulmonary talcosis. Additional medical history includes inactive hepatitis C and fibromyalgia; she is human immunodeficiency virus negative. She lives in an apartment with her son in Winnipeg, Manitoba, Canada.
Her temperature was 38.2oC, her pulse 121 beats-per-minute, her blood pressure 92/59 mmHg, and her oxygen saturation was 94% while receiving 2 L/minute oxygen via nasal prongs. Physical examination revealed bilateral nodular lesions extending from the dorsum of her hands to her elbows (Figure 1). The nodules were firm and nontender with no overlying erythema. No epitrochlear or axillary lymphadenopathy was present, inconsistent with lymphangitic spread and more suggestive of distinct inoculation of different sites on the hands and forearms. A grade 2 systolic ejection murmur was heard at the right-upper-sternal border with no radiation. Other than clubbing, no peripheral signs of endocarditis were present.
Figure 1. Nodular lesions along the patient’s dorsum of her hand and along her forearm. The largest nodule is on the dorsum of her hand, reflecting the oldest nodule in the location of her earlier injection sites. The absence of lymphadenopathy and the presence of nodules in many locations beyond a single lymphatic drainage reflect separate inoculation events rather than lymphangitic spread.
The plastic surgery service was consulted to perform an excisional biopsy of one of the patient’s forearm nodules, which revealed necrotizing granulomas (Figure 2). Blood cultures were positive.
Figure 2. Suppurative granuloma with central necrosis and neutrophilic infiltration.
One of 2 original sets of blood cultures grew Mycobacterium mucogenicum and Stenotrophomonas maltophilia, identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF; Bruker Biotyper, Bruker Daltonics). Stenotrophomonas maltophilia was reported 2 days after blood draw and was susceptible to levofloxacin, trimethoprim-sulfamethoxazole, minocycline, and ceftazidime as determined by broth microdilution method and interpreted according to current Clinical and Laboratory Standards Institute (CLSI). Mycobacterium mucogenicum was reported 5 days after initial blood draw. Pathology from the patient’s excised forearm nodule demonstrated suppurative necrotizing granulomas associated with acid-fast bacilli on Fite’s stain, a peanut oil/xylene modification of Ziehl-Neelsen (see Figure 3). Within the nodule, foreign crystalline material was identified under examination with polarized light. Gram stain from the nodule revealed scant Gram-positive cocci and Gram-negative bacilli, but no organism grew on aerobic, anaerobic, or mycobacterial culture. Culture of fluid from her forearm abscess grew S maltophilia and Streptococcus pneumoniae. Transthoracic echocardiogram did not reveal any valvular vegetations or regurgitation.
Figure 3. Acid-fast bacilli (Fite’s stain) in the upper central part of the image. Crystalline material is seen in the lower left of the frame.
Although M mucogenicum susceptibilities were pending, the patient was treated with trimethoprim-sulfamethoxazole ([TMP-SMX] 4.5 mg/kg of the TMP component twice a day) and clarithromycin (500 milligrams orally twice a day), a regimen intended to treat S maltophilia as well as M mucogenicum. Treatment became complicated by a prolonged QTc on electrocardiogram after clarithromycin initiation; clarithromycin was changed to doxycycline (100 mg PO BID). Psychiatry was consulted to wean QTc-prolonging medications.
Antimicrobial susceptibility testing of the M mucogenicum isolate susceptibility testing demonstrated susceptibility to TMP-SMX, amikacin, cefoxitin, ciprofloxacin, clarithromycin, imipenem, linezolid, and moxifloxacin but resistance to doxycycline. Antimicrobial susceptibility was determined by broth microdilution and interpreted according to CLSI breakpoints. The patient’s prolonged QTc and psychiatric medications precluded the use of 2 oral agents with in vitro activity, and thus the patient was maintained on her existing regimen with a plan to change doxycycline to clarithromycin once QTc normalized. Multiple repeated blood cultures and mycobacterial blood culture were negative. Over the course of 12 weeks of therapy, the patient clinically improved and her nodules decreased in size and eventually disappeared altogether. Although the patient’s M mucogenicum bacteremia and nodular soft tissue infection resolved, she was subsequently diagnosed with endocarditis from other environmental organisms, including S maltophilia, and she was hospitalized for 6 weeks before being discharged home. During her admission for endocarditis, she was treated with TMP-SMX in addition to meropenem that would likely have therapeutic effect on residual M mucogenicum. Her most recent blood cultures 6 weeks after discharge are negative.
Patient Consent Statement
Written informed consent was obtained from the patient to describe her case and include pictures of her arms and nodule pathology. The design and publication of this work has been approved by the University of Manitoba Bannatyne Research Ethics Board (HS23928:H2020:227, approved May 4, 2020) and conforms to standards currently applied in Canada.
DISCUSSION
Mycobacterium mucogenicum is a rapidly growing nontuberculous mycobacterium (RGM) that routinely inhabits tap water [3, 4]. Mycobacterium mucogenicum’s ability to form biofilms and reproduce in environmental amoeba enables it to tolerate various forms of sanitization including mild chlorination [3]. Due to this fitness advantage in disinfected aqueous ecosystems, M mucogenicum is the most commonly identified RGM in tap water [5].
Mycobacterium mucogenicum infection has diverse clinical manifestations in both immunocompetent as well as immunocompromised hosts, although it is notorious for causing outbreaks of catheter-related blood stream infections among hemodialysis and oncology patients [3, 4, 6]. The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. To our knowledge, this is the second reported case of M mucogenicum infection associated with the injection of drugs [7]. Our patient’s polymicrobial bacteremia was due to injection of tap water from the same contaminated source that caused the granulomatous nodular inflammation in her forearms.
The concurrence of M mucogenicum and S maltophilia in the blood culture as well as the nodule may reflect a novel manifestation of mycobacterial coinfection with a Gram-negative bacillus. This phenomenon has been commonly described in patients with cystic fibrosis where horizontal gene transfer from pseudomonads contributes to the virulence of Mycobacterium abscessus [8]. Although polymicrobial culture positivity often suggests contamination, here the coexistence of RGM and Gram-negative bacillus may suggest the simultaneous inoculation of environmental symbionts.
Optimal treatment for M mucogenicum bacteremia and soft tissue infection remains unclear. If a single skin lesion is present, surgical excision should be considered. A combination of 2 agents, to which the isolate demonstrates in vitro susceptibility, is recommended to prevent the development of drug resistance [9, 10]. Mycobacterium mucogenicum is commonly susceptible to many antimicrobials including amikacin, cefoxitin, clarithromycin, imipenem, and TMP-SMX [3]. However, like other RGM, it remains resistant to first-line antituberculous medications.
CONCLUSIONS
As our case illustrates, among persons who inject drugs, bacteremia with RGM should not be considered a contaminant and may in fact point to other sites of infection. People who inject drugs often experience physical, psychiatric, and socioeconomic difficulties that limit their access to sterile injection equipment. Expanding harm reduction programs to increase accessibility of sterile paraphernalia could mitigate infectious complications of injection drug use and subsequent hospital admission. Antimicrobial options were significantly limited by our patient’s polypharmacy. This case further emphasizes the need for coordinated infectious disease, psychiatric, and addictions care. It is essential for infectious diseases specialists to incorporate harm reduction strategies into their patient interaction to prevent further infectious complications from intravenous drug use.
Acknowledgments
We thank our patient for her good sense of humor, her willingness to participate in this project, and her resilience in the face of difficult circumstances.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | AMITRIPTYLINE, CLARITHROMYCIN, FLUOXETINE HYDROCHLORIDE, HYDROMORPHONE, METHAMPHETAMINE, QUETIAPINE, RISPERIDONE, SULFAMETHOXAZOLE\TRIMETHOPRIM | DrugsGivenReaction | CC BY-NC-ND | 33447641 | 19,093,962 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Stenotrophomonas infection'. | Mycobacterium Mucogenicum Bacteremia and Nodular Soft Tissue Infection in a Person Who Uses Tap Water to Inject Drugs.
The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. In this study, we report a case of Mycobacterium mucogenicum bacteremia and associated nodular soft tissue infection in a person who uses tap water to inject drugs.
CASE
A 50-year-old female presented to a community hospital with a 24-hour history of fever and a right forearm abscess at the site of drug injection. The forearm abscess was incised and drained, and a sample was obtained for bacterial culture. Two peripheral blood cultures were collected before treatment with meropenem. The patient’s forearms demonstrated subcutaneous nodules that she maintained had increased in size slowly during the 2 years preceding her current hospital presentation.
The patient has psychiatric illness, of which intergenerational trauma is a probable factor [1, 2]; her parents attended Canada’s Indian Residential School system. She had been diagnosed with bipolar disorder, borderline personality disorder, and polysubstance use disorder. Her home medications included risperidone, quetiapine, fluoxetine, amitriptyline, and hydromorphone. Our patient injects cocaine on a daily basis and methamphetamine and opioids when cocaine is difficult to obtain. The patient injects her drugs using unfiltered tap water as sterile water ampules and filters are rarely accessible; she has a history of bacteremia from environmental organisms, including Sphingomonas spp, Microbacterium spp, Chryseobacterium indologenes, and Sphingobacterium spiritivorum. She denied sharing her injection paraphernalia and reusing her needles. At baseline, our patient is on home oxygen (2 L/minute) due to chronic obstructive pulmonary disease and pulmonary talcosis. Additional medical history includes inactive hepatitis C and fibromyalgia; she is human immunodeficiency virus negative. She lives in an apartment with her son in Winnipeg, Manitoba, Canada.
Her temperature was 38.2oC, her pulse 121 beats-per-minute, her blood pressure 92/59 mmHg, and her oxygen saturation was 94% while receiving 2 L/minute oxygen via nasal prongs. Physical examination revealed bilateral nodular lesions extending from the dorsum of her hands to her elbows (Figure 1). The nodules were firm and nontender with no overlying erythema. No epitrochlear or axillary lymphadenopathy was present, inconsistent with lymphangitic spread and more suggestive of distinct inoculation of different sites on the hands and forearms. A grade 2 systolic ejection murmur was heard at the right-upper-sternal border with no radiation. Other than clubbing, no peripheral signs of endocarditis were present.
Figure 1. Nodular lesions along the patient’s dorsum of her hand and along her forearm. The largest nodule is on the dorsum of her hand, reflecting the oldest nodule in the location of her earlier injection sites. The absence of lymphadenopathy and the presence of nodules in many locations beyond a single lymphatic drainage reflect separate inoculation events rather than lymphangitic spread.
The plastic surgery service was consulted to perform an excisional biopsy of one of the patient’s forearm nodules, which revealed necrotizing granulomas (Figure 2). Blood cultures were positive.
Figure 2. Suppurative granuloma with central necrosis and neutrophilic infiltration.
One of 2 original sets of blood cultures grew Mycobacterium mucogenicum and Stenotrophomonas maltophilia, identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF; Bruker Biotyper, Bruker Daltonics). Stenotrophomonas maltophilia was reported 2 days after blood draw and was susceptible to levofloxacin, trimethoprim-sulfamethoxazole, minocycline, and ceftazidime as determined by broth microdilution method and interpreted according to current Clinical and Laboratory Standards Institute (CLSI). Mycobacterium mucogenicum was reported 5 days after initial blood draw. Pathology from the patient’s excised forearm nodule demonstrated suppurative necrotizing granulomas associated with acid-fast bacilli on Fite’s stain, a peanut oil/xylene modification of Ziehl-Neelsen (see Figure 3). Within the nodule, foreign crystalline material was identified under examination with polarized light. Gram stain from the nodule revealed scant Gram-positive cocci and Gram-negative bacilli, but no organism grew on aerobic, anaerobic, or mycobacterial culture. Culture of fluid from her forearm abscess grew S maltophilia and Streptococcus pneumoniae. Transthoracic echocardiogram did not reveal any valvular vegetations or regurgitation.
Figure 3. Acid-fast bacilli (Fite’s stain) in the upper central part of the image. Crystalline material is seen in the lower left of the frame.
Although M mucogenicum susceptibilities were pending, the patient was treated with trimethoprim-sulfamethoxazole ([TMP-SMX] 4.5 mg/kg of the TMP component twice a day) and clarithromycin (500 milligrams orally twice a day), a regimen intended to treat S maltophilia as well as M mucogenicum. Treatment became complicated by a prolonged QTc on electrocardiogram after clarithromycin initiation; clarithromycin was changed to doxycycline (100 mg PO BID). Psychiatry was consulted to wean QTc-prolonging medications.
Antimicrobial susceptibility testing of the M mucogenicum isolate susceptibility testing demonstrated susceptibility to TMP-SMX, amikacin, cefoxitin, ciprofloxacin, clarithromycin, imipenem, linezolid, and moxifloxacin but resistance to doxycycline. Antimicrobial susceptibility was determined by broth microdilution and interpreted according to CLSI breakpoints. The patient’s prolonged QTc and psychiatric medications precluded the use of 2 oral agents with in vitro activity, and thus the patient was maintained on her existing regimen with a plan to change doxycycline to clarithromycin once QTc normalized. Multiple repeated blood cultures and mycobacterial blood culture were negative. Over the course of 12 weeks of therapy, the patient clinically improved and her nodules decreased in size and eventually disappeared altogether. Although the patient’s M mucogenicum bacteremia and nodular soft tissue infection resolved, she was subsequently diagnosed with endocarditis from other environmental organisms, including S maltophilia, and she was hospitalized for 6 weeks before being discharged home. During her admission for endocarditis, she was treated with TMP-SMX in addition to meropenem that would likely have therapeutic effect on residual M mucogenicum. Her most recent blood cultures 6 weeks after discharge are negative.
Patient Consent Statement
Written informed consent was obtained from the patient to describe her case and include pictures of her arms and nodule pathology. The design and publication of this work has been approved by the University of Manitoba Bannatyne Research Ethics Board (HS23928:H2020:227, approved May 4, 2020) and conforms to standards currently applied in Canada.
DISCUSSION
Mycobacterium mucogenicum is a rapidly growing nontuberculous mycobacterium (RGM) that routinely inhabits tap water [3, 4]. Mycobacterium mucogenicum’s ability to form biofilms and reproduce in environmental amoeba enables it to tolerate various forms of sanitization including mild chlorination [3]. Due to this fitness advantage in disinfected aqueous ecosystems, M mucogenicum is the most commonly identified RGM in tap water [5].
Mycobacterium mucogenicum infection has diverse clinical manifestations in both immunocompetent as well as immunocompromised hosts, although it is notorious for causing outbreaks of catheter-related blood stream infections among hemodialysis and oncology patients [3, 4, 6]. The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. To our knowledge, this is the second reported case of M mucogenicum infection associated with the injection of drugs [7]. Our patient’s polymicrobial bacteremia was due to injection of tap water from the same contaminated source that caused the granulomatous nodular inflammation in her forearms.
The concurrence of M mucogenicum and S maltophilia in the blood culture as well as the nodule may reflect a novel manifestation of mycobacterial coinfection with a Gram-negative bacillus. This phenomenon has been commonly described in patients with cystic fibrosis where horizontal gene transfer from pseudomonads contributes to the virulence of Mycobacterium abscessus [8]. Although polymicrobial culture positivity often suggests contamination, here the coexistence of RGM and Gram-negative bacillus may suggest the simultaneous inoculation of environmental symbionts.
Optimal treatment for M mucogenicum bacteremia and soft tissue infection remains unclear. If a single skin lesion is present, surgical excision should be considered. A combination of 2 agents, to which the isolate demonstrates in vitro susceptibility, is recommended to prevent the development of drug resistance [9, 10]. Mycobacterium mucogenicum is commonly susceptible to many antimicrobials including amikacin, cefoxitin, clarithromycin, imipenem, and TMP-SMX [3]. However, like other RGM, it remains resistant to first-line antituberculous medications.
CONCLUSIONS
As our case illustrates, among persons who inject drugs, bacteremia with RGM should not be considered a contaminant and may in fact point to other sites of infection. People who inject drugs often experience physical, psychiatric, and socioeconomic difficulties that limit their access to sterile injection equipment. Expanding harm reduction programs to increase accessibility of sterile paraphernalia could mitigate infectious complications of injection drug use and subsequent hospital admission. Antimicrobial options were significantly limited by our patient’s polypharmacy. This case further emphasizes the need for coordinated infectious disease, psychiatric, and addictions care. It is essential for infectious diseases specialists to incorporate harm reduction strategies into their patient interaction to prevent further infectious complications from intravenous drug use.
Acknowledgments
We thank our patient for her good sense of humor, her willingness to participate in this project, and her resilience in the face of difficult circumstances.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | AMITRIPTYLINE, CLARITHROMYCIN, FLUOXETINE HYDROCHLORIDE, HYDROMORPHONE, METHAMPHETAMINE, QUETIAPINE, RISPERIDONE, SULFAMETHOXAZOLE\TRIMETHOPRIM | DrugsGivenReaction | CC BY-NC-ND | 33447641 | 19,093,962 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Streptococcal infection'. | Mycobacterium Mucogenicum Bacteremia and Nodular Soft Tissue Infection in a Person Who Uses Tap Water to Inject Drugs.
The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. In this study, we report a case of Mycobacterium mucogenicum bacteremia and associated nodular soft tissue infection in a person who uses tap water to inject drugs.
CASE
A 50-year-old female presented to a community hospital with a 24-hour history of fever and a right forearm abscess at the site of drug injection. The forearm abscess was incised and drained, and a sample was obtained for bacterial culture. Two peripheral blood cultures were collected before treatment with meropenem. The patient’s forearms demonstrated subcutaneous nodules that she maintained had increased in size slowly during the 2 years preceding her current hospital presentation.
The patient has psychiatric illness, of which intergenerational trauma is a probable factor [1, 2]; her parents attended Canada’s Indian Residential School system. She had been diagnosed with bipolar disorder, borderline personality disorder, and polysubstance use disorder. Her home medications included risperidone, quetiapine, fluoxetine, amitriptyline, and hydromorphone. Our patient injects cocaine on a daily basis and methamphetamine and opioids when cocaine is difficult to obtain. The patient injects her drugs using unfiltered tap water as sterile water ampules and filters are rarely accessible; she has a history of bacteremia from environmental organisms, including Sphingomonas spp, Microbacterium spp, Chryseobacterium indologenes, and Sphingobacterium spiritivorum. She denied sharing her injection paraphernalia and reusing her needles. At baseline, our patient is on home oxygen (2 L/minute) due to chronic obstructive pulmonary disease and pulmonary talcosis. Additional medical history includes inactive hepatitis C and fibromyalgia; she is human immunodeficiency virus negative. She lives in an apartment with her son in Winnipeg, Manitoba, Canada.
Her temperature was 38.2oC, her pulse 121 beats-per-minute, her blood pressure 92/59 mmHg, and her oxygen saturation was 94% while receiving 2 L/minute oxygen via nasal prongs. Physical examination revealed bilateral nodular lesions extending from the dorsum of her hands to her elbows (Figure 1). The nodules were firm and nontender with no overlying erythema. No epitrochlear or axillary lymphadenopathy was present, inconsistent with lymphangitic spread and more suggestive of distinct inoculation of different sites on the hands and forearms. A grade 2 systolic ejection murmur was heard at the right-upper-sternal border with no radiation. Other than clubbing, no peripheral signs of endocarditis were present.
Figure 1. Nodular lesions along the patient’s dorsum of her hand and along her forearm. The largest nodule is on the dorsum of her hand, reflecting the oldest nodule in the location of her earlier injection sites. The absence of lymphadenopathy and the presence of nodules in many locations beyond a single lymphatic drainage reflect separate inoculation events rather than lymphangitic spread.
The plastic surgery service was consulted to perform an excisional biopsy of one of the patient’s forearm nodules, which revealed necrotizing granulomas (Figure 2). Blood cultures were positive.
Figure 2. Suppurative granuloma with central necrosis and neutrophilic infiltration.
One of 2 original sets of blood cultures grew Mycobacterium mucogenicum and Stenotrophomonas maltophilia, identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF; Bruker Biotyper, Bruker Daltonics). Stenotrophomonas maltophilia was reported 2 days after blood draw and was susceptible to levofloxacin, trimethoprim-sulfamethoxazole, minocycline, and ceftazidime as determined by broth microdilution method and interpreted according to current Clinical and Laboratory Standards Institute (CLSI). Mycobacterium mucogenicum was reported 5 days after initial blood draw. Pathology from the patient’s excised forearm nodule demonstrated suppurative necrotizing granulomas associated with acid-fast bacilli on Fite’s stain, a peanut oil/xylene modification of Ziehl-Neelsen (see Figure 3). Within the nodule, foreign crystalline material was identified under examination with polarized light. Gram stain from the nodule revealed scant Gram-positive cocci and Gram-negative bacilli, but no organism grew on aerobic, anaerobic, or mycobacterial culture. Culture of fluid from her forearm abscess grew S maltophilia and Streptococcus pneumoniae. Transthoracic echocardiogram did not reveal any valvular vegetations or regurgitation.
Figure 3. Acid-fast bacilli (Fite’s stain) in the upper central part of the image. Crystalline material is seen in the lower left of the frame.
Although M mucogenicum susceptibilities were pending, the patient was treated with trimethoprim-sulfamethoxazole ([TMP-SMX] 4.5 mg/kg of the TMP component twice a day) and clarithromycin (500 milligrams orally twice a day), a regimen intended to treat S maltophilia as well as M mucogenicum. Treatment became complicated by a prolonged QTc on electrocardiogram after clarithromycin initiation; clarithromycin was changed to doxycycline (100 mg PO BID). Psychiatry was consulted to wean QTc-prolonging medications.
Antimicrobial susceptibility testing of the M mucogenicum isolate susceptibility testing demonstrated susceptibility to TMP-SMX, amikacin, cefoxitin, ciprofloxacin, clarithromycin, imipenem, linezolid, and moxifloxacin but resistance to doxycycline. Antimicrobial susceptibility was determined by broth microdilution and interpreted according to CLSI breakpoints. The patient’s prolonged QTc and psychiatric medications precluded the use of 2 oral agents with in vitro activity, and thus the patient was maintained on her existing regimen with a plan to change doxycycline to clarithromycin once QTc normalized. Multiple repeated blood cultures and mycobacterial blood culture were negative. Over the course of 12 weeks of therapy, the patient clinically improved and her nodules decreased in size and eventually disappeared altogether. Although the patient’s M mucogenicum bacteremia and nodular soft tissue infection resolved, she was subsequently diagnosed with endocarditis from other environmental organisms, including S maltophilia, and she was hospitalized for 6 weeks before being discharged home. During her admission for endocarditis, she was treated with TMP-SMX in addition to meropenem that would likely have therapeutic effect on residual M mucogenicum. Her most recent blood cultures 6 weeks after discharge are negative.
Patient Consent Statement
Written informed consent was obtained from the patient to describe her case and include pictures of her arms and nodule pathology. The design and publication of this work has been approved by the University of Manitoba Bannatyne Research Ethics Board (HS23928:H2020:227, approved May 4, 2020) and conforms to standards currently applied in Canada.
DISCUSSION
Mycobacterium mucogenicum is a rapidly growing nontuberculous mycobacterium (RGM) that routinely inhabits tap water [3, 4]. Mycobacterium mucogenicum’s ability to form biofilms and reproduce in environmental amoeba enables it to tolerate various forms of sanitization including mild chlorination [3]. Due to this fitness advantage in disinfected aqueous ecosystems, M mucogenicum is the most commonly identified RGM in tap water [5].
Mycobacterium mucogenicum infection has diverse clinical manifestations in both immunocompetent as well as immunocompromised hosts, although it is notorious for causing outbreaks of catheter-related blood stream infections among hemodialysis and oncology patients [3, 4, 6]. The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. To our knowledge, this is the second reported case of M mucogenicum infection associated with the injection of drugs [7]. Our patient’s polymicrobial bacteremia was due to injection of tap water from the same contaminated source that caused the granulomatous nodular inflammation in her forearms.
The concurrence of M mucogenicum and S maltophilia in the blood culture as well as the nodule may reflect a novel manifestation of mycobacterial coinfection with a Gram-negative bacillus. This phenomenon has been commonly described in patients with cystic fibrosis where horizontal gene transfer from pseudomonads contributes to the virulence of Mycobacterium abscessus [8]. Although polymicrobial culture positivity often suggests contamination, here the coexistence of RGM and Gram-negative bacillus may suggest the simultaneous inoculation of environmental symbionts.
Optimal treatment for M mucogenicum bacteremia and soft tissue infection remains unclear. If a single skin lesion is present, surgical excision should be considered. A combination of 2 agents, to which the isolate demonstrates in vitro susceptibility, is recommended to prevent the development of drug resistance [9, 10]. Mycobacterium mucogenicum is commonly susceptible to many antimicrobials including amikacin, cefoxitin, clarithromycin, imipenem, and TMP-SMX [3]. However, like other RGM, it remains resistant to first-line antituberculous medications.
CONCLUSIONS
As our case illustrates, among persons who inject drugs, bacteremia with RGM should not be considered a contaminant and may in fact point to other sites of infection. People who inject drugs often experience physical, psychiatric, and socioeconomic difficulties that limit their access to sterile injection equipment. Expanding harm reduction programs to increase accessibility of sterile paraphernalia could mitigate infectious complications of injection drug use and subsequent hospital admission. Antimicrobial options were significantly limited by our patient’s polypharmacy. This case further emphasizes the need for coordinated infectious disease, psychiatric, and addictions care. It is essential for infectious diseases specialists to incorporate harm reduction strategies into their patient interaction to prevent further infectious complications from intravenous drug use.
Acknowledgments
We thank our patient for her good sense of humor, her willingness to participate in this project, and her resilience in the face of difficult circumstances.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | AMITRIPTYLINE, CLARITHROMYCIN, FLUOXETINE HYDROCHLORIDE, HYDROMORPHONE, METHAMPHETAMINE, QUETIAPINE, RISPERIDONE, SULFAMETHOXAZOLE\TRIMETHOPRIM | DrugsGivenReaction | CC BY-NC-ND | 33447641 | 19,093,962 | 2021-01 |
What was the administration route of drug 'CLARITHROMYCIN'? | Mycobacterium Mucogenicum Bacteremia and Nodular Soft Tissue Infection in a Person Who Uses Tap Water to Inject Drugs.
The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. In this study, we report a case of Mycobacterium mucogenicum bacteremia and associated nodular soft tissue infection in a person who uses tap water to inject drugs.
CASE
A 50-year-old female presented to a community hospital with a 24-hour history of fever and a right forearm abscess at the site of drug injection. The forearm abscess was incised and drained, and a sample was obtained for bacterial culture. Two peripheral blood cultures were collected before treatment with meropenem. The patient’s forearms demonstrated subcutaneous nodules that she maintained had increased in size slowly during the 2 years preceding her current hospital presentation.
The patient has psychiatric illness, of which intergenerational trauma is a probable factor [1, 2]; her parents attended Canada’s Indian Residential School system. She had been diagnosed with bipolar disorder, borderline personality disorder, and polysubstance use disorder. Her home medications included risperidone, quetiapine, fluoxetine, amitriptyline, and hydromorphone. Our patient injects cocaine on a daily basis and methamphetamine and opioids when cocaine is difficult to obtain. The patient injects her drugs using unfiltered tap water as sterile water ampules and filters are rarely accessible; she has a history of bacteremia from environmental organisms, including Sphingomonas spp, Microbacterium spp, Chryseobacterium indologenes, and Sphingobacterium spiritivorum. She denied sharing her injection paraphernalia and reusing her needles. At baseline, our patient is on home oxygen (2 L/minute) due to chronic obstructive pulmonary disease and pulmonary talcosis. Additional medical history includes inactive hepatitis C and fibromyalgia; she is human immunodeficiency virus negative. She lives in an apartment with her son in Winnipeg, Manitoba, Canada.
Her temperature was 38.2oC, her pulse 121 beats-per-minute, her blood pressure 92/59 mmHg, and her oxygen saturation was 94% while receiving 2 L/minute oxygen via nasal prongs. Physical examination revealed bilateral nodular lesions extending from the dorsum of her hands to her elbows (Figure 1). The nodules were firm and nontender with no overlying erythema. No epitrochlear or axillary lymphadenopathy was present, inconsistent with lymphangitic spread and more suggestive of distinct inoculation of different sites on the hands and forearms. A grade 2 systolic ejection murmur was heard at the right-upper-sternal border with no radiation. Other than clubbing, no peripheral signs of endocarditis were present.
Figure 1. Nodular lesions along the patient’s dorsum of her hand and along her forearm. The largest nodule is on the dorsum of her hand, reflecting the oldest nodule in the location of her earlier injection sites. The absence of lymphadenopathy and the presence of nodules in many locations beyond a single lymphatic drainage reflect separate inoculation events rather than lymphangitic spread.
The plastic surgery service was consulted to perform an excisional biopsy of one of the patient’s forearm nodules, which revealed necrotizing granulomas (Figure 2). Blood cultures were positive.
Figure 2. Suppurative granuloma with central necrosis and neutrophilic infiltration.
One of 2 original sets of blood cultures grew Mycobacterium mucogenicum and Stenotrophomonas maltophilia, identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF; Bruker Biotyper, Bruker Daltonics). Stenotrophomonas maltophilia was reported 2 days after blood draw and was susceptible to levofloxacin, trimethoprim-sulfamethoxazole, minocycline, and ceftazidime as determined by broth microdilution method and interpreted according to current Clinical and Laboratory Standards Institute (CLSI). Mycobacterium mucogenicum was reported 5 days after initial blood draw. Pathology from the patient’s excised forearm nodule demonstrated suppurative necrotizing granulomas associated with acid-fast bacilli on Fite’s stain, a peanut oil/xylene modification of Ziehl-Neelsen (see Figure 3). Within the nodule, foreign crystalline material was identified under examination with polarized light. Gram stain from the nodule revealed scant Gram-positive cocci and Gram-negative bacilli, but no organism grew on aerobic, anaerobic, or mycobacterial culture. Culture of fluid from her forearm abscess grew S maltophilia and Streptococcus pneumoniae. Transthoracic echocardiogram did not reveal any valvular vegetations or regurgitation.
Figure 3. Acid-fast bacilli (Fite’s stain) in the upper central part of the image. Crystalline material is seen in the lower left of the frame.
Although M mucogenicum susceptibilities were pending, the patient was treated with trimethoprim-sulfamethoxazole ([TMP-SMX] 4.5 mg/kg of the TMP component twice a day) and clarithromycin (500 milligrams orally twice a day), a regimen intended to treat S maltophilia as well as M mucogenicum. Treatment became complicated by a prolonged QTc on electrocardiogram after clarithromycin initiation; clarithromycin was changed to doxycycline (100 mg PO BID). Psychiatry was consulted to wean QTc-prolonging medications.
Antimicrobial susceptibility testing of the M mucogenicum isolate susceptibility testing demonstrated susceptibility to TMP-SMX, amikacin, cefoxitin, ciprofloxacin, clarithromycin, imipenem, linezolid, and moxifloxacin but resistance to doxycycline. Antimicrobial susceptibility was determined by broth microdilution and interpreted according to CLSI breakpoints. The patient’s prolonged QTc and psychiatric medications precluded the use of 2 oral agents with in vitro activity, and thus the patient was maintained on her existing regimen with a plan to change doxycycline to clarithromycin once QTc normalized. Multiple repeated blood cultures and mycobacterial blood culture were negative. Over the course of 12 weeks of therapy, the patient clinically improved and her nodules decreased in size and eventually disappeared altogether. Although the patient’s M mucogenicum bacteremia and nodular soft tissue infection resolved, she was subsequently diagnosed with endocarditis from other environmental organisms, including S maltophilia, and she was hospitalized for 6 weeks before being discharged home. During her admission for endocarditis, she was treated with TMP-SMX in addition to meropenem that would likely have therapeutic effect on residual M mucogenicum. Her most recent blood cultures 6 weeks after discharge are negative.
Patient Consent Statement
Written informed consent was obtained from the patient to describe her case and include pictures of her arms and nodule pathology. The design and publication of this work has been approved by the University of Manitoba Bannatyne Research Ethics Board (HS23928:H2020:227, approved May 4, 2020) and conforms to standards currently applied in Canada.
DISCUSSION
Mycobacterium mucogenicum is a rapidly growing nontuberculous mycobacterium (RGM) that routinely inhabits tap water [3, 4]. Mycobacterium mucogenicum’s ability to form biofilms and reproduce in environmental amoeba enables it to tolerate various forms of sanitization including mild chlorination [3]. Due to this fitness advantage in disinfected aqueous ecosystems, M mucogenicum is the most commonly identified RGM in tap water [5].
Mycobacterium mucogenicum infection has diverse clinical manifestations in both immunocompetent as well as immunocompromised hosts, although it is notorious for causing outbreaks of catheter-related blood stream infections among hemodialysis and oncology patients [3, 4, 6]. The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. To our knowledge, this is the second reported case of M mucogenicum infection associated with the injection of drugs [7]. Our patient’s polymicrobial bacteremia was due to injection of tap water from the same contaminated source that caused the granulomatous nodular inflammation in her forearms.
The concurrence of M mucogenicum and S maltophilia in the blood culture as well as the nodule may reflect a novel manifestation of mycobacterial coinfection with a Gram-negative bacillus. This phenomenon has been commonly described in patients with cystic fibrosis where horizontal gene transfer from pseudomonads contributes to the virulence of Mycobacterium abscessus [8]. Although polymicrobial culture positivity often suggests contamination, here the coexistence of RGM and Gram-negative bacillus may suggest the simultaneous inoculation of environmental symbionts.
Optimal treatment for M mucogenicum bacteremia and soft tissue infection remains unclear. If a single skin lesion is present, surgical excision should be considered. A combination of 2 agents, to which the isolate demonstrates in vitro susceptibility, is recommended to prevent the development of drug resistance [9, 10]. Mycobacterium mucogenicum is commonly susceptible to many antimicrobials including amikacin, cefoxitin, clarithromycin, imipenem, and TMP-SMX [3]. However, like other RGM, it remains resistant to first-line antituberculous medications.
CONCLUSIONS
As our case illustrates, among persons who inject drugs, bacteremia with RGM should not be considered a contaminant and may in fact point to other sites of infection. People who inject drugs often experience physical, psychiatric, and socioeconomic difficulties that limit their access to sterile injection equipment. Expanding harm reduction programs to increase accessibility of sterile paraphernalia could mitigate infectious complications of injection drug use and subsequent hospital admission. Antimicrobial options were significantly limited by our patient’s polypharmacy. This case further emphasizes the need for coordinated infectious disease, psychiatric, and addictions care. It is essential for infectious diseases specialists to incorporate harm reduction strategies into their patient interaction to prevent further infectious complications from intravenous drug use.
Acknowledgments
We thank our patient for her good sense of humor, her willingness to participate in this project, and her resilience in the face of difficult circumstances.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33447641 | 19,093,962 | 2021-01 |
What was the administration route of drug 'METHAMPHETAMINE'? | Mycobacterium Mucogenicum Bacteremia and Nodular Soft Tissue Infection in a Person Who Uses Tap Water to Inject Drugs.
The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. In this study, we report a case of Mycobacterium mucogenicum bacteremia and associated nodular soft tissue infection in a person who uses tap water to inject drugs.
CASE
A 50-year-old female presented to a community hospital with a 24-hour history of fever and a right forearm abscess at the site of drug injection. The forearm abscess was incised and drained, and a sample was obtained for bacterial culture. Two peripheral blood cultures were collected before treatment with meropenem. The patient’s forearms demonstrated subcutaneous nodules that she maintained had increased in size slowly during the 2 years preceding her current hospital presentation.
The patient has psychiatric illness, of which intergenerational trauma is a probable factor [1, 2]; her parents attended Canada’s Indian Residential School system. She had been diagnosed with bipolar disorder, borderline personality disorder, and polysubstance use disorder. Her home medications included risperidone, quetiapine, fluoxetine, amitriptyline, and hydromorphone. Our patient injects cocaine on a daily basis and methamphetamine and opioids when cocaine is difficult to obtain. The patient injects her drugs using unfiltered tap water as sterile water ampules and filters are rarely accessible; she has a history of bacteremia from environmental organisms, including Sphingomonas spp, Microbacterium spp, Chryseobacterium indologenes, and Sphingobacterium spiritivorum. She denied sharing her injection paraphernalia and reusing her needles. At baseline, our patient is on home oxygen (2 L/minute) due to chronic obstructive pulmonary disease and pulmonary talcosis. Additional medical history includes inactive hepatitis C and fibromyalgia; she is human immunodeficiency virus negative. She lives in an apartment with her son in Winnipeg, Manitoba, Canada.
Her temperature was 38.2oC, her pulse 121 beats-per-minute, her blood pressure 92/59 mmHg, and her oxygen saturation was 94% while receiving 2 L/minute oxygen via nasal prongs. Physical examination revealed bilateral nodular lesions extending from the dorsum of her hands to her elbows (Figure 1). The nodules were firm and nontender with no overlying erythema. No epitrochlear or axillary lymphadenopathy was present, inconsistent with lymphangitic spread and more suggestive of distinct inoculation of different sites on the hands and forearms. A grade 2 systolic ejection murmur was heard at the right-upper-sternal border with no radiation. Other than clubbing, no peripheral signs of endocarditis were present.
Figure 1. Nodular lesions along the patient’s dorsum of her hand and along her forearm. The largest nodule is on the dorsum of her hand, reflecting the oldest nodule in the location of her earlier injection sites. The absence of lymphadenopathy and the presence of nodules in many locations beyond a single lymphatic drainage reflect separate inoculation events rather than lymphangitic spread.
The plastic surgery service was consulted to perform an excisional biopsy of one of the patient’s forearm nodules, which revealed necrotizing granulomas (Figure 2). Blood cultures were positive.
Figure 2. Suppurative granuloma with central necrosis and neutrophilic infiltration.
One of 2 original sets of blood cultures grew Mycobacterium mucogenicum and Stenotrophomonas maltophilia, identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF; Bruker Biotyper, Bruker Daltonics). Stenotrophomonas maltophilia was reported 2 days after blood draw and was susceptible to levofloxacin, trimethoprim-sulfamethoxazole, minocycline, and ceftazidime as determined by broth microdilution method and interpreted according to current Clinical and Laboratory Standards Institute (CLSI). Mycobacterium mucogenicum was reported 5 days after initial blood draw. Pathology from the patient’s excised forearm nodule demonstrated suppurative necrotizing granulomas associated with acid-fast bacilli on Fite’s stain, a peanut oil/xylene modification of Ziehl-Neelsen (see Figure 3). Within the nodule, foreign crystalline material was identified under examination with polarized light. Gram stain from the nodule revealed scant Gram-positive cocci and Gram-negative bacilli, but no organism grew on aerobic, anaerobic, or mycobacterial culture. Culture of fluid from her forearm abscess grew S maltophilia and Streptococcus pneumoniae. Transthoracic echocardiogram did not reveal any valvular vegetations or regurgitation.
Figure 3. Acid-fast bacilli (Fite’s stain) in the upper central part of the image. Crystalline material is seen in the lower left of the frame.
Although M mucogenicum susceptibilities were pending, the patient was treated with trimethoprim-sulfamethoxazole ([TMP-SMX] 4.5 mg/kg of the TMP component twice a day) and clarithromycin (500 milligrams orally twice a day), a regimen intended to treat S maltophilia as well as M mucogenicum. Treatment became complicated by a prolonged QTc on electrocardiogram after clarithromycin initiation; clarithromycin was changed to doxycycline (100 mg PO BID). Psychiatry was consulted to wean QTc-prolonging medications.
Antimicrobial susceptibility testing of the M mucogenicum isolate susceptibility testing demonstrated susceptibility to TMP-SMX, amikacin, cefoxitin, ciprofloxacin, clarithromycin, imipenem, linezolid, and moxifloxacin but resistance to doxycycline. Antimicrobial susceptibility was determined by broth microdilution and interpreted according to CLSI breakpoints. The patient’s prolonged QTc and psychiatric medications precluded the use of 2 oral agents with in vitro activity, and thus the patient was maintained on her existing regimen with a plan to change doxycycline to clarithromycin once QTc normalized. Multiple repeated blood cultures and mycobacterial blood culture were negative. Over the course of 12 weeks of therapy, the patient clinically improved and her nodules decreased in size and eventually disappeared altogether. Although the patient’s M mucogenicum bacteremia and nodular soft tissue infection resolved, she was subsequently diagnosed with endocarditis from other environmental organisms, including S maltophilia, and she was hospitalized for 6 weeks before being discharged home. During her admission for endocarditis, she was treated with TMP-SMX in addition to meropenem that would likely have therapeutic effect on residual M mucogenicum. Her most recent blood cultures 6 weeks after discharge are negative.
Patient Consent Statement
Written informed consent was obtained from the patient to describe her case and include pictures of her arms and nodule pathology. The design and publication of this work has been approved by the University of Manitoba Bannatyne Research Ethics Board (HS23928:H2020:227, approved May 4, 2020) and conforms to standards currently applied in Canada.
DISCUSSION
Mycobacterium mucogenicum is a rapidly growing nontuberculous mycobacterium (RGM) that routinely inhabits tap water [3, 4]. Mycobacterium mucogenicum’s ability to form biofilms and reproduce in environmental amoeba enables it to tolerate various forms of sanitization including mild chlorination [3]. Due to this fitness advantage in disinfected aqueous ecosystems, M mucogenicum is the most commonly identified RGM in tap water [5].
Mycobacterium mucogenicum infection has diverse clinical manifestations in both immunocompetent as well as immunocompromised hosts, although it is notorious for causing outbreaks of catheter-related blood stream infections among hemodialysis and oncology patients [3, 4, 6]. The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. To our knowledge, this is the second reported case of M mucogenicum infection associated with the injection of drugs [7]. Our patient’s polymicrobial bacteremia was due to injection of tap water from the same contaminated source that caused the granulomatous nodular inflammation in her forearms.
The concurrence of M mucogenicum and S maltophilia in the blood culture as well as the nodule may reflect a novel manifestation of mycobacterial coinfection with a Gram-negative bacillus. This phenomenon has been commonly described in patients with cystic fibrosis where horizontal gene transfer from pseudomonads contributes to the virulence of Mycobacterium abscessus [8]. Although polymicrobial culture positivity often suggests contamination, here the coexistence of RGM and Gram-negative bacillus may suggest the simultaneous inoculation of environmental symbionts.
Optimal treatment for M mucogenicum bacteremia and soft tissue infection remains unclear. If a single skin lesion is present, surgical excision should be considered. A combination of 2 agents, to which the isolate demonstrates in vitro susceptibility, is recommended to prevent the development of drug resistance [9, 10]. Mycobacterium mucogenicum is commonly susceptible to many antimicrobials including amikacin, cefoxitin, clarithromycin, imipenem, and TMP-SMX [3]. However, like other RGM, it remains resistant to first-line antituberculous medications.
CONCLUSIONS
As our case illustrates, among persons who inject drugs, bacteremia with RGM should not be considered a contaminant and may in fact point to other sites of infection. People who inject drugs often experience physical, psychiatric, and socioeconomic difficulties that limit their access to sterile injection equipment. Expanding harm reduction programs to increase accessibility of sterile paraphernalia could mitigate infectious complications of injection drug use and subsequent hospital admission. Antimicrobial options were significantly limited by our patient’s polypharmacy. This case further emphasizes the need for coordinated infectious disease, psychiatric, and addictions care. It is essential for infectious diseases specialists to incorporate harm reduction strategies into their patient interaction to prevent further infectious complications from intravenous drug use.
Acknowledgments
We thank our patient for her good sense of humor, her willingness to participate in this project, and her resilience in the face of difficult circumstances.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33447641 | 19,093,962 | 2021-01 |
What was the dosage of drug 'CLARITHROMYCIN'? | Mycobacterium Mucogenicum Bacteremia and Nodular Soft Tissue Infection in a Person Who Uses Tap Water to Inject Drugs.
The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. In this study, we report a case of Mycobacterium mucogenicum bacteremia and associated nodular soft tissue infection in a person who uses tap water to inject drugs.
CASE
A 50-year-old female presented to a community hospital with a 24-hour history of fever and a right forearm abscess at the site of drug injection. The forearm abscess was incised and drained, and a sample was obtained for bacterial culture. Two peripheral blood cultures were collected before treatment with meropenem. The patient’s forearms demonstrated subcutaneous nodules that she maintained had increased in size slowly during the 2 years preceding her current hospital presentation.
The patient has psychiatric illness, of which intergenerational trauma is a probable factor [1, 2]; her parents attended Canada’s Indian Residential School system. She had been diagnosed with bipolar disorder, borderline personality disorder, and polysubstance use disorder. Her home medications included risperidone, quetiapine, fluoxetine, amitriptyline, and hydromorphone. Our patient injects cocaine on a daily basis and methamphetamine and opioids when cocaine is difficult to obtain. The patient injects her drugs using unfiltered tap water as sterile water ampules and filters are rarely accessible; she has a history of bacteremia from environmental organisms, including Sphingomonas spp, Microbacterium spp, Chryseobacterium indologenes, and Sphingobacterium spiritivorum. She denied sharing her injection paraphernalia and reusing her needles. At baseline, our patient is on home oxygen (2 L/minute) due to chronic obstructive pulmonary disease and pulmonary talcosis. Additional medical history includes inactive hepatitis C and fibromyalgia; she is human immunodeficiency virus negative. She lives in an apartment with her son in Winnipeg, Manitoba, Canada.
Her temperature was 38.2oC, her pulse 121 beats-per-minute, her blood pressure 92/59 mmHg, and her oxygen saturation was 94% while receiving 2 L/minute oxygen via nasal prongs. Physical examination revealed bilateral nodular lesions extending from the dorsum of her hands to her elbows (Figure 1). The nodules were firm and nontender with no overlying erythema. No epitrochlear or axillary lymphadenopathy was present, inconsistent with lymphangitic spread and more suggestive of distinct inoculation of different sites on the hands and forearms. A grade 2 systolic ejection murmur was heard at the right-upper-sternal border with no radiation. Other than clubbing, no peripheral signs of endocarditis were present.
Figure 1. Nodular lesions along the patient’s dorsum of her hand and along her forearm. The largest nodule is on the dorsum of her hand, reflecting the oldest nodule in the location of her earlier injection sites. The absence of lymphadenopathy and the presence of nodules in many locations beyond a single lymphatic drainage reflect separate inoculation events rather than lymphangitic spread.
The plastic surgery service was consulted to perform an excisional biopsy of one of the patient’s forearm nodules, which revealed necrotizing granulomas (Figure 2). Blood cultures were positive.
Figure 2. Suppurative granuloma with central necrosis and neutrophilic infiltration.
One of 2 original sets of blood cultures grew Mycobacterium mucogenicum and Stenotrophomonas maltophilia, identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF; Bruker Biotyper, Bruker Daltonics). Stenotrophomonas maltophilia was reported 2 days after blood draw and was susceptible to levofloxacin, trimethoprim-sulfamethoxazole, minocycline, and ceftazidime as determined by broth microdilution method and interpreted according to current Clinical and Laboratory Standards Institute (CLSI). Mycobacterium mucogenicum was reported 5 days after initial blood draw. Pathology from the patient’s excised forearm nodule demonstrated suppurative necrotizing granulomas associated with acid-fast bacilli on Fite’s stain, a peanut oil/xylene modification of Ziehl-Neelsen (see Figure 3). Within the nodule, foreign crystalline material was identified under examination with polarized light. Gram stain from the nodule revealed scant Gram-positive cocci and Gram-negative bacilli, but no organism grew on aerobic, anaerobic, or mycobacterial culture. Culture of fluid from her forearm abscess grew S maltophilia and Streptococcus pneumoniae. Transthoracic echocardiogram did not reveal any valvular vegetations or regurgitation.
Figure 3. Acid-fast bacilli (Fite’s stain) in the upper central part of the image. Crystalline material is seen in the lower left of the frame.
Although M mucogenicum susceptibilities were pending, the patient was treated with trimethoprim-sulfamethoxazole ([TMP-SMX] 4.5 mg/kg of the TMP component twice a day) and clarithromycin (500 milligrams orally twice a day), a regimen intended to treat S maltophilia as well as M mucogenicum. Treatment became complicated by a prolonged QTc on electrocardiogram after clarithromycin initiation; clarithromycin was changed to doxycycline (100 mg PO BID). Psychiatry was consulted to wean QTc-prolonging medications.
Antimicrobial susceptibility testing of the M mucogenicum isolate susceptibility testing demonstrated susceptibility to TMP-SMX, amikacin, cefoxitin, ciprofloxacin, clarithromycin, imipenem, linezolid, and moxifloxacin but resistance to doxycycline. Antimicrobial susceptibility was determined by broth microdilution and interpreted according to CLSI breakpoints. The patient’s prolonged QTc and psychiatric medications precluded the use of 2 oral agents with in vitro activity, and thus the patient was maintained on her existing regimen with a plan to change doxycycline to clarithromycin once QTc normalized. Multiple repeated blood cultures and mycobacterial blood culture were negative. Over the course of 12 weeks of therapy, the patient clinically improved and her nodules decreased in size and eventually disappeared altogether. Although the patient’s M mucogenicum bacteremia and nodular soft tissue infection resolved, she was subsequently diagnosed with endocarditis from other environmental organisms, including S maltophilia, and she was hospitalized for 6 weeks before being discharged home. During her admission for endocarditis, she was treated with TMP-SMX in addition to meropenem that would likely have therapeutic effect on residual M mucogenicum. Her most recent blood cultures 6 weeks after discharge are negative.
Patient Consent Statement
Written informed consent was obtained from the patient to describe her case and include pictures of her arms and nodule pathology. The design and publication of this work has been approved by the University of Manitoba Bannatyne Research Ethics Board (HS23928:H2020:227, approved May 4, 2020) and conforms to standards currently applied in Canada.
DISCUSSION
Mycobacterium mucogenicum is a rapidly growing nontuberculous mycobacterium (RGM) that routinely inhabits tap water [3, 4]. Mycobacterium mucogenicum’s ability to form biofilms and reproduce in environmental amoeba enables it to tolerate various forms of sanitization including mild chlorination [3]. Due to this fitness advantage in disinfected aqueous ecosystems, M mucogenicum is the most commonly identified RGM in tap water [5].
Mycobacterium mucogenicum infection has diverse clinical manifestations in both immunocompetent as well as immunocompromised hosts, although it is notorious for causing outbreaks of catheter-related blood stream infections among hemodialysis and oncology patients [3, 4, 6]. The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. To our knowledge, this is the second reported case of M mucogenicum infection associated with the injection of drugs [7]. Our patient’s polymicrobial bacteremia was due to injection of tap water from the same contaminated source that caused the granulomatous nodular inflammation in her forearms.
The concurrence of M mucogenicum and S maltophilia in the blood culture as well as the nodule may reflect a novel manifestation of mycobacterial coinfection with a Gram-negative bacillus. This phenomenon has been commonly described in patients with cystic fibrosis where horizontal gene transfer from pseudomonads contributes to the virulence of Mycobacterium abscessus [8]. Although polymicrobial culture positivity often suggests contamination, here the coexistence of RGM and Gram-negative bacillus may suggest the simultaneous inoculation of environmental symbionts.
Optimal treatment for M mucogenicum bacteremia and soft tissue infection remains unclear. If a single skin lesion is present, surgical excision should be considered. A combination of 2 agents, to which the isolate demonstrates in vitro susceptibility, is recommended to prevent the development of drug resistance [9, 10]. Mycobacterium mucogenicum is commonly susceptible to many antimicrobials including amikacin, cefoxitin, clarithromycin, imipenem, and TMP-SMX [3]. However, like other RGM, it remains resistant to first-line antituberculous medications.
CONCLUSIONS
As our case illustrates, among persons who inject drugs, bacteremia with RGM should not be considered a contaminant and may in fact point to other sites of infection. People who inject drugs often experience physical, psychiatric, and socioeconomic difficulties that limit their access to sterile injection equipment. Expanding harm reduction programs to increase accessibility of sterile paraphernalia could mitigate infectious complications of injection drug use and subsequent hospital admission. Antimicrobial options were significantly limited by our patient’s polypharmacy. This case further emphasizes the need for coordinated infectious disease, psychiatric, and addictions care. It is essential for infectious diseases specialists to incorporate harm reduction strategies into their patient interaction to prevent further infectious complications from intravenous drug use.
Acknowledgments
We thank our patient for her good sense of humor, her willingness to participate in this project, and her resilience in the face of difficult circumstances.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | 1000 MILLIGRAM DAILY; | DrugDosageText | CC BY-NC-ND | 33447641 | 19,093,962 | 2021-01 |
What was the dosage of drug 'SULFAMETHOXAZOLE\TRIMETHOPRIM'? | Mycobacterium Mucogenicum Bacteremia and Nodular Soft Tissue Infection in a Person Who Uses Tap Water to Inject Drugs.
The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. In this study, we report a case of Mycobacterium mucogenicum bacteremia and associated nodular soft tissue infection in a person who uses tap water to inject drugs.
CASE
A 50-year-old female presented to a community hospital with a 24-hour history of fever and a right forearm abscess at the site of drug injection. The forearm abscess was incised and drained, and a sample was obtained for bacterial culture. Two peripheral blood cultures were collected before treatment with meropenem. The patient’s forearms demonstrated subcutaneous nodules that she maintained had increased in size slowly during the 2 years preceding her current hospital presentation.
The patient has psychiatric illness, of which intergenerational trauma is a probable factor [1, 2]; her parents attended Canada’s Indian Residential School system. She had been diagnosed with bipolar disorder, borderline personality disorder, and polysubstance use disorder. Her home medications included risperidone, quetiapine, fluoxetine, amitriptyline, and hydromorphone. Our patient injects cocaine on a daily basis and methamphetamine and opioids when cocaine is difficult to obtain. The patient injects her drugs using unfiltered tap water as sterile water ampules and filters are rarely accessible; she has a history of bacteremia from environmental organisms, including Sphingomonas spp, Microbacterium spp, Chryseobacterium indologenes, and Sphingobacterium spiritivorum. She denied sharing her injection paraphernalia and reusing her needles. At baseline, our patient is on home oxygen (2 L/minute) due to chronic obstructive pulmonary disease and pulmonary talcosis. Additional medical history includes inactive hepatitis C and fibromyalgia; she is human immunodeficiency virus negative. She lives in an apartment with her son in Winnipeg, Manitoba, Canada.
Her temperature was 38.2oC, her pulse 121 beats-per-minute, her blood pressure 92/59 mmHg, and her oxygen saturation was 94% while receiving 2 L/minute oxygen via nasal prongs. Physical examination revealed bilateral nodular lesions extending from the dorsum of her hands to her elbows (Figure 1). The nodules were firm and nontender with no overlying erythema. No epitrochlear or axillary lymphadenopathy was present, inconsistent with lymphangitic spread and more suggestive of distinct inoculation of different sites on the hands and forearms. A grade 2 systolic ejection murmur was heard at the right-upper-sternal border with no radiation. Other than clubbing, no peripheral signs of endocarditis were present.
Figure 1. Nodular lesions along the patient’s dorsum of her hand and along her forearm. The largest nodule is on the dorsum of her hand, reflecting the oldest nodule in the location of her earlier injection sites. The absence of lymphadenopathy and the presence of nodules in many locations beyond a single lymphatic drainage reflect separate inoculation events rather than lymphangitic spread.
The plastic surgery service was consulted to perform an excisional biopsy of one of the patient’s forearm nodules, which revealed necrotizing granulomas (Figure 2). Blood cultures were positive.
Figure 2. Suppurative granuloma with central necrosis and neutrophilic infiltration.
One of 2 original sets of blood cultures grew Mycobacterium mucogenicum and Stenotrophomonas maltophilia, identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF; Bruker Biotyper, Bruker Daltonics). Stenotrophomonas maltophilia was reported 2 days after blood draw and was susceptible to levofloxacin, trimethoprim-sulfamethoxazole, minocycline, and ceftazidime as determined by broth microdilution method and interpreted according to current Clinical and Laboratory Standards Institute (CLSI). Mycobacterium mucogenicum was reported 5 days after initial blood draw. Pathology from the patient’s excised forearm nodule demonstrated suppurative necrotizing granulomas associated with acid-fast bacilli on Fite’s stain, a peanut oil/xylene modification of Ziehl-Neelsen (see Figure 3). Within the nodule, foreign crystalline material was identified under examination with polarized light. Gram stain from the nodule revealed scant Gram-positive cocci and Gram-negative bacilli, but no organism grew on aerobic, anaerobic, or mycobacterial culture. Culture of fluid from her forearm abscess grew S maltophilia and Streptococcus pneumoniae. Transthoracic echocardiogram did not reveal any valvular vegetations or regurgitation.
Figure 3. Acid-fast bacilli (Fite’s stain) in the upper central part of the image. Crystalline material is seen in the lower left of the frame.
Although M mucogenicum susceptibilities were pending, the patient was treated with trimethoprim-sulfamethoxazole ([TMP-SMX] 4.5 mg/kg of the TMP component twice a day) and clarithromycin (500 milligrams orally twice a day), a regimen intended to treat S maltophilia as well as M mucogenicum. Treatment became complicated by a prolonged QTc on electrocardiogram after clarithromycin initiation; clarithromycin was changed to doxycycline (100 mg PO BID). Psychiatry was consulted to wean QTc-prolonging medications.
Antimicrobial susceptibility testing of the M mucogenicum isolate susceptibility testing demonstrated susceptibility to TMP-SMX, amikacin, cefoxitin, ciprofloxacin, clarithromycin, imipenem, linezolid, and moxifloxacin but resistance to doxycycline. Antimicrobial susceptibility was determined by broth microdilution and interpreted according to CLSI breakpoints. The patient’s prolonged QTc and psychiatric medications precluded the use of 2 oral agents with in vitro activity, and thus the patient was maintained on her existing regimen with a plan to change doxycycline to clarithromycin once QTc normalized. Multiple repeated blood cultures and mycobacterial blood culture were negative. Over the course of 12 weeks of therapy, the patient clinically improved and her nodules decreased in size and eventually disappeared altogether. Although the patient’s M mucogenicum bacteremia and nodular soft tissue infection resolved, she was subsequently diagnosed with endocarditis from other environmental organisms, including S maltophilia, and she was hospitalized for 6 weeks before being discharged home. During her admission for endocarditis, she was treated with TMP-SMX in addition to meropenem that would likely have therapeutic effect on residual M mucogenicum. Her most recent blood cultures 6 weeks after discharge are negative.
Patient Consent Statement
Written informed consent was obtained from the patient to describe her case and include pictures of her arms and nodule pathology. The design and publication of this work has been approved by the University of Manitoba Bannatyne Research Ethics Board (HS23928:H2020:227, approved May 4, 2020) and conforms to standards currently applied in Canada.
DISCUSSION
Mycobacterium mucogenicum is a rapidly growing nontuberculous mycobacterium (RGM) that routinely inhabits tap water [3, 4]. Mycobacterium mucogenicum’s ability to form biofilms and reproduce in environmental amoeba enables it to tolerate various forms of sanitization including mild chlorination [3]. Due to this fitness advantage in disinfected aqueous ecosystems, M mucogenicum is the most commonly identified RGM in tap water [5].
Mycobacterium mucogenicum infection has diverse clinical manifestations in both immunocompetent as well as immunocompromised hosts, although it is notorious for causing outbreaks of catheter-related blood stream infections among hemodialysis and oncology patients [3, 4, 6]. The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. To our knowledge, this is the second reported case of M mucogenicum infection associated with the injection of drugs [7]. Our patient’s polymicrobial bacteremia was due to injection of tap water from the same contaminated source that caused the granulomatous nodular inflammation in her forearms.
The concurrence of M mucogenicum and S maltophilia in the blood culture as well as the nodule may reflect a novel manifestation of mycobacterial coinfection with a Gram-negative bacillus. This phenomenon has been commonly described in patients with cystic fibrosis where horizontal gene transfer from pseudomonads contributes to the virulence of Mycobacterium abscessus [8]. Although polymicrobial culture positivity often suggests contamination, here the coexistence of RGM and Gram-negative bacillus may suggest the simultaneous inoculation of environmental symbionts.
Optimal treatment for M mucogenicum bacteremia and soft tissue infection remains unclear. If a single skin lesion is present, surgical excision should be considered. A combination of 2 agents, to which the isolate demonstrates in vitro susceptibility, is recommended to prevent the development of drug resistance [9, 10]. Mycobacterium mucogenicum is commonly susceptible to many antimicrobials including amikacin, cefoxitin, clarithromycin, imipenem, and TMP-SMX [3]. However, like other RGM, it remains resistant to first-line antituberculous medications.
CONCLUSIONS
As our case illustrates, among persons who inject drugs, bacteremia with RGM should not be considered a contaminant and may in fact point to other sites of infection. People who inject drugs often experience physical, psychiatric, and socioeconomic difficulties that limit their access to sterile injection equipment. Expanding harm reduction programs to increase accessibility of sterile paraphernalia could mitigate infectious complications of injection drug use and subsequent hospital admission. Antimicrobial options were significantly limited by our patient’s polypharmacy. This case further emphasizes the need for coordinated infectious disease, psychiatric, and addictions care. It is essential for infectious diseases specialists to incorporate harm reduction strategies into their patient interaction to prevent further infectious complications from intravenous drug use.
Acknowledgments
We thank our patient for her good sense of humor, her willingness to participate in this project, and her resilience in the face of difficult circumstances.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | 9 MG/KG DAILY; | DrugDosageText | CC BY-NC-ND | 33447641 | 19,093,962 | 2021-01 |
What was the outcome of reaction 'Abscess'? | Mycobacterium Mucogenicum Bacteremia and Nodular Soft Tissue Infection in a Person Who Uses Tap Water to Inject Drugs.
The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. In this study, we report a case of Mycobacterium mucogenicum bacteremia and associated nodular soft tissue infection in a person who uses tap water to inject drugs.
CASE
A 50-year-old female presented to a community hospital with a 24-hour history of fever and a right forearm abscess at the site of drug injection. The forearm abscess was incised and drained, and a sample was obtained for bacterial culture. Two peripheral blood cultures were collected before treatment with meropenem. The patient’s forearms demonstrated subcutaneous nodules that she maintained had increased in size slowly during the 2 years preceding her current hospital presentation.
The patient has psychiatric illness, of which intergenerational trauma is a probable factor [1, 2]; her parents attended Canada’s Indian Residential School system. She had been diagnosed with bipolar disorder, borderline personality disorder, and polysubstance use disorder. Her home medications included risperidone, quetiapine, fluoxetine, amitriptyline, and hydromorphone. Our patient injects cocaine on a daily basis and methamphetamine and opioids when cocaine is difficult to obtain. The patient injects her drugs using unfiltered tap water as sterile water ampules and filters are rarely accessible; she has a history of bacteremia from environmental organisms, including Sphingomonas spp, Microbacterium spp, Chryseobacterium indologenes, and Sphingobacterium spiritivorum. She denied sharing her injection paraphernalia and reusing her needles. At baseline, our patient is on home oxygen (2 L/minute) due to chronic obstructive pulmonary disease and pulmonary talcosis. Additional medical history includes inactive hepatitis C and fibromyalgia; she is human immunodeficiency virus negative. She lives in an apartment with her son in Winnipeg, Manitoba, Canada.
Her temperature was 38.2oC, her pulse 121 beats-per-minute, her blood pressure 92/59 mmHg, and her oxygen saturation was 94% while receiving 2 L/minute oxygen via nasal prongs. Physical examination revealed bilateral nodular lesions extending from the dorsum of her hands to her elbows (Figure 1). The nodules were firm and nontender with no overlying erythema. No epitrochlear or axillary lymphadenopathy was present, inconsistent with lymphangitic spread and more suggestive of distinct inoculation of different sites on the hands and forearms. A grade 2 systolic ejection murmur was heard at the right-upper-sternal border with no radiation. Other than clubbing, no peripheral signs of endocarditis were present.
Figure 1. Nodular lesions along the patient’s dorsum of her hand and along her forearm. The largest nodule is on the dorsum of her hand, reflecting the oldest nodule in the location of her earlier injection sites. The absence of lymphadenopathy and the presence of nodules in many locations beyond a single lymphatic drainage reflect separate inoculation events rather than lymphangitic spread.
The plastic surgery service was consulted to perform an excisional biopsy of one of the patient’s forearm nodules, which revealed necrotizing granulomas (Figure 2). Blood cultures were positive.
Figure 2. Suppurative granuloma with central necrosis and neutrophilic infiltration.
One of 2 original sets of blood cultures grew Mycobacterium mucogenicum and Stenotrophomonas maltophilia, identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF; Bruker Biotyper, Bruker Daltonics). Stenotrophomonas maltophilia was reported 2 days after blood draw and was susceptible to levofloxacin, trimethoprim-sulfamethoxazole, minocycline, and ceftazidime as determined by broth microdilution method and interpreted according to current Clinical and Laboratory Standards Institute (CLSI). Mycobacterium mucogenicum was reported 5 days after initial blood draw. Pathology from the patient’s excised forearm nodule demonstrated suppurative necrotizing granulomas associated with acid-fast bacilli on Fite’s stain, a peanut oil/xylene modification of Ziehl-Neelsen (see Figure 3). Within the nodule, foreign crystalline material was identified under examination with polarized light. Gram stain from the nodule revealed scant Gram-positive cocci and Gram-negative bacilli, but no organism grew on aerobic, anaerobic, or mycobacterial culture. Culture of fluid from her forearm abscess grew S maltophilia and Streptococcus pneumoniae. Transthoracic echocardiogram did not reveal any valvular vegetations or regurgitation.
Figure 3. Acid-fast bacilli (Fite’s stain) in the upper central part of the image. Crystalline material is seen in the lower left of the frame.
Although M mucogenicum susceptibilities were pending, the patient was treated with trimethoprim-sulfamethoxazole ([TMP-SMX] 4.5 mg/kg of the TMP component twice a day) and clarithromycin (500 milligrams orally twice a day), a regimen intended to treat S maltophilia as well as M mucogenicum. Treatment became complicated by a prolonged QTc on electrocardiogram after clarithromycin initiation; clarithromycin was changed to doxycycline (100 mg PO BID). Psychiatry was consulted to wean QTc-prolonging medications.
Antimicrobial susceptibility testing of the M mucogenicum isolate susceptibility testing demonstrated susceptibility to TMP-SMX, amikacin, cefoxitin, ciprofloxacin, clarithromycin, imipenem, linezolid, and moxifloxacin but resistance to doxycycline. Antimicrobial susceptibility was determined by broth microdilution and interpreted according to CLSI breakpoints. The patient’s prolonged QTc and psychiatric medications precluded the use of 2 oral agents with in vitro activity, and thus the patient was maintained on her existing regimen with a plan to change doxycycline to clarithromycin once QTc normalized. Multiple repeated blood cultures and mycobacterial blood culture were negative. Over the course of 12 weeks of therapy, the patient clinically improved and her nodules decreased in size and eventually disappeared altogether. Although the patient’s M mucogenicum bacteremia and nodular soft tissue infection resolved, she was subsequently diagnosed with endocarditis from other environmental organisms, including S maltophilia, and she was hospitalized for 6 weeks before being discharged home. During her admission for endocarditis, she was treated with TMP-SMX in addition to meropenem that would likely have therapeutic effect on residual M mucogenicum. Her most recent blood cultures 6 weeks after discharge are negative.
Patient Consent Statement
Written informed consent was obtained from the patient to describe her case and include pictures of her arms and nodule pathology. The design and publication of this work has been approved by the University of Manitoba Bannatyne Research Ethics Board (HS23928:H2020:227, approved May 4, 2020) and conforms to standards currently applied in Canada.
DISCUSSION
Mycobacterium mucogenicum is a rapidly growing nontuberculous mycobacterium (RGM) that routinely inhabits tap water [3, 4]. Mycobacterium mucogenicum’s ability to form biofilms and reproduce in environmental amoeba enables it to tolerate various forms of sanitization including mild chlorination [3]. Due to this fitness advantage in disinfected aqueous ecosystems, M mucogenicum is the most commonly identified RGM in tap water [5].
Mycobacterium mucogenicum infection has diverse clinical manifestations in both immunocompetent as well as immunocompromised hosts, although it is notorious for causing outbreaks of catheter-related blood stream infections among hemodialysis and oncology patients [3, 4, 6]. The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. To our knowledge, this is the second reported case of M mucogenicum infection associated with the injection of drugs [7]. Our patient’s polymicrobial bacteremia was due to injection of tap water from the same contaminated source that caused the granulomatous nodular inflammation in her forearms.
The concurrence of M mucogenicum and S maltophilia in the blood culture as well as the nodule may reflect a novel manifestation of mycobacterial coinfection with a Gram-negative bacillus. This phenomenon has been commonly described in patients with cystic fibrosis where horizontal gene transfer from pseudomonads contributes to the virulence of Mycobacterium abscessus [8]. Although polymicrobial culture positivity often suggests contamination, here the coexistence of RGM and Gram-negative bacillus may suggest the simultaneous inoculation of environmental symbionts.
Optimal treatment for M mucogenicum bacteremia and soft tissue infection remains unclear. If a single skin lesion is present, surgical excision should be considered. A combination of 2 agents, to which the isolate demonstrates in vitro susceptibility, is recommended to prevent the development of drug resistance [9, 10]. Mycobacterium mucogenicum is commonly susceptible to many antimicrobials including amikacin, cefoxitin, clarithromycin, imipenem, and TMP-SMX [3]. However, like other RGM, it remains resistant to first-line antituberculous medications.
CONCLUSIONS
As our case illustrates, among persons who inject drugs, bacteremia with RGM should not be considered a contaminant and may in fact point to other sites of infection. People who inject drugs often experience physical, psychiatric, and socioeconomic difficulties that limit their access to sterile injection equipment. Expanding harm reduction programs to increase accessibility of sterile paraphernalia could mitigate infectious complications of injection drug use and subsequent hospital admission. Antimicrobial options were significantly limited by our patient’s polypharmacy. This case further emphasizes the need for coordinated infectious disease, psychiatric, and addictions care. It is essential for infectious diseases specialists to incorporate harm reduction strategies into their patient interaction to prevent further infectious complications from intravenous drug use.
Acknowledgments
We thank our patient for her good sense of humor, her willingness to participate in this project, and her resilience in the face of difficult circumstances.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | Recovering | ReactionOutcome | CC BY-NC-ND | 33447641 | 19,093,962 | 2021-01 |
What was the outcome of reaction 'Bacteraemia'? | Mycobacterium Mucogenicum Bacteremia and Nodular Soft Tissue Infection in a Person Who Uses Tap Water to Inject Drugs.
The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. In this study, we report a case of Mycobacterium mucogenicum bacteremia and associated nodular soft tissue infection in a person who uses tap water to inject drugs.
CASE
A 50-year-old female presented to a community hospital with a 24-hour history of fever and a right forearm abscess at the site of drug injection. The forearm abscess was incised and drained, and a sample was obtained for bacterial culture. Two peripheral blood cultures were collected before treatment with meropenem. The patient’s forearms demonstrated subcutaneous nodules that she maintained had increased in size slowly during the 2 years preceding her current hospital presentation.
The patient has psychiatric illness, of which intergenerational trauma is a probable factor [1, 2]; her parents attended Canada’s Indian Residential School system. She had been diagnosed with bipolar disorder, borderline personality disorder, and polysubstance use disorder. Her home medications included risperidone, quetiapine, fluoxetine, amitriptyline, and hydromorphone. Our patient injects cocaine on a daily basis and methamphetamine and opioids when cocaine is difficult to obtain. The patient injects her drugs using unfiltered tap water as sterile water ampules and filters are rarely accessible; she has a history of bacteremia from environmental organisms, including Sphingomonas spp, Microbacterium spp, Chryseobacterium indologenes, and Sphingobacterium spiritivorum. She denied sharing her injection paraphernalia and reusing her needles. At baseline, our patient is on home oxygen (2 L/minute) due to chronic obstructive pulmonary disease and pulmonary talcosis. Additional medical history includes inactive hepatitis C and fibromyalgia; she is human immunodeficiency virus negative. She lives in an apartment with her son in Winnipeg, Manitoba, Canada.
Her temperature was 38.2oC, her pulse 121 beats-per-minute, her blood pressure 92/59 mmHg, and her oxygen saturation was 94% while receiving 2 L/minute oxygen via nasal prongs. Physical examination revealed bilateral nodular lesions extending from the dorsum of her hands to her elbows (Figure 1). The nodules were firm and nontender with no overlying erythema. No epitrochlear or axillary lymphadenopathy was present, inconsistent with lymphangitic spread and more suggestive of distinct inoculation of different sites on the hands and forearms. A grade 2 systolic ejection murmur was heard at the right-upper-sternal border with no radiation. Other than clubbing, no peripheral signs of endocarditis were present.
Figure 1. Nodular lesions along the patient’s dorsum of her hand and along her forearm. The largest nodule is on the dorsum of her hand, reflecting the oldest nodule in the location of her earlier injection sites. The absence of lymphadenopathy and the presence of nodules in many locations beyond a single lymphatic drainage reflect separate inoculation events rather than lymphangitic spread.
The plastic surgery service was consulted to perform an excisional biopsy of one of the patient’s forearm nodules, which revealed necrotizing granulomas (Figure 2). Blood cultures were positive.
Figure 2. Suppurative granuloma with central necrosis and neutrophilic infiltration.
One of 2 original sets of blood cultures grew Mycobacterium mucogenicum and Stenotrophomonas maltophilia, identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF; Bruker Biotyper, Bruker Daltonics). Stenotrophomonas maltophilia was reported 2 days after blood draw and was susceptible to levofloxacin, trimethoprim-sulfamethoxazole, minocycline, and ceftazidime as determined by broth microdilution method and interpreted according to current Clinical and Laboratory Standards Institute (CLSI). Mycobacterium mucogenicum was reported 5 days after initial blood draw. Pathology from the patient’s excised forearm nodule demonstrated suppurative necrotizing granulomas associated with acid-fast bacilli on Fite’s stain, a peanut oil/xylene modification of Ziehl-Neelsen (see Figure 3). Within the nodule, foreign crystalline material was identified under examination with polarized light. Gram stain from the nodule revealed scant Gram-positive cocci and Gram-negative bacilli, but no organism grew on aerobic, anaerobic, or mycobacterial culture. Culture of fluid from her forearm abscess grew S maltophilia and Streptococcus pneumoniae. Transthoracic echocardiogram did not reveal any valvular vegetations or regurgitation.
Figure 3. Acid-fast bacilli (Fite’s stain) in the upper central part of the image. Crystalline material is seen in the lower left of the frame.
Although M mucogenicum susceptibilities were pending, the patient was treated with trimethoprim-sulfamethoxazole ([TMP-SMX] 4.5 mg/kg of the TMP component twice a day) and clarithromycin (500 milligrams orally twice a day), a regimen intended to treat S maltophilia as well as M mucogenicum. Treatment became complicated by a prolonged QTc on electrocardiogram after clarithromycin initiation; clarithromycin was changed to doxycycline (100 mg PO BID). Psychiatry was consulted to wean QTc-prolonging medications.
Antimicrobial susceptibility testing of the M mucogenicum isolate susceptibility testing demonstrated susceptibility to TMP-SMX, amikacin, cefoxitin, ciprofloxacin, clarithromycin, imipenem, linezolid, and moxifloxacin but resistance to doxycycline. Antimicrobial susceptibility was determined by broth microdilution and interpreted according to CLSI breakpoints. The patient’s prolonged QTc and psychiatric medications precluded the use of 2 oral agents with in vitro activity, and thus the patient was maintained on her existing regimen with a plan to change doxycycline to clarithromycin once QTc normalized. Multiple repeated blood cultures and mycobacterial blood culture were negative. Over the course of 12 weeks of therapy, the patient clinically improved and her nodules decreased in size and eventually disappeared altogether. Although the patient’s M mucogenicum bacteremia and nodular soft tissue infection resolved, she was subsequently diagnosed with endocarditis from other environmental organisms, including S maltophilia, and she was hospitalized for 6 weeks before being discharged home. During her admission for endocarditis, she was treated with TMP-SMX in addition to meropenem that would likely have therapeutic effect on residual M mucogenicum. Her most recent blood cultures 6 weeks after discharge are negative.
Patient Consent Statement
Written informed consent was obtained from the patient to describe her case and include pictures of her arms and nodule pathology. The design and publication of this work has been approved by the University of Manitoba Bannatyne Research Ethics Board (HS23928:H2020:227, approved May 4, 2020) and conforms to standards currently applied in Canada.
DISCUSSION
Mycobacterium mucogenicum is a rapidly growing nontuberculous mycobacterium (RGM) that routinely inhabits tap water [3, 4]. Mycobacterium mucogenicum’s ability to form biofilms and reproduce in environmental amoeba enables it to tolerate various forms of sanitization including mild chlorination [3]. Due to this fitness advantage in disinfected aqueous ecosystems, M mucogenicum is the most commonly identified RGM in tap water [5].
Mycobacterium mucogenicum infection has diverse clinical manifestations in both immunocompetent as well as immunocompromised hosts, although it is notorious for causing outbreaks of catheter-related blood stream infections among hemodialysis and oncology patients [3, 4, 6]. The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. To our knowledge, this is the second reported case of M mucogenicum infection associated with the injection of drugs [7]. Our patient’s polymicrobial bacteremia was due to injection of tap water from the same contaminated source that caused the granulomatous nodular inflammation in her forearms.
The concurrence of M mucogenicum and S maltophilia in the blood culture as well as the nodule may reflect a novel manifestation of mycobacterial coinfection with a Gram-negative bacillus. This phenomenon has been commonly described in patients with cystic fibrosis where horizontal gene transfer from pseudomonads contributes to the virulence of Mycobacterium abscessus [8]. Although polymicrobial culture positivity often suggests contamination, here the coexistence of RGM and Gram-negative bacillus may suggest the simultaneous inoculation of environmental symbionts.
Optimal treatment for M mucogenicum bacteremia and soft tissue infection remains unclear. If a single skin lesion is present, surgical excision should be considered. A combination of 2 agents, to which the isolate demonstrates in vitro susceptibility, is recommended to prevent the development of drug resistance [9, 10]. Mycobacterium mucogenicum is commonly susceptible to many antimicrobials including amikacin, cefoxitin, clarithromycin, imipenem, and TMP-SMX [3]. However, like other RGM, it remains resistant to first-line antituberculous medications.
CONCLUSIONS
As our case illustrates, among persons who inject drugs, bacteremia with RGM should not be considered a contaminant and may in fact point to other sites of infection. People who inject drugs often experience physical, psychiatric, and socioeconomic difficulties that limit their access to sterile injection equipment. Expanding harm reduction programs to increase accessibility of sterile paraphernalia could mitigate infectious complications of injection drug use and subsequent hospital admission. Antimicrobial options were significantly limited by our patient’s polypharmacy. This case further emphasizes the need for coordinated infectious disease, psychiatric, and addictions care. It is essential for infectious diseases specialists to incorporate harm reduction strategies into their patient interaction to prevent further infectious complications from intravenous drug use.
Acknowledgments
We thank our patient for her good sense of humor, her willingness to participate in this project, and her resilience in the face of difficult circumstances.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | Recovering | ReactionOutcome | CC BY-NC-ND | 33447641 | 19,093,962 | 2021-01 |
What was the outcome of reaction 'Chronic obstructive pulmonary disease'? | Mycobacterium Mucogenicum Bacteremia and Nodular Soft Tissue Infection in a Person Who Uses Tap Water to Inject Drugs.
The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. In this study, we report a case of Mycobacterium mucogenicum bacteremia and associated nodular soft tissue infection in a person who uses tap water to inject drugs.
CASE
A 50-year-old female presented to a community hospital with a 24-hour history of fever and a right forearm abscess at the site of drug injection. The forearm abscess was incised and drained, and a sample was obtained for bacterial culture. Two peripheral blood cultures were collected before treatment with meropenem. The patient’s forearms demonstrated subcutaneous nodules that she maintained had increased in size slowly during the 2 years preceding her current hospital presentation.
The patient has psychiatric illness, of which intergenerational trauma is a probable factor [1, 2]; her parents attended Canada’s Indian Residential School system. She had been diagnosed with bipolar disorder, borderline personality disorder, and polysubstance use disorder. Her home medications included risperidone, quetiapine, fluoxetine, amitriptyline, and hydromorphone. Our patient injects cocaine on a daily basis and methamphetamine and opioids when cocaine is difficult to obtain. The patient injects her drugs using unfiltered tap water as sterile water ampules and filters are rarely accessible; she has a history of bacteremia from environmental organisms, including Sphingomonas spp, Microbacterium spp, Chryseobacterium indologenes, and Sphingobacterium spiritivorum. She denied sharing her injection paraphernalia and reusing her needles. At baseline, our patient is on home oxygen (2 L/minute) due to chronic obstructive pulmonary disease and pulmonary talcosis. Additional medical history includes inactive hepatitis C and fibromyalgia; she is human immunodeficiency virus negative. She lives in an apartment with her son in Winnipeg, Manitoba, Canada.
Her temperature was 38.2oC, her pulse 121 beats-per-minute, her blood pressure 92/59 mmHg, and her oxygen saturation was 94% while receiving 2 L/minute oxygen via nasal prongs. Physical examination revealed bilateral nodular lesions extending from the dorsum of her hands to her elbows (Figure 1). The nodules were firm and nontender with no overlying erythema. No epitrochlear or axillary lymphadenopathy was present, inconsistent with lymphangitic spread and more suggestive of distinct inoculation of different sites on the hands and forearms. A grade 2 systolic ejection murmur was heard at the right-upper-sternal border with no radiation. Other than clubbing, no peripheral signs of endocarditis were present.
Figure 1. Nodular lesions along the patient’s dorsum of her hand and along her forearm. The largest nodule is on the dorsum of her hand, reflecting the oldest nodule in the location of her earlier injection sites. The absence of lymphadenopathy and the presence of nodules in many locations beyond a single lymphatic drainage reflect separate inoculation events rather than lymphangitic spread.
The plastic surgery service was consulted to perform an excisional biopsy of one of the patient’s forearm nodules, which revealed necrotizing granulomas (Figure 2). Blood cultures were positive.
Figure 2. Suppurative granuloma with central necrosis and neutrophilic infiltration.
One of 2 original sets of blood cultures grew Mycobacterium mucogenicum and Stenotrophomonas maltophilia, identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF; Bruker Biotyper, Bruker Daltonics). Stenotrophomonas maltophilia was reported 2 days after blood draw and was susceptible to levofloxacin, trimethoprim-sulfamethoxazole, minocycline, and ceftazidime as determined by broth microdilution method and interpreted according to current Clinical and Laboratory Standards Institute (CLSI). Mycobacterium mucogenicum was reported 5 days after initial blood draw. Pathology from the patient’s excised forearm nodule demonstrated suppurative necrotizing granulomas associated with acid-fast bacilli on Fite’s stain, a peanut oil/xylene modification of Ziehl-Neelsen (see Figure 3). Within the nodule, foreign crystalline material was identified under examination with polarized light. Gram stain from the nodule revealed scant Gram-positive cocci and Gram-negative bacilli, but no organism grew on aerobic, anaerobic, or mycobacterial culture. Culture of fluid from her forearm abscess grew S maltophilia and Streptococcus pneumoniae. Transthoracic echocardiogram did not reveal any valvular vegetations or regurgitation.
Figure 3. Acid-fast bacilli (Fite’s stain) in the upper central part of the image. Crystalline material is seen in the lower left of the frame.
Although M mucogenicum susceptibilities were pending, the patient was treated with trimethoprim-sulfamethoxazole ([TMP-SMX] 4.5 mg/kg of the TMP component twice a day) and clarithromycin (500 milligrams orally twice a day), a regimen intended to treat S maltophilia as well as M mucogenicum. Treatment became complicated by a prolonged QTc on electrocardiogram after clarithromycin initiation; clarithromycin was changed to doxycycline (100 mg PO BID). Psychiatry was consulted to wean QTc-prolonging medications.
Antimicrobial susceptibility testing of the M mucogenicum isolate susceptibility testing demonstrated susceptibility to TMP-SMX, amikacin, cefoxitin, ciprofloxacin, clarithromycin, imipenem, linezolid, and moxifloxacin but resistance to doxycycline. Antimicrobial susceptibility was determined by broth microdilution and interpreted according to CLSI breakpoints. The patient’s prolonged QTc and psychiatric medications precluded the use of 2 oral agents with in vitro activity, and thus the patient was maintained on her existing regimen with a plan to change doxycycline to clarithromycin once QTc normalized. Multiple repeated blood cultures and mycobacterial blood culture were negative. Over the course of 12 weeks of therapy, the patient clinically improved and her nodules decreased in size and eventually disappeared altogether. Although the patient’s M mucogenicum bacteremia and nodular soft tissue infection resolved, she was subsequently diagnosed with endocarditis from other environmental organisms, including S maltophilia, and she was hospitalized for 6 weeks before being discharged home. During her admission for endocarditis, she was treated with TMP-SMX in addition to meropenem that would likely have therapeutic effect on residual M mucogenicum. Her most recent blood cultures 6 weeks after discharge are negative.
Patient Consent Statement
Written informed consent was obtained from the patient to describe her case and include pictures of her arms and nodule pathology. The design and publication of this work has been approved by the University of Manitoba Bannatyne Research Ethics Board (HS23928:H2020:227, approved May 4, 2020) and conforms to standards currently applied in Canada.
DISCUSSION
Mycobacterium mucogenicum is a rapidly growing nontuberculous mycobacterium (RGM) that routinely inhabits tap water [3, 4]. Mycobacterium mucogenicum’s ability to form biofilms and reproduce in environmental amoeba enables it to tolerate various forms of sanitization including mild chlorination [3]. Due to this fitness advantage in disinfected aqueous ecosystems, M mucogenicum is the most commonly identified RGM in tap water [5].
Mycobacterium mucogenicum infection has diverse clinical manifestations in both immunocompetent as well as immunocompromised hosts, although it is notorious for causing outbreaks of catheter-related blood stream infections among hemodialysis and oncology patients [3, 4, 6]. The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. To our knowledge, this is the second reported case of M mucogenicum infection associated with the injection of drugs [7]. Our patient’s polymicrobial bacteremia was due to injection of tap water from the same contaminated source that caused the granulomatous nodular inflammation in her forearms.
The concurrence of M mucogenicum and S maltophilia in the blood culture as well as the nodule may reflect a novel manifestation of mycobacterial coinfection with a Gram-negative bacillus. This phenomenon has been commonly described in patients with cystic fibrosis where horizontal gene transfer from pseudomonads contributes to the virulence of Mycobacterium abscessus [8]. Although polymicrobial culture positivity often suggests contamination, here the coexistence of RGM and Gram-negative bacillus may suggest the simultaneous inoculation of environmental symbionts.
Optimal treatment for M mucogenicum bacteremia and soft tissue infection remains unclear. If a single skin lesion is present, surgical excision should be considered. A combination of 2 agents, to which the isolate demonstrates in vitro susceptibility, is recommended to prevent the development of drug resistance [9, 10]. Mycobacterium mucogenicum is commonly susceptible to many antimicrobials including amikacin, cefoxitin, clarithromycin, imipenem, and TMP-SMX [3]. However, like other RGM, it remains resistant to first-line antituberculous medications.
CONCLUSIONS
As our case illustrates, among persons who inject drugs, bacteremia with RGM should not be considered a contaminant and may in fact point to other sites of infection. People who inject drugs often experience physical, psychiatric, and socioeconomic difficulties that limit their access to sterile injection equipment. Expanding harm reduction programs to increase accessibility of sterile paraphernalia could mitigate infectious complications of injection drug use and subsequent hospital admission. Antimicrobial options were significantly limited by our patient’s polypharmacy. This case further emphasizes the need for coordinated infectious disease, psychiatric, and addictions care. It is essential for infectious diseases specialists to incorporate harm reduction strategies into their patient interaction to prevent further infectious complications from intravenous drug use.
Acknowledgments
We thank our patient for her good sense of humor, her willingness to participate in this project, and her resilience in the face of difficult circumstances.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | Recovering | ReactionOutcome | CC BY-NC-ND | 33447641 | 19,093,962 | 2021-01 |
What was the outcome of reaction 'Drug abuse'? | Mycobacterium Mucogenicum Bacteremia and Nodular Soft Tissue Infection in a Person Who Uses Tap Water to Inject Drugs.
The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. In this study, we report a case of Mycobacterium mucogenicum bacteremia and associated nodular soft tissue infection in a person who uses tap water to inject drugs.
CASE
A 50-year-old female presented to a community hospital with a 24-hour history of fever and a right forearm abscess at the site of drug injection. The forearm abscess was incised and drained, and a sample was obtained for bacterial culture. Two peripheral blood cultures were collected before treatment with meropenem. The patient’s forearms demonstrated subcutaneous nodules that she maintained had increased in size slowly during the 2 years preceding her current hospital presentation.
The patient has psychiatric illness, of which intergenerational trauma is a probable factor [1, 2]; her parents attended Canada’s Indian Residential School system. She had been diagnosed with bipolar disorder, borderline personality disorder, and polysubstance use disorder. Her home medications included risperidone, quetiapine, fluoxetine, amitriptyline, and hydromorphone. Our patient injects cocaine on a daily basis and methamphetamine and opioids when cocaine is difficult to obtain. The patient injects her drugs using unfiltered tap water as sterile water ampules and filters are rarely accessible; she has a history of bacteremia from environmental organisms, including Sphingomonas spp, Microbacterium spp, Chryseobacterium indologenes, and Sphingobacterium spiritivorum. She denied sharing her injection paraphernalia and reusing her needles. At baseline, our patient is on home oxygen (2 L/minute) due to chronic obstructive pulmonary disease and pulmonary talcosis. Additional medical history includes inactive hepatitis C and fibromyalgia; she is human immunodeficiency virus negative. She lives in an apartment with her son in Winnipeg, Manitoba, Canada.
Her temperature was 38.2oC, her pulse 121 beats-per-minute, her blood pressure 92/59 mmHg, and her oxygen saturation was 94% while receiving 2 L/minute oxygen via nasal prongs. Physical examination revealed bilateral nodular lesions extending from the dorsum of her hands to her elbows (Figure 1). The nodules were firm and nontender with no overlying erythema. No epitrochlear or axillary lymphadenopathy was present, inconsistent with lymphangitic spread and more suggestive of distinct inoculation of different sites on the hands and forearms. A grade 2 systolic ejection murmur was heard at the right-upper-sternal border with no radiation. Other than clubbing, no peripheral signs of endocarditis were present.
Figure 1. Nodular lesions along the patient’s dorsum of her hand and along her forearm. The largest nodule is on the dorsum of her hand, reflecting the oldest nodule in the location of her earlier injection sites. The absence of lymphadenopathy and the presence of nodules in many locations beyond a single lymphatic drainage reflect separate inoculation events rather than lymphangitic spread.
The plastic surgery service was consulted to perform an excisional biopsy of one of the patient’s forearm nodules, which revealed necrotizing granulomas (Figure 2). Blood cultures were positive.
Figure 2. Suppurative granuloma with central necrosis and neutrophilic infiltration.
One of 2 original sets of blood cultures grew Mycobacterium mucogenicum and Stenotrophomonas maltophilia, identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF; Bruker Biotyper, Bruker Daltonics). Stenotrophomonas maltophilia was reported 2 days after blood draw and was susceptible to levofloxacin, trimethoprim-sulfamethoxazole, minocycline, and ceftazidime as determined by broth microdilution method and interpreted according to current Clinical and Laboratory Standards Institute (CLSI). Mycobacterium mucogenicum was reported 5 days after initial blood draw. Pathology from the patient’s excised forearm nodule demonstrated suppurative necrotizing granulomas associated with acid-fast bacilli on Fite’s stain, a peanut oil/xylene modification of Ziehl-Neelsen (see Figure 3). Within the nodule, foreign crystalline material was identified under examination with polarized light. Gram stain from the nodule revealed scant Gram-positive cocci and Gram-negative bacilli, but no organism grew on aerobic, anaerobic, or mycobacterial culture. Culture of fluid from her forearm abscess grew S maltophilia and Streptococcus pneumoniae. Transthoracic echocardiogram did not reveal any valvular vegetations or regurgitation.
Figure 3. Acid-fast bacilli (Fite’s stain) in the upper central part of the image. Crystalline material is seen in the lower left of the frame.
Although M mucogenicum susceptibilities were pending, the patient was treated with trimethoprim-sulfamethoxazole ([TMP-SMX] 4.5 mg/kg of the TMP component twice a day) and clarithromycin (500 milligrams orally twice a day), a regimen intended to treat S maltophilia as well as M mucogenicum. Treatment became complicated by a prolonged QTc on electrocardiogram after clarithromycin initiation; clarithromycin was changed to doxycycline (100 mg PO BID). Psychiatry was consulted to wean QTc-prolonging medications.
Antimicrobial susceptibility testing of the M mucogenicum isolate susceptibility testing demonstrated susceptibility to TMP-SMX, amikacin, cefoxitin, ciprofloxacin, clarithromycin, imipenem, linezolid, and moxifloxacin but resistance to doxycycline. Antimicrobial susceptibility was determined by broth microdilution and interpreted according to CLSI breakpoints. The patient’s prolonged QTc and psychiatric medications precluded the use of 2 oral agents with in vitro activity, and thus the patient was maintained on her existing regimen with a plan to change doxycycline to clarithromycin once QTc normalized. Multiple repeated blood cultures and mycobacterial blood culture were negative. Over the course of 12 weeks of therapy, the patient clinically improved and her nodules decreased in size and eventually disappeared altogether. Although the patient’s M mucogenicum bacteremia and nodular soft tissue infection resolved, she was subsequently diagnosed with endocarditis from other environmental organisms, including S maltophilia, and she was hospitalized for 6 weeks before being discharged home. During her admission for endocarditis, she was treated with TMP-SMX in addition to meropenem that would likely have therapeutic effect on residual M mucogenicum. Her most recent blood cultures 6 weeks after discharge are negative.
Patient Consent Statement
Written informed consent was obtained from the patient to describe her case and include pictures of her arms and nodule pathology. The design and publication of this work has been approved by the University of Manitoba Bannatyne Research Ethics Board (HS23928:H2020:227, approved May 4, 2020) and conforms to standards currently applied in Canada.
DISCUSSION
Mycobacterium mucogenicum is a rapidly growing nontuberculous mycobacterium (RGM) that routinely inhabits tap water [3, 4]. Mycobacterium mucogenicum’s ability to form biofilms and reproduce in environmental amoeba enables it to tolerate various forms of sanitization including mild chlorination [3]. Due to this fitness advantage in disinfected aqueous ecosystems, M mucogenicum is the most commonly identified RGM in tap water [5].
Mycobacterium mucogenicum infection has diverse clinical manifestations in both immunocompetent as well as immunocompromised hosts, although it is notorious for causing outbreaks of catheter-related blood stream infections among hemodialysis and oncology patients [3, 4, 6]. The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. To our knowledge, this is the second reported case of M mucogenicum infection associated with the injection of drugs [7]. Our patient’s polymicrobial bacteremia was due to injection of tap water from the same contaminated source that caused the granulomatous nodular inflammation in her forearms.
The concurrence of M mucogenicum and S maltophilia in the blood culture as well as the nodule may reflect a novel manifestation of mycobacterial coinfection with a Gram-negative bacillus. This phenomenon has been commonly described in patients with cystic fibrosis where horizontal gene transfer from pseudomonads contributes to the virulence of Mycobacterium abscessus [8]. Although polymicrobial culture positivity often suggests contamination, here the coexistence of RGM and Gram-negative bacillus may suggest the simultaneous inoculation of environmental symbionts.
Optimal treatment for M mucogenicum bacteremia and soft tissue infection remains unclear. If a single skin lesion is present, surgical excision should be considered. A combination of 2 agents, to which the isolate demonstrates in vitro susceptibility, is recommended to prevent the development of drug resistance [9, 10]. Mycobacterium mucogenicum is commonly susceptible to many antimicrobials including amikacin, cefoxitin, clarithromycin, imipenem, and TMP-SMX [3]. However, like other RGM, it remains resistant to first-line antituberculous medications.
CONCLUSIONS
As our case illustrates, among persons who inject drugs, bacteremia with RGM should not be considered a contaminant and may in fact point to other sites of infection. People who inject drugs often experience physical, psychiatric, and socioeconomic difficulties that limit their access to sterile injection equipment. Expanding harm reduction programs to increase accessibility of sterile paraphernalia could mitigate infectious complications of injection drug use and subsequent hospital admission. Antimicrobial options were significantly limited by our patient’s polypharmacy. This case further emphasizes the need for coordinated infectious disease, psychiatric, and addictions care. It is essential for infectious diseases specialists to incorporate harm reduction strategies into their patient interaction to prevent further infectious complications from intravenous drug use.
Acknowledgments
We thank our patient for her good sense of humor, her willingness to participate in this project, and her resilience in the face of difficult circumstances.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | Recovering | ReactionOutcome | CC BY-NC-ND | 33447641 | 19,093,962 | 2021-01 |
What was the outcome of reaction 'Electrocardiogram QT prolonged'? | Mycobacterium Mucogenicum Bacteremia and Nodular Soft Tissue Infection in a Person Who Uses Tap Water to Inject Drugs.
The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. In this study, we report a case of Mycobacterium mucogenicum bacteremia and associated nodular soft tissue infection in a person who uses tap water to inject drugs.
CASE
A 50-year-old female presented to a community hospital with a 24-hour history of fever and a right forearm abscess at the site of drug injection. The forearm abscess was incised and drained, and a sample was obtained for bacterial culture. Two peripheral blood cultures were collected before treatment with meropenem. The patient’s forearms demonstrated subcutaneous nodules that she maintained had increased in size slowly during the 2 years preceding her current hospital presentation.
The patient has psychiatric illness, of which intergenerational trauma is a probable factor [1, 2]; her parents attended Canada’s Indian Residential School system. She had been diagnosed with bipolar disorder, borderline personality disorder, and polysubstance use disorder. Her home medications included risperidone, quetiapine, fluoxetine, amitriptyline, and hydromorphone. Our patient injects cocaine on a daily basis and methamphetamine and opioids when cocaine is difficult to obtain. The patient injects her drugs using unfiltered tap water as sterile water ampules and filters are rarely accessible; she has a history of bacteremia from environmental organisms, including Sphingomonas spp, Microbacterium spp, Chryseobacterium indologenes, and Sphingobacterium spiritivorum. She denied sharing her injection paraphernalia and reusing her needles. At baseline, our patient is on home oxygen (2 L/minute) due to chronic obstructive pulmonary disease and pulmonary talcosis. Additional medical history includes inactive hepatitis C and fibromyalgia; she is human immunodeficiency virus negative. She lives in an apartment with her son in Winnipeg, Manitoba, Canada.
Her temperature was 38.2oC, her pulse 121 beats-per-minute, her blood pressure 92/59 mmHg, and her oxygen saturation was 94% while receiving 2 L/minute oxygen via nasal prongs. Physical examination revealed bilateral nodular lesions extending from the dorsum of her hands to her elbows (Figure 1). The nodules were firm and nontender with no overlying erythema. No epitrochlear or axillary lymphadenopathy was present, inconsistent with lymphangitic spread and more suggestive of distinct inoculation of different sites on the hands and forearms. A grade 2 systolic ejection murmur was heard at the right-upper-sternal border with no radiation. Other than clubbing, no peripheral signs of endocarditis were present.
Figure 1. Nodular lesions along the patient’s dorsum of her hand and along her forearm. The largest nodule is on the dorsum of her hand, reflecting the oldest nodule in the location of her earlier injection sites. The absence of lymphadenopathy and the presence of nodules in many locations beyond a single lymphatic drainage reflect separate inoculation events rather than lymphangitic spread.
The plastic surgery service was consulted to perform an excisional biopsy of one of the patient’s forearm nodules, which revealed necrotizing granulomas (Figure 2). Blood cultures were positive.
Figure 2. Suppurative granuloma with central necrosis and neutrophilic infiltration.
One of 2 original sets of blood cultures grew Mycobacterium mucogenicum and Stenotrophomonas maltophilia, identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF; Bruker Biotyper, Bruker Daltonics). Stenotrophomonas maltophilia was reported 2 days after blood draw and was susceptible to levofloxacin, trimethoprim-sulfamethoxazole, minocycline, and ceftazidime as determined by broth microdilution method and interpreted according to current Clinical and Laboratory Standards Institute (CLSI). Mycobacterium mucogenicum was reported 5 days after initial blood draw. Pathology from the patient’s excised forearm nodule demonstrated suppurative necrotizing granulomas associated with acid-fast bacilli on Fite’s stain, a peanut oil/xylene modification of Ziehl-Neelsen (see Figure 3). Within the nodule, foreign crystalline material was identified under examination with polarized light. Gram stain from the nodule revealed scant Gram-positive cocci and Gram-negative bacilli, but no organism grew on aerobic, anaerobic, or mycobacterial culture. Culture of fluid from her forearm abscess grew S maltophilia and Streptococcus pneumoniae. Transthoracic echocardiogram did not reveal any valvular vegetations or regurgitation.
Figure 3. Acid-fast bacilli (Fite’s stain) in the upper central part of the image. Crystalline material is seen in the lower left of the frame.
Although M mucogenicum susceptibilities were pending, the patient was treated with trimethoprim-sulfamethoxazole ([TMP-SMX] 4.5 mg/kg of the TMP component twice a day) and clarithromycin (500 milligrams orally twice a day), a regimen intended to treat S maltophilia as well as M mucogenicum. Treatment became complicated by a prolonged QTc on electrocardiogram after clarithromycin initiation; clarithromycin was changed to doxycycline (100 mg PO BID). Psychiatry was consulted to wean QTc-prolonging medications.
Antimicrobial susceptibility testing of the M mucogenicum isolate susceptibility testing demonstrated susceptibility to TMP-SMX, amikacin, cefoxitin, ciprofloxacin, clarithromycin, imipenem, linezolid, and moxifloxacin but resistance to doxycycline. Antimicrobial susceptibility was determined by broth microdilution and interpreted according to CLSI breakpoints. The patient’s prolonged QTc and psychiatric medications precluded the use of 2 oral agents with in vitro activity, and thus the patient was maintained on her existing regimen with a plan to change doxycycline to clarithromycin once QTc normalized. Multiple repeated blood cultures and mycobacterial blood culture were negative. Over the course of 12 weeks of therapy, the patient clinically improved and her nodules decreased in size and eventually disappeared altogether. Although the patient’s M mucogenicum bacteremia and nodular soft tissue infection resolved, she was subsequently diagnosed with endocarditis from other environmental organisms, including S maltophilia, and she was hospitalized for 6 weeks before being discharged home. During her admission for endocarditis, she was treated with TMP-SMX in addition to meropenem that would likely have therapeutic effect on residual M mucogenicum. Her most recent blood cultures 6 weeks after discharge are negative.
Patient Consent Statement
Written informed consent was obtained from the patient to describe her case and include pictures of her arms and nodule pathology. The design and publication of this work has been approved by the University of Manitoba Bannatyne Research Ethics Board (HS23928:H2020:227, approved May 4, 2020) and conforms to standards currently applied in Canada.
DISCUSSION
Mycobacterium mucogenicum is a rapidly growing nontuberculous mycobacterium (RGM) that routinely inhabits tap water [3, 4]. Mycobacterium mucogenicum’s ability to form biofilms and reproduce in environmental amoeba enables it to tolerate various forms of sanitization including mild chlorination [3]. Due to this fitness advantage in disinfected aqueous ecosystems, M mucogenicum is the most commonly identified RGM in tap water [5].
Mycobacterium mucogenicum infection has diverse clinical manifestations in both immunocompetent as well as immunocompromised hosts, although it is notorious for causing outbreaks of catheter-related blood stream infections among hemodialysis and oncology patients [3, 4, 6]. The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. To our knowledge, this is the second reported case of M mucogenicum infection associated with the injection of drugs [7]. Our patient’s polymicrobial bacteremia was due to injection of tap water from the same contaminated source that caused the granulomatous nodular inflammation in her forearms.
The concurrence of M mucogenicum and S maltophilia in the blood culture as well as the nodule may reflect a novel manifestation of mycobacterial coinfection with a Gram-negative bacillus. This phenomenon has been commonly described in patients with cystic fibrosis where horizontal gene transfer from pseudomonads contributes to the virulence of Mycobacterium abscessus [8]. Although polymicrobial culture positivity often suggests contamination, here the coexistence of RGM and Gram-negative bacillus may suggest the simultaneous inoculation of environmental symbionts.
Optimal treatment for M mucogenicum bacteremia and soft tissue infection remains unclear. If a single skin lesion is present, surgical excision should be considered. A combination of 2 agents, to which the isolate demonstrates in vitro susceptibility, is recommended to prevent the development of drug resistance [9, 10]. Mycobacterium mucogenicum is commonly susceptible to many antimicrobials including amikacin, cefoxitin, clarithromycin, imipenem, and TMP-SMX [3]. However, like other RGM, it remains resistant to first-line antituberculous medications.
CONCLUSIONS
As our case illustrates, among persons who inject drugs, bacteremia with RGM should not be considered a contaminant and may in fact point to other sites of infection. People who inject drugs often experience physical, psychiatric, and socioeconomic difficulties that limit their access to sterile injection equipment. Expanding harm reduction programs to increase accessibility of sterile paraphernalia could mitigate infectious complications of injection drug use and subsequent hospital admission. Antimicrobial options were significantly limited by our patient’s polypharmacy. This case further emphasizes the need for coordinated infectious disease, psychiatric, and addictions care. It is essential for infectious diseases specialists to incorporate harm reduction strategies into their patient interaction to prevent further infectious complications from intravenous drug use.
Acknowledgments
We thank our patient for her good sense of humor, her willingness to participate in this project, and her resilience in the face of difficult circumstances.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | Recovering | ReactionOutcome | CC BY-NC-ND | 33447641 | 19,093,962 | 2021-01 |
What was the outcome of reaction 'Endocarditis'? | Mycobacterium Mucogenicum Bacteremia and Nodular Soft Tissue Infection in a Person Who Uses Tap Water to Inject Drugs.
The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. In this study, we report a case of Mycobacterium mucogenicum bacteremia and associated nodular soft tissue infection in a person who uses tap water to inject drugs.
CASE
A 50-year-old female presented to a community hospital with a 24-hour history of fever and a right forearm abscess at the site of drug injection. The forearm abscess was incised and drained, and a sample was obtained for bacterial culture. Two peripheral blood cultures were collected before treatment with meropenem. The patient’s forearms demonstrated subcutaneous nodules that she maintained had increased in size slowly during the 2 years preceding her current hospital presentation.
The patient has psychiatric illness, of which intergenerational trauma is a probable factor [1, 2]; her parents attended Canada’s Indian Residential School system. She had been diagnosed with bipolar disorder, borderline personality disorder, and polysubstance use disorder. Her home medications included risperidone, quetiapine, fluoxetine, amitriptyline, and hydromorphone. Our patient injects cocaine on a daily basis and methamphetamine and opioids when cocaine is difficult to obtain. The patient injects her drugs using unfiltered tap water as sterile water ampules and filters are rarely accessible; she has a history of bacteremia from environmental organisms, including Sphingomonas spp, Microbacterium spp, Chryseobacterium indologenes, and Sphingobacterium spiritivorum. She denied sharing her injection paraphernalia and reusing her needles. At baseline, our patient is on home oxygen (2 L/minute) due to chronic obstructive pulmonary disease and pulmonary talcosis. Additional medical history includes inactive hepatitis C and fibromyalgia; she is human immunodeficiency virus negative. She lives in an apartment with her son in Winnipeg, Manitoba, Canada.
Her temperature was 38.2oC, her pulse 121 beats-per-minute, her blood pressure 92/59 mmHg, and her oxygen saturation was 94% while receiving 2 L/minute oxygen via nasal prongs. Physical examination revealed bilateral nodular lesions extending from the dorsum of her hands to her elbows (Figure 1). The nodules were firm and nontender with no overlying erythema. No epitrochlear or axillary lymphadenopathy was present, inconsistent with lymphangitic spread and more suggestive of distinct inoculation of different sites on the hands and forearms. A grade 2 systolic ejection murmur was heard at the right-upper-sternal border with no radiation. Other than clubbing, no peripheral signs of endocarditis were present.
Figure 1. Nodular lesions along the patient’s dorsum of her hand and along her forearm. The largest nodule is on the dorsum of her hand, reflecting the oldest nodule in the location of her earlier injection sites. The absence of lymphadenopathy and the presence of nodules in many locations beyond a single lymphatic drainage reflect separate inoculation events rather than lymphangitic spread.
The plastic surgery service was consulted to perform an excisional biopsy of one of the patient’s forearm nodules, which revealed necrotizing granulomas (Figure 2). Blood cultures were positive.
Figure 2. Suppurative granuloma with central necrosis and neutrophilic infiltration.
One of 2 original sets of blood cultures grew Mycobacterium mucogenicum and Stenotrophomonas maltophilia, identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF; Bruker Biotyper, Bruker Daltonics). Stenotrophomonas maltophilia was reported 2 days after blood draw and was susceptible to levofloxacin, trimethoprim-sulfamethoxazole, minocycline, and ceftazidime as determined by broth microdilution method and interpreted according to current Clinical and Laboratory Standards Institute (CLSI). Mycobacterium mucogenicum was reported 5 days after initial blood draw. Pathology from the patient’s excised forearm nodule demonstrated suppurative necrotizing granulomas associated with acid-fast bacilli on Fite’s stain, a peanut oil/xylene modification of Ziehl-Neelsen (see Figure 3). Within the nodule, foreign crystalline material was identified under examination with polarized light. Gram stain from the nodule revealed scant Gram-positive cocci and Gram-negative bacilli, but no organism grew on aerobic, anaerobic, or mycobacterial culture. Culture of fluid from her forearm abscess grew S maltophilia and Streptococcus pneumoniae. Transthoracic echocardiogram did not reveal any valvular vegetations or regurgitation.
Figure 3. Acid-fast bacilli (Fite’s stain) in the upper central part of the image. Crystalline material is seen in the lower left of the frame.
Although M mucogenicum susceptibilities were pending, the patient was treated with trimethoprim-sulfamethoxazole ([TMP-SMX] 4.5 mg/kg of the TMP component twice a day) and clarithromycin (500 milligrams orally twice a day), a regimen intended to treat S maltophilia as well as M mucogenicum. Treatment became complicated by a prolonged QTc on electrocardiogram after clarithromycin initiation; clarithromycin was changed to doxycycline (100 mg PO BID). Psychiatry was consulted to wean QTc-prolonging medications.
Antimicrobial susceptibility testing of the M mucogenicum isolate susceptibility testing demonstrated susceptibility to TMP-SMX, amikacin, cefoxitin, ciprofloxacin, clarithromycin, imipenem, linezolid, and moxifloxacin but resistance to doxycycline. Antimicrobial susceptibility was determined by broth microdilution and interpreted according to CLSI breakpoints. The patient’s prolonged QTc and psychiatric medications precluded the use of 2 oral agents with in vitro activity, and thus the patient was maintained on her existing regimen with a plan to change doxycycline to clarithromycin once QTc normalized. Multiple repeated blood cultures and mycobacterial blood culture were negative. Over the course of 12 weeks of therapy, the patient clinically improved and her nodules decreased in size and eventually disappeared altogether. Although the patient’s M mucogenicum bacteremia and nodular soft tissue infection resolved, she was subsequently diagnosed with endocarditis from other environmental organisms, including S maltophilia, and she was hospitalized for 6 weeks before being discharged home. During her admission for endocarditis, she was treated with TMP-SMX in addition to meropenem that would likely have therapeutic effect on residual M mucogenicum. Her most recent blood cultures 6 weeks after discharge are negative.
Patient Consent Statement
Written informed consent was obtained from the patient to describe her case and include pictures of her arms and nodule pathology. The design and publication of this work has been approved by the University of Manitoba Bannatyne Research Ethics Board (HS23928:H2020:227, approved May 4, 2020) and conforms to standards currently applied in Canada.
DISCUSSION
Mycobacterium mucogenicum is a rapidly growing nontuberculous mycobacterium (RGM) that routinely inhabits tap water [3, 4]. Mycobacterium mucogenicum’s ability to form biofilms and reproduce in environmental amoeba enables it to tolerate various forms of sanitization including mild chlorination [3]. Due to this fitness advantage in disinfected aqueous ecosystems, M mucogenicum is the most commonly identified RGM in tap water [5].
Mycobacterium mucogenicum infection has diverse clinical manifestations in both immunocompetent as well as immunocompromised hosts, although it is notorious for causing outbreaks of catheter-related blood stream infections among hemodialysis and oncology patients [3, 4, 6]. The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. To our knowledge, this is the second reported case of M mucogenicum infection associated with the injection of drugs [7]. Our patient’s polymicrobial bacteremia was due to injection of tap water from the same contaminated source that caused the granulomatous nodular inflammation in her forearms.
The concurrence of M mucogenicum and S maltophilia in the blood culture as well as the nodule may reflect a novel manifestation of mycobacterial coinfection with a Gram-negative bacillus. This phenomenon has been commonly described in patients with cystic fibrosis where horizontal gene transfer from pseudomonads contributes to the virulence of Mycobacterium abscessus [8]. Although polymicrobial culture positivity often suggests contamination, here the coexistence of RGM and Gram-negative bacillus may suggest the simultaneous inoculation of environmental symbionts.
Optimal treatment for M mucogenicum bacteremia and soft tissue infection remains unclear. If a single skin lesion is present, surgical excision should be considered. A combination of 2 agents, to which the isolate demonstrates in vitro susceptibility, is recommended to prevent the development of drug resistance [9, 10]. Mycobacterium mucogenicum is commonly susceptible to many antimicrobials including amikacin, cefoxitin, clarithromycin, imipenem, and TMP-SMX [3]. However, like other RGM, it remains resistant to first-line antituberculous medications.
CONCLUSIONS
As our case illustrates, among persons who inject drugs, bacteremia with RGM should not be considered a contaminant and may in fact point to other sites of infection. People who inject drugs often experience physical, psychiatric, and socioeconomic difficulties that limit their access to sterile injection equipment. Expanding harm reduction programs to increase accessibility of sterile paraphernalia could mitigate infectious complications of injection drug use and subsequent hospital admission. Antimicrobial options were significantly limited by our patient’s polypharmacy. This case further emphasizes the need for coordinated infectious disease, psychiatric, and addictions care. It is essential for infectious diseases specialists to incorporate harm reduction strategies into their patient interaction to prevent further infectious complications from intravenous drug use.
Acknowledgments
We thank our patient for her good sense of humor, her willingness to participate in this project, and her resilience in the face of difficult circumstances.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | Recovering | ReactionOutcome | CC BY-NC-ND | 33447641 | 19,093,962 | 2021-01 |
What was the outcome of reaction 'Lung disorder'? | Mycobacterium Mucogenicum Bacteremia and Nodular Soft Tissue Infection in a Person Who Uses Tap Water to Inject Drugs.
The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. In this study, we report a case of Mycobacterium mucogenicum bacteremia and associated nodular soft tissue infection in a person who uses tap water to inject drugs.
CASE
A 50-year-old female presented to a community hospital with a 24-hour history of fever and a right forearm abscess at the site of drug injection. The forearm abscess was incised and drained, and a sample was obtained for bacterial culture. Two peripheral blood cultures were collected before treatment with meropenem. The patient’s forearms demonstrated subcutaneous nodules that she maintained had increased in size slowly during the 2 years preceding her current hospital presentation.
The patient has psychiatric illness, of which intergenerational trauma is a probable factor [1, 2]; her parents attended Canada’s Indian Residential School system. She had been diagnosed with bipolar disorder, borderline personality disorder, and polysubstance use disorder. Her home medications included risperidone, quetiapine, fluoxetine, amitriptyline, and hydromorphone. Our patient injects cocaine on a daily basis and methamphetamine and opioids when cocaine is difficult to obtain. The patient injects her drugs using unfiltered tap water as sterile water ampules and filters are rarely accessible; she has a history of bacteremia from environmental organisms, including Sphingomonas spp, Microbacterium spp, Chryseobacterium indologenes, and Sphingobacterium spiritivorum. She denied sharing her injection paraphernalia and reusing her needles. At baseline, our patient is on home oxygen (2 L/minute) due to chronic obstructive pulmonary disease and pulmonary talcosis. Additional medical history includes inactive hepatitis C and fibromyalgia; she is human immunodeficiency virus negative. She lives in an apartment with her son in Winnipeg, Manitoba, Canada.
Her temperature was 38.2oC, her pulse 121 beats-per-minute, her blood pressure 92/59 mmHg, and her oxygen saturation was 94% while receiving 2 L/minute oxygen via nasal prongs. Physical examination revealed bilateral nodular lesions extending from the dorsum of her hands to her elbows (Figure 1). The nodules were firm and nontender with no overlying erythema. No epitrochlear or axillary lymphadenopathy was present, inconsistent with lymphangitic spread and more suggestive of distinct inoculation of different sites on the hands and forearms. A grade 2 systolic ejection murmur was heard at the right-upper-sternal border with no radiation. Other than clubbing, no peripheral signs of endocarditis were present.
Figure 1. Nodular lesions along the patient’s dorsum of her hand and along her forearm. The largest nodule is on the dorsum of her hand, reflecting the oldest nodule in the location of her earlier injection sites. The absence of lymphadenopathy and the presence of nodules in many locations beyond a single lymphatic drainage reflect separate inoculation events rather than lymphangitic spread.
The plastic surgery service was consulted to perform an excisional biopsy of one of the patient’s forearm nodules, which revealed necrotizing granulomas (Figure 2). Blood cultures were positive.
Figure 2. Suppurative granuloma with central necrosis and neutrophilic infiltration.
One of 2 original sets of blood cultures grew Mycobacterium mucogenicum and Stenotrophomonas maltophilia, identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF; Bruker Biotyper, Bruker Daltonics). Stenotrophomonas maltophilia was reported 2 days after blood draw and was susceptible to levofloxacin, trimethoprim-sulfamethoxazole, minocycline, and ceftazidime as determined by broth microdilution method and interpreted according to current Clinical and Laboratory Standards Institute (CLSI). Mycobacterium mucogenicum was reported 5 days after initial blood draw. Pathology from the patient’s excised forearm nodule demonstrated suppurative necrotizing granulomas associated with acid-fast bacilli on Fite’s stain, a peanut oil/xylene modification of Ziehl-Neelsen (see Figure 3). Within the nodule, foreign crystalline material was identified under examination with polarized light. Gram stain from the nodule revealed scant Gram-positive cocci and Gram-negative bacilli, but no organism grew on aerobic, anaerobic, or mycobacterial culture. Culture of fluid from her forearm abscess grew S maltophilia and Streptococcus pneumoniae. Transthoracic echocardiogram did not reveal any valvular vegetations or regurgitation.
Figure 3. Acid-fast bacilli (Fite’s stain) in the upper central part of the image. Crystalline material is seen in the lower left of the frame.
Although M mucogenicum susceptibilities were pending, the patient was treated with trimethoprim-sulfamethoxazole ([TMP-SMX] 4.5 mg/kg of the TMP component twice a day) and clarithromycin (500 milligrams orally twice a day), a regimen intended to treat S maltophilia as well as M mucogenicum. Treatment became complicated by a prolonged QTc on electrocardiogram after clarithromycin initiation; clarithromycin was changed to doxycycline (100 mg PO BID). Psychiatry was consulted to wean QTc-prolonging medications.
Antimicrobial susceptibility testing of the M mucogenicum isolate susceptibility testing demonstrated susceptibility to TMP-SMX, amikacin, cefoxitin, ciprofloxacin, clarithromycin, imipenem, linezolid, and moxifloxacin but resistance to doxycycline. Antimicrobial susceptibility was determined by broth microdilution and interpreted according to CLSI breakpoints. The patient’s prolonged QTc and psychiatric medications precluded the use of 2 oral agents with in vitro activity, and thus the patient was maintained on her existing regimen with a plan to change doxycycline to clarithromycin once QTc normalized. Multiple repeated blood cultures and mycobacterial blood culture were negative. Over the course of 12 weeks of therapy, the patient clinically improved and her nodules decreased in size and eventually disappeared altogether. Although the patient’s M mucogenicum bacteremia and nodular soft tissue infection resolved, she was subsequently diagnosed with endocarditis from other environmental organisms, including S maltophilia, and she was hospitalized for 6 weeks before being discharged home. During her admission for endocarditis, she was treated with TMP-SMX in addition to meropenem that would likely have therapeutic effect on residual M mucogenicum. Her most recent blood cultures 6 weeks after discharge are negative.
Patient Consent Statement
Written informed consent was obtained from the patient to describe her case and include pictures of her arms and nodule pathology. The design and publication of this work has been approved by the University of Manitoba Bannatyne Research Ethics Board (HS23928:H2020:227, approved May 4, 2020) and conforms to standards currently applied in Canada.
DISCUSSION
Mycobacterium mucogenicum is a rapidly growing nontuberculous mycobacterium (RGM) that routinely inhabits tap water [3, 4]. Mycobacterium mucogenicum’s ability to form biofilms and reproduce in environmental amoeba enables it to tolerate various forms of sanitization including mild chlorination [3]. Due to this fitness advantage in disinfected aqueous ecosystems, M mucogenicum is the most commonly identified RGM in tap water [5].
Mycobacterium mucogenicum infection has diverse clinical manifestations in both immunocompetent as well as immunocompromised hosts, although it is notorious for causing outbreaks of catheter-related blood stream infections among hemodialysis and oncology patients [3, 4, 6]. The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. To our knowledge, this is the second reported case of M mucogenicum infection associated with the injection of drugs [7]. Our patient’s polymicrobial bacteremia was due to injection of tap water from the same contaminated source that caused the granulomatous nodular inflammation in her forearms.
The concurrence of M mucogenicum and S maltophilia in the blood culture as well as the nodule may reflect a novel manifestation of mycobacterial coinfection with a Gram-negative bacillus. This phenomenon has been commonly described in patients with cystic fibrosis where horizontal gene transfer from pseudomonads contributes to the virulence of Mycobacterium abscessus [8]. Although polymicrobial culture positivity often suggests contamination, here the coexistence of RGM and Gram-negative bacillus may suggest the simultaneous inoculation of environmental symbionts.
Optimal treatment for M mucogenicum bacteremia and soft tissue infection remains unclear. If a single skin lesion is present, surgical excision should be considered. A combination of 2 agents, to which the isolate demonstrates in vitro susceptibility, is recommended to prevent the development of drug resistance [9, 10]. Mycobacterium mucogenicum is commonly susceptible to many antimicrobials including amikacin, cefoxitin, clarithromycin, imipenem, and TMP-SMX [3]. However, like other RGM, it remains resistant to first-line antituberculous medications.
CONCLUSIONS
As our case illustrates, among persons who inject drugs, bacteremia with RGM should not be considered a contaminant and may in fact point to other sites of infection. People who inject drugs often experience physical, psychiatric, and socioeconomic difficulties that limit their access to sterile injection equipment. Expanding harm reduction programs to increase accessibility of sterile paraphernalia could mitigate infectious complications of injection drug use and subsequent hospital admission. Antimicrobial options were significantly limited by our patient’s polypharmacy. This case further emphasizes the need for coordinated infectious disease, psychiatric, and addictions care. It is essential for infectious diseases specialists to incorporate harm reduction strategies into their patient interaction to prevent further infectious complications from intravenous drug use.
Acknowledgments
We thank our patient for her good sense of humor, her willingness to participate in this project, and her resilience in the face of difficult circumstances.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | Recovering | ReactionOutcome | CC BY-NC-ND | 33447641 | 19,093,962 | 2021-01 |
What was the outcome of reaction 'Mycobacterial infection'? | Mycobacterium Mucogenicum Bacteremia and Nodular Soft Tissue Infection in a Person Who Uses Tap Water to Inject Drugs.
The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. In this study, we report a case of Mycobacterium mucogenicum bacteremia and associated nodular soft tissue infection in a person who uses tap water to inject drugs.
CASE
A 50-year-old female presented to a community hospital with a 24-hour history of fever and a right forearm abscess at the site of drug injection. The forearm abscess was incised and drained, and a sample was obtained for bacterial culture. Two peripheral blood cultures were collected before treatment with meropenem. The patient’s forearms demonstrated subcutaneous nodules that she maintained had increased in size slowly during the 2 years preceding her current hospital presentation.
The patient has psychiatric illness, of which intergenerational trauma is a probable factor [1, 2]; her parents attended Canada’s Indian Residential School system. She had been diagnosed with bipolar disorder, borderline personality disorder, and polysubstance use disorder. Her home medications included risperidone, quetiapine, fluoxetine, amitriptyline, and hydromorphone. Our patient injects cocaine on a daily basis and methamphetamine and opioids when cocaine is difficult to obtain. The patient injects her drugs using unfiltered tap water as sterile water ampules and filters are rarely accessible; she has a history of bacteremia from environmental organisms, including Sphingomonas spp, Microbacterium spp, Chryseobacterium indologenes, and Sphingobacterium spiritivorum. She denied sharing her injection paraphernalia and reusing her needles. At baseline, our patient is on home oxygen (2 L/minute) due to chronic obstructive pulmonary disease and pulmonary talcosis. Additional medical history includes inactive hepatitis C and fibromyalgia; she is human immunodeficiency virus negative. She lives in an apartment with her son in Winnipeg, Manitoba, Canada.
Her temperature was 38.2oC, her pulse 121 beats-per-minute, her blood pressure 92/59 mmHg, and her oxygen saturation was 94% while receiving 2 L/minute oxygen via nasal prongs. Physical examination revealed bilateral nodular lesions extending from the dorsum of her hands to her elbows (Figure 1). The nodules were firm and nontender with no overlying erythema. No epitrochlear or axillary lymphadenopathy was present, inconsistent with lymphangitic spread and more suggestive of distinct inoculation of different sites on the hands and forearms. A grade 2 systolic ejection murmur was heard at the right-upper-sternal border with no radiation. Other than clubbing, no peripheral signs of endocarditis were present.
Figure 1. Nodular lesions along the patient’s dorsum of her hand and along her forearm. The largest nodule is on the dorsum of her hand, reflecting the oldest nodule in the location of her earlier injection sites. The absence of lymphadenopathy and the presence of nodules in many locations beyond a single lymphatic drainage reflect separate inoculation events rather than lymphangitic spread.
The plastic surgery service was consulted to perform an excisional biopsy of one of the patient’s forearm nodules, which revealed necrotizing granulomas (Figure 2). Blood cultures were positive.
Figure 2. Suppurative granuloma with central necrosis and neutrophilic infiltration.
One of 2 original sets of blood cultures grew Mycobacterium mucogenicum and Stenotrophomonas maltophilia, identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF; Bruker Biotyper, Bruker Daltonics). Stenotrophomonas maltophilia was reported 2 days after blood draw and was susceptible to levofloxacin, trimethoprim-sulfamethoxazole, minocycline, and ceftazidime as determined by broth microdilution method and interpreted according to current Clinical and Laboratory Standards Institute (CLSI). Mycobacterium mucogenicum was reported 5 days after initial blood draw. Pathology from the patient’s excised forearm nodule demonstrated suppurative necrotizing granulomas associated with acid-fast bacilli on Fite’s stain, a peanut oil/xylene modification of Ziehl-Neelsen (see Figure 3). Within the nodule, foreign crystalline material was identified under examination with polarized light. Gram stain from the nodule revealed scant Gram-positive cocci and Gram-negative bacilli, but no organism grew on aerobic, anaerobic, or mycobacterial culture. Culture of fluid from her forearm abscess grew S maltophilia and Streptococcus pneumoniae. Transthoracic echocardiogram did not reveal any valvular vegetations or regurgitation.
Figure 3. Acid-fast bacilli (Fite’s stain) in the upper central part of the image. Crystalline material is seen in the lower left of the frame.
Although M mucogenicum susceptibilities were pending, the patient was treated with trimethoprim-sulfamethoxazole ([TMP-SMX] 4.5 mg/kg of the TMP component twice a day) and clarithromycin (500 milligrams orally twice a day), a regimen intended to treat S maltophilia as well as M mucogenicum. Treatment became complicated by a prolonged QTc on electrocardiogram after clarithromycin initiation; clarithromycin was changed to doxycycline (100 mg PO BID). Psychiatry was consulted to wean QTc-prolonging medications.
Antimicrobial susceptibility testing of the M mucogenicum isolate susceptibility testing demonstrated susceptibility to TMP-SMX, amikacin, cefoxitin, ciprofloxacin, clarithromycin, imipenem, linezolid, and moxifloxacin but resistance to doxycycline. Antimicrobial susceptibility was determined by broth microdilution and interpreted according to CLSI breakpoints. The patient’s prolonged QTc and psychiatric medications precluded the use of 2 oral agents with in vitro activity, and thus the patient was maintained on her existing regimen with a plan to change doxycycline to clarithromycin once QTc normalized. Multiple repeated blood cultures and mycobacterial blood culture were negative. Over the course of 12 weeks of therapy, the patient clinically improved and her nodules decreased in size and eventually disappeared altogether. Although the patient’s M mucogenicum bacteremia and nodular soft tissue infection resolved, she was subsequently diagnosed with endocarditis from other environmental organisms, including S maltophilia, and she was hospitalized for 6 weeks before being discharged home. During her admission for endocarditis, she was treated with TMP-SMX in addition to meropenem that would likely have therapeutic effect on residual M mucogenicum. Her most recent blood cultures 6 weeks after discharge are negative.
Patient Consent Statement
Written informed consent was obtained from the patient to describe her case and include pictures of her arms and nodule pathology. The design and publication of this work has been approved by the University of Manitoba Bannatyne Research Ethics Board (HS23928:H2020:227, approved May 4, 2020) and conforms to standards currently applied in Canada.
DISCUSSION
Mycobacterium mucogenicum is a rapidly growing nontuberculous mycobacterium (RGM) that routinely inhabits tap water [3, 4]. Mycobacterium mucogenicum’s ability to form biofilms and reproduce in environmental amoeba enables it to tolerate various forms of sanitization including mild chlorination [3]. Due to this fitness advantage in disinfected aqueous ecosystems, M mucogenicum is the most commonly identified RGM in tap water [5].
Mycobacterium mucogenicum infection has diverse clinical manifestations in both immunocompetent as well as immunocompromised hosts, although it is notorious for causing outbreaks of catheter-related blood stream infections among hemodialysis and oncology patients [3, 4, 6]. The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. To our knowledge, this is the second reported case of M mucogenicum infection associated with the injection of drugs [7]. Our patient’s polymicrobial bacteremia was due to injection of tap water from the same contaminated source that caused the granulomatous nodular inflammation in her forearms.
The concurrence of M mucogenicum and S maltophilia in the blood culture as well as the nodule may reflect a novel manifestation of mycobacterial coinfection with a Gram-negative bacillus. This phenomenon has been commonly described in patients with cystic fibrosis where horizontal gene transfer from pseudomonads contributes to the virulence of Mycobacterium abscessus [8]. Although polymicrobial culture positivity often suggests contamination, here the coexistence of RGM and Gram-negative bacillus may suggest the simultaneous inoculation of environmental symbionts.
Optimal treatment for M mucogenicum bacteremia and soft tissue infection remains unclear. If a single skin lesion is present, surgical excision should be considered. A combination of 2 agents, to which the isolate demonstrates in vitro susceptibility, is recommended to prevent the development of drug resistance [9, 10]. Mycobacterium mucogenicum is commonly susceptible to many antimicrobials including amikacin, cefoxitin, clarithromycin, imipenem, and TMP-SMX [3]. However, like other RGM, it remains resistant to first-line antituberculous medications.
CONCLUSIONS
As our case illustrates, among persons who inject drugs, bacteremia with RGM should not be considered a contaminant and may in fact point to other sites of infection. People who inject drugs often experience physical, psychiatric, and socioeconomic difficulties that limit their access to sterile injection equipment. Expanding harm reduction programs to increase accessibility of sterile paraphernalia could mitigate infectious complications of injection drug use and subsequent hospital admission. Antimicrobial options were significantly limited by our patient’s polypharmacy. This case further emphasizes the need for coordinated infectious disease, psychiatric, and addictions care. It is essential for infectious diseases specialists to incorporate harm reduction strategies into their patient interaction to prevent further infectious complications from intravenous drug use.
Acknowledgments
We thank our patient for her good sense of humor, her willingness to participate in this project, and her resilience in the face of difficult circumstances.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | Recovered | ReactionOutcome | CC BY-NC-ND | 33447641 | 19,093,962 | 2021-01 |
What was the outcome of reaction 'Stenotrophomonas infection'? | Mycobacterium Mucogenicum Bacteremia and Nodular Soft Tissue Infection in a Person Who Uses Tap Water to Inject Drugs.
The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. In this study, we report a case of Mycobacterium mucogenicum bacteremia and associated nodular soft tissue infection in a person who uses tap water to inject drugs.
CASE
A 50-year-old female presented to a community hospital with a 24-hour history of fever and a right forearm abscess at the site of drug injection. The forearm abscess was incised and drained, and a sample was obtained for bacterial culture. Two peripheral blood cultures were collected before treatment with meropenem. The patient’s forearms demonstrated subcutaneous nodules that she maintained had increased in size slowly during the 2 years preceding her current hospital presentation.
The patient has psychiatric illness, of which intergenerational trauma is a probable factor [1, 2]; her parents attended Canada’s Indian Residential School system. She had been diagnosed with bipolar disorder, borderline personality disorder, and polysubstance use disorder. Her home medications included risperidone, quetiapine, fluoxetine, amitriptyline, and hydromorphone. Our patient injects cocaine on a daily basis and methamphetamine and opioids when cocaine is difficult to obtain. The patient injects her drugs using unfiltered tap water as sterile water ampules and filters are rarely accessible; she has a history of bacteremia from environmental organisms, including Sphingomonas spp, Microbacterium spp, Chryseobacterium indologenes, and Sphingobacterium spiritivorum. She denied sharing her injection paraphernalia and reusing her needles. At baseline, our patient is on home oxygen (2 L/minute) due to chronic obstructive pulmonary disease and pulmonary talcosis. Additional medical history includes inactive hepatitis C and fibromyalgia; she is human immunodeficiency virus negative. She lives in an apartment with her son in Winnipeg, Manitoba, Canada.
Her temperature was 38.2oC, her pulse 121 beats-per-minute, her blood pressure 92/59 mmHg, and her oxygen saturation was 94% while receiving 2 L/minute oxygen via nasal prongs. Physical examination revealed bilateral nodular lesions extending from the dorsum of her hands to her elbows (Figure 1). The nodules were firm and nontender with no overlying erythema. No epitrochlear or axillary lymphadenopathy was present, inconsistent with lymphangitic spread and more suggestive of distinct inoculation of different sites on the hands and forearms. A grade 2 systolic ejection murmur was heard at the right-upper-sternal border with no radiation. Other than clubbing, no peripheral signs of endocarditis were present.
Figure 1. Nodular lesions along the patient’s dorsum of her hand and along her forearm. The largest nodule is on the dorsum of her hand, reflecting the oldest nodule in the location of her earlier injection sites. The absence of lymphadenopathy and the presence of nodules in many locations beyond a single lymphatic drainage reflect separate inoculation events rather than lymphangitic spread.
The plastic surgery service was consulted to perform an excisional biopsy of one of the patient’s forearm nodules, which revealed necrotizing granulomas (Figure 2). Blood cultures were positive.
Figure 2. Suppurative granuloma with central necrosis and neutrophilic infiltration.
One of 2 original sets of blood cultures grew Mycobacterium mucogenicum and Stenotrophomonas maltophilia, identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF; Bruker Biotyper, Bruker Daltonics). Stenotrophomonas maltophilia was reported 2 days after blood draw and was susceptible to levofloxacin, trimethoprim-sulfamethoxazole, minocycline, and ceftazidime as determined by broth microdilution method and interpreted according to current Clinical and Laboratory Standards Institute (CLSI). Mycobacterium mucogenicum was reported 5 days after initial blood draw. Pathology from the patient’s excised forearm nodule demonstrated suppurative necrotizing granulomas associated with acid-fast bacilli on Fite’s stain, a peanut oil/xylene modification of Ziehl-Neelsen (see Figure 3). Within the nodule, foreign crystalline material was identified under examination with polarized light. Gram stain from the nodule revealed scant Gram-positive cocci and Gram-negative bacilli, but no organism grew on aerobic, anaerobic, or mycobacterial culture. Culture of fluid from her forearm abscess grew S maltophilia and Streptococcus pneumoniae. Transthoracic echocardiogram did not reveal any valvular vegetations or regurgitation.
Figure 3. Acid-fast bacilli (Fite’s stain) in the upper central part of the image. Crystalline material is seen in the lower left of the frame.
Although M mucogenicum susceptibilities were pending, the patient was treated with trimethoprim-sulfamethoxazole ([TMP-SMX] 4.5 mg/kg of the TMP component twice a day) and clarithromycin (500 milligrams orally twice a day), a regimen intended to treat S maltophilia as well as M mucogenicum. Treatment became complicated by a prolonged QTc on electrocardiogram after clarithromycin initiation; clarithromycin was changed to doxycycline (100 mg PO BID). Psychiatry was consulted to wean QTc-prolonging medications.
Antimicrobial susceptibility testing of the M mucogenicum isolate susceptibility testing demonstrated susceptibility to TMP-SMX, amikacin, cefoxitin, ciprofloxacin, clarithromycin, imipenem, linezolid, and moxifloxacin but resistance to doxycycline. Antimicrobial susceptibility was determined by broth microdilution and interpreted according to CLSI breakpoints. The patient’s prolonged QTc and psychiatric medications precluded the use of 2 oral agents with in vitro activity, and thus the patient was maintained on her existing regimen with a plan to change doxycycline to clarithromycin once QTc normalized. Multiple repeated blood cultures and mycobacterial blood culture were negative. Over the course of 12 weeks of therapy, the patient clinically improved and her nodules decreased in size and eventually disappeared altogether. Although the patient’s M mucogenicum bacteremia and nodular soft tissue infection resolved, she was subsequently diagnosed with endocarditis from other environmental organisms, including S maltophilia, and she was hospitalized for 6 weeks before being discharged home. During her admission for endocarditis, she was treated with TMP-SMX in addition to meropenem that would likely have therapeutic effect on residual M mucogenicum. Her most recent blood cultures 6 weeks after discharge are negative.
Patient Consent Statement
Written informed consent was obtained from the patient to describe her case and include pictures of her arms and nodule pathology. The design and publication of this work has been approved by the University of Manitoba Bannatyne Research Ethics Board (HS23928:H2020:227, approved May 4, 2020) and conforms to standards currently applied in Canada.
DISCUSSION
Mycobacterium mucogenicum is a rapidly growing nontuberculous mycobacterium (RGM) that routinely inhabits tap water [3, 4]. Mycobacterium mucogenicum’s ability to form biofilms and reproduce in environmental amoeba enables it to tolerate various forms of sanitization including mild chlorination [3]. Due to this fitness advantage in disinfected aqueous ecosystems, M mucogenicum is the most commonly identified RGM in tap water [5].
Mycobacterium mucogenicum infection has diverse clinical manifestations in both immunocompetent as well as immunocompromised hosts, although it is notorious for causing outbreaks of catheter-related blood stream infections among hemodialysis and oncology patients [3, 4, 6]. The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. To our knowledge, this is the second reported case of M mucogenicum infection associated with the injection of drugs [7]. Our patient’s polymicrobial bacteremia was due to injection of tap water from the same contaminated source that caused the granulomatous nodular inflammation in her forearms.
The concurrence of M mucogenicum and S maltophilia in the blood culture as well as the nodule may reflect a novel manifestation of mycobacterial coinfection with a Gram-negative bacillus. This phenomenon has been commonly described in patients with cystic fibrosis where horizontal gene transfer from pseudomonads contributes to the virulence of Mycobacterium abscessus [8]. Although polymicrobial culture positivity often suggests contamination, here the coexistence of RGM and Gram-negative bacillus may suggest the simultaneous inoculation of environmental symbionts.
Optimal treatment for M mucogenicum bacteremia and soft tissue infection remains unclear. If a single skin lesion is present, surgical excision should be considered. A combination of 2 agents, to which the isolate demonstrates in vitro susceptibility, is recommended to prevent the development of drug resistance [9, 10]. Mycobacterium mucogenicum is commonly susceptible to many antimicrobials including amikacin, cefoxitin, clarithromycin, imipenem, and TMP-SMX [3]. However, like other RGM, it remains resistant to first-line antituberculous medications.
CONCLUSIONS
As our case illustrates, among persons who inject drugs, bacteremia with RGM should not be considered a contaminant and may in fact point to other sites of infection. People who inject drugs often experience physical, psychiatric, and socioeconomic difficulties that limit their access to sterile injection equipment. Expanding harm reduction programs to increase accessibility of sterile paraphernalia could mitigate infectious complications of injection drug use and subsequent hospital admission. Antimicrobial options were significantly limited by our patient’s polypharmacy. This case further emphasizes the need for coordinated infectious disease, psychiatric, and addictions care. It is essential for infectious diseases specialists to incorporate harm reduction strategies into their patient interaction to prevent further infectious complications from intravenous drug use.
Acknowledgments
We thank our patient for her good sense of humor, her willingness to participate in this project, and her resilience in the face of difficult circumstances.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | Recovering | ReactionOutcome | CC BY-NC-ND | 33447641 | 19,093,962 | 2021-01 |
What was the outcome of reaction 'Streptococcal infection'? | Mycobacterium Mucogenicum Bacteremia and Nodular Soft Tissue Infection in a Person Who Uses Tap Water to Inject Drugs.
The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. In this study, we report a case of Mycobacterium mucogenicum bacteremia and associated nodular soft tissue infection in a person who uses tap water to inject drugs.
CASE
A 50-year-old female presented to a community hospital with a 24-hour history of fever and a right forearm abscess at the site of drug injection. The forearm abscess was incised and drained, and a sample was obtained for bacterial culture. Two peripheral blood cultures were collected before treatment with meropenem. The patient’s forearms demonstrated subcutaneous nodules that she maintained had increased in size slowly during the 2 years preceding her current hospital presentation.
The patient has psychiatric illness, of which intergenerational trauma is a probable factor [1, 2]; her parents attended Canada’s Indian Residential School system. She had been diagnosed with bipolar disorder, borderline personality disorder, and polysubstance use disorder. Her home medications included risperidone, quetiapine, fluoxetine, amitriptyline, and hydromorphone. Our patient injects cocaine on a daily basis and methamphetamine and opioids when cocaine is difficult to obtain. The patient injects her drugs using unfiltered tap water as sterile water ampules and filters are rarely accessible; she has a history of bacteremia from environmental organisms, including Sphingomonas spp, Microbacterium spp, Chryseobacterium indologenes, and Sphingobacterium spiritivorum. She denied sharing her injection paraphernalia and reusing her needles. At baseline, our patient is on home oxygen (2 L/minute) due to chronic obstructive pulmonary disease and pulmonary talcosis. Additional medical history includes inactive hepatitis C and fibromyalgia; she is human immunodeficiency virus negative. She lives in an apartment with her son in Winnipeg, Manitoba, Canada.
Her temperature was 38.2oC, her pulse 121 beats-per-minute, her blood pressure 92/59 mmHg, and her oxygen saturation was 94% while receiving 2 L/minute oxygen via nasal prongs. Physical examination revealed bilateral nodular lesions extending from the dorsum of her hands to her elbows (Figure 1). The nodules were firm and nontender with no overlying erythema. No epitrochlear or axillary lymphadenopathy was present, inconsistent with lymphangitic spread and more suggestive of distinct inoculation of different sites on the hands and forearms. A grade 2 systolic ejection murmur was heard at the right-upper-sternal border with no radiation. Other than clubbing, no peripheral signs of endocarditis were present.
Figure 1. Nodular lesions along the patient’s dorsum of her hand and along her forearm. The largest nodule is on the dorsum of her hand, reflecting the oldest nodule in the location of her earlier injection sites. The absence of lymphadenopathy and the presence of nodules in many locations beyond a single lymphatic drainage reflect separate inoculation events rather than lymphangitic spread.
The plastic surgery service was consulted to perform an excisional biopsy of one of the patient’s forearm nodules, which revealed necrotizing granulomas (Figure 2). Blood cultures were positive.
Figure 2. Suppurative granuloma with central necrosis and neutrophilic infiltration.
One of 2 original sets of blood cultures grew Mycobacterium mucogenicum and Stenotrophomonas maltophilia, identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF; Bruker Biotyper, Bruker Daltonics). Stenotrophomonas maltophilia was reported 2 days after blood draw and was susceptible to levofloxacin, trimethoprim-sulfamethoxazole, minocycline, and ceftazidime as determined by broth microdilution method and interpreted according to current Clinical and Laboratory Standards Institute (CLSI). Mycobacterium mucogenicum was reported 5 days after initial blood draw. Pathology from the patient’s excised forearm nodule demonstrated suppurative necrotizing granulomas associated with acid-fast bacilli on Fite’s stain, a peanut oil/xylene modification of Ziehl-Neelsen (see Figure 3). Within the nodule, foreign crystalline material was identified under examination with polarized light. Gram stain from the nodule revealed scant Gram-positive cocci and Gram-negative bacilli, but no organism grew on aerobic, anaerobic, or mycobacterial culture. Culture of fluid from her forearm abscess grew S maltophilia and Streptococcus pneumoniae. Transthoracic echocardiogram did not reveal any valvular vegetations or regurgitation.
Figure 3. Acid-fast bacilli (Fite’s stain) in the upper central part of the image. Crystalline material is seen in the lower left of the frame.
Although M mucogenicum susceptibilities were pending, the patient was treated with trimethoprim-sulfamethoxazole ([TMP-SMX] 4.5 mg/kg of the TMP component twice a day) and clarithromycin (500 milligrams orally twice a day), a regimen intended to treat S maltophilia as well as M mucogenicum. Treatment became complicated by a prolonged QTc on electrocardiogram after clarithromycin initiation; clarithromycin was changed to doxycycline (100 mg PO BID). Psychiatry was consulted to wean QTc-prolonging medications.
Antimicrobial susceptibility testing of the M mucogenicum isolate susceptibility testing demonstrated susceptibility to TMP-SMX, amikacin, cefoxitin, ciprofloxacin, clarithromycin, imipenem, linezolid, and moxifloxacin but resistance to doxycycline. Antimicrobial susceptibility was determined by broth microdilution and interpreted according to CLSI breakpoints. The patient’s prolonged QTc and psychiatric medications precluded the use of 2 oral agents with in vitro activity, and thus the patient was maintained on her existing regimen with a plan to change doxycycline to clarithromycin once QTc normalized. Multiple repeated blood cultures and mycobacterial blood culture were negative. Over the course of 12 weeks of therapy, the patient clinically improved and her nodules decreased in size and eventually disappeared altogether. Although the patient’s M mucogenicum bacteremia and nodular soft tissue infection resolved, she was subsequently diagnosed with endocarditis from other environmental organisms, including S maltophilia, and she was hospitalized for 6 weeks before being discharged home. During her admission for endocarditis, she was treated with TMP-SMX in addition to meropenem that would likely have therapeutic effect on residual M mucogenicum. Her most recent blood cultures 6 weeks after discharge are negative.
Patient Consent Statement
Written informed consent was obtained from the patient to describe her case and include pictures of her arms and nodule pathology. The design and publication of this work has been approved by the University of Manitoba Bannatyne Research Ethics Board (HS23928:H2020:227, approved May 4, 2020) and conforms to standards currently applied in Canada.
DISCUSSION
Mycobacterium mucogenicum is a rapidly growing nontuberculous mycobacterium (RGM) that routinely inhabits tap water [3, 4]. Mycobacterium mucogenicum’s ability to form biofilms and reproduce in environmental amoeba enables it to tolerate various forms of sanitization including mild chlorination [3]. Due to this fitness advantage in disinfected aqueous ecosystems, M mucogenicum is the most commonly identified RGM in tap water [5].
Mycobacterium mucogenicum infection has diverse clinical manifestations in both immunocompetent as well as immunocompromised hosts, although it is notorious for causing outbreaks of catheter-related blood stream infections among hemodialysis and oncology patients [3, 4, 6]. The ongoing North American epidemic of intravenous opioid and methamphetamine use increases the occurrence of bacteremia from environmental organisms. To our knowledge, this is the second reported case of M mucogenicum infection associated with the injection of drugs [7]. Our patient’s polymicrobial bacteremia was due to injection of tap water from the same contaminated source that caused the granulomatous nodular inflammation in her forearms.
The concurrence of M mucogenicum and S maltophilia in the blood culture as well as the nodule may reflect a novel manifestation of mycobacterial coinfection with a Gram-negative bacillus. This phenomenon has been commonly described in patients with cystic fibrosis where horizontal gene transfer from pseudomonads contributes to the virulence of Mycobacterium abscessus [8]. Although polymicrobial culture positivity often suggests contamination, here the coexistence of RGM and Gram-negative bacillus may suggest the simultaneous inoculation of environmental symbionts.
Optimal treatment for M mucogenicum bacteremia and soft tissue infection remains unclear. If a single skin lesion is present, surgical excision should be considered. A combination of 2 agents, to which the isolate demonstrates in vitro susceptibility, is recommended to prevent the development of drug resistance [9, 10]. Mycobacterium mucogenicum is commonly susceptible to many antimicrobials including amikacin, cefoxitin, clarithromycin, imipenem, and TMP-SMX [3]. However, like other RGM, it remains resistant to first-line antituberculous medications.
CONCLUSIONS
As our case illustrates, among persons who inject drugs, bacteremia with RGM should not be considered a contaminant and may in fact point to other sites of infection. People who inject drugs often experience physical, psychiatric, and socioeconomic difficulties that limit their access to sterile injection equipment. Expanding harm reduction programs to increase accessibility of sterile paraphernalia could mitigate infectious complications of injection drug use and subsequent hospital admission. Antimicrobial options were significantly limited by our patient’s polypharmacy. This case further emphasizes the need for coordinated infectious disease, psychiatric, and addictions care. It is essential for infectious diseases specialists to incorporate harm reduction strategies into their patient interaction to prevent further infectious complications from intravenous drug use.
Acknowledgments
We thank our patient for her good sense of humor, her willingness to participate in this project, and her resilience in the face of difficult circumstances.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. | Recovering | ReactionOutcome | CC BY-NC-ND | 33447641 | 19,093,962 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Bone density decreased'. | Beyond the guidelines management of juvenile idiopathic arthritis: a case report of a girl with polyarticular disease refractory to multiple treatment options and Leri Weill syndrome.
The last two decades brought new treatment options and high quality guidelines into the paediatric rheumatologic practice. Nevertheless, a number of patients still present a diagnostic and therapeutic challenge due to combination of vague symptoms and unresponsiveness to available treatment modalities.
We report a case of sixteen years old girl suffering from polyarticular type of juvenile idiopathic arthritis refractory to multiple treatment options. She first presented at the age of 4 with swelling and contractures of both knees. Her symptoms were initially unresponsive to nonsteroidal anti-inflammatory drugs and progressed despite treatment with intraarticular and systemic glucocorticoids and methotrexate. Throughout the years, she received several biologics together with continuous administration of nonsteroidal anti-inflammatory drugs and disease modifying anti-rheumatic drugs as well as intraarticular and systemic glucocorticoids in disease flares. However, none of this options provided a permanent remission, so various other modalities, as well as other possible diagnoses were constantly being considered. Eventually she became dependent on a daily dose of systemic glucocorticoids. In 2018, the treatment with Janus kinase inhibitor tofacitinib was initiated, which led to gradual amelioration of musculoskeletal symptoms, improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic glucocorticoids. As the swelling of the wrists subsided for the first time in many years, Madelung's deformity was noticed, first clinically, and later radiographically as well. Genetic analysis revealed short-stature homeobox gene deficiency and confirmed the diagnosis of Leri Weill syndrome.
This case report emphasizes the need for reporting refractory, complicated cases from everyday clinical practice in order to build-up the overall knowledge and share experience which is complementary to available guidelines. Individual reports of difficult to treat cases, especially when additional diagnoses are involved, can be helpful for physicians treating patients with common rheumatological diseases such as juvenile idiopathic arthritis.
Background
Joint pain and/or swelling with limited range of motion is a common manifestation of many paediatric diseases, most notably wide range of rheumatic conditions. If both of these symptoms are present for longer than 6 weeks in a patient younger than 16 years of age, a diagnosis of juvenile idiopathic arthritis (JIA), the most common childhood rheumatic disease, should be considered [1]. JIA is heterogenous disease that encompasses different subtypes of childhood arthritis defined depending on the number of affected joints and/or presence of the enthesitis and/or sacroiliitis. Nevertheless, alongside JIA, there is a wide range of loosely related noninflammatory causes of a swollen joint in children, especially in the absence of clinical signs of inflammation. Lysosomal storage diseases (LSD) such as mucopolysaccharidosis type I (MPS I), Gaucher disease type I and Fabry disease all have prominent musculoskeletal symptoms early in the course of the disease, and are often first seen by a pediatric rheumatologist [2–8]. However, the underlying mechanism of those disorders does not directly involve the immune mediated inflammatory response, but rather an inflammation caused by genetic defects and subsequent perturbations at the protein level. More specifically, in Gaucher disease, bone marrow infiltration with histiocytes causes acute attacks of pain, which may be mistaken for arthritis in the vicinity of a joint [5, 8]. In Fabry disease, episodes of neuropathic pain in hands, feet, wrists, ankles (acroparesthesias), often associated with fever, malaise and elevated inflammation markers, can mimic a rheumatic condition, such as an inflammatory arthritis [3, 9]. Finally, joint stiffness and contractures are characteristic for some types of MPS, the so called „attenuated“ forms like Hurler-Scheie syndrome, which have a less severe presentation and progress silently over the years, making the diagnosis a challenge [3, 10, 11]. On the other hand, some congenital conditions, such as Madelung and Madelung-type deformities resulting from the premature closure of the medial volar aspect of the distal radial physis, might cause similar symptoms [12]. Hence, it is not a rarity that some of the children with LSD and congenital deformities are treated for prolonged periods of time as having an inflammatory arthritis, despite the lack of appropriate response [13].
With regard to the treatment of JIA, various modalities emerged over the last two decades, revolutionizing the pediatric rheumatology practice [14]. Majority of the presently available guidelines recommend a step-up approach, starting with nonsteroidal anti-inflammatory drugs (NSAID) and intraarticular glucocorticoid injections (IAGI), followed by conventional and biologic disease modifying anti-rheumatic drugs (cDMARD and bDMARD), respectively [15]. Moreover, despite many known adverse effects, systemic glucocorticoids (GC) are still being used as an important therapeutic option for wide range of complications associated with JIA (e.g., macrophage activation syndrome, myocarditis, pericarditis, pleuritis, peritonitis, uveitis and severe anaemia), as well as a bridge therapy in severe forms of JIA before the full effect of other treatment modalities has been achieved [16]. Those modalities nowadays primarily involve tumor necrosis factor alpha (TNFα) inhibitors (TNFi), such as etanercept, adalimumab and infliximab, and non-TNFi, such as anti-interleukin-6 (anti-IL-6) agent tocilizumab and a selective T-cell co-stimulation modulator abatacept [17, 18]. Furthermore, new medications are continuously being investigated [19, 20].
Together with the expansion of new treatment modalities, efforts have been made to introduce the treat-to-target (T2T) model in pediatric rheumatologic practice [21]. Signs and symptoms control, prevention of structural damage of joints and optimization of linear growth and pubertal development, as well as abolition of inflammation, have all been set as treatment goals. Essentially, this model advocates that therapy should be revised and adjusted based on regular disease activity assessments to reach and maintain the treatment target. Special attention should be paid to preventing or minimizing the side effects of systemic GC given their negative effect on growth and pubertal development. Consequently, their long-term use to maintain treatment target should be avoided, especially considering that GC dependence demonstrates the inadequacy of chosen treatment. The shared decision making, as well as multidisciplinary approach, have been recognized as exceptionally valuable for assurance of better adherence to treatment and subsequently improvement of outcome and overall prognosis.
Unfortunately, despite all these achievements, only 14 % of patients with rheumatoid factor (RF) negative and 0 % with RF positive polyarticular JIA achieves the remission off medications within five years, implying that JIA treatment requires a long-lasting commitment [22]. Hence, it comes as no surprise that every clinician involved in the care of children with JIA patients eventually sees one with disease not responding to acclaimed treatment options (i.e. NSAIDs, cDMARDS, bDMARDS) [15]. At that point, the consideration of additional treatment modalities seems like a valid course of action, but sometimes alternative diagnosis should be considered as well. Here, we present one such case, a girl with long standing polyarticular JIA refractory to many standard treatment modalities, with symptoms suggestive of other diseases.
Case presentation
A four-year-old first came to our attention in February 2008 due to painful swelling and contractures of both knees. Her symptoms started a year earlier and were not associated with any discernible trigger such as infection or trauma. Moreover, the symptoms were not responding to NSAIDs and she soon developed a severe morning stiffness lasting for up to three hours. Her birth history as well as psychomotor development prior to disease evolution was unremarkable. She was born as a first child into a family of non-consanguine parents, with no relatives having the similar symptoms.
The initial laboratory findings showed persistently elevated inflammatory markers (erythrocyte sedimentation rate (ESR) up to 100 mm/h and C-reactive protein (CRP) up to 100 mg/dL), with negative RF and antinuclear antibody (ANA) screen, and normal immunoglobulin levels. Despite the initial treatment with GC and methotrexate (MTX), her symptoms progressed affecting elbows, wrists, ankles and small joints of both hands. Moreover, she developed a severe uveitis of the left eye. In November 2008 biologic therapy with infliximab was started, with initially good response. Unfortunately, this lasted only for a few months and frequent relapses necessitated switching to adalimumab in April 2011. Again, there was an initial period of remission followed by progressive exacerbation characterized by swelling and pain in some joints, and persistent contracture of others. Other diagnosis, such as mucopolysaccharidosis and systemic lupus erythematosus (SLE) were suspected, but metabolic and immunological screening were negative, respectively. Beside ESR and CRP, the increased values of IL-6 (up to 75 pg/mL) and TNF-alfa (up to 20 pg/mL) were measured.
In November 2012 therapy was cycled to non-TNFi, tocilizumab, which led only to a short period of remission. Finally, in September 2014, etanercept was introduced, again with the lack of permanent response. Along with four different bDMARDs she continuously received cDMARD methotrexate, and for a short period of time leflunomide. During the periods of disease flare, bridge therapy with intraarticular and/or systemic GC was used, and soon she was dependent on a daily dose of GC. Eventually, this led to the development of iatrogenic Cushing syndrome with characteristic appearance, growth retardation and low bone mineral density, regardless of the vitamin D and ibandronic acid therapy. Since every attempt to wean off GC inevitably led to disease flare, from June to December 2016 she received cyclophosphamide (6x) and rituximab (3x), again without achieving a sustained remission. Afterwards, for a short period of time she was given metformin but without an appropriate improvement in musculoskeletal symptoms (Fig. 1).
Fig. 1 Schematic representation of treatment modalities during the time. 2007 – 2020 - the period of treatment, NSAID - nonsteroidal anti-inflammatory drug, IFX - infliximab, ADA - adalimumab, TOC - tocilizumab, ETC - etanercept, DMARD - disease modifying anti-rheumatic drug, MTX - methotrexate, CFM - cyclophosphamide, RTX - rituximab, MTF - metformin, MMF - mycophenolate mofetil, CYC - cyclosporine, TFA - tofacitinib, p.o. - per os, i.a. - intraarticular, i.v. - intravenous, GC - glucocorticoids
During the 2017, at the age of 13, the trial of mycophenolate mofetil (MMF) followed by the trial of cyclosporin was initiated, but the patient nevertheless remained GC dependent. Both shoulders, elbows, radiocarpal joints, metacarpophalangeal (MCP), proximal interphalangeal (PIP), distal interphalangeal (DIP) joints and both knees had restricted range of movement, and repeated IAGI were necessary to alleviate the symptoms. Finally, in 2018, the treatment with Janus kinase (JAK) inhibitor tofacitinib was initiated, which lead to gradual amelioration of musculoskeletal symptoms and improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic GC. Moreover, as the swelling of the wrists subsided for the first time in many years, Madelung deformity was noticed by clinical examination. Interestingly, it was only then, in 2019, that the deformity was for the first time described on x-ray (Fig. 2), although x-ray and MRI imaging of both hands were previously performed on many occasions in order to assess the inflammation (Figs. 3 and 4). Nevertheless, subsequent analysis by experienced musculoskeletal radiologist revealed characteristic bilateral signs of Madelung deformity dating back in 2015 and 2017 (Fig. 3), with the MRI showing the Vickers and radiotriquetral ligament (Fig. 4). The finding of those two ligaments allowed the distinguishing between Madelung deformity and pseudo-Madelung deformity, which includes post-traumatic and post-infective forms, forms associated with Turner syndrome, multiple hereditary exostoses and Ollier disease [23]. Unfortunately, due to the parent’s refusal, no further radiological assessment was performed, so we have not documented the other important aspects of Madelung deformity, such as radial shortening and diaphysis bowing, nor the mesolimbic shortening of limbs characteristic for Leri Weill syndrome.
Fig. 2 The anteroposterior radiograph of left hand at the age of 14. Note the increased volar angulation of distal radius, wedge shaped carpus with proximally positioned lunate and a characteristic notch on the distal radius (white arrow), which are the features of the Madelung deformity [12]
Fig. 3 The anteroposterior radiograph of both hands at the age of 10 (a) and 13 (b), and of the left hand at the age of 14 (c). Note the bowing of the distal radius, an increased radial inclination (~ 30°) with the deformation of the carpus that acquired a triangular appearance and widening of the distal radial-ulnar joint bilaterally, which are the typical features of Madelung deformity. Dorsal subluxation of the ulnar head is not seen as lateral images of the wrist were not taken. Osteopenia of carpal bones and periarticular osteopenia of MCP, PIP and DIP joints related to JIA are present. No relevant changes are observed during the time
Fig. 4 MRI coronal T1-weighted (a), proton density BLADE fluid sensitive sequence (b), post contrast T1-weighted coronal fat sat sequence (c) and post contrast T1-weighted axial fat sat sequence (d) images of both hands at the age of 13. Note the radiotriquetral ligament (red arrow) and Vickers ligament (green arrow) (a, b). Note the inflammatory changes characterized by postcontrast imbibition in carpal joints and MCP joints (red circle), as well as tenosynovitis of flexor tendons related to JIA, more prominent on the left hand (c, d)
Although our patient was simultaneously followed by pediatric endocrinologist from age of 11, her short stature, along with delayed menarche, and Cushingoid appearance, was attributed to the prolonged use of GC. It was only after the Madelung’s deformity was observed that genetic causes, primarily Leri Weill syndrome, were taken into consideration. Genetic analysis was performed by commercially available SALSA MLPA Probemix P018 SHOX (MRC-Holland, Amsterdam, The Netherland) according to the manufacturer’s recommendations. The MLPA mix included probes for each exon of SHOX, one probe just before the promoter region as well as probes covering a region downstream of the gene. The results revealed one copy of sixteen probes (10 probes for Xp22-PAR1 from CNE2 to CNE9, 4 probes for SHOX area downstream, 1 probe for CRLF2 in PAR1 region and 1 probe for CSF2RA in PAR1 region), with the size of the smallest deletion of 766,5 kb. Based on the genetic testing and imaging findings of Madelung deformity, the diagnosis of Leri Weill syndrome was established, and parents were advised to undergo further genetic testing of both the patient and themselves, which they rejected.
Currently, our patient has many consequences of the adverse course of the disease and prolonged GC treatment, such as joint contractures of elbows, wrists, DIPs, PIPs, hips, knees and MCPs and low bone density, respectively. She developed secondary sex characteristics only after the therapy with estradiol was initiated at the age of 14. Nevertheless, after the discontinuation of GC and subsequent discontinuation of estradiol, she finally had a menarche at the age of 15, along with a long-awaited growth spurt.
Discussion and Conclusion
Children with rheumatic diseases, their families, as well as their treating physicians are dealt with numerous issues and dilemmas regarding either the disease itself or ongoing treatment modalities. Besides, the diagnosis of rheumatic diseases in children is regularly made by excluding wide range of other diseases, with no pathognomonic tests and/or criteria. Therefore, even after the classification criteria are fulfilled, the diagnosis should be revised if new symptoms emerge or if the recommended treatment options are failing.
In our patient, a variety of steroid-sparing agents with different mechanisms of action have been employed with limited or no clinical success. Some of these agents were used in line with current treatment recommendations, but many were used based on anecdotal reports [24–28]. Finally, due to signs of systemic inflammation characterized by increased inflammatory markers (CRP and ESR) and cytokines (IL-6 and TNF-alfa), which is indicative for the activation of JAK/STAT pathway, treatment with tofacitinib, a first generation JAK inhibitor, was initiated with a good clinical response. Several clinical trials in adults with rheumatoid and psoriatic arthritis have given solid evidence about the use of tofacitinib, while the results of a phase 3 randomized double blind placebo controlled withdrawal study in patients with polyarticular JIA showed improvement in symptoms, less disease flares and improved functional ability, together with a clinical amelioration of disease activity [29, 30]. Moreover, tofacitinib is an oral agent, and the challenge of using biologics requiring injection or infusion for an extended length of time, especially in children, should not be overlooked.
Along with the various treatment modalities, the different diagnosis was constantly being considered in our patient. Firstly, due to persistent contracture in some joints with little or no signs of swelling, LSDs such as mucopolysaccharidosis type I, Gaucher disease type I and Fabry disease were investigated. Besides, other inflammatory causes like systemic lupus erythematosus were also excluded. Lastly, the diagnosis of Leri Weill syndrome characterized by deletions in SHOX gene and Madelung deformity was established. This painful deformity of the wrist was first described in 1878 by the German surgeon Otto Madelung in adolescents between the ages 8 and 14 [12]. Although initially asymptomatic, the patients often went on to develop pain, loss of grip strength and reduced mobility, which were the symptoms present in our patient even after the inflammation was tackled with tofacitinib. Moreover, the features of Leri Weill syndrome include the short stature, which was also one of the dominant finding in the presented patient. Yet, the growth deficit caused by SHOX haploinsufficiency in Leri Weill syndrome is around 2 standard deviation scores (SDS) [31], while our patient had a SDS of -5,5. Besides, due to a prolonged use of GC, our patient had a full blown Cushingoid appearance, low bone density, delayed puberty and growth retardation. Therefore, the possible explanation for the short stature and growth delay in our patient includes multifactorial aetiology. Firstly, it is well known that extended GC treatment leads to a defect in bone turnover (and formation) due to impaired osteoblastogenesis and osteoclastogenesis, and may have direct effects on the growth plate [32]. Additionally, higher prepubertal glucocorticoid level appears to delay early and late pubertal timing of healthy girls, particularly the onset of pubertal growth spurt and menarche [33]. Moreover, it has been shown that girls with polyarticular juvenile idiopathic arthritis are significantly more likely to present with short stature even 6 months after stopping the steroid therapy [34]. Finally, the product of SHOX gene is implicated in bone development and regulation of chondrocyte differentiation, which clarifies the association of SHOX gene haploinsufficiency with idiopathic short stature, as well as short stature in Turner syndrome and Leri Weill dyschondrosteosis [31].
In the presented case, the diagnosis of the Madelung deformity and Leri Weill syndrome was delayed due to the concomitant active inflammation caused by JIA taking the focus from other possible causes of pain in the wrists. However, as subsequent analysis by experienced musculoskeletal radiologist has shown, the characteristic signs of the Madelung deformity were present few years before the final diagnosis was reached, emphasizing once again the importance of multidisciplinary approach and close collaboration of many subspecialists in the care of children with rheumatic diseases. Nevertheless, this lag probably did not influence the therapeutic management in our particular patient; although positive effect on final height was observed with growth hormone therapy in patients with Leri Weill syndrome, due to the matching influence of GC and lack of agreement with her parents, this treatment option was avoided in our patient [35].
In conclusion, this case report emphasizes the difficulties and challenges in management of patient with long-standing polyarticular JIA refractory to wide range of treatment modalities. Although many high-quality guidelines are available for treatment of JIA patients, there is still need for individual reports of difficult to treat cases, especially when additional diagnosis are involved. While Leri Weill syndrome is extensively reported in the literature, to the best of our knowledge, our case report describes it for the first time along with JIA. Taking all these into account, we strongly encourage the aggregation of similar patients and establishment of the common ground that will help clinician to decide upon the introduction of treatment options outside of the contemporary guidelines.
Abbreviations
JIAJuvenile idiopathic arthritis
LSDLysosomal storage disease
MPSMucopolysaccharidosis
NSAIDNonsteroidal anti-inflammatory drug
cDMARDConventional disease modifying anti-rheumatic drug
bDMARDBiologic disease modifying anti-rheumatic drug
IAGIIntraarticular glucocorticoid injection
GCGlucocorticoids
MASMacrophage activation syndrome
TNFiTumor necrosis factor inhibitor
T2TTreat-to-target
RFRheumatoid factor
ESRErythrocyte sedimentation rate
CRPC-reactive protein
ANAAntinuclear antibody
MTXMethotrexate
SLESystemic lupus erythematosus
TNFαTumor necrosis factor alpha
anti-IL-6Anti-interleukin-6
MMFMycophenolate mofetil
MCPMetacarpophalangeal
PIPProximal interphalangeal
DIPDistal interphalangeal
JAKJanus kinase
MRIMagnetic resonance imaging
SHOXShort-stature homeobox
JAK/STATJanus kinase/signal transducer and activator of transcription proteins
SDSStandard deviation score
GnRHGonadotropin-releasing hormone
HPGHypothalamic-pituitary-gonadal
IFXInfliximab
ADAAdalimumab
TOCTocilizumab
ETCEtanercept
CFMCyclophosphamide
RTXRituximab
MTFMetformin
CYCCyclosporine
TFATofacitinib
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Acknowledgements
We thank parents for availability of publishing medical history of their daughter.
Authors’ contributions
VV and AS have equally contributed to the paper. VV: medical charts review, literature search, creation of figures and tables and manuscript draft preparation. AS: medical charts review, literature search, creation of figures and tables and manuscript draft preparation RV: radiographic images interpretation, manuscript draft preparation. MV: clinical care and the final revision of the manuscript. MH: clinical care and the final revision of the manuscript. LL: clinical care, medical charts review, literature search, creation of figures and tables, manuscript draft preparation, final revision of the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. / Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the parents for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | ADALIMUMAB, CYCLOPHOSPHAMIDE, CYCLOSPORINE, ETANERCEPT, IBUPROFEN, INDOMETHACIN, INFLIXIMAB, LEFLUNOMIDE, MELOXICAM, METFORMIN HYDROCHLORIDE, METHOTREXATE, METHYLPREDNISOLONE SODIUM SUCCINATE, MYCOPHENOLATE MOFETIL, NAPROXEN SODIUM, PREDNISONE, RITUXIMAB, TOCILIZUMAB, TOFACITINIB | DrugsGivenReaction | CC BY | 33451288 | 18,970,451 | 2021-01-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cushing^s syndrome'. | Beyond the guidelines management of juvenile idiopathic arthritis: a case report of a girl with polyarticular disease refractory to multiple treatment options and Leri Weill syndrome.
The last two decades brought new treatment options and high quality guidelines into the paediatric rheumatologic practice. Nevertheless, a number of patients still present a diagnostic and therapeutic challenge due to combination of vague symptoms and unresponsiveness to available treatment modalities.
We report a case of sixteen years old girl suffering from polyarticular type of juvenile idiopathic arthritis refractory to multiple treatment options. She first presented at the age of 4 with swelling and contractures of both knees. Her symptoms were initially unresponsive to nonsteroidal anti-inflammatory drugs and progressed despite treatment with intraarticular and systemic glucocorticoids and methotrexate. Throughout the years, she received several biologics together with continuous administration of nonsteroidal anti-inflammatory drugs and disease modifying anti-rheumatic drugs as well as intraarticular and systemic glucocorticoids in disease flares. However, none of this options provided a permanent remission, so various other modalities, as well as other possible diagnoses were constantly being considered. Eventually she became dependent on a daily dose of systemic glucocorticoids. In 2018, the treatment with Janus kinase inhibitor tofacitinib was initiated, which led to gradual amelioration of musculoskeletal symptoms, improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic glucocorticoids. As the swelling of the wrists subsided for the first time in many years, Madelung's deformity was noticed, first clinically, and later radiographically as well. Genetic analysis revealed short-stature homeobox gene deficiency and confirmed the diagnosis of Leri Weill syndrome.
This case report emphasizes the need for reporting refractory, complicated cases from everyday clinical practice in order to build-up the overall knowledge and share experience which is complementary to available guidelines. Individual reports of difficult to treat cases, especially when additional diagnoses are involved, can be helpful for physicians treating patients with common rheumatological diseases such as juvenile idiopathic arthritis.
Background
Joint pain and/or swelling with limited range of motion is a common manifestation of many paediatric diseases, most notably wide range of rheumatic conditions. If both of these symptoms are present for longer than 6 weeks in a patient younger than 16 years of age, a diagnosis of juvenile idiopathic arthritis (JIA), the most common childhood rheumatic disease, should be considered [1]. JIA is heterogenous disease that encompasses different subtypes of childhood arthritis defined depending on the number of affected joints and/or presence of the enthesitis and/or sacroiliitis. Nevertheless, alongside JIA, there is a wide range of loosely related noninflammatory causes of a swollen joint in children, especially in the absence of clinical signs of inflammation. Lysosomal storage diseases (LSD) such as mucopolysaccharidosis type I (MPS I), Gaucher disease type I and Fabry disease all have prominent musculoskeletal symptoms early in the course of the disease, and are often first seen by a pediatric rheumatologist [2–8]. However, the underlying mechanism of those disorders does not directly involve the immune mediated inflammatory response, but rather an inflammation caused by genetic defects and subsequent perturbations at the protein level. More specifically, in Gaucher disease, bone marrow infiltration with histiocytes causes acute attacks of pain, which may be mistaken for arthritis in the vicinity of a joint [5, 8]. In Fabry disease, episodes of neuropathic pain in hands, feet, wrists, ankles (acroparesthesias), often associated with fever, malaise and elevated inflammation markers, can mimic a rheumatic condition, such as an inflammatory arthritis [3, 9]. Finally, joint stiffness and contractures are characteristic for some types of MPS, the so called „attenuated“ forms like Hurler-Scheie syndrome, which have a less severe presentation and progress silently over the years, making the diagnosis a challenge [3, 10, 11]. On the other hand, some congenital conditions, such as Madelung and Madelung-type deformities resulting from the premature closure of the medial volar aspect of the distal radial physis, might cause similar symptoms [12]. Hence, it is not a rarity that some of the children with LSD and congenital deformities are treated for prolonged periods of time as having an inflammatory arthritis, despite the lack of appropriate response [13].
With regard to the treatment of JIA, various modalities emerged over the last two decades, revolutionizing the pediatric rheumatology practice [14]. Majority of the presently available guidelines recommend a step-up approach, starting with nonsteroidal anti-inflammatory drugs (NSAID) and intraarticular glucocorticoid injections (IAGI), followed by conventional and biologic disease modifying anti-rheumatic drugs (cDMARD and bDMARD), respectively [15]. Moreover, despite many known adverse effects, systemic glucocorticoids (GC) are still being used as an important therapeutic option for wide range of complications associated with JIA (e.g., macrophage activation syndrome, myocarditis, pericarditis, pleuritis, peritonitis, uveitis and severe anaemia), as well as a bridge therapy in severe forms of JIA before the full effect of other treatment modalities has been achieved [16]. Those modalities nowadays primarily involve tumor necrosis factor alpha (TNFα) inhibitors (TNFi), such as etanercept, adalimumab and infliximab, and non-TNFi, such as anti-interleukin-6 (anti-IL-6) agent tocilizumab and a selective T-cell co-stimulation modulator abatacept [17, 18]. Furthermore, new medications are continuously being investigated [19, 20].
Together with the expansion of new treatment modalities, efforts have been made to introduce the treat-to-target (T2T) model in pediatric rheumatologic practice [21]. Signs and symptoms control, prevention of structural damage of joints and optimization of linear growth and pubertal development, as well as abolition of inflammation, have all been set as treatment goals. Essentially, this model advocates that therapy should be revised and adjusted based on regular disease activity assessments to reach and maintain the treatment target. Special attention should be paid to preventing or minimizing the side effects of systemic GC given their negative effect on growth and pubertal development. Consequently, their long-term use to maintain treatment target should be avoided, especially considering that GC dependence demonstrates the inadequacy of chosen treatment. The shared decision making, as well as multidisciplinary approach, have been recognized as exceptionally valuable for assurance of better adherence to treatment and subsequently improvement of outcome and overall prognosis.
Unfortunately, despite all these achievements, only 14 % of patients with rheumatoid factor (RF) negative and 0 % with RF positive polyarticular JIA achieves the remission off medications within five years, implying that JIA treatment requires a long-lasting commitment [22]. Hence, it comes as no surprise that every clinician involved in the care of children with JIA patients eventually sees one with disease not responding to acclaimed treatment options (i.e. NSAIDs, cDMARDS, bDMARDS) [15]. At that point, the consideration of additional treatment modalities seems like a valid course of action, but sometimes alternative diagnosis should be considered as well. Here, we present one such case, a girl with long standing polyarticular JIA refractory to many standard treatment modalities, with symptoms suggestive of other diseases.
Case presentation
A four-year-old first came to our attention in February 2008 due to painful swelling and contractures of both knees. Her symptoms started a year earlier and were not associated with any discernible trigger such as infection or trauma. Moreover, the symptoms were not responding to NSAIDs and she soon developed a severe morning stiffness lasting for up to three hours. Her birth history as well as psychomotor development prior to disease evolution was unremarkable. She was born as a first child into a family of non-consanguine parents, with no relatives having the similar symptoms.
The initial laboratory findings showed persistently elevated inflammatory markers (erythrocyte sedimentation rate (ESR) up to 100 mm/h and C-reactive protein (CRP) up to 100 mg/dL), with negative RF and antinuclear antibody (ANA) screen, and normal immunoglobulin levels. Despite the initial treatment with GC and methotrexate (MTX), her symptoms progressed affecting elbows, wrists, ankles and small joints of both hands. Moreover, she developed a severe uveitis of the left eye. In November 2008 biologic therapy with infliximab was started, with initially good response. Unfortunately, this lasted only for a few months and frequent relapses necessitated switching to adalimumab in April 2011. Again, there was an initial period of remission followed by progressive exacerbation characterized by swelling and pain in some joints, and persistent contracture of others. Other diagnosis, such as mucopolysaccharidosis and systemic lupus erythematosus (SLE) were suspected, but metabolic and immunological screening were negative, respectively. Beside ESR and CRP, the increased values of IL-6 (up to 75 pg/mL) and TNF-alfa (up to 20 pg/mL) were measured.
In November 2012 therapy was cycled to non-TNFi, tocilizumab, which led only to a short period of remission. Finally, in September 2014, etanercept was introduced, again with the lack of permanent response. Along with four different bDMARDs she continuously received cDMARD methotrexate, and for a short period of time leflunomide. During the periods of disease flare, bridge therapy with intraarticular and/or systemic GC was used, and soon she was dependent on a daily dose of GC. Eventually, this led to the development of iatrogenic Cushing syndrome with characteristic appearance, growth retardation and low bone mineral density, regardless of the vitamin D and ibandronic acid therapy. Since every attempt to wean off GC inevitably led to disease flare, from June to December 2016 she received cyclophosphamide (6x) and rituximab (3x), again without achieving a sustained remission. Afterwards, for a short period of time she was given metformin but without an appropriate improvement in musculoskeletal symptoms (Fig. 1).
Fig. 1 Schematic representation of treatment modalities during the time. 2007 – 2020 - the period of treatment, NSAID - nonsteroidal anti-inflammatory drug, IFX - infliximab, ADA - adalimumab, TOC - tocilizumab, ETC - etanercept, DMARD - disease modifying anti-rheumatic drug, MTX - methotrexate, CFM - cyclophosphamide, RTX - rituximab, MTF - metformin, MMF - mycophenolate mofetil, CYC - cyclosporine, TFA - tofacitinib, p.o. - per os, i.a. - intraarticular, i.v. - intravenous, GC - glucocorticoids
During the 2017, at the age of 13, the trial of mycophenolate mofetil (MMF) followed by the trial of cyclosporin was initiated, but the patient nevertheless remained GC dependent. Both shoulders, elbows, radiocarpal joints, metacarpophalangeal (MCP), proximal interphalangeal (PIP), distal interphalangeal (DIP) joints and both knees had restricted range of movement, and repeated IAGI were necessary to alleviate the symptoms. Finally, in 2018, the treatment with Janus kinase (JAK) inhibitor tofacitinib was initiated, which lead to gradual amelioration of musculoskeletal symptoms and improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic GC. Moreover, as the swelling of the wrists subsided for the first time in many years, Madelung deformity was noticed by clinical examination. Interestingly, it was only then, in 2019, that the deformity was for the first time described on x-ray (Fig. 2), although x-ray and MRI imaging of both hands were previously performed on many occasions in order to assess the inflammation (Figs. 3 and 4). Nevertheless, subsequent analysis by experienced musculoskeletal radiologist revealed characteristic bilateral signs of Madelung deformity dating back in 2015 and 2017 (Fig. 3), with the MRI showing the Vickers and radiotriquetral ligament (Fig. 4). The finding of those two ligaments allowed the distinguishing between Madelung deformity and pseudo-Madelung deformity, which includes post-traumatic and post-infective forms, forms associated with Turner syndrome, multiple hereditary exostoses and Ollier disease [23]. Unfortunately, due to the parent’s refusal, no further radiological assessment was performed, so we have not documented the other important aspects of Madelung deformity, such as radial shortening and diaphysis bowing, nor the mesolimbic shortening of limbs characteristic for Leri Weill syndrome.
Fig. 2 The anteroposterior radiograph of left hand at the age of 14. Note the increased volar angulation of distal radius, wedge shaped carpus with proximally positioned lunate and a characteristic notch on the distal radius (white arrow), which are the features of the Madelung deformity [12]
Fig. 3 The anteroposterior radiograph of both hands at the age of 10 (a) and 13 (b), and of the left hand at the age of 14 (c). Note the bowing of the distal radius, an increased radial inclination (~ 30°) with the deformation of the carpus that acquired a triangular appearance and widening of the distal radial-ulnar joint bilaterally, which are the typical features of Madelung deformity. Dorsal subluxation of the ulnar head is not seen as lateral images of the wrist were not taken. Osteopenia of carpal bones and periarticular osteopenia of MCP, PIP and DIP joints related to JIA are present. No relevant changes are observed during the time
Fig. 4 MRI coronal T1-weighted (a), proton density BLADE fluid sensitive sequence (b), post contrast T1-weighted coronal fat sat sequence (c) and post contrast T1-weighted axial fat sat sequence (d) images of both hands at the age of 13. Note the radiotriquetral ligament (red arrow) and Vickers ligament (green arrow) (a, b). Note the inflammatory changes characterized by postcontrast imbibition in carpal joints and MCP joints (red circle), as well as tenosynovitis of flexor tendons related to JIA, more prominent on the left hand (c, d)
Although our patient was simultaneously followed by pediatric endocrinologist from age of 11, her short stature, along with delayed menarche, and Cushingoid appearance, was attributed to the prolonged use of GC. It was only after the Madelung’s deformity was observed that genetic causes, primarily Leri Weill syndrome, were taken into consideration. Genetic analysis was performed by commercially available SALSA MLPA Probemix P018 SHOX (MRC-Holland, Amsterdam, The Netherland) according to the manufacturer’s recommendations. The MLPA mix included probes for each exon of SHOX, one probe just before the promoter region as well as probes covering a region downstream of the gene. The results revealed one copy of sixteen probes (10 probes for Xp22-PAR1 from CNE2 to CNE9, 4 probes for SHOX area downstream, 1 probe for CRLF2 in PAR1 region and 1 probe for CSF2RA in PAR1 region), with the size of the smallest deletion of 766,5 kb. Based on the genetic testing and imaging findings of Madelung deformity, the diagnosis of Leri Weill syndrome was established, and parents were advised to undergo further genetic testing of both the patient and themselves, which they rejected.
Currently, our patient has many consequences of the adverse course of the disease and prolonged GC treatment, such as joint contractures of elbows, wrists, DIPs, PIPs, hips, knees and MCPs and low bone density, respectively. She developed secondary sex characteristics only after the therapy with estradiol was initiated at the age of 14. Nevertheless, after the discontinuation of GC and subsequent discontinuation of estradiol, she finally had a menarche at the age of 15, along with a long-awaited growth spurt.
Discussion and Conclusion
Children with rheumatic diseases, their families, as well as their treating physicians are dealt with numerous issues and dilemmas regarding either the disease itself or ongoing treatment modalities. Besides, the diagnosis of rheumatic diseases in children is regularly made by excluding wide range of other diseases, with no pathognomonic tests and/or criteria. Therefore, even after the classification criteria are fulfilled, the diagnosis should be revised if new symptoms emerge or if the recommended treatment options are failing.
In our patient, a variety of steroid-sparing agents with different mechanisms of action have been employed with limited or no clinical success. Some of these agents were used in line with current treatment recommendations, but many were used based on anecdotal reports [24–28]. Finally, due to signs of systemic inflammation characterized by increased inflammatory markers (CRP and ESR) and cytokines (IL-6 and TNF-alfa), which is indicative for the activation of JAK/STAT pathway, treatment with tofacitinib, a first generation JAK inhibitor, was initiated with a good clinical response. Several clinical trials in adults with rheumatoid and psoriatic arthritis have given solid evidence about the use of tofacitinib, while the results of a phase 3 randomized double blind placebo controlled withdrawal study in patients with polyarticular JIA showed improvement in symptoms, less disease flares and improved functional ability, together with a clinical amelioration of disease activity [29, 30]. Moreover, tofacitinib is an oral agent, and the challenge of using biologics requiring injection or infusion for an extended length of time, especially in children, should not be overlooked.
Along with the various treatment modalities, the different diagnosis was constantly being considered in our patient. Firstly, due to persistent contracture in some joints with little or no signs of swelling, LSDs such as mucopolysaccharidosis type I, Gaucher disease type I and Fabry disease were investigated. Besides, other inflammatory causes like systemic lupus erythematosus were also excluded. Lastly, the diagnosis of Leri Weill syndrome characterized by deletions in SHOX gene and Madelung deformity was established. This painful deformity of the wrist was first described in 1878 by the German surgeon Otto Madelung in adolescents between the ages 8 and 14 [12]. Although initially asymptomatic, the patients often went on to develop pain, loss of grip strength and reduced mobility, which were the symptoms present in our patient even after the inflammation was tackled with tofacitinib. Moreover, the features of Leri Weill syndrome include the short stature, which was also one of the dominant finding in the presented patient. Yet, the growth deficit caused by SHOX haploinsufficiency in Leri Weill syndrome is around 2 standard deviation scores (SDS) [31], while our patient had a SDS of -5,5. Besides, due to a prolonged use of GC, our patient had a full blown Cushingoid appearance, low bone density, delayed puberty and growth retardation. Therefore, the possible explanation for the short stature and growth delay in our patient includes multifactorial aetiology. Firstly, it is well known that extended GC treatment leads to a defect in bone turnover (and formation) due to impaired osteoblastogenesis and osteoclastogenesis, and may have direct effects on the growth plate [32]. Additionally, higher prepubertal glucocorticoid level appears to delay early and late pubertal timing of healthy girls, particularly the onset of pubertal growth spurt and menarche [33]. Moreover, it has been shown that girls with polyarticular juvenile idiopathic arthritis are significantly more likely to present with short stature even 6 months after stopping the steroid therapy [34]. Finally, the product of SHOX gene is implicated in bone development and regulation of chondrocyte differentiation, which clarifies the association of SHOX gene haploinsufficiency with idiopathic short stature, as well as short stature in Turner syndrome and Leri Weill dyschondrosteosis [31].
In the presented case, the diagnosis of the Madelung deformity and Leri Weill syndrome was delayed due to the concomitant active inflammation caused by JIA taking the focus from other possible causes of pain in the wrists. However, as subsequent analysis by experienced musculoskeletal radiologist has shown, the characteristic signs of the Madelung deformity were present few years before the final diagnosis was reached, emphasizing once again the importance of multidisciplinary approach and close collaboration of many subspecialists in the care of children with rheumatic diseases. Nevertheless, this lag probably did not influence the therapeutic management in our particular patient; although positive effect on final height was observed with growth hormone therapy in patients with Leri Weill syndrome, due to the matching influence of GC and lack of agreement with her parents, this treatment option was avoided in our patient [35].
In conclusion, this case report emphasizes the difficulties and challenges in management of patient with long-standing polyarticular JIA refractory to wide range of treatment modalities. Although many high-quality guidelines are available for treatment of JIA patients, there is still need for individual reports of difficult to treat cases, especially when additional diagnosis are involved. While Leri Weill syndrome is extensively reported in the literature, to the best of our knowledge, our case report describes it for the first time along with JIA. Taking all these into account, we strongly encourage the aggregation of similar patients and establishment of the common ground that will help clinician to decide upon the introduction of treatment options outside of the contemporary guidelines.
Abbreviations
JIAJuvenile idiopathic arthritis
LSDLysosomal storage disease
MPSMucopolysaccharidosis
NSAIDNonsteroidal anti-inflammatory drug
cDMARDConventional disease modifying anti-rheumatic drug
bDMARDBiologic disease modifying anti-rheumatic drug
IAGIIntraarticular glucocorticoid injection
GCGlucocorticoids
MASMacrophage activation syndrome
TNFiTumor necrosis factor inhibitor
T2TTreat-to-target
RFRheumatoid factor
ESRErythrocyte sedimentation rate
CRPC-reactive protein
ANAAntinuclear antibody
MTXMethotrexate
SLESystemic lupus erythematosus
TNFαTumor necrosis factor alpha
anti-IL-6Anti-interleukin-6
MMFMycophenolate mofetil
MCPMetacarpophalangeal
PIPProximal interphalangeal
DIPDistal interphalangeal
JAKJanus kinase
MRIMagnetic resonance imaging
SHOXShort-stature homeobox
JAK/STATJanus kinase/signal transducer and activator of transcription proteins
SDSStandard deviation score
GnRHGonadotropin-releasing hormone
HPGHypothalamic-pituitary-gonadal
IFXInfliximab
ADAAdalimumab
TOCTocilizumab
ETCEtanercept
CFMCyclophosphamide
RTXRituximab
MTFMetformin
CYCCyclosporine
TFATofacitinib
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Acknowledgements
We thank parents for availability of publishing medical history of their daughter.
Authors’ contributions
VV and AS have equally contributed to the paper. VV: medical charts review, literature search, creation of figures and tables and manuscript draft preparation. AS: medical charts review, literature search, creation of figures and tables and manuscript draft preparation RV: radiographic images interpretation, manuscript draft preparation. MV: clinical care and the final revision of the manuscript. MH: clinical care and the final revision of the manuscript. LL: clinical care, medical charts review, literature search, creation of figures and tables, manuscript draft preparation, final revision of the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. / Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the parents for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | ADALIMUMAB, CYCLOPHOSPHAMIDE, CYCLOSPORINE, ETANERCEPT, IBUPROFEN, INDOMETHACIN, INFLIXIMAB, LEFLUNOMIDE, MELOXICAM, METFORMIN HYDROCHLORIDE, METHOTREXATE, METHYLPREDNISOLONE SODIUM SUCCINATE, MYCOPHENOLATE MOFETIL, NAPROXEN SODIUM, PREDNISONE, RITUXIMAB, TOCILIZUMAB, TOFACITINIB | DrugsGivenReaction | CC BY | 33451288 | 18,970,451 | 2021-01-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Delayed menarche'. | Beyond the guidelines management of juvenile idiopathic arthritis: a case report of a girl with polyarticular disease refractory to multiple treatment options and Leri Weill syndrome.
The last two decades brought new treatment options and high quality guidelines into the paediatric rheumatologic practice. Nevertheless, a number of patients still present a diagnostic and therapeutic challenge due to combination of vague symptoms and unresponsiveness to available treatment modalities.
We report a case of sixteen years old girl suffering from polyarticular type of juvenile idiopathic arthritis refractory to multiple treatment options. She first presented at the age of 4 with swelling and contractures of both knees. Her symptoms were initially unresponsive to nonsteroidal anti-inflammatory drugs and progressed despite treatment with intraarticular and systemic glucocorticoids and methotrexate. Throughout the years, she received several biologics together with continuous administration of nonsteroidal anti-inflammatory drugs and disease modifying anti-rheumatic drugs as well as intraarticular and systemic glucocorticoids in disease flares. However, none of this options provided a permanent remission, so various other modalities, as well as other possible diagnoses were constantly being considered. Eventually she became dependent on a daily dose of systemic glucocorticoids. In 2018, the treatment with Janus kinase inhibitor tofacitinib was initiated, which led to gradual amelioration of musculoskeletal symptoms, improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic glucocorticoids. As the swelling of the wrists subsided for the first time in many years, Madelung's deformity was noticed, first clinically, and later radiographically as well. Genetic analysis revealed short-stature homeobox gene deficiency and confirmed the diagnosis of Leri Weill syndrome.
This case report emphasizes the need for reporting refractory, complicated cases from everyday clinical practice in order to build-up the overall knowledge and share experience which is complementary to available guidelines. Individual reports of difficult to treat cases, especially when additional diagnoses are involved, can be helpful for physicians treating patients with common rheumatological diseases such as juvenile idiopathic arthritis.
Background
Joint pain and/or swelling with limited range of motion is a common manifestation of many paediatric diseases, most notably wide range of rheumatic conditions. If both of these symptoms are present for longer than 6 weeks in a patient younger than 16 years of age, a diagnosis of juvenile idiopathic arthritis (JIA), the most common childhood rheumatic disease, should be considered [1]. JIA is heterogenous disease that encompasses different subtypes of childhood arthritis defined depending on the number of affected joints and/or presence of the enthesitis and/or sacroiliitis. Nevertheless, alongside JIA, there is a wide range of loosely related noninflammatory causes of a swollen joint in children, especially in the absence of clinical signs of inflammation. Lysosomal storage diseases (LSD) such as mucopolysaccharidosis type I (MPS I), Gaucher disease type I and Fabry disease all have prominent musculoskeletal symptoms early in the course of the disease, and are often first seen by a pediatric rheumatologist [2–8]. However, the underlying mechanism of those disorders does not directly involve the immune mediated inflammatory response, but rather an inflammation caused by genetic defects and subsequent perturbations at the protein level. More specifically, in Gaucher disease, bone marrow infiltration with histiocytes causes acute attacks of pain, which may be mistaken for arthritis in the vicinity of a joint [5, 8]. In Fabry disease, episodes of neuropathic pain in hands, feet, wrists, ankles (acroparesthesias), often associated with fever, malaise and elevated inflammation markers, can mimic a rheumatic condition, such as an inflammatory arthritis [3, 9]. Finally, joint stiffness and contractures are characteristic for some types of MPS, the so called „attenuated“ forms like Hurler-Scheie syndrome, which have a less severe presentation and progress silently over the years, making the diagnosis a challenge [3, 10, 11]. On the other hand, some congenital conditions, such as Madelung and Madelung-type deformities resulting from the premature closure of the medial volar aspect of the distal radial physis, might cause similar symptoms [12]. Hence, it is not a rarity that some of the children with LSD and congenital deformities are treated for prolonged periods of time as having an inflammatory arthritis, despite the lack of appropriate response [13].
With regard to the treatment of JIA, various modalities emerged over the last two decades, revolutionizing the pediatric rheumatology practice [14]. Majority of the presently available guidelines recommend a step-up approach, starting with nonsteroidal anti-inflammatory drugs (NSAID) and intraarticular glucocorticoid injections (IAGI), followed by conventional and biologic disease modifying anti-rheumatic drugs (cDMARD and bDMARD), respectively [15]. Moreover, despite many known adverse effects, systemic glucocorticoids (GC) are still being used as an important therapeutic option for wide range of complications associated with JIA (e.g., macrophage activation syndrome, myocarditis, pericarditis, pleuritis, peritonitis, uveitis and severe anaemia), as well as a bridge therapy in severe forms of JIA before the full effect of other treatment modalities has been achieved [16]. Those modalities nowadays primarily involve tumor necrosis factor alpha (TNFα) inhibitors (TNFi), such as etanercept, adalimumab and infliximab, and non-TNFi, such as anti-interleukin-6 (anti-IL-6) agent tocilizumab and a selective T-cell co-stimulation modulator abatacept [17, 18]. Furthermore, new medications are continuously being investigated [19, 20].
Together with the expansion of new treatment modalities, efforts have been made to introduce the treat-to-target (T2T) model in pediatric rheumatologic practice [21]. Signs and symptoms control, prevention of structural damage of joints and optimization of linear growth and pubertal development, as well as abolition of inflammation, have all been set as treatment goals. Essentially, this model advocates that therapy should be revised and adjusted based on regular disease activity assessments to reach and maintain the treatment target. Special attention should be paid to preventing or minimizing the side effects of systemic GC given their negative effect on growth and pubertal development. Consequently, their long-term use to maintain treatment target should be avoided, especially considering that GC dependence demonstrates the inadequacy of chosen treatment. The shared decision making, as well as multidisciplinary approach, have been recognized as exceptionally valuable for assurance of better adherence to treatment and subsequently improvement of outcome and overall prognosis.
Unfortunately, despite all these achievements, only 14 % of patients with rheumatoid factor (RF) negative and 0 % with RF positive polyarticular JIA achieves the remission off medications within five years, implying that JIA treatment requires a long-lasting commitment [22]. Hence, it comes as no surprise that every clinician involved in the care of children with JIA patients eventually sees one with disease not responding to acclaimed treatment options (i.e. NSAIDs, cDMARDS, bDMARDS) [15]. At that point, the consideration of additional treatment modalities seems like a valid course of action, but sometimes alternative diagnosis should be considered as well. Here, we present one such case, a girl with long standing polyarticular JIA refractory to many standard treatment modalities, with symptoms suggestive of other diseases.
Case presentation
A four-year-old first came to our attention in February 2008 due to painful swelling and contractures of both knees. Her symptoms started a year earlier and were not associated with any discernible trigger such as infection or trauma. Moreover, the symptoms were not responding to NSAIDs and she soon developed a severe morning stiffness lasting for up to three hours. Her birth history as well as psychomotor development prior to disease evolution was unremarkable. She was born as a first child into a family of non-consanguine parents, with no relatives having the similar symptoms.
The initial laboratory findings showed persistently elevated inflammatory markers (erythrocyte sedimentation rate (ESR) up to 100 mm/h and C-reactive protein (CRP) up to 100 mg/dL), with negative RF and antinuclear antibody (ANA) screen, and normal immunoglobulin levels. Despite the initial treatment with GC and methotrexate (MTX), her symptoms progressed affecting elbows, wrists, ankles and small joints of both hands. Moreover, she developed a severe uveitis of the left eye. In November 2008 biologic therapy with infliximab was started, with initially good response. Unfortunately, this lasted only for a few months and frequent relapses necessitated switching to adalimumab in April 2011. Again, there was an initial period of remission followed by progressive exacerbation characterized by swelling and pain in some joints, and persistent contracture of others. Other diagnosis, such as mucopolysaccharidosis and systemic lupus erythematosus (SLE) were suspected, but metabolic and immunological screening were negative, respectively. Beside ESR and CRP, the increased values of IL-6 (up to 75 pg/mL) and TNF-alfa (up to 20 pg/mL) were measured.
In November 2012 therapy was cycled to non-TNFi, tocilizumab, which led only to a short period of remission. Finally, in September 2014, etanercept was introduced, again with the lack of permanent response. Along with four different bDMARDs she continuously received cDMARD methotrexate, and for a short period of time leflunomide. During the periods of disease flare, bridge therapy with intraarticular and/or systemic GC was used, and soon she was dependent on a daily dose of GC. Eventually, this led to the development of iatrogenic Cushing syndrome with characteristic appearance, growth retardation and low bone mineral density, regardless of the vitamin D and ibandronic acid therapy. Since every attempt to wean off GC inevitably led to disease flare, from June to December 2016 she received cyclophosphamide (6x) and rituximab (3x), again without achieving a sustained remission. Afterwards, for a short period of time she was given metformin but without an appropriate improvement in musculoskeletal symptoms (Fig. 1).
Fig. 1 Schematic representation of treatment modalities during the time. 2007 – 2020 - the period of treatment, NSAID - nonsteroidal anti-inflammatory drug, IFX - infliximab, ADA - adalimumab, TOC - tocilizumab, ETC - etanercept, DMARD - disease modifying anti-rheumatic drug, MTX - methotrexate, CFM - cyclophosphamide, RTX - rituximab, MTF - metformin, MMF - mycophenolate mofetil, CYC - cyclosporine, TFA - tofacitinib, p.o. - per os, i.a. - intraarticular, i.v. - intravenous, GC - glucocorticoids
During the 2017, at the age of 13, the trial of mycophenolate mofetil (MMF) followed by the trial of cyclosporin was initiated, but the patient nevertheless remained GC dependent. Both shoulders, elbows, radiocarpal joints, metacarpophalangeal (MCP), proximal interphalangeal (PIP), distal interphalangeal (DIP) joints and both knees had restricted range of movement, and repeated IAGI were necessary to alleviate the symptoms. Finally, in 2018, the treatment with Janus kinase (JAK) inhibitor tofacitinib was initiated, which lead to gradual amelioration of musculoskeletal symptoms and improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic GC. Moreover, as the swelling of the wrists subsided for the first time in many years, Madelung deformity was noticed by clinical examination. Interestingly, it was only then, in 2019, that the deformity was for the first time described on x-ray (Fig. 2), although x-ray and MRI imaging of both hands were previously performed on many occasions in order to assess the inflammation (Figs. 3 and 4). Nevertheless, subsequent analysis by experienced musculoskeletal radiologist revealed characteristic bilateral signs of Madelung deformity dating back in 2015 and 2017 (Fig. 3), with the MRI showing the Vickers and radiotriquetral ligament (Fig. 4). The finding of those two ligaments allowed the distinguishing between Madelung deformity and pseudo-Madelung deformity, which includes post-traumatic and post-infective forms, forms associated with Turner syndrome, multiple hereditary exostoses and Ollier disease [23]. Unfortunately, due to the parent’s refusal, no further radiological assessment was performed, so we have not documented the other important aspects of Madelung deformity, such as radial shortening and diaphysis bowing, nor the mesolimbic shortening of limbs characteristic for Leri Weill syndrome.
Fig. 2 The anteroposterior radiograph of left hand at the age of 14. Note the increased volar angulation of distal radius, wedge shaped carpus with proximally positioned lunate and a characteristic notch on the distal radius (white arrow), which are the features of the Madelung deformity [12]
Fig. 3 The anteroposterior radiograph of both hands at the age of 10 (a) and 13 (b), and of the left hand at the age of 14 (c). Note the bowing of the distal radius, an increased radial inclination (~ 30°) with the deformation of the carpus that acquired a triangular appearance and widening of the distal radial-ulnar joint bilaterally, which are the typical features of Madelung deformity. Dorsal subluxation of the ulnar head is not seen as lateral images of the wrist were not taken. Osteopenia of carpal bones and periarticular osteopenia of MCP, PIP and DIP joints related to JIA are present. No relevant changes are observed during the time
Fig. 4 MRI coronal T1-weighted (a), proton density BLADE fluid sensitive sequence (b), post contrast T1-weighted coronal fat sat sequence (c) and post contrast T1-weighted axial fat sat sequence (d) images of both hands at the age of 13. Note the radiotriquetral ligament (red arrow) and Vickers ligament (green arrow) (a, b). Note the inflammatory changes characterized by postcontrast imbibition in carpal joints and MCP joints (red circle), as well as tenosynovitis of flexor tendons related to JIA, more prominent on the left hand (c, d)
Although our patient was simultaneously followed by pediatric endocrinologist from age of 11, her short stature, along with delayed menarche, and Cushingoid appearance, was attributed to the prolonged use of GC. It was only after the Madelung’s deformity was observed that genetic causes, primarily Leri Weill syndrome, were taken into consideration. Genetic analysis was performed by commercially available SALSA MLPA Probemix P018 SHOX (MRC-Holland, Amsterdam, The Netherland) according to the manufacturer’s recommendations. The MLPA mix included probes for each exon of SHOX, one probe just before the promoter region as well as probes covering a region downstream of the gene. The results revealed one copy of sixteen probes (10 probes for Xp22-PAR1 from CNE2 to CNE9, 4 probes for SHOX area downstream, 1 probe for CRLF2 in PAR1 region and 1 probe for CSF2RA in PAR1 region), with the size of the smallest deletion of 766,5 kb. Based on the genetic testing and imaging findings of Madelung deformity, the diagnosis of Leri Weill syndrome was established, and parents were advised to undergo further genetic testing of both the patient and themselves, which they rejected.
Currently, our patient has many consequences of the adverse course of the disease and prolonged GC treatment, such as joint contractures of elbows, wrists, DIPs, PIPs, hips, knees and MCPs and low bone density, respectively. She developed secondary sex characteristics only after the therapy with estradiol was initiated at the age of 14. Nevertheless, after the discontinuation of GC and subsequent discontinuation of estradiol, she finally had a menarche at the age of 15, along with a long-awaited growth spurt.
Discussion and Conclusion
Children with rheumatic diseases, their families, as well as their treating physicians are dealt with numerous issues and dilemmas regarding either the disease itself or ongoing treatment modalities. Besides, the diagnosis of rheumatic diseases in children is regularly made by excluding wide range of other diseases, with no pathognomonic tests and/or criteria. Therefore, even after the classification criteria are fulfilled, the diagnosis should be revised if new symptoms emerge or if the recommended treatment options are failing.
In our patient, a variety of steroid-sparing agents with different mechanisms of action have been employed with limited or no clinical success. Some of these agents were used in line with current treatment recommendations, but many were used based on anecdotal reports [24–28]. Finally, due to signs of systemic inflammation characterized by increased inflammatory markers (CRP and ESR) and cytokines (IL-6 and TNF-alfa), which is indicative for the activation of JAK/STAT pathway, treatment with tofacitinib, a first generation JAK inhibitor, was initiated with a good clinical response. Several clinical trials in adults with rheumatoid and psoriatic arthritis have given solid evidence about the use of tofacitinib, while the results of a phase 3 randomized double blind placebo controlled withdrawal study in patients with polyarticular JIA showed improvement in symptoms, less disease flares and improved functional ability, together with a clinical amelioration of disease activity [29, 30]. Moreover, tofacitinib is an oral agent, and the challenge of using biologics requiring injection or infusion for an extended length of time, especially in children, should not be overlooked.
Along with the various treatment modalities, the different diagnosis was constantly being considered in our patient. Firstly, due to persistent contracture in some joints with little or no signs of swelling, LSDs such as mucopolysaccharidosis type I, Gaucher disease type I and Fabry disease were investigated. Besides, other inflammatory causes like systemic lupus erythematosus were also excluded. Lastly, the diagnosis of Leri Weill syndrome characterized by deletions in SHOX gene and Madelung deformity was established. This painful deformity of the wrist was first described in 1878 by the German surgeon Otto Madelung in adolescents between the ages 8 and 14 [12]. Although initially asymptomatic, the patients often went on to develop pain, loss of grip strength and reduced mobility, which were the symptoms present in our patient even after the inflammation was tackled with tofacitinib. Moreover, the features of Leri Weill syndrome include the short stature, which was also one of the dominant finding in the presented patient. Yet, the growth deficit caused by SHOX haploinsufficiency in Leri Weill syndrome is around 2 standard deviation scores (SDS) [31], while our patient had a SDS of -5,5. Besides, due to a prolonged use of GC, our patient had a full blown Cushingoid appearance, low bone density, delayed puberty and growth retardation. Therefore, the possible explanation for the short stature and growth delay in our patient includes multifactorial aetiology. Firstly, it is well known that extended GC treatment leads to a defect in bone turnover (and formation) due to impaired osteoblastogenesis and osteoclastogenesis, and may have direct effects on the growth plate [32]. Additionally, higher prepubertal glucocorticoid level appears to delay early and late pubertal timing of healthy girls, particularly the onset of pubertal growth spurt and menarche [33]. Moreover, it has been shown that girls with polyarticular juvenile idiopathic arthritis are significantly more likely to present with short stature even 6 months after stopping the steroid therapy [34]. Finally, the product of SHOX gene is implicated in bone development and regulation of chondrocyte differentiation, which clarifies the association of SHOX gene haploinsufficiency with idiopathic short stature, as well as short stature in Turner syndrome and Leri Weill dyschondrosteosis [31].
In the presented case, the diagnosis of the Madelung deformity and Leri Weill syndrome was delayed due to the concomitant active inflammation caused by JIA taking the focus from other possible causes of pain in the wrists. However, as subsequent analysis by experienced musculoskeletal radiologist has shown, the characteristic signs of the Madelung deformity were present few years before the final diagnosis was reached, emphasizing once again the importance of multidisciplinary approach and close collaboration of many subspecialists in the care of children with rheumatic diseases. Nevertheless, this lag probably did not influence the therapeutic management in our particular patient; although positive effect on final height was observed with growth hormone therapy in patients with Leri Weill syndrome, due to the matching influence of GC and lack of agreement with her parents, this treatment option was avoided in our patient [35].
In conclusion, this case report emphasizes the difficulties and challenges in management of patient with long-standing polyarticular JIA refractory to wide range of treatment modalities. Although many high-quality guidelines are available for treatment of JIA patients, there is still need for individual reports of difficult to treat cases, especially when additional diagnosis are involved. While Leri Weill syndrome is extensively reported in the literature, to the best of our knowledge, our case report describes it for the first time along with JIA. Taking all these into account, we strongly encourage the aggregation of similar patients and establishment of the common ground that will help clinician to decide upon the introduction of treatment options outside of the contemporary guidelines.
Abbreviations
JIAJuvenile idiopathic arthritis
LSDLysosomal storage disease
MPSMucopolysaccharidosis
NSAIDNonsteroidal anti-inflammatory drug
cDMARDConventional disease modifying anti-rheumatic drug
bDMARDBiologic disease modifying anti-rheumatic drug
IAGIIntraarticular glucocorticoid injection
GCGlucocorticoids
MASMacrophage activation syndrome
TNFiTumor necrosis factor inhibitor
T2TTreat-to-target
RFRheumatoid factor
ESRErythrocyte sedimentation rate
CRPC-reactive protein
ANAAntinuclear antibody
MTXMethotrexate
SLESystemic lupus erythematosus
TNFαTumor necrosis factor alpha
anti-IL-6Anti-interleukin-6
MMFMycophenolate mofetil
MCPMetacarpophalangeal
PIPProximal interphalangeal
DIPDistal interphalangeal
JAKJanus kinase
MRIMagnetic resonance imaging
SHOXShort-stature homeobox
JAK/STATJanus kinase/signal transducer and activator of transcription proteins
SDSStandard deviation score
GnRHGonadotropin-releasing hormone
HPGHypothalamic-pituitary-gonadal
IFXInfliximab
ADAAdalimumab
TOCTocilizumab
ETCEtanercept
CFMCyclophosphamide
RTXRituximab
MTFMetformin
CYCCyclosporine
TFATofacitinib
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Acknowledgements
We thank parents for availability of publishing medical history of their daughter.
Authors’ contributions
VV and AS have equally contributed to the paper. VV: medical charts review, literature search, creation of figures and tables and manuscript draft preparation. AS: medical charts review, literature search, creation of figures and tables and manuscript draft preparation RV: radiographic images interpretation, manuscript draft preparation. MV: clinical care and the final revision of the manuscript. MH: clinical care and the final revision of the manuscript. LL: clinical care, medical charts review, literature search, creation of figures and tables, manuscript draft preparation, final revision of the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. / Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the parents for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | ADALIMUMAB, CYCLOPHOSPHAMIDE, CYCLOSPORINE, ETANERCEPT, IBUPROFEN, INDOMETHACIN, INFLIXIMAB, LEFLUNOMIDE, MELOXICAM, METFORMIN HYDROCHLORIDE, METHOTREXATE, METHYLPREDNISOLONE SODIUM SUCCINATE, MYCOPHENOLATE MOFETIL, NAPROXEN SODIUM, PREDNISONE, RITUXIMAB, TOCILIZUMAB, TOFACITINIB | DrugsGivenReaction | CC BY | 33451288 | 18,970,451 | 2021-01-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Delayed puberty'. | Beyond the guidelines management of juvenile idiopathic arthritis: a case report of a girl with polyarticular disease refractory to multiple treatment options and Leri Weill syndrome.
The last two decades brought new treatment options and high quality guidelines into the paediatric rheumatologic practice. Nevertheless, a number of patients still present a diagnostic and therapeutic challenge due to combination of vague symptoms and unresponsiveness to available treatment modalities.
We report a case of sixteen years old girl suffering from polyarticular type of juvenile idiopathic arthritis refractory to multiple treatment options. She first presented at the age of 4 with swelling and contractures of both knees. Her symptoms were initially unresponsive to nonsteroidal anti-inflammatory drugs and progressed despite treatment with intraarticular and systemic glucocorticoids and methotrexate. Throughout the years, she received several biologics together with continuous administration of nonsteroidal anti-inflammatory drugs and disease modifying anti-rheumatic drugs as well as intraarticular and systemic glucocorticoids in disease flares. However, none of this options provided a permanent remission, so various other modalities, as well as other possible diagnoses were constantly being considered. Eventually she became dependent on a daily dose of systemic glucocorticoids. In 2018, the treatment with Janus kinase inhibitor tofacitinib was initiated, which led to gradual amelioration of musculoskeletal symptoms, improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic glucocorticoids. As the swelling of the wrists subsided for the first time in many years, Madelung's deformity was noticed, first clinically, and later radiographically as well. Genetic analysis revealed short-stature homeobox gene deficiency and confirmed the diagnosis of Leri Weill syndrome.
This case report emphasizes the need for reporting refractory, complicated cases from everyday clinical practice in order to build-up the overall knowledge and share experience which is complementary to available guidelines. Individual reports of difficult to treat cases, especially when additional diagnoses are involved, can be helpful for physicians treating patients with common rheumatological diseases such as juvenile idiopathic arthritis.
Background
Joint pain and/or swelling with limited range of motion is a common manifestation of many paediatric diseases, most notably wide range of rheumatic conditions. If both of these symptoms are present for longer than 6 weeks in a patient younger than 16 years of age, a diagnosis of juvenile idiopathic arthritis (JIA), the most common childhood rheumatic disease, should be considered [1]. JIA is heterogenous disease that encompasses different subtypes of childhood arthritis defined depending on the number of affected joints and/or presence of the enthesitis and/or sacroiliitis. Nevertheless, alongside JIA, there is a wide range of loosely related noninflammatory causes of a swollen joint in children, especially in the absence of clinical signs of inflammation. Lysosomal storage diseases (LSD) such as mucopolysaccharidosis type I (MPS I), Gaucher disease type I and Fabry disease all have prominent musculoskeletal symptoms early in the course of the disease, and are often first seen by a pediatric rheumatologist [2–8]. However, the underlying mechanism of those disorders does not directly involve the immune mediated inflammatory response, but rather an inflammation caused by genetic defects and subsequent perturbations at the protein level. More specifically, in Gaucher disease, bone marrow infiltration with histiocytes causes acute attacks of pain, which may be mistaken for arthritis in the vicinity of a joint [5, 8]. In Fabry disease, episodes of neuropathic pain in hands, feet, wrists, ankles (acroparesthesias), often associated with fever, malaise and elevated inflammation markers, can mimic a rheumatic condition, such as an inflammatory arthritis [3, 9]. Finally, joint stiffness and contractures are characteristic for some types of MPS, the so called „attenuated“ forms like Hurler-Scheie syndrome, which have a less severe presentation and progress silently over the years, making the diagnosis a challenge [3, 10, 11]. On the other hand, some congenital conditions, such as Madelung and Madelung-type deformities resulting from the premature closure of the medial volar aspect of the distal radial physis, might cause similar symptoms [12]. Hence, it is not a rarity that some of the children with LSD and congenital deformities are treated for prolonged periods of time as having an inflammatory arthritis, despite the lack of appropriate response [13].
With regard to the treatment of JIA, various modalities emerged over the last two decades, revolutionizing the pediatric rheumatology practice [14]. Majority of the presently available guidelines recommend a step-up approach, starting with nonsteroidal anti-inflammatory drugs (NSAID) and intraarticular glucocorticoid injections (IAGI), followed by conventional and biologic disease modifying anti-rheumatic drugs (cDMARD and bDMARD), respectively [15]. Moreover, despite many known adverse effects, systemic glucocorticoids (GC) are still being used as an important therapeutic option for wide range of complications associated with JIA (e.g., macrophage activation syndrome, myocarditis, pericarditis, pleuritis, peritonitis, uveitis and severe anaemia), as well as a bridge therapy in severe forms of JIA before the full effect of other treatment modalities has been achieved [16]. Those modalities nowadays primarily involve tumor necrosis factor alpha (TNFα) inhibitors (TNFi), such as etanercept, adalimumab and infliximab, and non-TNFi, such as anti-interleukin-6 (anti-IL-6) agent tocilizumab and a selective T-cell co-stimulation modulator abatacept [17, 18]. Furthermore, new medications are continuously being investigated [19, 20].
Together with the expansion of new treatment modalities, efforts have been made to introduce the treat-to-target (T2T) model in pediatric rheumatologic practice [21]. Signs and symptoms control, prevention of structural damage of joints and optimization of linear growth and pubertal development, as well as abolition of inflammation, have all been set as treatment goals. Essentially, this model advocates that therapy should be revised and adjusted based on regular disease activity assessments to reach and maintain the treatment target. Special attention should be paid to preventing or minimizing the side effects of systemic GC given their negative effect on growth and pubertal development. Consequently, their long-term use to maintain treatment target should be avoided, especially considering that GC dependence demonstrates the inadequacy of chosen treatment. The shared decision making, as well as multidisciplinary approach, have been recognized as exceptionally valuable for assurance of better adherence to treatment and subsequently improvement of outcome and overall prognosis.
Unfortunately, despite all these achievements, only 14 % of patients with rheumatoid factor (RF) negative and 0 % with RF positive polyarticular JIA achieves the remission off medications within five years, implying that JIA treatment requires a long-lasting commitment [22]. Hence, it comes as no surprise that every clinician involved in the care of children with JIA patients eventually sees one with disease not responding to acclaimed treatment options (i.e. NSAIDs, cDMARDS, bDMARDS) [15]. At that point, the consideration of additional treatment modalities seems like a valid course of action, but sometimes alternative diagnosis should be considered as well. Here, we present one such case, a girl with long standing polyarticular JIA refractory to many standard treatment modalities, with symptoms suggestive of other diseases.
Case presentation
A four-year-old first came to our attention in February 2008 due to painful swelling and contractures of both knees. Her symptoms started a year earlier and were not associated with any discernible trigger such as infection or trauma. Moreover, the symptoms were not responding to NSAIDs and she soon developed a severe morning stiffness lasting for up to three hours. Her birth history as well as psychomotor development prior to disease evolution was unremarkable. She was born as a first child into a family of non-consanguine parents, with no relatives having the similar symptoms.
The initial laboratory findings showed persistently elevated inflammatory markers (erythrocyte sedimentation rate (ESR) up to 100 mm/h and C-reactive protein (CRP) up to 100 mg/dL), with negative RF and antinuclear antibody (ANA) screen, and normal immunoglobulin levels. Despite the initial treatment with GC and methotrexate (MTX), her symptoms progressed affecting elbows, wrists, ankles and small joints of both hands. Moreover, she developed a severe uveitis of the left eye. In November 2008 biologic therapy with infliximab was started, with initially good response. Unfortunately, this lasted only for a few months and frequent relapses necessitated switching to adalimumab in April 2011. Again, there was an initial period of remission followed by progressive exacerbation characterized by swelling and pain in some joints, and persistent contracture of others. Other diagnosis, such as mucopolysaccharidosis and systemic lupus erythematosus (SLE) were suspected, but metabolic and immunological screening were negative, respectively. Beside ESR and CRP, the increased values of IL-6 (up to 75 pg/mL) and TNF-alfa (up to 20 pg/mL) were measured.
In November 2012 therapy was cycled to non-TNFi, tocilizumab, which led only to a short period of remission. Finally, in September 2014, etanercept was introduced, again with the lack of permanent response. Along with four different bDMARDs she continuously received cDMARD methotrexate, and for a short period of time leflunomide. During the periods of disease flare, bridge therapy with intraarticular and/or systemic GC was used, and soon she was dependent on a daily dose of GC. Eventually, this led to the development of iatrogenic Cushing syndrome with characteristic appearance, growth retardation and low bone mineral density, regardless of the vitamin D and ibandronic acid therapy. Since every attempt to wean off GC inevitably led to disease flare, from June to December 2016 she received cyclophosphamide (6x) and rituximab (3x), again without achieving a sustained remission. Afterwards, for a short period of time she was given metformin but without an appropriate improvement in musculoskeletal symptoms (Fig. 1).
Fig. 1 Schematic representation of treatment modalities during the time. 2007 – 2020 - the period of treatment, NSAID - nonsteroidal anti-inflammatory drug, IFX - infliximab, ADA - adalimumab, TOC - tocilizumab, ETC - etanercept, DMARD - disease modifying anti-rheumatic drug, MTX - methotrexate, CFM - cyclophosphamide, RTX - rituximab, MTF - metformin, MMF - mycophenolate mofetil, CYC - cyclosporine, TFA - tofacitinib, p.o. - per os, i.a. - intraarticular, i.v. - intravenous, GC - glucocorticoids
During the 2017, at the age of 13, the trial of mycophenolate mofetil (MMF) followed by the trial of cyclosporin was initiated, but the patient nevertheless remained GC dependent. Both shoulders, elbows, radiocarpal joints, metacarpophalangeal (MCP), proximal interphalangeal (PIP), distal interphalangeal (DIP) joints and both knees had restricted range of movement, and repeated IAGI were necessary to alleviate the symptoms. Finally, in 2018, the treatment with Janus kinase (JAK) inhibitor tofacitinib was initiated, which lead to gradual amelioration of musculoskeletal symptoms and improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic GC. Moreover, as the swelling of the wrists subsided for the first time in many years, Madelung deformity was noticed by clinical examination. Interestingly, it was only then, in 2019, that the deformity was for the first time described on x-ray (Fig. 2), although x-ray and MRI imaging of both hands were previously performed on many occasions in order to assess the inflammation (Figs. 3 and 4). Nevertheless, subsequent analysis by experienced musculoskeletal radiologist revealed characteristic bilateral signs of Madelung deformity dating back in 2015 and 2017 (Fig. 3), with the MRI showing the Vickers and radiotriquetral ligament (Fig. 4). The finding of those two ligaments allowed the distinguishing between Madelung deformity and pseudo-Madelung deformity, which includes post-traumatic and post-infective forms, forms associated with Turner syndrome, multiple hereditary exostoses and Ollier disease [23]. Unfortunately, due to the parent’s refusal, no further radiological assessment was performed, so we have not documented the other important aspects of Madelung deformity, such as radial shortening and diaphysis bowing, nor the mesolimbic shortening of limbs characteristic for Leri Weill syndrome.
Fig. 2 The anteroposterior radiograph of left hand at the age of 14. Note the increased volar angulation of distal radius, wedge shaped carpus with proximally positioned lunate and a characteristic notch on the distal radius (white arrow), which are the features of the Madelung deformity [12]
Fig. 3 The anteroposterior radiograph of both hands at the age of 10 (a) and 13 (b), and of the left hand at the age of 14 (c). Note the bowing of the distal radius, an increased radial inclination (~ 30°) with the deformation of the carpus that acquired a triangular appearance and widening of the distal radial-ulnar joint bilaterally, which are the typical features of Madelung deformity. Dorsal subluxation of the ulnar head is not seen as lateral images of the wrist were not taken. Osteopenia of carpal bones and periarticular osteopenia of MCP, PIP and DIP joints related to JIA are present. No relevant changes are observed during the time
Fig. 4 MRI coronal T1-weighted (a), proton density BLADE fluid sensitive sequence (b), post contrast T1-weighted coronal fat sat sequence (c) and post contrast T1-weighted axial fat sat sequence (d) images of both hands at the age of 13. Note the radiotriquetral ligament (red arrow) and Vickers ligament (green arrow) (a, b). Note the inflammatory changes characterized by postcontrast imbibition in carpal joints and MCP joints (red circle), as well as tenosynovitis of flexor tendons related to JIA, more prominent on the left hand (c, d)
Although our patient was simultaneously followed by pediatric endocrinologist from age of 11, her short stature, along with delayed menarche, and Cushingoid appearance, was attributed to the prolonged use of GC. It was only after the Madelung’s deformity was observed that genetic causes, primarily Leri Weill syndrome, were taken into consideration. Genetic analysis was performed by commercially available SALSA MLPA Probemix P018 SHOX (MRC-Holland, Amsterdam, The Netherland) according to the manufacturer’s recommendations. The MLPA mix included probes for each exon of SHOX, one probe just before the promoter region as well as probes covering a region downstream of the gene. The results revealed one copy of sixteen probes (10 probes for Xp22-PAR1 from CNE2 to CNE9, 4 probes for SHOX area downstream, 1 probe for CRLF2 in PAR1 region and 1 probe for CSF2RA in PAR1 region), with the size of the smallest deletion of 766,5 kb. Based on the genetic testing and imaging findings of Madelung deformity, the diagnosis of Leri Weill syndrome was established, and parents were advised to undergo further genetic testing of both the patient and themselves, which they rejected.
Currently, our patient has many consequences of the adverse course of the disease and prolonged GC treatment, such as joint contractures of elbows, wrists, DIPs, PIPs, hips, knees and MCPs and low bone density, respectively. She developed secondary sex characteristics only after the therapy with estradiol was initiated at the age of 14. Nevertheless, after the discontinuation of GC and subsequent discontinuation of estradiol, she finally had a menarche at the age of 15, along with a long-awaited growth spurt.
Discussion and Conclusion
Children with rheumatic diseases, their families, as well as their treating physicians are dealt with numerous issues and dilemmas regarding either the disease itself or ongoing treatment modalities. Besides, the diagnosis of rheumatic diseases in children is regularly made by excluding wide range of other diseases, with no pathognomonic tests and/or criteria. Therefore, even after the classification criteria are fulfilled, the diagnosis should be revised if new symptoms emerge or if the recommended treatment options are failing.
In our patient, a variety of steroid-sparing agents with different mechanisms of action have been employed with limited or no clinical success. Some of these agents were used in line with current treatment recommendations, but many were used based on anecdotal reports [24–28]. Finally, due to signs of systemic inflammation characterized by increased inflammatory markers (CRP and ESR) and cytokines (IL-6 and TNF-alfa), which is indicative for the activation of JAK/STAT pathway, treatment with tofacitinib, a first generation JAK inhibitor, was initiated with a good clinical response. Several clinical trials in adults with rheumatoid and psoriatic arthritis have given solid evidence about the use of tofacitinib, while the results of a phase 3 randomized double blind placebo controlled withdrawal study in patients with polyarticular JIA showed improvement in symptoms, less disease flares and improved functional ability, together with a clinical amelioration of disease activity [29, 30]. Moreover, tofacitinib is an oral agent, and the challenge of using biologics requiring injection or infusion for an extended length of time, especially in children, should not be overlooked.
Along with the various treatment modalities, the different diagnosis was constantly being considered in our patient. Firstly, due to persistent contracture in some joints with little or no signs of swelling, LSDs such as mucopolysaccharidosis type I, Gaucher disease type I and Fabry disease were investigated. Besides, other inflammatory causes like systemic lupus erythematosus were also excluded. Lastly, the diagnosis of Leri Weill syndrome characterized by deletions in SHOX gene and Madelung deformity was established. This painful deformity of the wrist was first described in 1878 by the German surgeon Otto Madelung in adolescents between the ages 8 and 14 [12]. Although initially asymptomatic, the patients often went on to develop pain, loss of grip strength and reduced mobility, which were the symptoms present in our patient even after the inflammation was tackled with tofacitinib. Moreover, the features of Leri Weill syndrome include the short stature, which was also one of the dominant finding in the presented patient. Yet, the growth deficit caused by SHOX haploinsufficiency in Leri Weill syndrome is around 2 standard deviation scores (SDS) [31], while our patient had a SDS of -5,5. Besides, due to a prolonged use of GC, our patient had a full blown Cushingoid appearance, low bone density, delayed puberty and growth retardation. Therefore, the possible explanation for the short stature and growth delay in our patient includes multifactorial aetiology. Firstly, it is well known that extended GC treatment leads to a defect in bone turnover (and formation) due to impaired osteoblastogenesis and osteoclastogenesis, and may have direct effects on the growth plate [32]. Additionally, higher prepubertal glucocorticoid level appears to delay early and late pubertal timing of healthy girls, particularly the onset of pubertal growth spurt and menarche [33]. Moreover, it has been shown that girls with polyarticular juvenile idiopathic arthritis are significantly more likely to present with short stature even 6 months after stopping the steroid therapy [34]. Finally, the product of SHOX gene is implicated in bone development and regulation of chondrocyte differentiation, which clarifies the association of SHOX gene haploinsufficiency with idiopathic short stature, as well as short stature in Turner syndrome and Leri Weill dyschondrosteosis [31].
In the presented case, the diagnosis of the Madelung deformity and Leri Weill syndrome was delayed due to the concomitant active inflammation caused by JIA taking the focus from other possible causes of pain in the wrists. However, as subsequent analysis by experienced musculoskeletal radiologist has shown, the characteristic signs of the Madelung deformity were present few years before the final diagnosis was reached, emphasizing once again the importance of multidisciplinary approach and close collaboration of many subspecialists in the care of children with rheumatic diseases. Nevertheless, this lag probably did not influence the therapeutic management in our particular patient; although positive effect on final height was observed with growth hormone therapy in patients with Leri Weill syndrome, due to the matching influence of GC and lack of agreement with her parents, this treatment option was avoided in our patient [35].
In conclusion, this case report emphasizes the difficulties and challenges in management of patient with long-standing polyarticular JIA refractory to wide range of treatment modalities. Although many high-quality guidelines are available for treatment of JIA patients, there is still need for individual reports of difficult to treat cases, especially when additional diagnosis are involved. While Leri Weill syndrome is extensively reported in the literature, to the best of our knowledge, our case report describes it for the first time along with JIA. Taking all these into account, we strongly encourage the aggregation of similar patients and establishment of the common ground that will help clinician to decide upon the introduction of treatment options outside of the contemporary guidelines.
Abbreviations
JIAJuvenile idiopathic arthritis
LSDLysosomal storage disease
MPSMucopolysaccharidosis
NSAIDNonsteroidal anti-inflammatory drug
cDMARDConventional disease modifying anti-rheumatic drug
bDMARDBiologic disease modifying anti-rheumatic drug
IAGIIntraarticular glucocorticoid injection
GCGlucocorticoids
MASMacrophage activation syndrome
TNFiTumor necrosis factor inhibitor
T2TTreat-to-target
RFRheumatoid factor
ESRErythrocyte sedimentation rate
CRPC-reactive protein
ANAAntinuclear antibody
MTXMethotrexate
SLESystemic lupus erythematosus
TNFαTumor necrosis factor alpha
anti-IL-6Anti-interleukin-6
MMFMycophenolate mofetil
MCPMetacarpophalangeal
PIPProximal interphalangeal
DIPDistal interphalangeal
JAKJanus kinase
MRIMagnetic resonance imaging
SHOXShort-stature homeobox
JAK/STATJanus kinase/signal transducer and activator of transcription proteins
SDSStandard deviation score
GnRHGonadotropin-releasing hormone
HPGHypothalamic-pituitary-gonadal
IFXInfliximab
ADAAdalimumab
TOCTocilizumab
ETCEtanercept
CFMCyclophosphamide
RTXRituximab
MTFMetformin
CYCCyclosporine
TFATofacitinib
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank parents for availability of publishing medical history of their daughter.
Authors’ contributions
VV and AS have equally contributed to the paper. VV: medical charts review, literature search, creation of figures and tables and manuscript draft preparation. AS: medical charts review, literature search, creation of figures and tables and manuscript draft preparation RV: radiographic images interpretation, manuscript draft preparation. MV: clinical care and the final revision of the manuscript. MH: clinical care and the final revision of the manuscript. LL: clinical care, medical charts review, literature search, creation of figures and tables, manuscript draft preparation, final revision of the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. / Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the parents for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | ADALIMUMAB, CYCLOPHOSPHAMIDE, CYCLOSPORINE, ETANERCEPT, IBUPROFEN, INDOMETHACIN, INFLIXIMAB, LEFLUNOMIDE, MELOXICAM, METFORMIN HYDROCHLORIDE, METHOTREXATE, METHYLPREDNISOLONE SODIUM SUCCINATE, MYCOPHENOLATE MOFETIL, NAPROXEN SODIUM, PREDNISONE, RITUXIMAB, TOCILIZUMAB, TOFACITINIB | DrugsGivenReaction | CC BY | 33451288 | 18,970,451 | 2021-01-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Growth retardation'. | Beyond the guidelines management of juvenile idiopathic arthritis: a case report of a girl with polyarticular disease refractory to multiple treatment options and Leri Weill syndrome.
The last two decades brought new treatment options and high quality guidelines into the paediatric rheumatologic practice. Nevertheless, a number of patients still present a diagnostic and therapeutic challenge due to combination of vague symptoms and unresponsiveness to available treatment modalities.
We report a case of sixteen years old girl suffering from polyarticular type of juvenile idiopathic arthritis refractory to multiple treatment options. She first presented at the age of 4 with swelling and contractures of both knees. Her symptoms were initially unresponsive to nonsteroidal anti-inflammatory drugs and progressed despite treatment with intraarticular and systemic glucocorticoids and methotrexate. Throughout the years, she received several biologics together with continuous administration of nonsteroidal anti-inflammatory drugs and disease modifying anti-rheumatic drugs as well as intraarticular and systemic glucocorticoids in disease flares. However, none of this options provided a permanent remission, so various other modalities, as well as other possible diagnoses were constantly being considered. Eventually she became dependent on a daily dose of systemic glucocorticoids. In 2018, the treatment with Janus kinase inhibitor tofacitinib was initiated, which led to gradual amelioration of musculoskeletal symptoms, improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic glucocorticoids. As the swelling of the wrists subsided for the first time in many years, Madelung's deformity was noticed, first clinically, and later radiographically as well. Genetic analysis revealed short-stature homeobox gene deficiency and confirmed the diagnosis of Leri Weill syndrome.
This case report emphasizes the need for reporting refractory, complicated cases from everyday clinical practice in order to build-up the overall knowledge and share experience which is complementary to available guidelines. Individual reports of difficult to treat cases, especially when additional diagnoses are involved, can be helpful for physicians treating patients with common rheumatological diseases such as juvenile idiopathic arthritis.
Background
Joint pain and/or swelling with limited range of motion is a common manifestation of many paediatric diseases, most notably wide range of rheumatic conditions. If both of these symptoms are present for longer than 6 weeks in a patient younger than 16 years of age, a diagnosis of juvenile idiopathic arthritis (JIA), the most common childhood rheumatic disease, should be considered [1]. JIA is heterogenous disease that encompasses different subtypes of childhood arthritis defined depending on the number of affected joints and/or presence of the enthesitis and/or sacroiliitis. Nevertheless, alongside JIA, there is a wide range of loosely related noninflammatory causes of a swollen joint in children, especially in the absence of clinical signs of inflammation. Lysosomal storage diseases (LSD) such as mucopolysaccharidosis type I (MPS I), Gaucher disease type I and Fabry disease all have prominent musculoskeletal symptoms early in the course of the disease, and are often first seen by a pediatric rheumatologist [2–8]. However, the underlying mechanism of those disorders does not directly involve the immune mediated inflammatory response, but rather an inflammation caused by genetic defects and subsequent perturbations at the protein level. More specifically, in Gaucher disease, bone marrow infiltration with histiocytes causes acute attacks of pain, which may be mistaken for arthritis in the vicinity of a joint [5, 8]. In Fabry disease, episodes of neuropathic pain in hands, feet, wrists, ankles (acroparesthesias), often associated with fever, malaise and elevated inflammation markers, can mimic a rheumatic condition, such as an inflammatory arthritis [3, 9]. Finally, joint stiffness and contractures are characteristic for some types of MPS, the so called „attenuated“ forms like Hurler-Scheie syndrome, which have a less severe presentation and progress silently over the years, making the diagnosis a challenge [3, 10, 11]. On the other hand, some congenital conditions, such as Madelung and Madelung-type deformities resulting from the premature closure of the medial volar aspect of the distal radial physis, might cause similar symptoms [12]. Hence, it is not a rarity that some of the children with LSD and congenital deformities are treated for prolonged periods of time as having an inflammatory arthritis, despite the lack of appropriate response [13].
With regard to the treatment of JIA, various modalities emerged over the last two decades, revolutionizing the pediatric rheumatology practice [14]. Majority of the presently available guidelines recommend a step-up approach, starting with nonsteroidal anti-inflammatory drugs (NSAID) and intraarticular glucocorticoid injections (IAGI), followed by conventional and biologic disease modifying anti-rheumatic drugs (cDMARD and bDMARD), respectively [15]. Moreover, despite many known adverse effects, systemic glucocorticoids (GC) are still being used as an important therapeutic option for wide range of complications associated with JIA (e.g., macrophage activation syndrome, myocarditis, pericarditis, pleuritis, peritonitis, uveitis and severe anaemia), as well as a bridge therapy in severe forms of JIA before the full effect of other treatment modalities has been achieved [16]. Those modalities nowadays primarily involve tumor necrosis factor alpha (TNFα) inhibitors (TNFi), such as etanercept, adalimumab and infliximab, and non-TNFi, such as anti-interleukin-6 (anti-IL-6) agent tocilizumab and a selective T-cell co-stimulation modulator abatacept [17, 18]. Furthermore, new medications are continuously being investigated [19, 20].
Together with the expansion of new treatment modalities, efforts have been made to introduce the treat-to-target (T2T) model in pediatric rheumatologic practice [21]. Signs and symptoms control, prevention of structural damage of joints and optimization of linear growth and pubertal development, as well as abolition of inflammation, have all been set as treatment goals. Essentially, this model advocates that therapy should be revised and adjusted based on regular disease activity assessments to reach and maintain the treatment target. Special attention should be paid to preventing or minimizing the side effects of systemic GC given their negative effect on growth and pubertal development. Consequently, their long-term use to maintain treatment target should be avoided, especially considering that GC dependence demonstrates the inadequacy of chosen treatment. The shared decision making, as well as multidisciplinary approach, have been recognized as exceptionally valuable for assurance of better adherence to treatment and subsequently improvement of outcome and overall prognosis.
Unfortunately, despite all these achievements, only 14 % of patients with rheumatoid factor (RF) negative and 0 % with RF positive polyarticular JIA achieves the remission off medications within five years, implying that JIA treatment requires a long-lasting commitment [22]. Hence, it comes as no surprise that every clinician involved in the care of children with JIA patients eventually sees one with disease not responding to acclaimed treatment options (i.e. NSAIDs, cDMARDS, bDMARDS) [15]. At that point, the consideration of additional treatment modalities seems like a valid course of action, but sometimes alternative diagnosis should be considered as well. Here, we present one such case, a girl with long standing polyarticular JIA refractory to many standard treatment modalities, with symptoms suggestive of other diseases.
Case presentation
A four-year-old first came to our attention in February 2008 due to painful swelling and contractures of both knees. Her symptoms started a year earlier and were not associated with any discernible trigger such as infection or trauma. Moreover, the symptoms were not responding to NSAIDs and she soon developed a severe morning stiffness lasting for up to three hours. Her birth history as well as psychomotor development prior to disease evolution was unremarkable. She was born as a first child into a family of non-consanguine parents, with no relatives having the similar symptoms.
The initial laboratory findings showed persistently elevated inflammatory markers (erythrocyte sedimentation rate (ESR) up to 100 mm/h and C-reactive protein (CRP) up to 100 mg/dL), with negative RF and antinuclear antibody (ANA) screen, and normal immunoglobulin levels. Despite the initial treatment with GC and methotrexate (MTX), her symptoms progressed affecting elbows, wrists, ankles and small joints of both hands. Moreover, she developed a severe uveitis of the left eye. In November 2008 biologic therapy with infliximab was started, with initially good response. Unfortunately, this lasted only for a few months and frequent relapses necessitated switching to adalimumab in April 2011. Again, there was an initial period of remission followed by progressive exacerbation characterized by swelling and pain in some joints, and persistent contracture of others. Other diagnosis, such as mucopolysaccharidosis and systemic lupus erythematosus (SLE) were suspected, but metabolic and immunological screening were negative, respectively. Beside ESR and CRP, the increased values of IL-6 (up to 75 pg/mL) and TNF-alfa (up to 20 pg/mL) were measured.
In November 2012 therapy was cycled to non-TNFi, tocilizumab, which led only to a short period of remission. Finally, in September 2014, etanercept was introduced, again with the lack of permanent response. Along with four different bDMARDs she continuously received cDMARD methotrexate, and for a short period of time leflunomide. During the periods of disease flare, bridge therapy with intraarticular and/or systemic GC was used, and soon she was dependent on a daily dose of GC. Eventually, this led to the development of iatrogenic Cushing syndrome with characteristic appearance, growth retardation and low bone mineral density, regardless of the vitamin D and ibandronic acid therapy. Since every attempt to wean off GC inevitably led to disease flare, from June to December 2016 she received cyclophosphamide (6x) and rituximab (3x), again without achieving a sustained remission. Afterwards, for a short period of time she was given metformin but without an appropriate improvement in musculoskeletal symptoms (Fig. 1).
Fig. 1 Schematic representation of treatment modalities during the time. 2007 – 2020 - the period of treatment, NSAID - nonsteroidal anti-inflammatory drug, IFX - infliximab, ADA - adalimumab, TOC - tocilizumab, ETC - etanercept, DMARD - disease modifying anti-rheumatic drug, MTX - methotrexate, CFM - cyclophosphamide, RTX - rituximab, MTF - metformin, MMF - mycophenolate mofetil, CYC - cyclosporine, TFA - tofacitinib, p.o. - per os, i.a. - intraarticular, i.v. - intravenous, GC - glucocorticoids
During the 2017, at the age of 13, the trial of mycophenolate mofetil (MMF) followed by the trial of cyclosporin was initiated, but the patient nevertheless remained GC dependent. Both shoulders, elbows, radiocarpal joints, metacarpophalangeal (MCP), proximal interphalangeal (PIP), distal interphalangeal (DIP) joints and both knees had restricted range of movement, and repeated IAGI were necessary to alleviate the symptoms. Finally, in 2018, the treatment with Janus kinase (JAK) inhibitor tofacitinib was initiated, which lead to gradual amelioration of musculoskeletal symptoms and improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic GC. Moreover, as the swelling of the wrists subsided for the first time in many years, Madelung deformity was noticed by clinical examination. Interestingly, it was only then, in 2019, that the deformity was for the first time described on x-ray (Fig. 2), although x-ray and MRI imaging of both hands were previously performed on many occasions in order to assess the inflammation (Figs. 3 and 4). Nevertheless, subsequent analysis by experienced musculoskeletal radiologist revealed characteristic bilateral signs of Madelung deformity dating back in 2015 and 2017 (Fig. 3), with the MRI showing the Vickers and radiotriquetral ligament (Fig. 4). The finding of those two ligaments allowed the distinguishing between Madelung deformity and pseudo-Madelung deformity, which includes post-traumatic and post-infective forms, forms associated with Turner syndrome, multiple hereditary exostoses and Ollier disease [23]. Unfortunately, due to the parent’s refusal, no further radiological assessment was performed, so we have not documented the other important aspects of Madelung deformity, such as radial shortening and diaphysis bowing, nor the mesolimbic shortening of limbs characteristic for Leri Weill syndrome.
Fig. 2 The anteroposterior radiograph of left hand at the age of 14. Note the increased volar angulation of distal radius, wedge shaped carpus with proximally positioned lunate and a characteristic notch on the distal radius (white arrow), which are the features of the Madelung deformity [12]
Fig. 3 The anteroposterior radiograph of both hands at the age of 10 (a) and 13 (b), and of the left hand at the age of 14 (c). Note the bowing of the distal radius, an increased radial inclination (~ 30°) with the deformation of the carpus that acquired a triangular appearance and widening of the distal radial-ulnar joint bilaterally, which are the typical features of Madelung deformity. Dorsal subluxation of the ulnar head is not seen as lateral images of the wrist were not taken. Osteopenia of carpal bones and periarticular osteopenia of MCP, PIP and DIP joints related to JIA are present. No relevant changes are observed during the time
Fig. 4 MRI coronal T1-weighted (a), proton density BLADE fluid sensitive sequence (b), post contrast T1-weighted coronal fat sat sequence (c) and post contrast T1-weighted axial fat sat sequence (d) images of both hands at the age of 13. Note the radiotriquetral ligament (red arrow) and Vickers ligament (green arrow) (a, b). Note the inflammatory changes characterized by postcontrast imbibition in carpal joints and MCP joints (red circle), as well as tenosynovitis of flexor tendons related to JIA, more prominent on the left hand (c, d)
Although our patient was simultaneously followed by pediatric endocrinologist from age of 11, her short stature, along with delayed menarche, and Cushingoid appearance, was attributed to the prolonged use of GC. It was only after the Madelung’s deformity was observed that genetic causes, primarily Leri Weill syndrome, were taken into consideration. Genetic analysis was performed by commercially available SALSA MLPA Probemix P018 SHOX (MRC-Holland, Amsterdam, The Netherland) according to the manufacturer’s recommendations. The MLPA mix included probes for each exon of SHOX, one probe just before the promoter region as well as probes covering a region downstream of the gene. The results revealed one copy of sixteen probes (10 probes for Xp22-PAR1 from CNE2 to CNE9, 4 probes for SHOX area downstream, 1 probe for CRLF2 in PAR1 region and 1 probe for CSF2RA in PAR1 region), with the size of the smallest deletion of 766,5 kb. Based on the genetic testing and imaging findings of Madelung deformity, the diagnosis of Leri Weill syndrome was established, and parents were advised to undergo further genetic testing of both the patient and themselves, which they rejected.
Currently, our patient has many consequences of the adverse course of the disease and prolonged GC treatment, such as joint contractures of elbows, wrists, DIPs, PIPs, hips, knees and MCPs and low bone density, respectively. She developed secondary sex characteristics only after the therapy with estradiol was initiated at the age of 14. Nevertheless, after the discontinuation of GC and subsequent discontinuation of estradiol, she finally had a menarche at the age of 15, along with a long-awaited growth spurt.
Discussion and Conclusion
Children with rheumatic diseases, their families, as well as their treating physicians are dealt with numerous issues and dilemmas regarding either the disease itself or ongoing treatment modalities. Besides, the diagnosis of rheumatic diseases in children is regularly made by excluding wide range of other diseases, with no pathognomonic tests and/or criteria. Therefore, even after the classification criteria are fulfilled, the diagnosis should be revised if new symptoms emerge or if the recommended treatment options are failing.
In our patient, a variety of steroid-sparing agents with different mechanisms of action have been employed with limited or no clinical success. Some of these agents were used in line with current treatment recommendations, but many were used based on anecdotal reports [24–28]. Finally, due to signs of systemic inflammation characterized by increased inflammatory markers (CRP and ESR) and cytokines (IL-6 and TNF-alfa), which is indicative for the activation of JAK/STAT pathway, treatment with tofacitinib, a first generation JAK inhibitor, was initiated with a good clinical response. Several clinical trials in adults with rheumatoid and psoriatic arthritis have given solid evidence about the use of tofacitinib, while the results of a phase 3 randomized double blind placebo controlled withdrawal study in patients with polyarticular JIA showed improvement in symptoms, less disease flares and improved functional ability, together with a clinical amelioration of disease activity [29, 30]. Moreover, tofacitinib is an oral agent, and the challenge of using biologics requiring injection or infusion for an extended length of time, especially in children, should not be overlooked.
Along with the various treatment modalities, the different diagnosis was constantly being considered in our patient. Firstly, due to persistent contracture in some joints with little or no signs of swelling, LSDs such as mucopolysaccharidosis type I, Gaucher disease type I and Fabry disease were investigated. Besides, other inflammatory causes like systemic lupus erythematosus were also excluded. Lastly, the diagnosis of Leri Weill syndrome characterized by deletions in SHOX gene and Madelung deformity was established. This painful deformity of the wrist was first described in 1878 by the German surgeon Otto Madelung in adolescents between the ages 8 and 14 [12]. Although initially asymptomatic, the patients often went on to develop pain, loss of grip strength and reduced mobility, which were the symptoms present in our patient even after the inflammation was tackled with tofacitinib. Moreover, the features of Leri Weill syndrome include the short stature, which was also one of the dominant finding in the presented patient. Yet, the growth deficit caused by SHOX haploinsufficiency in Leri Weill syndrome is around 2 standard deviation scores (SDS) [31], while our patient had a SDS of -5,5. Besides, due to a prolonged use of GC, our patient had a full blown Cushingoid appearance, low bone density, delayed puberty and growth retardation. Therefore, the possible explanation for the short stature and growth delay in our patient includes multifactorial aetiology. Firstly, it is well known that extended GC treatment leads to a defect in bone turnover (and formation) due to impaired osteoblastogenesis and osteoclastogenesis, and may have direct effects on the growth plate [32]. Additionally, higher prepubertal glucocorticoid level appears to delay early and late pubertal timing of healthy girls, particularly the onset of pubertal growth spurt and menarche [33]. Moreover, it has been shown that girls with polyarticular juvenile idiopathic arthritis are significantly more likely to present with short stature even 6 months after stopping the steroid therapy [34]. Finally, the product of SHOX gene is implicated in bone development and regulation of chondrocyte differentiation, which clarifies the association of SHOX gene haploinsufficiency with idiopathic short stature, as well as short stature in Turner syndrome and Leri Weill dyschondrosteosis [31].
In the presented case, the diagnosis of the Madelung deformity and Leri Weill syndrome was delayed due to the concomitant active inflammation caused by JIA taking the focus from other possible causes of pain in the wrists. However, as subsequent analysis by experienced musculoskeletal radiologist has shown, the characteristic signs of the Madelung deformity were present few years before the final diagnosis was reached, emphasizing once again the importance of multidisciplinary approach and close collaboration of many subspecialists in the care of children with rheumatic diseases. Nevertheless, this lag probably did not influence the therapeutic management in our particular patient; although positive effect on final height was observed with growth hormone therapy in patients with Leri Weill syndrome, due to the matching influence of GC and lack of agreement with her parents, this treatment option was avoided in our patient [35].
In conclusion, this case report emphasizes the difficulties and challenges in management of patient with long-standing polyarticular JIA refractory to wide range of treatment modalities. Although many high-quality guidelines are available for treatment of JIA patients, there is still need for individual reports of difficult to treat cases, especially when additional diagnosis are involved. While Leri Weill syndrome is extensively reported in the literature, to the best of our knowledge, our case report describes it for the first time along with JIA. Taking all these into account, we strongly encourage the aggregation of similar patients and establishment of the common ground that will help clinician to decide upon the introduction of treatment options outside of the contemporary guidelines.
Abbreviations
JIAJuvenile idiopathic arthritis
LSDLysosomal storage disease
MPSMucopolysaccharidosis
NSAIDNonsteroidal anti-inflammatory drug
cDMARDConventional disease modifying anti-rheumatic drug
bDMARDBiologic disease modifying anti-rheumatic drug
IAGIIntraarticular glucocorticoid injection
GCGlucocorticoids
MASMacrophage activation syndrome
TNFiTumor necrosis factor inhibitor
T2TTreat-to-target
RFRheumatoid factor
ESRErythrocyte sedimentation rate
CRPC-reactive protein
ANAAntinuclear antibody
MTXMethotrexate
SLESystemic lupus erythematosus
TNFαTumor necrosis factor alpha
anti-IL-6Anti-interleukin-6
MMFMycophenolate mofetil
MCPMetacarpophalangeal
PIPProximal interphalangeal
DIPDistal interphalangeal
JAKJanus kinase
MRIMagnetic resonance imaging
SHOXShort-stature homeobox
JAK/STATJanus kinase/signal transducer and activator of transcription proteins
SDSStandard deviation score
GnRHGonadotropin-releasing hormone
HPGHypothalamic-pituitary-gonadal
IFXInfliximab
ADAAdalimumab
TOCTocilizumab
ETCEtanercept
CFMCyclophosphamide
RTXRituximab
MTFMetformin
CYCCyclosporine
TFATofacitinib
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank parents for availability of publishing medical history of their daughter.
Authors’ contributions
VV and AS have equally contributed to the paper. VV: medical charts review, literature search, creation of figures and tables and manuscript draft preparation. AS: medical charts review, literature search, creation of figures and tables and manuscript draft preparation RV: radiographic images interpretation, manuscript draft preparation. MV: clinical care and the final revision of the manuscript. MH: clinical care and the final revision of the manuscript. LL: clinical care, medical charts review, literature search, creation of figures and tables, manuscript draft preparation, final revision of the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. / Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the parents for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | ADALIMUMAB, CYCLOPHOSPHAMIDE, CYCLOSPORINE, ETANERCEPT, IBUPROFEN, INDOMETHACIN, INFLIXIMAB, LEFLUNOMIDE, MELOXICAM, METFORMIN HYDROCHLORIDE, METHOTREXATE, METHYLPREDNISOLONE SODIUM SUCCINATE, MYCOPHENOLATE MOFETIL, NAPROXEN SODIUM, PREDNISONE, RITUXIMAB, TOCILIZUMAB, TOFACITINIB | DrugsGivenReaction | CC BY | 33451288 | 18,970,451 | 2021-01-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Short stature'. | Beyond the guidelines management of juvenile idiopathic arthritis: a case report of a girl with polyarticular disease refractory to multiple treatment options and Leri Weill syndrome.
The last two decades brought new treatment options and high quality guidelines into the paediatric rheumatologic practice. Nevertheless, a number of patients still present a diagnostic and therapeutic challenge due to combination of vague symptoms and unresponsiveness to available treatment modalities.
We report a case of sixteen years old girl suffering from polyarticular type of juvenile idiopathic arthritis refractory to multiple treatment options. She first presented at the age of 4 with swelling and contractures of both knees. Her symptoms were initially unresponsive to nonsteroidal anti-inflammatory drugs and progressed despite treatment with intraarticular and systemic glucocorticoids and methotrexate. Throughout the years, she received several biologics together with continuous administration of nonsteroidal anti-inflammatory drugs and disease modifying anti-rheumatic drugs as well as intraarticular and systemic glucocorticoids in disease flares. However, none of this options provided a permanent remission, so various other modalities, as well as other possible diagnoses were constantly being considered. Eventually she became dependent on a daily dose of systemic glucocorticoids. In 2018, the treatment with Janus kinase inhibitor tofacitinib was initiated, which led to gradual amelioration of musculoskeletal symptoms, improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic glucocorticoids. As the swelling of the wrists subsided for the first time in many years, Madelung's deformity was noticed, first clinically, and later radiographically as well. Genetic analysis revealed short-stature homeobox gene deficiency and confirmed the diagnosis of Leri Weill syndrome.
This case report emphasizes the need for reporting refractory, complicated cases from everyday clinical practice in order to build-up the overall knowledge and share experience which is complementary to available guidelines. Individual reports of difficult to treat cases, especially when additional diagnoses are involved, can be helpful for physicians treating patients with common rheumatological diseases such as juvenile idiopathic arthritis.
Background
Joint pain and/or swelling with limited range of motion is a common manifestation of many paediatric diseases, most notably wide range of rheumatic conditions. If both of these symptoms are present for longer than 6 weeks in a patient younger than 16 years of age, a diagnosis of juvenile idiopathic arthritis (JIA), the most common childhood rheumatic disease, should be considered [1]. JIA is heterogenous disease that encompasses different subtypes of childhood arthritis defined depending on the number of affected joints and/or presence of the enthesitis and/or sacroiliitis. Nevertheless, alongside JIA, there is a wide range of loosely related noninflammatory causes of a swollen joint in children, especially in the absence of clinical signs of inflammation. Lysosomal storage diseases (LSD) such as mucopolysaccharidosis type I (MPS I), Gaucher disease type I and Fabry disease all have prominent musculoskeletal symptoms early in the course of the disease, and are often first seen by a pediatric rheumatologist [2–8]. However, the underlying mechanism of those disorders does not directly involve the immune mediated inflammatory response, but rather an inflammation caused by genetic defects and subsequent perturbations at the protein level. More specifically, in Gaucher disease, bone marrow infiltration with histiocytes causes acute attacks of pain, which may be mistaken for arthritis in the vicinity of a joint [5, 8]. In Fabry disease, episodes of neuropathic pain in hands, feet, wrists, ankles (acroparesthesias), often associated with fever, malaise and elevated inflammation markers, can mimic a rheumatic condition, such as an inflammatory arthritis [3, 9]. Finally, joint stiffness and contractures are characteristic for some types of MPS, the so called „attenuated“ forms like Hurler-Scheie syndrome, which have a less severe presentation and progress silently over the years, making the diagnosis a challenge [3, 10, 11]. On the other hand, some congenital conditions, such as Madelung and Madelung-type deformities resulting from the premature closure of the medial volar aspect of the distal radial physis, might cause similar symptoms [12]. Hence, it is not a rarity that some of the children with LSD and congenital deformities are treated for prolonged periods of time as having an inflammatory arthritis, despite the lack of appropriate response [13].
With regard to the treatment of JIA, various modalities emerged over the last two decades, revolutionizing the pediatric rheumatology practice [14]. Majority of the presently available guidelines recommend a step-up approach, starting with nonsteroidal anti-inflammatory drugs (NSAID) and intraarticular glucocorticoid injections (IAGI), followed by conventional and biologic disease modifying anti-rheumatic drugs (cDMARD and bDMARD), respectively [15]. Moreover, despite many known adverse effects, systemic glucocorticoids (GC) are still being used as an important therapeutic option for wide range of complications associated with JIA (e.g., macrophage activation syndrome, myocarditis, pericarditis, pleuritis, peritonitis, uveitis and severe anaemia), as well as a bridge therapy in severe forms of JIA before the full effect of other treatment modalities has been achieved [16]. Those modalities nowadays primarily involve tumor necrosis factor alpha (TNFα) inhibitors (TNFi), such as etanercept, adalimumab and infliximab, and non-TNFi, such as anti-interleukin-6 (anti-IL-6) agent tocilizumab and a selective T-cell co-stimulation modulator abatacept [17, 18]. Furthermore, new medications are continuously being investigated [19, 20].
Together with the expansion of new treatment modalities, efforts have been made to introduce the treat-to-target (T2T) model in pediatric rheumatologic practice [21]. Signs and symptoms control, prevention of structural damage of joints and optimization of linear growth and pubertal development, as well as abolition of inflammation, have all been set as treatment goals. Essentially, this model advocates that therapy should be revised and adjusted based on regular disease activity assessments to reach and maintain the treatment target. Special attention should be paid to preventing or minimizing the side effects of systemic GC given their negative effect on growth and pubertal development. Consequently, their long-term use to maintain treatment target should be avoided, especially considering that GC dependence demonstrates the inadequacy of chosen treatment. The shared decision making, as well as multidisciplinary approach, have been recognized as exceptionally valuable for assurance of better adherence to treatment and subsequently improvement of outcome and overall prognosis.
Unfortunately, despite all these achievements, only 14 % of patients with rheumatoid factor (RF) negative and 0 % with RF positive polyarticular JIA achieves the remission off medications within five years, implying that JIA treatment requires a long-lasting commitment [22]. Hence, it comes as no surprise that every clinician involved in the care of children with JIA patients eventually sees one with disease not responding to acclaimed treatment options (i.e. NSAIDs, cDMARDS, bDMARDS) [15]. At that point, the consideration of additional treatment modalities seems like a valid course of action, but sometimes alternative diagnosis should be considered as well. Here, we present one such case, a girl with long standing polyarticular JIA refractory to many standard treatment modalities, with symptoms suggestive of other diseases.
Case presentation
A four-year-old first came to our attention in February 2008 due to painful swelling and contractures of both knees. Her symptoms started a year earlier and were not associated with any discernible trigger such as infection or trauma. Moreover, the symptoms were not responding to NSAIDs and she soon developed a severe morning stiffness lasting for up to three hours. Her birth history as well as psychomotor development prior to disease evolution was unremarkable. She was born as a first child into a family of non-consanguine parents, with no relatives having the similar symptoms.
The initial laboratory findings showed persistently elevated inflammatory markers (erythrocyte sedimentation rate (ESR) up to 100 mm/h and C-reactive protein (CRP) up to 100 mg/dL), with negative RF and antinuclear antibody (ANA) screen, and normal immunoglobulin levels. Despite the initial treatment with GC and methotrexate (MTX), her symptoms progressed affecting elbows, wrists, ankles and small joints of both hands. Moreover, she developed a severe uveitis of the left eye. In November 2008 biologic therapy with infliximab was started, with initially good response. Unfortunately, this lasted only for a few months and frequent relapses necessitated switching to adalimumab in April 2011. Again, there was an initial period of remission followed by progressive exacerbation characterized by swelling and pain in some joints, and persistent contracture of others. Other diagnosis, such as mucopolysaccharidosis and systemic lupus erythematosus (SLE) were suspected, but metabolic and immunological screening were negative, respectively. Beside ESR and CRP, the increased values of IL-6 (up to 75 pg/mL) and TNF-alfa (up to 20 pg/mL) were measured.
In November 2012 therapy was cycled to non-TNFi, tocilizumab, which led only to a short period of remission. Finally, in September 2014, etanercept was introduced, again with the lack of permanent response. Along with four different bDMARDs she continuously received cDMARD methotrexate, and for a short period of time leflunomide. During the periods of disease flare, bridge therapy with intraarticular and/or systemic GC was used, and soon she was dependent on a daily dose of GC. Eventually, this led to the development of iatrogenic Cushing syndrome with characteristic appearance, growth retardation and low bone mineral density, regardless of the vitamin D and ibandronic acid therapy. Since every attempt to wean off GC inevitably led to disease flare, from June to December 2016 she received cyclophosphamide (6x) and rituximab (3x), again without achieving a sustained remission. Afterwards, for a short period of time she was given metformin but without an appropriate improvement in musculoskeletal symptoms (Fig. 1).
Fig. 1 Schematic representation of treatment modalities during the time. 2007 – 2020 - the period of treatment, NSAID - nonsteroidal anti-inflammatory drug, IFX - infliximab, ADA - adalimumab, TOC - tocilizumab, ETC - etanercept, DMARD - disease modifying anti-rheumatic drug, MTX - methotrexate, CFM - cyclophosphamide, RTX - rituximab, MTF - metformin, MMF - mycophenolate mofetil, CYC - cyclosporine, TFA - tofacitinib, p.o. - per os, i.a. - intraarticular, i.v. - intravenous, GC - glucocorticoids
During the 2017, at the age of 13, the trial of mycophenolate mofetil (MMF) followed by the trial of cyclosporin was initiated, but the patient nevertheless remained GC dependent. Both shoulders, elbows, radiocarpal joints, metacarpophalangeal (MCP), proximal interphalangeal (PIP), distal interphalangeal (DIP) joints and both knees had restricted range of movement, and repeated IAGI were necessary to alleviate the symptoms. Finally, in 2018, the treatment with Janus kinase (JAK) inhibitor tofacitinib was initiated, which lead to gradual amelioration of musculoskeletal symptoms and improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic GC. Moreover, as the swelling of the wrists subsided for the first time in many years, Madelung deformity was noticed by clinical examination. Interestingly, it was only then, in 2019, that the deformity was for the first time described on x-ray (Fig. 2), although x-ray and MRI imaging of both hands were previously performed on many occasions in order to assess the inflammation (Figs. 3 and 4). Nevertheless, subsequent analysis by experienced musculoskeletal radiologist revealed characteristic bilateral signs of Madelung deformity dating back in 2015 and 2017 (Fig. 3), with the MRI showing the Vickers and radiotriquetral ligament (Fig. 4). The finding of those two ligaments allowed the distinguishing between Madelung deformity and pseudo-Madelung deformity, which includes post-traumatic and post-infective forms, forms associated with Turner syndrome, multiple hereditary exostoses and Ollier disease [23]. Unfortunately, due to the parent’s refusal, no further radiological assessment was performed, so we have not documented the other important aspects of Madelung deformity, such as radial shortening and diaphysis bowing, nor the mesolimbic shortening of limbs characteristic for Leri Weill syndrome.
Fig. 2 The anteroposterior radiograph of left hand at the age of 14. Note the increased volar angulation of distal radius, wedge shaped carpus with proximally positioned lunate and a characteristic notch on the distal radius (white arrow), which are the features of the Madelung deformity [12]
Fig. 3 The anteroposterior radiograph of both hands at the age of 10 (a) and 13 (b), and of the left hand at the age of 14 (c). Note the bowing of the distal radius, an increased radial inclination (~ 30°) with the deformation of the carpus that acquired a triangular appearance and widening of the distal radial-ulnar joint bilaterally, which are the typical features of Madelung deformity. Dorsal subluxation of the ulnar head is not seen as lateral images of the wrist were not taken. Osteopenia of carpal bones and periarticular osteopenia of MCP, PIP and DIP joints related to JIA are present. No relevant changes are observed during the time
Fig. 4 MRI coronal T1-weighted (a), proton density BLADE fluid sensitive sequence (b), post contrast T1-weighted coronal fat sat sequence (c) and post contrast T1-weighted axial fat sat sequence (d) images of both hands at the age of 13. Note the radiotriquetral ligament (red arrow) and Vickers ligament (green arrow) (a, b). Note the inflammatory changes characterized by postcontrast imbibition in carpal joints and MCP joints (red circle), as well as tenosynovitis of flexor tendons related to JIA, more prominent on the left hand (c, d)
Although our patient was simultaneously followed by pediatric endocrinologist from age of 11, her short stature, along with delayed menarche, and Cushingoid appearance, was attributed to the prolonged use of GC. It was only after the Madelung’s deformity was observed that genetic causes, primarily Leri Weill syndrome, were taken into consideration. Genetic analysis was performed by commercially available SALSA MLPA Probemix P018 SHOX (MRC-Holland, Amsterdam, The Netherland) according to the manufacturer’s recommendations. The MLPA mix included probes for each exon of SHOX, one probe just before the promoter region as well as probes covering a region downstream of the gene. The results revealed one copy of sixteen probes (10 probes for Xp22-PAR1 from CNE2 to CNE9, 4 probes for SHOX area downstream, 1 probe for CRLF2 in PAR1 region and 1 probe for CSF2RA in PAR1 region), with the size of the smallest deletion of 766,5 kb. Based on the genetic testing and imaging findings of Madelung deformity, the diagnosis of Leri Weill syndrome was established, and parents were advised to undergo further genetic testing of both the patient and themselves, which they rejected.
Currently, our patient has many consequences of the adverse course of the disease and prolonged GC treatment, such as joint contractures of elbows, wrists, DIPs, PIPs, hips, knees and MCPs and low bone density, respectively. She developed secondary sex characteristics only after the therapy with estradiol was initiated at the age of 14. Nevertheless, after the discontinuation of GC and subsequent discontinuation of estradiol, she finally had a menarche at the age of 15, along with a long-awaited growth spurt.
Discussion and Conclusion
Children with rheumatic diseases, their families, as well as their treating physicians are dealt with numerous issues and dilemmas regarding either the disease itself or ongoing treatment modalities. Besides, the diagnosis of rheumatic diseases in children is regularly made by excluding wide range of other diseases, with no pathognomonic tests and/or criteria. Therefore, even after the classification criteria are fulfilled, the diagnosis should be revised if new symptoms emerge or if the recommended treatment options are failing.
In our patient, a variety of steroid-sparing agents with different mechanisms of action have been employed with limited or no clinical success. Some of these agents were used in line with current treatment recommendations, but many were used based on anecdotal reports [24–28]. Finally, due to signs of systemic inflammation characterized by increased inflammatory markers (CRP and ESR) and cytokines (IL-6 and TNF-alfa), which is indicative for the activation of JAK/STAT pathway, treatment with tofacitinib, a first generation JAK inhibitor, was initiated with a good clinical response. Several clinical trials in adults with rheumatoid and psoriatic arthritis have given solid evidence about the use of tofacitinib, while the results of a phase 3 randomized double blind placebo controlled withdrawal study in patients with polyarticular JIA showed improvement in symptoms, less disease flares and improved functional ability, together with a clinical amelioration of disease activity [29, 30]. Moreover, tofacitinib is an oral agent, and the challenge of using biologics requiring injection or infusion for an extended length of time, especially in children, should not be overlooked.
Along with the various treatment modalities, the different diagnosis was constantly being considered in our patient. Firstly, due to persistent contracture in some joints with little or no signs of swelling, LSDs such as mucopolysaccharidosis type I, Gaucher disease type I and Fabry disease were investigated. Besides, other inflammatory causes like systemic lupus erythematosus were also excluded. Lastly, the diagnosis of Leri Weill syndrome characterized by deletions in SHOX gene and Madelung deformity was established. This painful deformity of the wrist was first described in 1878 by the German surgeon Otto Madelung in adolescents between the ages 8 and 14 [12]. Although initially asymptomatic, the patients often went on to develop pain, loss of grip strength and reduced mobility, which were the symptoms present in our patient even after the inflammation was tackled with tofacitinib. Moreover, the features of Leri Weill syndrome include the short stature, which was also one of the dominant finding in the presented patient. Yet, the growth deficit caused by SHOX haploinsufficiency in Leri Weill syndrome is around 2 standard deviation scores (SDS) [31], while our patient had a SDS of -5,5. Besides, due to a prolonged use of GC, our patient had a full blown Cushingoid appearance, low bone density, delayed puberty and growth retardation. Therefore, the possible explanation for the short stature and growth delay in our patient includes multifactorial aetiology. Firstly, it is well known that extended GC treatment leads to a defect in bone turnover (and formation) due to impaired osteoblastogenesis and osteoclastogenesis, and may have direct effects on the growth plate [32]. Additionally, higher prepubertal glucocorticoid level appears to delay early and late pubertal timing of healthy girls, particularly the onset of pubertal growth spurt and menarche [33]. Moreover, it has been shown that girls with polyarticular juvenile idiopathic arthritis are significantly more likely to present with short stature even 6 months after stopping the steroid therapy [34]. Finally, the product of SHOX gene is implicated in bone development and regulation of chondrocyte differentiation, which clarifies the association of SHOX gene haploinsufficiency with idiopathic short stature, as well as short stature in Turner syndrome and Leri Weill dyschondrosteosis [31].
In the presented case, the diagnosis of the Madelung deformity and Leri Weill syndrome was delayed due to the concomitant active inflammation caused by JIA taking the focus from other possible causes of pain in the wrists. However, as subsequent analysis by experienced musculoskeletal radiologist has shown, the characteristic signs of the Madelung deformity were present few years before the final diagnosis was reached, emphasizing once again the importance of multidisciplinary approach and close collaboration of many subspecialists in the care of children with rheumatic diseases. Nevertheless, this lag probably did not influence the therapeutic management in our particular patient; although positive effect on final height was observed with growth hormone therapy in patients with Leri Weill syndrome, due to the matching influence of GC and lack of agreement with her parents, this treatment option was avoided in our patient [35].
In conclusion, this case report emphasizes the difficulties and challenges in management of patient with long-standing polyarticular JIA refractory to wide range of treatment modalities. Although many high-quality guidelines are available for treatment of JIA patients, there is still need for individual reports of difficult to treat cases, especially when additional diagnosis are involved. While Leri Weill syndrome is extensively reported in the literature, to the best of our knowledge, our case report describes it for the first time along with JIA. Taking all these into account, we strongly encourage the aggregation of similar patients and establishment of the common ground that will help clinician to decide upon the introduction of treatment options outside of the contemporary guidelines.
Abbreviations
JIAJuvenile idiopathic arthritis
LSDLysosomal storage disease
MPSMucopolysaccharidosis
NSAIDNonsteroidal anti-inflammatory drug
cDMARDConventional disease modifying anti-rheumatic drug
bDMARDBiologic disease modifying anti-rheumatic drug
IAGIIntraarticular glucocorticoid injection
GCGlucocorticoids
MASMacrophage activation syndrome
TNFiTumor necrosis factor inhibitor
T2TTreat-to-target
RFRheumatoid factor
ESRErythrocyte sedimentation rate
CRPC-reactive protein
ANAAntinuclear antibody
MTXMethotrexate
SLESystemic lupus erythematosus
TNFαTumor necrosis factor alpha
anti-IL-6Anti-interleukin-6
MMFMycophenolate mofetil
MCPMetacarpophalangeal
PIPProximal interphalangeal
DIPDistal interphalangeal
JAKJanus kinase
MRIMagnetic resonance imaging
SHOXShort-stature homeobox
JAK/STATJanus kinase/signal transducer and activator of transcription proteins
SDSStandard deviation score
GnRHGonadotropin-releasing hormone
HPGHypothalamic-pituitary-gonadal
IFXInfliximab
ADAAdalimumab
TOCTocilizumab
ETCEtanercept
CFMCyclophosphamide
RTXRituximab
MTFMetformin
CYCCyclosporine
TFATofacitinib
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Acknowledgements
We thank parents for availability of publishing medical history of their daughter.
Authors’ contributions
VV and AS have equally contributed to the paper. VV: medical charts review, literature search, creation of figures and tables and manuscript draft preparation. AS: medical charts review, literature search, creation of figures and tables and manuscript draft preparation RV: radiographic images interpretation, manuscript draft preparation. MV: clinical care and the final revision of the manuscript. MH: clinical care and the final revision of the manuscript. LL: clinical care, medical charts review, literature search, creation of figures and tables, manuscript draft preparation, final revision of the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. / Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the parents for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | ADALIMUMAB, CYCLOPHOSPHAMIDE, CYCLOSPORINE, ETANERCEPT, IBUPROFEN, INDOMETHACIN, INFLIXIMAB, LEFLUNOMIDE, MELOXICAM, METFORMIN HYDROCHLORIDE, METHOTREXATE, METHYLPREDNISOLONE SODIUM SUCCINATE, MYCOPHENOLATE MOFETIL, NAPROXEN SODIUM, PREDNISONE, RITUXIMAB, TOCILIZUMAB, TOFACITINIB | DrugsGivenReaction | CC BY | 33451288 | 18,970,451 | 2021-01-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Uveitis'. | Beyond the guidelines management of juvenile idiopathic arthritis: a case report of a girl with polyarticular disease refractory to multiple treatment options and Leri Weill syndrome.
The last two decades brought new treatment options and high quality guidelines into the paediatric rheumatologic practice. Nevertheless, a number of patients still present a diagnostic and therapeutic challenge due to combination of vague symptoms and unresponsiveness to available treatment modalities.
We report a case of sixteen years old girl suffering from polyarticular type of juvenile idiopathic arthritis refractory to multiple treatment options. She first presented at the age of 4 with swelling and contractures of both knees. Her symptoms were initially unresponsive to nonsteroidal anti-inflammatory drugs and progressed despite treatment with intraarticular and systemic glucocorticoids and methotrexate. Throughout the years, she received several biologics together with continuous administration of nonsteroidal anti-inflammatory drugs and disease modifying anti-rheumatic drugs as well as intraarticular and systemic glucocorticoids in disease flares. However, none of this options provided a permanent remission, so various other modalities, as well as other possible diagnoses were constantly being considered. Eventually she became dependent on a daily dose of systemic glucocorticoids. In 2018, the treatment with Janus kinase inhibitor tofacitinib was initiated, which led to gradual amelioration of musculoskeletal symptoms, improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic glucocorticoids. As the swelling of the wrists subsided for the first time in many years, Madelung's deformity was noticed, first clinically, and later radiographically as well. Genetic analysis revealed short-stature homeobox gene deficiency and confirmed the diagnosis of Leri Weill syndrome.
This case report emphasizes the need for reporting refractory, complicated cases from everyday clinical practice in order to build-up the overall knowledge and share experience which is complementary to available guidelines. Individual reports of difficult to treat cases, especially when additional diagnoses are involved, can be helpful for physicians treating patients with common rheumatological diseases such as juvenile idiopathic arthritis.
Background
Joint pain and/or swelling with limited range of motion is a common manifestation of many paediatric diseases, most notably wide range of rheumatic conditions. If both of these symptoms are present for longer than 6 weeks in a patient younger than 16 years of age, a diagnosis of juvenile idiopathic arthritis (JIA), the most common childhood rheumatic disease, should be considered [1]. JIA is heterogenous disease that encompasses different subtypes of childhood arthritis defined depending on the number of affected joints and/or presence of the enthesitis and/or sacroiliitis. Nevertheless, alongside JIA, there is a wide range of loosely related noninflammatory causes of a swollen joint in children, especially in the absence of clinical signs of inflammation. Lysosomal storage diseases (LSD) such as mucopolysaccharidosis type I (MPS I), Gaucher disease type I and Fabry disease all have prominent musculoskeletal symptoms early in the course of the disease, and are often first seen by a pediatric rheumatologist [2–8]. However, the underlying mechanism of those disorders does not directly involve the immune mediated inflammatory response, but rather an inflammation caused by genetic defects and subsequent perturbations at the protein level. More specifically, in Gaucher disease, bone marrow infiltration with histiocytes causes acute attacks of pain, which may be mistaken for arthritis in the vicinity of a joint [5, 8]. In Fabry disease, episodes of neuropathic pain in hands, feet, wrists, ankles (acroparesthesias), often associated with fever, malaise and elevated inflammation markers, can mimic a rheumatic condition, such as an inflammatory arthritis [3, 9]. Finally, joint stiffness and contractures are characteristic for some types of MPS, the so called „attenuated“ forms like Hurler-Scheie syndrome, which have a less severe presentation and progress silently over the years, making the diagnosis a challenge [3, 10, 11]. On the other hand, some congenital conditions, such as Madelung and Madelung-type deformities resulting from the premature closure of the medial volar aspect of the distal radial physis, might cause similar symptoms [12]. Hence, it is not a rarity that some of the children with LSD and congenital deformities are treated for prolonged periods of time as having an inflammatory arthritis, despite the lack of appropriate response [13].
With regard to the treatment of JIA, various modalities emerged over the last two decades, revolutionizing the pediatric rheumatology practice [14]. Majority of the presently available guidelines recommend a step-up approach, starting with nonsteroidal anti-inflammatory drugs (NSAID) and intraarticular glucocorticoid injections (IAGI), followed by conventional and biologic disease modifying anti-rheumatic drugs (cDMARD and bDMARD), respectively [15]. Moreover, despite many known adverse effects, systemic glucocorticoids (GC) are still being used as an important therapeutic option for wide range of complications associated with JIA (e.g., macrophage activation syndrome, myocarditis, pericarditis, pleuritis, peritonitis, uveitis and severe anaemia), as well as a bridge therapy in severe forms of JIA before the full effect of other treatment modalities has been achieved [16]. Those modalities nowadays primarily involve tumor necrosis factor alpha (TNFα) inhibitors (TNFi), such as etanercept, adalimumab and infliximab, and non-TNFi, such as anti-interleukin-6 (anti-IL-6) agent tocilizumab and a selective T-cell co-stimulation modulator abatacept [17, 18]. Furthermore, new medications are continuously being investigated [19, 20].
Together with the expansion of new treatment modalities, efforts have been made to introduce the treat-to-target (T2T) model in pediatric rheumatologic practice [21]. Signs and symptoms control, prevention of structural damage of joints and optimization of linear growth and pubertal development, as well as abolition of inflammation, have all been set as treatment goals. Essentially, this model advocates that therapy should be revised and adjusted based on regular disease activity assessments to reach and maintain the treatment target. Special attention should be paid to preventing or minimizing the side effects of systemic GC given their negative effect on growth and pubertal development. Consequently, their long-term use to maintain treatment target should be avoided, especially considering that GC dependence demonstrates the inadequacy of chosen treatment. The shared decision making, as well as multidisciplinary approach, have been recognized as exceptionally valuable for assurance of better adherence to treatment and subsequently improvement of outcome and overall prognosis.
Unfortunately, despite all these achievements, only 14 % of patients with rheumatoid factor (RF) negative and 0 % with RF positive polyarticular JIA achieves the remission off medications within five years, implying that JIA treatment requires a long-lasting commitment [22]. Hence, it comes as no surprise that every clinician involved in the care of children with JIA patients eventually sees one with disease not responding to acclaimed treatment options (i.e. NSAIDs, cDMARDS, bDMARDS) [15]. At that point, the consideration of additional treatment modalities seems like a valid course of action, but sometimes alternative diagnosis should be considered as well. Here, we present one such case, a girl with long standing polyarticular JIA refractory to many standard treatment modalities, with symptoms suggestive of other diseases.
Case presentation
A four-year-old first came to our attention in February 2008 due to painful swelling and contractures of both knees. Her symptoms started a year earlier and were not associated with any discernible trigger such as infection or trauma. Moreover, the symptoms were not responding to NSAIDs and she soon developed a severe morning stiffness lasting for up to three hours. Her birth history as well as psychomotor development prior to disease evolution was unremarkable. She was born as a first child into a family of non-consanguine parents, with no relatives having the similar symptoms.
The initial laboratory findings showed persistently elevated inflammatory markers (erythrocyte sedimentation rate (ESR) up to 100 mm/h and C-reactive protein (CRP) up to 100 mg/dL), with negative RF and antinuclear antibody (ANA) screen, and normal immunoglobulin levels. Despite the initial treatment with GC and methotrexate (MTX), her symptoms progressed affecting elbows, wrists, ankles and small joints of both hands. Moreover, she developed a severe uveitis of the left eye. In November 2008 biologic therapy with infliximab was started, with initially good response. Unfortunately, this lasted only for a few months and frequent relapses necessitated switching to adalimumab in April 2011. Again, there was an initial period of remission followed by progressive exacerbation characterized by swelling and pain in some joints, and persistent contracture of others. Other diagnosis, such as mucopolysaccharidosis and systemic lupus erythematosus (SLE) were suspected, but metabolic and immunological screening were negative, respectively. Beside ESR and CRP, the increased values of IL-6 (up to 75 pg/mL) and TNF-alfa (up to 20 pg/mL) were measured.
In November 2012 therapy was cycled to non-TNFi, tocilizumab, which led only to a short period of remission. Finally, in September 2014, etanercept was introduced, again with the lack of permanent response. Along with four different bDMARDs she continuously received cDMARD methotrexate, and for a short period of time leflunomide. During the periods of disease flare, bridge therapy with intraarticular and/or systemic GC was used, and soon she was dependent on a daily dose of GC. Eventually, this led to the development of iatrogenic Cushing syndrome with characteristic appearance, growth retardation and low bone mineral density, regardless of the vitamin D and ibandronic acid therapy. Since every attempt to wean off GC inevitably led to disease flare, from June to December 2016 she received cyclophosphamide (6x) and rituximab (3x), again without achieving a sustained remission. Afterwards, for a short period of time she was given metformin but without an appropriate improvement in musculoskeletal symptoms (Fig. 1).
Fig. 1 Schematic representation of treatment modalities during the time. 2007 – 2020 - the period of treatment, NSAID - nonsteroidal anti-inflammatory drug, IFX - infliximab, ADA - adalimumab, TOC - tocilizumab, ETC - etanercept, DMARD - disease modifying anti-rheumatic drug, MTX - methotrexate, CFM - cyclophosphamide, RTX - rituximab, MTF - metformin, MMF - mycophenolate mofetil, CYC - cyclosporine, TFA - tofacitinib, p.o. - per os, i.a. - intraarticular, i.v. - intravenous, GC - glucocorticoids
During the 2017, at the age of 13, the trial of mycophenolate mofetil (MMF) followed by the trial of cyclosporin was initiated, but the patient nevertheless remained GC dependent. Both shoulders, elbows, radiocarpal joints, metacarpophalangeal (MCP), proximal interphalangeal (PIP), distal interphalangeal (DIP) joints and both knees had restricted range of movement, and repeated IAGI were necessary to alleviate the symptoms. Finally, in 2018, the treatment with Janus kinase (JAK) inhibitor tofacitinib was initiated, which lead to gradual amelioration of musculoskeletal symptoms and improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic GC. Moreover, as the swelling of the wrists subsided for the first time in many years, Madelung deformity was noticed by clinical examination. Interestingly, it was only then, in 2019, that the deformity was for the first time described on x-ray (Fig. 2), although x-ray and MRI imaging of both hands were previously performed on many occasions in order to assess the inflammation (Figs. 3 and 4). Nevertheless, subsequent analysis by experienced musculoskeletal radiologist revealed characteristic bilateral signs of Madelung deformity dating back in 2015 and 2017 (Fig. 3), with the MRI showing the Vickers and radiotriquetral ligament (Fig. 4). The finding of those two ligaments allowed the distinguishing between Madelung deformity and pseudo-Madelung deformity, which includes post-traumatic and post-infective forms, forms associated with Turner syndrome, multiple hereditary exostoses and Ollier disease [23]. Unfortunately, due to the parent’s refusal, no further radiological assessment was performed, so we have not documented the other important aspects of Madelung deformity, such as radial shortening and diaphysis bowing, nor the mesolimbic shortening of limbs characteristic for Leri Weill syndrome.
Fig. 2 The anteroposterior radiograph of left hand at the age of 14. Note the increased volar angulation of distal radius, wedge shaped carpus with proximally positioned lunate and a characteristic notch on the distal radius (white arrow), which are the features of the Madelung deformity [12]
Fig. 3 The anteroposterior radiograph of both hands at the age of 10 (a) and 13 (b), and of the left hand at the age of 14 (c). Note the bowing of the distal radius, an increased radial inclination (~ 30°) with the deformation of the carpus that acquired a triangular appearance and widening of the distal radial-ulnar joint bilaterally, which are the typical features of Madelung deformity. Dorsal subluxation of the ulnar head is not seen as lateral images of the wrist were not taken. Osteopenia of carpal bones and periarticular osteopenia of MCP, PIP and DIP joints related to JIA are present. No relevant changes are observed during the time
Fig. 4 MRI coronal T1-weighted (a), proton density BLADE fluid sensitive sequence (b), post contrast T1-weighted coronal fat sat sequence (c) and post contrast T1-weighted axial fat sat sequence (d) images of both hands at the age of 13. Note the radiotriquetral ligament (red arrow) and Vickers ligament (green arrow) (a, b). Note the inflammatory changes characterized by postcontrast imbibition in carpal joints and MCP joints (red circle), as well as tenosynovitis of flexor tendons related to JIA, more prominent on the left hand (c, d)
Although our patient was simultaneously followed by pediatric endocrinologist from age of 11, her short stature, along with delayed menarche, and Cushingoid appearance, was attributed to the prolonged use of GC. It was only after the Madelung’s deformity was observed that genetic causes, primarily Leri Weill syndrome, were taken into consideration. Genetic analysis was performed by commercially available SALSA MLPA Probemix P018 SHOX (MRC-Holland, Amsterdam, The Netherland) according to the manufacturer’s recommendations. The MLPA mix included probes for each exon of SHOX, one probe just before the promoter region as well as probes covering a region downstream of the gene. The results revealed one copy of sixteen probes (10 probes for Xp22-PAR1 from CNE2 to CNE9, 4 probes for SHOX area downstream, 1 probe for CRLF2 in PAR1 region and 1 probe for CSF2RA in PAR1 region), with the size of the smallest deletion of 766,5 kb. Based on the genetic testing and imaging findings of Madelung deformity, the diagnosis of Leri Weill syndrome was established, and parents were advised to undergo further genetic testing of both the patient and themselves, which they rejected.
Currently, our patient has many consequences of the adverse course of the disease and prolonged GC treatment, such as joint contractures of elbows, wrists, DIPs, PIPs, hips, knees and MCPs and low bone density, respectively. She developed secondary sex characteristics only after the therapy with estradiol was initiated at the age of 14. Nevertheless, after the discontinuation of GC and subsequent discontinuation of estradiol, she finally had a menarche at the age of 15, along with a long-awaited growth spurt.
Discussion and Conclusion
Children with rheumatic diseases, their families, as well as their treating physicians are dealt with numerous issues and dilemmas regarding either the disease itself or ongoing treatment modalities. Besides, the diagnosis of rheumatic diseases in children is regularly made by excluding wide range of other diseases, with no pathognomonic tests and/or criteria. Therefore, even after the classification criteria are fulfilled, the diagnosis should be revised if new symptoms emerge or if the recommended treatment options are failing.
In our patient, a variety of steroid-sparing agents with different mechanisms of action have been employed with limited or no clinical success. Some of these agents were used in line with current treatment recommendations, but many were used based on anecdotal reports [24–28]. Finally, due to signs of systemic inflammation characterized by increased inflammatory markers (CRP and ESR) and cytokines (IL-6 and TNF-alfa), which is indicative for the activation of JAK/STAT pathway, treatment with tofacitinib, a first generation JAK inhibitor, was initiated with a good clinical response. Several clinical trials in adults with rheumatoid and psoriatic arthritis have given solid evidence about the use of tofacitinib, while the results of a phase 3 randomized double blind placebo controlled withdrawal study in patients with polyarticular JIA showed improvement in symptoms, less disease flares and improved functional ability, together with a clinical amelioration of disease activity [29, 30]. Moreover, tofacitinib is an oral agent, and the challenge of using biologics requiring injection or infusion for an extended length of time, especially in children, should not be overlooked.
Along with the various treatment modalities, the different diagnosis was constantly being considered in our patient. Firstly, due to persistent contracture in some joints with little or no signs of swelling, LSDs such as mucopolysaccharidosis type I, Gaucher disease type I and Fabry disease were investigated. Besides, other inflammatory causes like systemic lupus erythematosus were also excluded. Lastly, the diagnosis of Leri Weill syndrome characterized by deletions in SHOX gene and Madelung deformity was established. This painful deformity of the wrist was first described in 1878 by the German surgeon Otto Madelung in adolescents between the ages 8 and 14 [12]. Although initially asymptomatic, the patients often went on to develop pain, loss of grip strength and reduced mobility, which were the symptoms present in our patient even after the inflammation was tackled with tofacitinib. Moreover, the features of Leri Weill syndrome include the short stature, which was also one of the dominant finding in the presented patient. Yet, the growth deficit caused by SHOX haploinsufficiency in Leri Weill syndrome is around 2 standard deviation scores (SDS) [31], while our patient had a SDS of -5,5. Besides, due to a prolonged use of GC, our patient had a full blown Cushingoid appearance, low bone density, delayed puberty and growth retardation. Therefore, the possible explanation for the short stature and growth delay in our patient includes multifactorial aetiology. Firstly, it is well known that extended GC treatment leads to a defect in bone turnover (and formation) due to impaired osteoblastogenesis and osteoclastogenesis, and may have direct effects on the growth plate [32]. Additionally, higher prepubertal glucocorticoid level appears to delay early and late pubertal timing of healthy girls, particularly the onset of pubertal growth spurt and menarche [33]. Moreover, it has been shown that girls with polyarticular juvenile idiopathic arthritis are significantly more likely to present with short stature even 6 months after stopping the steroid therapy [34]. Finally, the product of SHOX gene is implicated in bone development and regulation of chondrocyte differentiation, which clarifies the association of SHOX gene haploinsufficiency with idiopathic short stature, as well as short stature in Turner syndrome and Leri Weill dyschondrosteosis [31].
In the presented case, the diagnosis of the Madelung deformity and Leri Weill syndrome was delayed due to the concomitant active inflammation caused by JIA taking the focus from other possible causes of pain in the wrists. However, as subsequent analysis by experienced musculoskeletal radiologist has shown, the characteristic signs of the Madelung deformity were present few years before the final diagnosis was reached, emphasizing once again the importance of multidisciplinary approach and close collaboration of many subspecialists in the care of children with rheumatic diseases. Nevertheless, this lag probably did not influence the therapeutic management in our particular patient; although positive effect on final height was observed with growth hormone therapy in patients with Leri Weill syndrome, due to the matching influence of GC and lack of agreement with her parents, this treatment option was avoided in our patient [35].
In conclusion, this case report emphasizes the difficulties and challenges in management of patient with long-standing polyarticular JIA refractory to wide range of treatment modalities. Although many high-quality guidelines are available for treatment of JIA patients, there is still need for individual reports of difficult to treat cases, especially when additional diagnosis are involved. While Leri Weill syndrome is extensively reported in the literature, to the best of our knowledge, our case report describes it for the first time along with JIA. Taking all these into account, we strongly encourage the aggregation of similar patients and establishment of the common ground that will help clinician to decide upon the introduction of treatment options outside of the contemporary guidelines.
Abbreviations
JIAJuvenile idiopathic arthritis
LSDLysosomal storage disease
MPSMucopolysaccharidosis
NSAIDNonsteroidal anti-inflammatory drug
cDMARDConventional disease modifying anti-rheumatic drug
bDMARDBiologic disease modifying anti-rheumatic drug
IAGIIntraarticular glucocorticoid injection
GCGlucocorticoids
MASMacrophage activation syndrome
TNFiTumor necrosis factor inhibitor
T2TTreat-to-target
RFRheumatoid factor
ESRErythrocyte sedimentation rate
CRPC-reactive protein
ANAAntinuclear antibody
MTXMethotrexate
SLESystemic lupus erythematosus
TNFαTumor necrosis factor alpha
anti-IL-6Anti-interleukin-6
MMFMycophenolate mofetil
MCPMetacarpophalangeal
PIPProximal interphalangeal
DIPDistal interphalangeal
JAKJanus kinase
MRIMagnetic resonance imaging
SHOXShort-stature homeobox
JAK/STATJanus kinase/signal transducer and activator of transcription proteins
SDSStandard deviation score
GnRHGonadotropin-releasing hormone
HPGHypothalamic-pituitary-gonadal
IFXInfliximab
ADAAdalimumab
TOCTocilizumab
ETCEtanercept
CFMCyclophosphamide
RTXRituximab
MTFMetformin
CYCCyclosporine
TFATofacitinib
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank parents for availability of publishing medical history of their daughter.
Authors’ contributions
VV and AS have equally contributed to the paper. VV: medical charts review, literature search, creation of figures and tables and manuscript draft preparation. AS: medical charts review, literature search, creation of figures and tables and manuscript draft preparation RV: radiographic images interpretation, manuscript draft preparation. MV: clinical care and the final revision of the manuscript. MH: clinical care and the final revision of the manuscript. LL: clinical care, medical charts review, literature search, creation of figures and tables, manuscript draft preparation, final revision of the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. / Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the parents for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | METHOTREXATE | DrugsGivenReaction | CC BY | 33451288 | 18,812,085 | 2021-01-15 |
What was the outcome of reaction 'Bone density decreased'? | Beyond the guidelines management of juvenile idiopathic arthritis: a case report of a girl with polyarticular disease refractory to multiple treatment options and Leri Weill syndrome.
The last two decades brought new treatment options and high quality guidelines into the paediatric rheumatologic practice. Nevertheless, a number of patients still present a diagnostic and therapeutic challenge due to combination of vague symptoms and unresponsiveness to available treatment modalities.
We report a case of sixteen years old girl suffering from polyarticular type of juvenile idiopathic arthritis refractory to multiple treatment options. She first presented at the age of 4 with swelling and contractures of both knees. Her symptoms were initially unresponsive to nonsteroidal anti-inflammatory drugs and progressed despite treatment with intraarticular and systemic glucocorticoids and methotrexate. Throughout the years, she received several biologics together with continuous administration of nonsteroidal anti-inflammatory drugs and disease modifying anti-rheumatic drugs as well as intraarticular and systemic glucocorticoids in disease flares. However, none of this options provided a permanent remission, so various other modalities, as well as other possible diagnoses were constantly being considered. Eventually she became dependent on a daily dose of systemic glucocorticoids. In 2018, the treatment with Janus kinase inhibitor tofacitinib was initiated, which led to gradual amelioration of musculoskeletal symptoms, improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic glucocorticoids. As the swelling of the wrists subsided for the first time in many years, Madelung's deformity was noticed, first clinically, and later radiographically as well. Genetic analysis revealed short-stature homeobox gene deficiency and confirmed the diagnosis of Leri Weill syndrome.
This case report emphasizes the need for reporting refractory, complicated cases from everyday clinical practice in order to build-up the overall knowledge and share experience which is complementary to available guidelines. Individual reports of difficult to treat cases, especially when additional diagnoses are involved, can be helpful for physicians treating patients with common rheumatological diseases such as juvenile idiopathic arthritis.
Background
Joint pain and/or swelling with limited range of motion is a common manifestation of many paediatric diseases, most notably wide range of rheumatic conditions. If both of these symptoms are present for longer than 6 weeks in a patient younger than 16 years of age, a diagnosis of juvenile idiopathic arthritis (JIA), the most common childhood rheumatic disease, should be considered [1]. JIA is heterogenous disease that encompasses different subtypes of childhood arthritis defined depending on the number of affected joints and/or presence of the enthesitis and/or sacroiliitis. Nevertheless, alongside JIA, there is a wide range of loosely related noninflammatory causes of a swollen joint in children, especially in the absence of clinical signs of inflammation. Lysosomal storage diseases (LSD) such as mucopolysaccharidosis type I (MPS I), Gaucher disease type I and Fabry disease all have prominent musculoskeletal symptoms early in the course of the disease, and are often first seen by a pediatric rheumatologist [2–8]. However, the underlying mechanism of those disorders does not directly involve the immune mediated inflammatory response, but rather an inflammation caused by genetic defects and subsequent perturbations at the protein level. More specifically, in Gaucher disease, bone marrow infiltration with histiocytes causes acute attacks of pain, which may be mistaken for arthritis in the vicinity of a joint [5, 8]. In Fabry disease, episodes of neuropathic pain in hands, feet, wrists, ankles (acroparesthesias), often associated with fever, malaise and elevated inflammation markers, can mimic a rheumatic condition, such as an inflammatory arthritis [3, 9]. Finally, joint stiffness and contractures are characteristic for some types of MPS, the so called „attenuated“ forms like Hurler-Scheie syndrome, which have a less severe presentation and progress silently over the years, making the diagnosis a challenge [3, 10, 11]. On the other hand, some congenital conditions, such as Madelung and Madelung-type deformities resulting from the premature closure of the medial volar aspect of the distal radial physis, might cause similar symptoms [12]. Hence, it is not a rarity that some of the children with LSD and congenital deformities are treated for prolonged periods of time as having an inflammatory arthritis, despite the lack of appropriate response [13].
With regard to the treatment of JIA, various modalities emerged over the last two decades, revolutionizing the pediatric rheumatology practice [14]. Majority of the presently available guidelines recommend a step-up approach, starting with nonsteroidal anti-inflammatory drugs (NSAID) and intraarticular glucocorticoid injections (IAGI), followed by conventional and biologic disease modifying anti-rheumatic drugs (cDMARD and bDMARD), respectively [15]. Moreover, despite many known adverse effects, systemic glucocorticoids (GC) are still being used as an important therapeutic option for wide range of complications associated with JIA (e.g., macrophage activation syndrome, myocarditis, pericarditis, pleuritis, peritonitis, uveitis and severe anaemia), as well as a bridge therapy in severe forms of JIA before the full effect of other treatment modalities has been achieved [16]. Those modalities nowadays primarily involve tumor necrosis factor alpha (TNFα) inhibitors (TNFi), such as etanercept, adalimumab and infliximab, and non-TNFi, such as anti-interleukin-6 (anti-IL-6) agent tocilizumab and a selective T-cell co-stimulation modulator abatacept [17, 18]. Furthermore, new medications are continuously being investigated [19, 20].
Together with the expansion of new treatment modalities, efforts have been made to introduce the treat-to-target (T2T) model in pediatric rheumatologic practice [21]. Signs and symptoms control, prevention of structural damage of joints and optimization of linear growth and pubertal development, as well as abolition of inflammation, have all been set as treatment goals. Essentially, this model advocates that therapy should be revised and adjusted based on regular disease activity assessments to reach and maintain the treatment target. Special attention should be paid to preventing or minimizing the side effects of systemic GC given their negative effect on growth and pubertal development. Consequently, their long-term use to maintain treatment target should be avoided, especially considering that GC dependence demonstrates the inadequacy of chosen treatment. The shared decision making, as well as multidisciplinary approach, have been recognized as exceptionally valuable for assurance of better adherence to treatment and subsequently improvement of outcome and overall prognosis.
Unfortunately, despite all these achievements, only 14 % of patients with rheumatoid factor (RF) negative and 0 % with RF positive polyarticular JIA achieves the remission off medications within five years, implying that JIA treatment requires a long-lasting commitment [22]. Hence, it comes as no surprise that every clinician involved in the care of children with JIA patients eventually sees one with disease not responding to acclaimed treatment options (i.e. NSAIDs, cDMARDS, bDMARDS) [15]. At that point, the consideration of additional treatment modalities seems like a valid course of action, but sometimes alternative diagnosis should be considered as well. Here, we present one such case, a girl with long standing polyarticular JIA refractory to many standard treatment modalities, with symptoms suggestive of other diseases.
Case presentation
A four-year-old first came to our attention in February 2008 due to painful swelling and contractures of both knees. Her symptoms started a year earlier and were not associated with any discernible trigger such as infection or trauma. Moreover, the symptoms were not responding to NSAIDs and she soon developed a severe morning stiffness lasting for up to three hours. Her birth history as well as psychomotor development prior to disease evolution was unremarkable. She was born as a first child into a family of non-consanguine parents, with no relatives having the similar symptoms.
The initial laboratory findings showed persistently elevated inflammatory markers (erythrocyte sedimentation rate (ESR) up to 100 mm/h and C-reactive protein (CRP) up to 100 mg/dL), with negative RF and antinuclear antibody (ANA) screen, and normal immunoglobulin levels. Despite the initial treatment with GC and methotrexate (MTX), her symptoms progressed affecting elbows, wrists, ankles and small joints of both hands. Moreover, she developed a severe uveitis of the left eye. In November 2008 biologic therapy with infliximab was started, with initially good response. Unfortunately, this lasted only for a few months and frequent relapses necessitated switching to adalimumab in April 2011. Again, there was an initial period of remission followed by progressive exacerbation characterized by swelling and pain in some joints, and persistent contracture of others. Other diagnosis, such as mucopolysaccharidosis and systemic lupus erythematosus (SLE) were suspected, but metabolic and immunological screening were negative, respectively. Beside ESR and CRP, the increased values of IL-6 (up to 75 pg/mL) and TNF-alfa (up to 20 pg/mL) were measured.
In November 2012 therapy was cycled to non-TNFi, tocilizumab, which led only to a short period of remission. Finally, in September 2014, etanercept was introduced, again with the lack of permanent response. Along with four different bDMARDs she continuously received cDMARD methotrexate, and for a short period of time leflunomide. During the periods of disease flare, bridge therapy with intraarticular and/or systemic GC was used, and soon she was dependent on a daily dose of GC. Eventually, this led to the development of iatrogenic Cushing syndrome with characteristic appearance, growth retardation and low bone mineral density, regardless of the vitamin D and ibandronic acid therapy. Since every attempt to wean off GC inevitably led to disease flare, from June to December 2016 she received cyclophosphamide (6x) and rituximab (3x), again without achieving a sustained remission. Afterwards, for a short period of time she was given metformin but without an appropriate improvement in musculoskeletal symptoms (Fig. 1).
Fig. 1 Schematic representation of treatment modalities during the time. 2007 – 2020 - the period of treatment, NSAID - nonsteroidal anti-inflammatory drug, IFX - infliximab, ADA - adalimumab, TOC - tocilizumab, ETC - etanercept, DMARD - disease modifying anti-rheumatic drug, MTX - methotrexate, CFM - cyclophosphamide, RTX - rituximab, MTF - metformin, MMF - mycophenolate mofetil, CYC - cyclosporine, TFA - tofacitinib, p.o. - per os, i.a. - intraarticular, i.v. - intravenous, GC - glucocorticoids
During the 2017, at the age of 13, the trial of mycophenolate mofetil (MMF) followed by the trial of cyclosporin was initiated, but the patient nevertheless remained GC dependent. Both shoulders, elbows, radiocarpal joints, metacarpophalangeal (MCP), proximal interphalangeal (PIP), distal interphalangeal (DIP) joints and both knees had restricted range of movement, and repeated IAGI were necessary to alleviate the symptoms. Finally, in 2018, the treatment with Janus kinase (JAK) inhibitor tofacitinib was initiated, which lead to gradual amelioration of musculoskeletal symptoms and improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic GC. Moreover, as the swelling of the wrists subsided for the first time in many years, Madelung deformity was noticed by clinical examination. Interestingly, it was only then, in 2019, that the deformity was for the first time described on x-ray (Fig. 2), although x-ray and MRI imaging of both hands were previously performed on many occasions in order to assess the inflammation (Figs. 3 and 4). Nevertheless, subsequent analysis by experienced musculoskeletal radiologist revealed characteristic bilateral signs of Madelung deformity dating back in 2015 and 2017 (Fig. 3), with the MRI showing the Vickers and radiotriquetral ligament (Fig. 4). The finding of those two ligaments allowed the distinguishing between Madelung deformity and pseudo-Madelung deformity, which includes post-traumatic and post-infective forms, forms associated with Turner syndrome, multiple hereditary exostoses and Ollier disease [23]. Unfortunately, due to the parent’s refusal, no further radiological assessment was performed, so we have not documented the other important aspects of Madelung deformity, such as radial shortening and diaphysis bowing, nor the mesolimbic shortening of limbs characteristic for Leri Weill syndrome.
Fig. 2 The anteroposterior radiograph of left hand at the age of 14. Note the increased volar angulation of distal radius, wedge shaped carpus with proximally positioned lunate and a characteristic notch on the distal radius (white arrow), which are the features of the Madelung deformity [12]
Fig. 3 The anteroposterior radiograph of both hands at the age of 10 (a) and 13 (b), and of the left hand at the age of 14 (c). Note the bowing of the distal radius, an increased radial inclination (~ 30°) with the deformation of the carpus that acquired a triangular appearance and widening of the distal radial-ulnar joint bilaterally, which are the typical features of Madelung deformity. Dorsal subluxation of the ulnar head is not seen as lateral images of the wrist were not taken. Osteopenia of carpal bones and periarticular osteopenia of MCP, PIP and DIP joints related to JIA are present. No relevant changes are observed during the time
Fig. 4 MRI coronal T1-weighted (a), proton density BLADE fluid sensitive sequence (b), post contrast T1-weighted coronal fat sat sequence (c) and post contrast T1-weighted axial fat sat sequence (d) images of both hands at the age of 13. Note the radiotriquetral ligament (red arrow) and Vickers ligament (green arrow) (a, b). Note the inflammatory changes characterized by postcontrast imbibition in carpal joints and MCP joints (red circle), as well as tenosynovitis of flexor tendons related to JIA, more prominent on the left hand (c, d)
Although our patient was simultaneously followed by pediatric endocrinologist from age of 11, her short stature, along with delayed menarche, and Cushingoid appearance, was attributed to the prolonged use of GC. It was only after the Madelung’s deformity was observed that genetic causes, primarily Leri Weill syndrome, were taken into consideration. Genetic analysis was performed by commercially available SALSA MLPA Probemix P018 SHOX (MRC-Holland, Amsterdam, The Netherland) according to the manufacturer’s recommendations. The MLPA mix included probes for each exon of SHOX, one probe just before the promoter region as well as probes covering a region downstream of the gene. The results revealed one copy of sixteen probes (10 probes for Xp22-PAR1 from CNE2 to CNE9, 4 probes for SHOX area downstream, 1 probe for CRLF2 in PAR1 region and 1 probe for CSF2RA in PAR1 region), with the size of the smallest deletion of 766,5 kb. Based on the genetic testing and imaging findings of Madelung deformity, the diagnosis of Leri Weill syndrome was established, and parents were advised to undergo further genetic testing of both the patient and themselves, which they rejected.
Currently, our patient has many consequences of the adverse course of the disease and prolonged GC treatment, such as joint contractures of elbows, wrists, DIPs, PIPs, hips, knees and MCPs and low bone density, respectively. She developed secondary sex characteristics only after the therapy with estradiol was initiated at the age of 14. Nevertheless, after the discontinuation of GC and subsequent discontinuation of estradiol, she finally had a menarche at the age of 15, along with a long-awaited growth spurt.
Discussion and Conclusion
Children with rheumatic diseases, their families, as well as their treating physicians are dealt with numerous issues and dilemmas regarding either the disease itself or ongoing treatment modalities. Besides, the diagnosis of rheumatic diseases in children is regularly made by excluding wide range of other diseases, with no pathognomonic tests and/or criteria. Therefore, even after the classification criteria are fulfilled, the diagnosis should be revised if new symptoms emerge or if the recommended treatment options are failing.
In our patient, a variety of steroid-sparing agents with different mechanisms of action have been employed with limited or no clinical success. Some of these agents were used in line with current treatment recommendations, but many were used based on anecdotal reports [24–28]. Finally, due to signs of systemic inflammation characterized by increased inflammatory markers (CRP and ESR) and cytokines (IL-6 and TNF-alfa), which is indicative for the activation of JAK/STAT pathway, treatment with tofacitinib, a first generation JAK inhibitor, was initiated with a good clinical response. Several clinical trials in adults with rheumatoid and psoriatic arthritis have given solid evidence about the use of tofacitinib, while the results of a phase 3 randomized double blind placebo controlled withdrawal study in patients with polyarticular JIA showed improvement in symptoms, less disease flares and improved functional ability, together with a clinical amelioration of disease activity [29, 30]. Moreover, tofacitinib is an oral agent, and the challenge of using biologics requiring injection or infusion for an extended length of time, especially in children, should not be overlooked.
Along with the various treatment modalities, the different diagnosis was constantly being considered in our patient. Firstly, due to persistent contracture in some joints with little or no signs of swelling, LSDs such as mucopolysaccharidosis type I, Gaucher disease type I and Fabry disease were investigated. Besides, other inflammatory causes like systemic lupus erythematosus were also excluded. Lastly, the diagnosis of Leri Weill syndrome characterized by deletions in SHOX gene and Madelung deformity was established. This painful deformity of the wrist was first described in 1878 by the German surgeon Otto Madelung in adolescents between the ages 8 and 14 [12]. Although initially asymptomatic, the patients often went on to develop pain, loss of grip strength and reduced mobility, which were the symptoms present in our patient even after the inflammation was tackled with tofacitinib. Moreover, the features of Leri Weill syndrome include the short stature, which was also one of the dominant finding in the presented patient. Yet, the growth deficit caused by SHOX haploinsufficiency in Leri Weill syndrome is around 2 standard deviation scores (SDS) [31], while our patient had a SDS of -5,5. Besides, due to a prolonged use of GC, our patient had a full blown Cushingoid appearance, low bone density, delayed puberty and growth retardation. Therefore, the possible explanation for the short stature and growth delay in our patient includes multifactorial aetiology. Firstly, it is well known that extended GC treatment leads to a defect in bone turnover (and formation) due to impaired osteoblastogenesis and osteoclastogenesis, and may have direct effects on the growth plate [32]. Additionally, higher prepubertal glucocorticoid level appears to delay early and late pubertal timing of healthy girls, particularly the onset of pubertal growth spurt and menarche [33]. Moreover, it has been shown that girls with polyarticular juvenile idiopathic arthritis are significantly more likely to present with short stature even 6 months after stopping the steroid therapy [34]. Finally, the product of SHOX gene is implicated in bone development and regulation of chondrocyte differentiation, which clarifies the association of SHOX gene haploinsufficiency with idiopathic short stature, as well as short stature in Turner syndrome and Leri Weill dyschondrosteosis [31].
In the presented case, the diagnosis of the Madelung deformity and Leri Weill syndrome was delayed due to the concomitant active inflammation caused by JIA taking the focus from other possible causes of pain in the wrists. However, as subsequent analysis by experienced musculoskeletal radiologist has shown, the characteristic signs of the Madelung deformity were present few years before the final diagnosis was reached, emphasizing once again the importance of multidisciplinary approach and close collaboration of many subspecialists in the care of children with rheumatic diseases. Nevertheless, this lag probably did not influence the therapeutic management in our particular patient; although positive effect on final height was observed with growth hormone therapy in patients with Leri Weill syndrome, due to the matching influence of GC and lack of agreement with her parents, this treatment option was avoided in our patient [35].
In conclusion, this case report emphasizes the difficulties and challenges in management of patient with long-standing polyarticular JIA refractory to wide range of treatment modalities. Although many high-quality guidelines are available for treatment of JIA patients, there is still need for individual reports of difficult to treat cases, especially when additional diagnosis are involved. While Leri Weill syndrome is extensively reported in the literature, to the best of our knowledge, our case report describes it for the first time along with JIA. Taking all these into account, we strongly encourage the aggregation of similar patients and establishment of the common ground that will help clinician to decide upon the introduction of treatment options outside of the contemporary guidelines.
Abbreviations
JIAJuvenile idiopathic arthritis
LSDLysosomal storage disease
MPSMucopolysaccharidosis
NSAIDNonsteroidal anti-inflammatory drug
cDMARDConventional disease modifying anti-rheumatic drug
bDMARDBiologic disease modifying anti-rheumatic drug
IAGIIntraarticular glucocorticoid injection
GCGlucocorticoids
MASMacrophage activation syndrome
TNFiTumor necrosis factor inhibitor
T2TTreat-to-target
RFRheumatoid factor
ESRErythrocyte sedimentation rate
CRPC-reactive protein
ANAAntinuclear antibody
MTXMethotrexate
SLESystemic lupus erythematosus
TNFαTumor necrosis factor alpha
anti-IL-6Anti-interleukin-6
MMFMycophenolate mofetil
MCPMetacarpophalangeal
PIPProximal interphalangeal
DIPDistal interphalangeal
JAKJanus kinase
MRIMagnetic resonance imaging
SHOXShort-stature homeobox
JAK/STATJanus kinase/signal transducer and activator of transcription proteins
SDSStandard deviation score
GnRHGonadotropin-releasing hormone
HPGHypothalamic-pituitary-gonadal
IFXInfliximab
ADAAdalimumab
TOCTocilizumab
ETCEtanercept
CFMCyclophosphamide
RTXRituximab
MTFMetformin
CYCCyclosporine
TFATofacitinib
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank parents for availability of publishing medical history of their daughter.
Authors’ contributions
VV and AS have equally contributed to the paper. VV: medical charts review, literature search, creation of figures and tables and manuscript draft preparation. AS: medical charts review, literature search, creation of figures and tables and manuscript draft preparation RV: radiographic images interpretation, manuscript draft preparation. MV: clinical care and the final revision of the manuscript. MH: clinical care and the final revision of the manuscript. LL: clinical care, medical charts review, literature search, creation of figures and tables, manuscript draft preparation, final revision of the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. / Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the parents for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | Recovering | ReactionOutcome | CC BY | 33451288 | 18,970,451 | 2021-01-15 |
What was the outcome of reaction 'Cushing^s syndrome'? | Beyond the guidelines management of juvenile idiopathic arthritis: a case report of a girl with polyarticular disease refractory to multiple treatment options and Leri Weill syndrome.
The last two decades brought new treatment options and high quality guidelines into the paediatric rheumatologic practice. Nevertheless, a number of patients still present a diagnostic and therapeutic challenge due to combination of vague symptoms and unresponsiveness to available treatment modalities.
We report a case of sixteen years old girl suffering from polyarticular type of juvenile idiopathic arthritis refractory to multiple treatment options. She first presented at the age of 4 with swelling and contractures of both knees. Her symptoms were initially unresponsive to nonsteroidal anti-inflammatory drugs and progressed despite treatment with intraarticular and systemic glucocorticoids and methotrexate. Throughout the years, she received several biologics together with continuous administration of nonsteroidal anti-inflammatory drugs and disease modifying anti-rheumatic drugs as well as intraarticular and systemic glucocorticoids in disease flares. However, none of this options provided a permanent remission, so various other modalities, as well as other possible diagnoses were constantly being considered. Eventually she became dependent on a daily dose of systemic glucocorticoids. In 2018, the treatment with Janus kinase inhibitor tofacitinib was initiated, which led to gradual amelioration of musculoskeletal symptoms, improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic glucocorticoids. As the swelling of the wrists subsided for the first time in many years, Madelung's deformity was noticed, first clinically, and later radiographically as well. Genetic analysis revealed short-stature homeobox gene deficiency and confirmed the diagnosis of Leri Weill syndrome.
This case report emphasizes the need for reporting refractory, complicated cases from everyday clinical practice in order to build-up the overall knowledge and share experience which is complementary to available guidelines. Individual reports of difficult to treat cases, especially when additional diagnoses are involved, can be helpful for physicians treating patients with common rheumatological diseases such as juvenile idiopathic arthritis.
Background
Joint pain and/or swelling with limited range of motion is a common manifestation of many paediatric diseases, most notably wide range of rheumatic conditions. If both of these symptoms are present for longer than 6 weeks in a patient younger than 16 years of age, a diagnosis of juvenile idiopathic arthritis (JIA), the most common childhood rheumatic disease, should be considered [1]. JIA is heterogenous disease that encompasses different subtypes of childhood arthritis defined depending on the number of affected joints and/or presence of the enthesitis and/or sacroiliitis. Nevertheless, alongside JIA, there is a wide range of loosely related noninflammatory causes of a swollen joint in children, especially in the absence of clinical signs of inflammation. Lysosomal storage diseases (LSD) such as mucopolysaccharidosis type I (MPS I), Gaucher disease type I and Fabry disease all have prominent musculoskeletal symptoms early in the course of the disease, and are often first seen by a pediatric rheumatologist [2–8]. However, the underlying mechanism of those disorders does not directly involve the immune mediated inflammatory response, but rather an inflammation caused by genetic defects and subsequent perturbations at the protein level. More specifically, in Gaucher disease, bone marrow infiltration with histiocytes causes acute attacks of pain, which may be mistaken for arthritis in the vicinity of a joint [5, 8]. In Fabry disease, episodes of neuropathic pain in hands, feet, wrists, ankles (acroparesthesias), often associated with fever, malaise and elevated inflammation markers, can mimic a rheumatic condition, such as an inflammatory arthritis [3, 9]. Finally, joint stiffness and contractures are characteristic for some types of MPS, the so called „attenuated“ forms like Hurler-Scheie syndrome, which have a less severe presentation and progress silently over the years, making the diagnosis a challenge [3, 10, 11]. On the other hand, some congenital conditions, such as Madelung and Madelung-type deformities resulting from the premature closure of the medial volar aspect of the distal radial physis, might cause similar symptoms [12]. Hence, it is not a rarity that some of the children with LSD and congenital deformities are treated for prolonged periods of time as having an inflammatory arthritis, despite the lack of appropriate response [13].
With regard to the treatment of JIA, various modalities emerged over the last two decades, revolutionizing the pediatric rheumatology practice [14]. Majority of the presently available guidelines recommend a step-up approach, starting with nonsteroidal anti-inflammatory drugs (NSAID) and intraarticular glucocorticoid injections (IAGI), followed by conventional and biologic disease modifying anti-rheumatic drugs (cDMARD and bDMARD), respectively [15]. Moreover, despite many known adverse effects, systemic glucocorticoids (GC) are still being used as an important therapeutic option for wide range of complications associated with JIA (e.g., macrophage activation syndrome, myocarditis, pericarditis, pleuritis, peritonitis, uveitis and severe anaemia), as well as a bridge therapy in severe forms of JIA before the full effect of other treatment modalities has been achieved [16]. Those modalities nowadays primarily involve tumor necrosis factor alpha (TNFα) inhibitors (TNFi), such as etanercept, adalimumab and infliximab, and non-TNFi, such as anti-interleukin-6 (anti-IL-6) agent tocilizumab and a selective T-cell co-stimulation modulator abatacept [17, 18]. Furthermore, new medications are continuously being investigated [19, 20].
Together with the expansion of new treatment modalities, efforts have been made to introduce the treat-to-target (T2T) model in pediatric rheumatologic practice [21]. Signs and symptoms control, prevention of structural damage of joints and optimization of linear growth and pubertal development, as well as abolition of inflammation, have all been set as treatment goals. Essentially, this model advocates that therapy should be revised and adjusted based on regular disease activity assessments to reach and maintain the treatment target. Special attention should be paid to preventing or minimizing the side effects of systemic GC given their negative effect on growth and pubertal development. Consequently, their long-term use to maintain treatment target should be avoided, especially considering that GC dependence demonstrates the inadequacy of chosen treatment. The shared decision making, as well as multidisciplinary approach, have been recognized as exceptionally valuable for assurance of better adherence to treatment and subsequently improvement of outcome and overall prognosis.
Unfortunately, despite all these achievements, only 14 % of patients with rheumatoid factor (RF) negative and 0 % with RF positive polyarticular JIA achieves the remission off medications within five years, implying that JIA treatment requires a long-lasting commitment [22]. Hence, it comes as no surprise that every clinician involved in the care of children with JIA patients eventually sees one with disease not responding to acclaimed treatment options (i.e. NSAIDs, cDMARDS, bDMARDS) [15]. At that point, the consideration of additional treatment modalities seems like a valid course of action, but sometimes alternative diagnosis should be considered as well. Here, we present one such case, a girl with long standing polyarticular JIA refractory to many standard treatment modalities, with symptoms suggestive of other diseases.
Case presentation
A four-year-old first came to our attention in February 2008 due to painful swelling and contractures of both knees. Her symptoms started a year earlier and were not associated with any discernible trigger such as infection or trauma. Moreover, the symptoms were not responding to NSAIDs and she soon developed a severe morning stiffness lasting for up to three hours. Her birth history as well as psychomotor development prior to disease evolution was unremarkable. She was born as a first child into a family of non-consanguine parents, with no relatives having the similar symptoms.
The initial laboratory findings showed persistently elevated inflammatory markers (erythrocyte sedimentation rate (ESR) up to 100 mm/h and C-reactive protein (CRP) up to 100 mg/dL), with negative RF and antinuclear antibody (ANA) screen, and normal immunoglobulin levels. Despite the initial treatment with GC and methotrexate (MTX), her symptoms progressed affecting elbows, wrists, ankles and small joints of both hands. Moreover, she developed a severe uveitis of the left eye. In November 2008 biologic therapy with infliximab was started, with initially good response. Unfortunately, this lasted only for a few months and frequent relapses necessitated switching to adalimumab in April 2011. Again, there was an initial period of remission followed by progressive exacerbation characterized by swelling and pain in some joints, and persistent contracture of others. Other diagnosis, such as mucopolysaccharidosis and systemic lupus erythematosus (SLE) were suspected, but metabolic and immunological screening were negative, respectively. Beside ESR and CRP, the increased values of IL-6 (up to 75 pg/mL) and TNF-alfa (up to 20 pg/mL) were measured.
In November 2012 therapy was cycled to non-TNFi, tocilizumab, which led only to a short period of remission. Finally, in September 2014, etanercept was introduced, again with the lack of permanent response. Along with four different bDMARDs she continuously received cDMARD methotrexate, and for a short period of time leflunomide. During the periods of disease flare, bridge therapy with intraarticular and/or systemic GC was used, and soon she was dependent on a daily dose of GC. Eventually, this led to the development of iatrogenic Cushing syndrome with characteristic appearance, growth retardation and low bone mineral density, regardless of the vitamin D and ibandronic acid therapy. Since every attempt to wean off GC inevitably led to disease flare, from June to December 2016 she received cyclophosphamide (6x) and rituximab (3x), again without achieving a sustained remission. Afterwards, for a short period of time she was given metformin but without an appropriate improvement in musculoskeletal symptoms (Fig. 1).
Fig. 1 Schematic representation of treatment modalities during the time. 2007 – 2020 - the period of treatment, NSAID - nonsteroidal anti-inflammatory drug, IFX - infliximab, ADA - adalimumab, TOC - tocilizumab, ETC - etanercept, DMARD - disease modifying anti-rheumatic drug, MTX - methotrexate, CFM - cyclophosphamide, RTX - rituximab, MTF - metformin, MMF - mycophenolate mofetil, CYC - cyclosporine, TFA - tofacitinib, p.o. - per os, i.a. - intraarticular, i.v. - intravenous, GC - glucocorticoids
During the 2017, at the age of 13, the trial of mycophenolate mofetil (MMF) followed by the trial of cyclosporin was initiated, but the patient nevertheless remained GC dependent. Both shoulders, elbows, radiocarpal joints, metacarpophalangeal (MCP), proximal interphalangeal (PIP), distal interphalangeal (DIP) joints and both knees had restricted range of movement, and repeated IAGI were necessary to alleviate the symptoms. Finally, in 2018, the treatment with Janus kinase (JAK) inhibitor tofacitinib was initiated, which lead to gradual amelioration of musculoskeletal symptoms and improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic GC. Moreover, as the swelling of the wrists subsided for the first time in many years, Madelung deformity was noticed by clinical examination. Interestingly, it was only then, in 2019, that the deformity was for the first time described on x-ray (Fig. 2), although x-ray and MRI imaging of both hands were previously performed on many occasions in order to assess the inflammation (Figs. 3 and 4). Nevertheless, subsequent analysis by experienced musculoskeletal radiologist revealed characteristic bilateral signs of Madelung deformity dating back in 2015 and 2017 (Fig. 3), with the MRI showing the Vickers and radiotriquetral ligament (Fig. 4). The finding of those two ligaments allowed the distinguishing between Madelung deformity and pseudo-Madelung deformity, which includes post-traumatic and post-infective forms, forms associated with Turner syndrome, multiple hereditary exostoses and Ollier disease [23]. Unfortunately, due to the parent’s refusal, no further radiological assessment was performed, so we have not documented the other important aspects of Madelung deformity, such as radial shortening and diaphysis bowing, nor the mesolimbic shortening of limbs characteristic for Leri Weill syndrome.
Fig. 2 The anteroposterior radiograph of left hand at the age of 14. Note the increased volar angulation of distal radius, wedge shaped carpus with proximally positioned lunate and a characteristic notch on the distal radius (white arrow), which are the features of the Madelung deformity [12]
Fig. 3 The anteroposterior radiograph of both hands at the age of 10 (a) and 13 (b), and of the left hand at the age of 14 (c). Note the bowing of the distal radius, an increased radial inclination (~ 30°) with the deformation of the carpus that acquired a triangular appearance and widening of the distal radial-ulnar joint bilaterally, which are the typical features of Madelung deformity. Dorsal subluxation of the ulnar head is not seen as lateral images of the wrist were not taken. Osteopenia of carpal bones and periarticular osteopenia of MCP, PIP and DIP joints related to JIA are present. No relevant changes are observed during the time
Fig. 4 MRI coronal T1-weighted (a), proton density BLADE fluid sensitive sequence (b), post contrast T1-weighted coronal fat sat sequence (c) and post contrast T1-weighted axial fat sat sequence (d) images of both hands at the age of 13. Note the radiotriquetral ligament (red arrow) and Vickers ligament (green arrow) (a, b). Note the inflammatory changes characterized by postcontrast imbibition in carpal joints and MCP joints (red circle), as well as tenosynovitis of flexor tendons related to JIA, more prominent on the left hand (c, d)
Although our patient was simultaneously followed by pediatric endocrinologist from age of 11, her short stature, along with delayed menarche, and Cushingoid appearance, was attributed to the prolonged use of GC. It was only after the Madelung’s deformity was observed that genetic causes, primarily Leri Weill syndrome, were taken into consideration. Genetic analysis was performed by commercially available SALSA MLPA Probemix P018 SHOX (MRC-Holland, Amsterdam, The Netherland) according to the manufacturer’s recommendations. The MLPA mix included probes for each exon of SHOX, one probe just before the promoter region as well as probes covering a region downstream of the gene. The results revealed one copy of sixteen probes (10 probes for Xp22-PAR1 from CNE2 to CNE9, 4 probes for SHOX area downstream, 1 probe for CRLF2 in PAR1 region and 1 probe for CSF2RA in PAR1 region), with the size of the smallest deletion of 766,5 kb. Based on the genetic testing and imaging findings of Madelung deformity, the diagnosis of Leri Weill syndrome was established, and parents were advised to undergo further genetic testing of both the patient and themselves, which they rejected.
Currently, our patient has many consequences of the adverse course of the disease and prolonged GC treatment, such as joint contractures of elbows, wrists, DIPs, PIPs, hips, knees and MCPs and low bone density, respectively. She developed secondary sex characteristics only after the therapy with estradiol was initiated at the age of 14. Nevertheless, after the discontinuation of GC and subsequent discontinuation of estradiol, she finally had a menarche at the age of 15, along with a long-awaited growth spurt.
Discussion and Conclusion
Children with rheumatic diseases, their families, as well as their treating physicians are dealt with numerous issues and dilemmas regarding either the disease itself or ongoing treatment modalities. Besides, the diagnosis of rheumatic diseases in children is regularly made by excluding wide range of other diseases, with no pathognomonic tests and/or criteria. Therefore, even after the classification criteria are fulfilled, the diagnosis should be revised if new symptoms emerge or if the recommended treatment options are failing.
In our patient, a variety of steroid-sparing agents with different mechanisms of action have been employed with limited or no clinical success. Some of these agents were used in line with current treatment recommendations, but many were used based on anecdotal reports [24–28]. Finally, due to signs of systemic inflammation characterized by increased inflammatory markers (CRP and ESR) and cytokines (IL-6 and TNF-alfa), which is indicative for the activation of JAK/STAT pathway, treatment with tofacitinib, a first generation JAK inhibitor, was initiated with a good clinical response. Several clinical trials in adults with rheumatoid and psoriatic arthritis have given solid evidence about the use of tofacitinib, while the results of a phase 3 randomized double blind placebo controlled withdrawal study in patients with polyarticular JIA showed improvement in symptoms, less disease flares and improved functional ability, together with a clinical amelioration of disease activity [29, 30]. Moreover, tofacitinib is an oral agent, and the challenge of using biologics requiring injection or infusion for an extended length of time, especially in children, should not be overlooked.
Along with the various treatment modalities, the different diagnosis was constantly being considered in our patient. Firstly, due to persistent contracture in some joints with little or no signs of swelling, LSDs such as mucopolysaccharidosis type I, Gaucher disease type I and Fabry disease were investigated. Besides, other inflammatory causes like systemic lupus erythematosus were also excluded. Lastly, the diagnosis of Leri Weill syndrome characterized by deletions in SHOX gene and Madelung deformity was established. This painful deformity of the wrist was first described in 1878 by the German surgeon Otto Madelung in adolescents between the ages 8 and 14 [12]. Although initially asymptomatic, the patients often went on to develop pain, loss of grip strength and reduced mobility, which were the symptoms present in our patient even after the inflammation was tackled with tofacitinib. Moreover, the features of Leri Weill syndrome include the short stature, which was also one of the dominant finding in the presented patient. Yet, the growth deficit caused by SHOX haploinsufficiency in Leri Weill syndrome is around 2 standard deviation scores (SDS) [31], while our patient had a SDS of -5,5. Besides, due to a prolonged use of GC, our patient had a full blown Cushingoid appearance, low bone density, delayed puberty and growth retardation. Therefore, the possible explanation for the short stature and growth delay in our patient includes multifactorial aetiology. Firstly, it is well known that extended GC treatment leads to a defect in bone turnover (and formation) due to impaired osteoblastogenesis and osteoclastogenesis, and may have direct effects on the growth plate [32]. Additionally, higher prepubertal glucocorticoid level appears to delay early and late pubertal timing of healthy girls, particularly the onset of pubertal growth spurt and menarche [33]. Moreover, it has been shown that girls with polyarticular juvenile idiopathic arthritis are significantly more likely to present with short stature even 6 months after stopping the steroid therapy [34]. Finally, the product of SHOX gene is implicated in bone development and regulation of chondrocyte differentiation, which clarifies the association of SHOX gene haploinsufficiency with idiopathic short stature, as well as short stature in Turner syndrome and Leri Weill dyschondrosteosis [31].
In the presented case, the diagnosis of the Madelung deformity and Leri Weill syndrome was delayed due to the concomitant active inflammation caused by JIA taking the focus from other possible causes of pain in the wrists. However, as subsequent analysis by experienced musculoskeletal radiologist has shown, the characteristic signs of the Madelung deformity were present few years before the final diagnosis was reached, emphasizing once again the importance of multidisciplinary approach and close collaboration of many subspecialists in the care of children with rheumatic diseases. Nevertheless, this lag probably did not influence the therapeutic management in our particular patient; although positive effect on final height was observed with growth hormone therapy in patients with Leri Weill syndrome, due to the matching influence of GC and lack of agreement with her parents, this treatment option was avoided in our patient [35].
In conclusion, this case report emphasizes the difficulties and challenges in management of patient with long-standing polyarticular JIA refractory to wide range of treatment modalities. Although many high-quality guidelines are available for treatment of JIA patients, there is still need for individual reports of difficult to treat cases, especially when additional diagnosis are involved. While Leri Weill syndrome is extensively reported in the literature, to the best of our knowledge, our case report describes it for the first time along with JIA. Taking all these into account, we strongly encourage the aggregation of similar patients and establishment of the common ground that will help clinician to decide upon the introduction of treatment options outside of the contemporary guidelines.
Abbreviations
JIAJuvenile idiopathic arthritis
LSDLysosomal storage disease
MPSMucopolysaccharidosis
NSAIDNonsteroidal anti-inflammatory drug
cDMARDConventional disease modifying anti-rheumatic drug
bDMARDBiologic disease modifying anti-rheumatic drug
IAGIIntraarticular glucocorticoid injection
GCGlucocorticoids
MASMacrophage activation syndrome
TNFiTumor necrosis factor inhibitor
T2TTreat-to-target
RFRheumatoid factor
ESRErythrocyte sedimentation rate
CRPC-reactive protein
ANAAntinuclear antibody
MTXMethotrexate
SLESystemic lupus erythematosus
TNFαTumor necrosis factor alpha
anti-IL-6Anti-interleukin-6
MMFMycophenolate mofetil
MCPMetacarpophalangeal
PIPProximal interphalangeal
DIPDistal interphalangeal
JAKJanus kinase
MRIMagnetic resonance imaging
SHOXShort-stature homeobox
JAK/STATJanus kinase/signal transducer and activator of transcription proteins
SDSStandard deviation score
GnRHGonadotropin-releasing hormone
HPGHypothalamic-pituitary-gonadal
IFXInfliximab
ADAAdalimumab
TOCTocilizumab
ETCEtanercept
CFMCyclophosphamide
RTXRituximab
MTFMetformin
CYCCyclosporine
TFATofacitinib
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Acknowledgements
We thank parents for availability of publishing medical history of their daughter.
Authors’ contributions
VV and AS have equally contributed to the paper. VV: medical charts review, literature search, creation of figures and tables and manuscript draft preparation. AS: medical charts review, literature search, creation of figures and tables and manuscript draft preparation RV: radiographic images interpretation, manuscript draft preparation. MV: clinical care and the final revision of the manuscript. MH: clinical care and the final revision of the manuscript. LL: clinical care, medical charts review, literature search, creation of figures and tables, manuscript draft preparation, final revision of the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. / Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the parents for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | Recovering | ReactionOutcome | CC BY | 33451288 | 18,970,451 | 2021-01-15 |
What was the outcome of reaction 'Delayed menarche'? | Beyond the guidelines management of juvenile idiopathic arthritis: a case report of a girl with polyarticular disease refractory to multiple treatment options and Leri Weill syndrome.
The last two decades brought new treatment options and high quality guidelines into the paediatric rheumatologic practice. Nevertheless, a number of patients still present a diagnostic and therapeutic challenge due to combination of vague symptoms and unresponsiveness to available treatment modalities.
We report a case of sixteen years old girl suffering from polyarticular type of juvenile idiopathic arthritis refractory to multiple treatment options. She first presented at the age of 4 with swelling and contractures of both knees. Her symptoms were initially unresponsive to nonsteroidal anti-inflammatory drugs and progressed despite treatment with intraarticular and systemic glucocorticoids and methotrexate. Throughout the years, she received several biologics together with continuous administration of nonsteroidal anti-inflammatory drugs and disease modifying anti-rheumatic drugs as well as intraarticular and systemic glucocorticoids in disease flares. However, none of this options provided a permanent remission, so various other modalities, as well as other possible diagnoses were constantly being considered. Eventually she became dependent on a daily dose of systemic glucocorticoids. In 2018, the treatment with Janus kinase inhibitor tofacitinib was initiated, which led to gradual amelioration of musculoskeletal symptoms, improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic glucocorticoids. As the swelling of the wrists subsided for the first time in many years, Madelung's deformity was noticed, first clinically, and later radiographically as well. Genetic analysis revealed short-stature homeobox gene deficiency and confirmed the diagnosis of Leri Weill syndrome.
This case report emphasizes the need for reporting refractory, complicated cases from everyday clinical practice in order to build-up the overall knowledge and share experience which is complementary to available guidelines. Individual reports of difficult to treat cases, especially when additional diagnoses are involved, can be helpful for physicians treating patients with common rheumatological diseases such as juvenile idiopathic arthritis.
Background
Joint pain and/or swelling with limited range of motion is a common manifestation of many paediatric diseases, most notably wide range of rheumatic conditions. If both of these symptoms are present for longer than 6 weeks in a patient younger than 16 years of age, a diagnosis of juvenile idiopathic arthritis (JIA), the most common childhood rheumatic disease, should be considered [1]. JIA is heterogenous disease that encompasses different subtypes of childhood arthritis defined depending on the number of affected joints and/or presence of the enthesitis and/or sacroiliitis. Nevertheless, alongside JIA, there is a wide range of loosely related noninflammatory causes of a swollen joint in children, especially in the absence of clinical signs of inflammation. Lysosomal storage diseases (LSD) such as mucopolysaccharidosis type I (MPS I), Gaucher disease type I and Fabry disease all have prominent musculoskeletal symptoms early in the course of the disease, and are often first seen by a pediatric rheumatologist [2–8]. However, the underlying mechanism of those disorders does not directly involve the immune mediated inflammatory response, but rather an inflammation caused by genetic defects and subsequent perturbations at the protein level. More specifically, in Gaucher disease, bone marrow infiltration with histiocytes causes acute attacks of pain, which may be mistaken for arthritis in the vicinity of a joint [5, 8]. In Fabry disease, episodes of neuropathic pain in hands, feet, wrists, ankles (acroparesthesias), often associated with fever, malaise and elevated inflammation markers, can mimic a rheumatic condition, such as an inflammatory arthritis [3, 9]. Finally, joint stiffness and contractures are characteristic for some types of MPS, the so called „attenuated“ forms like Hurler-Scheie syndrome, which have a less severe presentation and progress silently over the years, making the diagnosis a challenge [3, 10, 11]. On the other hand, some congenital conditions, such as Madelung and Madelung-type deformities resulting from the premature closure of the medial volar aspect of the distal radial physis, might cause similar symptoms [12]. Hence, it is not a rarity that some of the children with LSD and congenital deformities are treated for prolonged periods of time as having an inflammatory arthritis, despite the lack of appropriate response [13].
With regard to the treatment of JIA, various modalities emerged over the last two decades, revolutionizing the pediatric rheumatology practice [14]. Majority of the presently available guidelines recommend a step-up approach, starting with nonsteroidal anti-inflammatory drugs (NSAID) and intraarticular glucocorticoid injections (IAGI), followed by conventional and biologic disease modifying anti-rheumatic drugs (cDMARD and bDMARD), respectively [15]. Moreover, despite many known adverse effects, systemic glucocorticoids (GC) are still being used as an important therapeutic option for wide range of complications associated with JIA (e.g., macrophage activation syndrome, myocarditis, pericarditis, pleuritis, peritonitis, uveitis and severe anaemia), as well as a bridge therapy in severe forms of JIA before the full effect of other treatment modalities has been achieved [16]. Those modalities nowadays primarily involve tumor necrosis factor alpha (TNFα) inhibitors (TNFi), such as etanercept, adalimumab and infliximab, and non-TNFi, such as anti-interleukin-6 (anti-IL-6) agent tocilizumab and a selective T-cell co-stimulation modulator abatacept [17, 18]. Furthermore, new medications are continuously being investigated [19, 20].
Together with the expansion of new treatment modalities, efforts have been made to introduce the treat-to-target (T2T) model in pediatric rheumatologic practice [21]. Signs and symptoms control, prevention of structural damage of joints and optimization of linear growth and pubertal development, as well as abolition of inflammation, have all been set as treatment goals. Essentially, this model advocates that therapy should be revised and adjusted based on regular disease activity assessments to reach and maintain the treatment target. Special attention should be paid to preventing or minimizing the side effects of systemic GC given their negative effect on growth and pubertal development. Consequently, their long-term use to maintain treatment target should be avoided, especially considering that GC dependence demonstrates the inadequacy of chosen treatment. The shared decision making, as well as multidisciplinary approach, have been recognized as exceptionally valuable for assurance of better adherence to treatment and subsequently improvement of outcome and overall prognosis.
Unfortunately, despite all these achievements, only 14 % of patients with rheumatoid factor (RF) negative and 0 % with RF positive polyarticular JIA achieves the remission off medications within five years, implying that JIA treatment requires a long-lasting commitment [22]. Hence, it comes as no surprise that every clinician involved in the care of children with JIA patients eventually sees one with disease not responding to acclaimed treatment options (i.e. NSAIDs, cDMARDS, bDMARDS) [15]. At that point, the consideration of additional treatment modalities seems like a valid course of action, but sometimes alternative diagnosis should be considered as well. Here, we present one such case, a girl with long standing polyarticular JIA refractory to many standard treatment modalities, with symptoms suggestive of other diseases.
Case presentation
A four-year-old first came to our attention in February 2008 due to painful swelling and contractures of both knees. Her symptoms started a year earlier and were not associated with any discernible trigger such as infection or trauma. Moreover, the symptoms were not responding to NSAIDs and she soon developed a severe morning stiffness lasting for up to three hours. Her birth history as well as psychomotor development prior to disease evolution was unremarkable. She was born as a first child into a family of non-consanguine parents, with no relatives having the similar symptoms.
The initial laboratory findings showed persistently elevated inflammatory markers (erythrocyte sedimentation rate (ESR) up to 100 mm/h and C-reactive protein (CRP) up to 100 mg/dL), with negative RF and antinuclear antibody (ANA) screen, and normal immunoglobulin levels. Despite the initial treatment with GC and methotrexate (MTX), her symptoms progressed affecting elbows, wrists, ankles and small joints of both hands. Moreover, she developed a severe uveitis of the left eye. In November 2008 biologic therapy with infliximab was started, with initially good response. Unfortunately, this lasted only for a few months and frequent relapses necessitated switching to adalimumab in April 2011. Again, there was an initial period of remission followed by progressive exacerbation characterized by swelling and pain in some joints, and persistent contracture of others. Other diagnosis, such as mucopolysaccharidosis and systemic lupus erythematosus (SLE) were suspected, but metabolic and immunological screening were negative, respectively. Beside ESR and CRP, the increased values of IL-6 (up to 75 pg/mL) and TNF-alfa (up to 20 pg/mL) were measured.
In November 2012 therapy was cycled to non-TNFi, tocilizumab, which led only to a short period of remission. Finally, in September 2014, etanercept was introduced, again with the lack of permanent response. Along with four different bDMARDs she continuously received cDMARD methotrexate, and for a short period of time leflunomide. During the periods of disease flare, bridge therapy with intraarticular and/or systemic GC was used, and soon she was dependent on a daily dose of GC. Eventually, this led to the development of iatrogenic Cushing syndrome with characteristic appearance, growth retardation and low bone mineral density, regardless of the vitamin D and ibandronic acid therapy. Since every attempt to wean off GC inevitably led to disease flare, from June to December 2016 she received cyclophosphamide (6x) and rituximab (3x), again without achieving a sustained remission. Afterwards, for a short period of time she was given metformin but without an appropriate improvement in musculoskeletal symptoms (Fig. 1).
Fig. 1 Schematic representation of treatment modalities during the time. 2007 – 2020 - the period of treatment, NSAID - nonsteroidal anti-inflammatory drug, IFX - infliximab, ADA - adalimumab, TOC - tocilizumab, ETC - etanercept, DMARD - disease modifying anti-rheumatic drug, MTX - methotrexate, CFM - cyclophosphamide, RTX - rituximab, MTF - metformin, MMF - mycophenolate mofetil, CYC - cyclosporine, TFA - tofacitinib, p.o. - per os, i.a. - intraarticular, i.v. - intravenous, GC - glucocorticoids
During the 2017, at the age of 13, the trial of mycophenolate mofetil (MMF) followed by the trial of cyclosporin was initiated, but the patient nevertheless remained GC dependent. Both shoulders, elbows, radiocarpal joints, metacarpophalangeal (MCP), proximal interphalangeal (PIP), distal interphalangeal (DIP) joints and both knees had restricted range of movement, and repeated IAGI were necessary to alleviate the symptoms. Finally, in 2018, the treatment with Janus kinase (JAK) inhibitor tofacitinib was initiated, which lead to gradual amelioration of musculoskeletal symptoms and improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic GC. Moreover, as the swelling of the wrists subsided for the first time in many years, Madelung deformity was noticed by clinical examination. Interestingly, it was only then, in 2019, that the deformity was for the first time described on x-ray (Fig. 2), although x-ray and MRI imaging of both hands were previously performed on many occasions in order to assess the inflammation (Figs. 3 and 4). Nevertheless, subsequent analysis by experienced musculoskeletal radiologist revealed characteristic bilateral signs of Madelung deformity dating back in 2015 and 2017 (Fig. 3), with the MRI showing the Vickers and radiotriquetral ligament (Fig. 4). The finding of those two ligaments allowed the distinguishing between Madelung deformity and pseudo-Madelung deformity, which includes post-traumatic and post-infective forms, forms associated with Turner syndrome, multiple hereditary exostoses and Ollier disease [23]. Unfortunately, due to the parent’s refusal, no further radiological assessment was performed, so we have not documented the other important aspects of Madelung deformity, such as radial shortening and diaphysis bowing, nor the mesolimbic shortening of limbs characteristic for Leri Weill syndrome.
Fig. 2 The anteroposterior radiograph of left hand at the age of 14. Note the increased volar angulation of distal radius, wedge shaped carpus with proximally positioned lunate and a characteristic notch on the distal radius (white arrow), which are the features of the Madelung deformity [12]
Fig. 3 The anteroposterior radiograph of both hands at the age of 10 (a) and 13 (b), and of the left hand at the age of 14 (c). Note the bowing of the distal radius, an increased radial inclination (~ 30°) with the deformation of the carpus that acquired a triangular appearance and widening of the distal radial-ulnar joint bilaterally, which are the typical features of Madelung deformity. Dorsal subluxation of the ulnar head is not seen as lateral images of the wrist were not taken. Osteopenia of carpal bones and periarticular osteopenia of MCP, PIP and DIP joints related to JIA are present. No relevant changes are observed during the time
Fig. 4 MRI coronal T1-weighted (a), proton density BLADE fluid sensitive sequence (b), post contrast T1-weighted coronal fat sat sequence (c) and post contrast T1-weighted axial fat sat sequence (d) images of both hands at the age of 13. Note the radiotriquetral ligament (red arrow) and Vickers ligament (green arrow) (a, b). Note the inflammatory changes characterized by postcontrast imbibition in carpal joints and MCP joints (red circle), as well as tenosynovitis of flexor tendons related to JIA, more prominent on the left hand (c, d)
Although our patient was simultaneously followed by pediatric endocrinologist from age of 11, her short stature, along with delayed menarche, and Cushingoid appearance, was attributed to the prolonged use of GC. It was only after the Madelung’s deformity was observed that genetic causes, primarily Leri Weill syndrome, were taken into consideration. Genetic analysis was performed by commercially available SALSA MLPA Probemix P018 SHOX (MRC-Holland, Amsterdam, The Netherland) according to the manufacturer’s recommendations. The MLPA mix included probes for each exon of SHOX, one probe just before the promoter region as well as probes covering a region downstream of the gene. The results revealed one copy of sixteen probes (10 probes for Xp22-PAR1 from CNE2 to CNE9, 4 probes for SHOX area downstream, 1 probe for CRLF2 in PAR1 region and 1 probe for CSF2RA in PAR1 region), with the size of the smallest deletion of 766,5 kb. Based on the genetic testing and imaging findings of Madelung deformity, the diagnosis of Leri Weill syndrome was established, and parents were advised to undergo further genetic testing of both the patient and themselves, which they rejected.
Currently, our patient has many consequences of the adverse course of the disease and prolonged GC treatment, such as joint contractures of elbows, wrists, DIPs, PIPs, hips, knees and MCPs and low bone density, respectively. She developed secondary sex characteristics only after the therapy with estradiol was initiated at the age of 14. Nevertheless, after the discontinuation of GC and subsequent discontinuation of estradiol, she finally had a menarche at the age of 15, along with a long-awaited growth spurt.
Discussion and Conclusion
Children with rheumatic diseases, their families, as well as their treating physicians are dealt with numerous issues and dilemmas regarding either the disease itself or ongoing treatment modalities. Besides, the diagnosis of rheumatic diseases in children is regularly made by excluding wide range of other diseases, with no pathognomonic tests and/or criteria. Therefore, even after the classification criteria are fulfilled, the diagnosis should be revised if new symptoms emerge or if the recommended treatment options are failing.
In our patient, a variety of steroid-sparing agents with different mechanisms of action have been employed with limited or no clinical success. Some of these agents were used in line with current treatment recommendations, but many were used based on anecdotal reports [24–28]. Finally, due to signs of systemic inflammation characterized by increased inflammatory markers (CRP and ESR) and cytokines (IL-6 and TNF-alfa), which is indicative for the activation of JAK/STAT pathway, treatment with tofacitinib, a first generation JAK inhibitor, was initiated with a good clinical response. Several clinical trials in adults with rheumatoid and psoriatic arthritis have given solid evidence about the use of tofacitinib, while the results of a phase 3 randomized double blind placebo controlled withdrawal study in patients with polyarticular JIA showed improvement in symptoms, less disease flares and improved functional ability, together with a clinical amelioration of disease activity [29, 30]. Moreover, tofacitinib is an oral agent, and the challenge of using biologics requiring injection or infusion for an extended length of time, especially in children, should not be overlooked.
Along with the various treatment modalities, the different diagnosis was constantly being considered in our patient. Firstly, due to persistent contracture in some joints with little or no signs of swelling, LSDs such as mucopolysaccharidosis type I, Gaucher disease type I and Fabry disease were investigated. Besides, other inflammatory causes like systemic lupus erythematosus were also excluded. Lastly, the diagnosis of Leri Weill syndrome characterized by deletions in SHOX gene and Madelung deformity was established. This painful deformity of the wrist was first described in 1878 by the German surgeon Otto Madelung in adolescents between the ages 8 and 14 [12]. Although initially asymptomatic, the patients often went on to develop pain, loss of grip strength and reduced mobility, which were the symptoms present in our patient even after the inflammation was tackled with tofacitinib. Moreover, the features of Leri Weill syndrome include the short stature, which was also one of the dominant finding in the presented patient. Yet, the growth deficit caused by SHOX haploinsufficiency in Leri Weill syndrome is around 2 standard deviation scores (SDS) [31], while our patient had a SDS of -5,5. Besides, due to a prolonged use of GC, our patient had a full blown Cushingoid appearance, low bone density, delayed puberty and growth retardation. Therefore, the possible explanation for the short stature and growth delay in our patient includes multifactorial aetiology. Firstly, it is well known that extended GC treatment leads to a defect in bone turnover (and formation) due to impaired osteoblastogenesis and osteoclastogenesis, and may have direct effects on the growth plate [32]. Additionally, higher prepubertal glucocorticoid level appears to delay early and late pubertal timing of healthy girls, particularly the onset of pubertal growth spurt and menarche [33]. Moreover, it has been shown that girls with polyarticular juvenile idiopathic arthritis are significantly more likely to present with short stature even 6 months after stopping the steroid therapy [34]. Finally, the product of SHOX gene is implicated in bone development and regulation of chondrocyte differentiation, which clarifies the association of SHOX gene haploinsufficiency with idiopathic short stature, as well as short stature in Turner syndrome and Leri Weill dyschondrosteosis [31].
In the presented case, the diagnosis of the Madelung deformity and Leri Weill syndrome was delayed due to the concomitant active inflammation caused by JIA taking the focus from other possible causes of pain in the wrists. However, as subsequent analysis by experienced musculoskeletal radiologist has shown, the characteristic signs of the Madelung deformity were present few years before the final diagnosis was reached, emphasizing once again the importance of multidisciplinary approach and close collaboration of many subspecialists in the care of children with rheumatic diseases. Nevertheless, this lag probably did not influence the therapeutic management in our particular patient; although positive effect on final height was observed with growth hormone therapy in patients with Leri Weill syndrome, due to the matching influence of GC and lack of agreement with her parents, this treatment option was avoided in our patient [35].
In conclusion, this case report emphasizes the difficulties and challenges in management of patient with long-standing polyarticular JIA refractory to wide range of treatment modalities. Although many high-quality guidelines are available for treatment of JIA patients, there is still need for individual reports of difficult to treat cases, especially when additional diagnosis are involved. While Leri Weill syndrome is extensively reported in the literature, to the best of our knowledge, our case report describes it for the first time along with JIA. Taking all these into account, we strongly encourage the aggregation of similar patients and establishment of the common ground that will help clinician to decide upon the introduction of treatment options outside of the contemporary guidelines.
Abbreviations
JIAJuvenile idiopathic arthritis
LSDLysosomal storage disease
MPSMucopolysaccharidosis
NSAIDNonsteroidal anti-inflammatory drug
cDMARDConventional disease modifying anti-rheumatic drug
bDMARDBiologic disease modifying anti-rheumatic drug
IAGIIntraarticular glucocorticoid injection
GCGlucocorticoids
MASMacrophage activation syndrome
TNFiTumor necrosis factor inhibitor
T2TTreat-to-target
RFRheumatoid factor
ESRErythrocyte sedimentation rate
CRPC-reactive protein
ANAAntinuclear antibody
MTXMethotrexate
SLESystemic lupus erythematosus
TNFαTumor necrosis factor alpha
anti-IL-6Anti-interleukin-6
MMFMycophenolate mofetil
MCPMetacarpophalangeal
PIPProximal interphalangeal
DIPDistal interphalangeal
JAKJanus kinase
MRIMagnetic resonance imaging
SHOXShort-stature homeobox
JAK/STATJanus kinase/signal transducer and activator of transcription proteins
SDSStandard deviation score
GnRHGonadotropin-releasing hormone
HPGHypothalamic-pituitary-gonadal
IFXInfliximab
ADAAdalimumab
TOCTocilizumab
ETCEtanercept
CFMCyclophosphamide
RTXRituximab
MTFMetformin
CYCCyclosporine
TFATofacitinib
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank parents for availability of publishing medical history of their daughter.
Authors’ contributions
VV and AS have equally contributed to the paper. VV: medical charts review, literature search, creation of figures and tables and manuscript draft preparation. AS: medical charts review, literature search, creation of figures and tables and manuscript draft preparation RV: radiographic images interpretation, manuscript draft preparation. MV: clinical care and the final revision of the manuscript. MH: clinical care and the final revision of the manuscript. LL: clinical care, medical charts review, literature search, creation of figures and tables, manuscript draft preparation, final revision of the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. / Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the parents for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33451288 | 18,970,451 | 2021-01-15 |
What was the outcome of reaction 'Delayed puberty'? | Beyond the guidelines management of juvenile idiopathic arthritis: a case report of a girl with polyarticular disease refractory to multiple treatment options and Leri Weill syndrome.
The last two decades brought new treatment options and high quality guidelines into the paediatric rheumatologic practice. Nevertheless, a number of patients still present a diagnostic and therapeutic challenge due to combination of vague symptoms and unresponsiveness to available treatment modalities.
We report a case of sixteen years old girl suffering from polyarticular type of juvenile idiopathic arthritis refractory to multiple treatment options. She first presented at the age of 4 with swelling and contractures of both knees. Her symptoms were initially unresponsive to nonsteroidal anti-inflammatory drugs and progressed despite treatment with intraarticular and systemic glucocorticoids and methotrexate. Throughout the years, she received several biologics together with continuous administration of nonsteroidal anti-inflammatory drugs and disease modifying anti-rheumatic drugs as well as intraarticular and systemic glucocorticoids in disease flares. However, none of this options provided a permanent remission, so various other modalities, as well as other possible diagnoses were constantly being considered. Eventually she became dependent on a daily dose of systemic glucocorticoids. In 2018, the treatment with Janus kinase inhibitor tofacitinib was initiated, which led to gradual amelioration of musculoskeletal symptoms, improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic glucocorticoids. As the swelling of the wrists subsided for the first time in many years, Madelung's deformity was noticed, first clinically, and later radiographically as well. Genetic analysis revealed short-stature homeobox gene deficiency and confirmed the diagnosis of Leri Weill syndrome.
This case report emphasizes the need for reporting refractory, complicated cases from everyday clinical practice in order to build-up the overall knowledge and share experience which is complementary to available guidelines. Individual reports of difficult to treat cases, especially when additional diagnoses are involved, can be helpful for physicians treating patients with common rheumatological diseases such as juvenile idiopathic arthritis.
Background
Joint pain and/or swelling with limited range of motion is a common manifestation of many paediatric diseases, most notably wide range of rheumatic conditions. If both of these symptoms are present for longer than 6 weeks in a patient younger than 16 years of age, a diagnosis of juvenile idiopathic arthritis (JIA), the most common childhood rheumatic disease, should be considered [1]. JIA is heterogenous disease that encompasses different subtypes of childhood arthritis defined depending on the number of affected joints and/or presence of the enthesitis and/or sacroiliitis. Nevertheless, alongside JIA, there is a wide range of loosely related noninflammatory causes of a swollen joint in children, especially in the absence of clinical signs of inflammation. Lysosomal storage diseases (LSD) such as mucopolysaccharidosis type I (MPS I), Gaucher disease type I and Fabry disease all have prominent musculoskeletal symptoms early in the course of the disease, and are often first seen by a pediatric rheumatologist [2–8]. However, the underlying mechanism of those disorders does not directly involve the immune mediated inflammatory response, but rather an inflammation caused by genetic defects and subsequent perturbations at the protein level. More specifically, in Gaucher disease, bone marrow infiltration with histiocytes causes acute attacks of pain, which may be mistaken for arthritis in the vicinity of a joint [5, 8]. In Fabry disease, episodes of neuropathic pain in hands, feet, wrists, ankles (acroparesthesias), often associated with fever, malaise and elevated inflammation markers, can mimic a rheumatic condition, such as an inflammatory arthritis [3, 9]. Finally, joint stiffness and contractures are characteristic for some types of MPS, the so called „attenuated“ forms like Hurler-Scheie syndrome, which have a less severe presentation and progress silently over the years, making the diagnosis a challenge [3, 10, 11]. On the other hand, some congenital conditions, such as Madelung and Madelung-type deformities resulting from the premature closure of the medial volar aspect of the distal radial physis, might cause similar symptoms [12]. Hence, it is not a rarity that some of the children with LSD and congenital deformities are treated for prolonged periods of time as having an inflammatory arthritis, despite the lack of appropriate response [13].
With regard to the treatment of JIA, various modalities emerged over the last two decades, revolutionizing the pediatric rheumatology practice [14]. Majority of the presently available guidelines recommend a step-up approach, starting with nonsteroidal anti-inflammatory drugs (NSAID) and intraarticular glucocorticoid injections (IAGI), followed by conventional and biologic disease modifying anti-rheumatic drugs (cDMARD and bDMARD), respectively [15]. Moreover, despite many known adverse effects, systemic glucocorticoids (GC) are still being used as an important therapeutic option for wide range of complications associated with JIA (e.g., macrophage activation syndrome, myocarditis, pericarditis, pleuritis, peritonitis, uveitis and severe anaemia), as well as a bridge therapy in severe forms of JIA before the full effect of other treatment modalities has been achieved [16]. Those modalities nowadays primarily involve tumor necrosis factor alpha (TNFα) inhibitors (TNFi), such as etanercept, adalimumab and infliximab, and non-TNFi, such as anti-interleukin-6 (anti-IL-6) agent tocilizumab and a selective T-cell co-stimulation modulator abatacept [17, 18]. Furthermore, new medications are continuously being investigated [19, 20].
Together with the expansion of new treatment modalities, efforts have been made to introduce the treat-to-target (T2T) model in pediatric rheumatologic practice [21]. Signs and symptoms control, prevention of structural damage of joints and optimization of linear growth and pubertal development, as well as abolition of inflammation, have all been set as treatment goals. Essentially, this model advocates that therapy should be revised and adjusted based on regular disease activity assessments to reach and maintain the treatment target. Special attention should be paid to preventing or minimizing the side effects of systemic GC given their negative effect on growth and pubertal development. Consequently, their long-term use to maintain treatment target should be avoided, especially considering that GC dependence demonstrates the inadequacy of chosen treatment. The shared decision making, as well as multidisciplinary approach, have been recognized as exceptionally valuable for assurance of better adherence to treatment and subsequently improvement of outcome and overall prognosis.
Unfortunately, despite all these achievements, only 14 % of patients with rheumatoid factor (RF) negative and 0 % with RF positive polyarticular JIA achieves the remission off medications within five years, implying that JIA treatment requires a long-lasting commitment [22]. Hence, it comes as no surprise that every clinician involved in the care of children with JIA patients eventually sees one with disease not responding to acclaimed treatment options (i.e. NSAIDs, cDMARDS, bDMARDS) [15]. At that point, the consideration of additional treatment modalities seems like a valid course of action, but sometimes alternative diagnosis should be considered as well. Here, we present one such case, a girl with long standing polyarticular JIA refractory to many standard treatment modalities, with symptoms suggestive of other diseases.
Case presentation
A four-year-old first came to our attention in February 2008 due to painful swelling and contractures of both knees. Her symptoms started a year earlier and were not associated with any discernible trigger such as infection or trauma. Moreover, the symptoms were not responding to NSAIDs and she soon developed a severe morning stiffness lasting for up to three hours. Her birth history as well as psychomotor development prior to disease evolution was unremarkable. She was born as a first child into a family of non-consanguine parents, with no relatives having the similar symptoms.
The initial laboratory findings showed persistently elevated inflammatory markers (erythrocyte sedimentation rate (ESR) up to 100 mm/h and C-reactive protein (CRP) up to 100 mg/dL), with negative RF and antinuclear antibody (ANA) screen, and normal immunoglobulin levels. Despite the initial treatment with GC and methotrexate (MTX), her symptoms progressed affecting elbows, wrists, ankles and small joints of both hands. Moreover, she developed a severe uveitis of the left eye. In November 2008 biologic therapy with infliximab was started, with initially good response. Unfortunately, this lasted only for a few months and frequent relapses necessitated switching to adalimumab in April 2011. Again, there was an initial period of remission followed by progressive exacerbation characterized by swelling and pain in some joints, and persistent contracture of others. Other diagnosis, such as mucopolysaccharidosis and systemic lupus erythematosus (SLE) were suspected, but metabolic and immunological screening were negative, respectively. Beside ESR and CRP, the increased values of IL-6 (up to 75 pg/mL) and TNF-alfa (up to 20 pg/mL) were measured.
In November 2012 therapy was cycled to non-TNFi, tocilizumab, which led only to a short period of remission. Finally, in September 2014, etanercept was introduced, again with the lack of permanent response. Along with four different bDMARDs she continuously received cDMARD methotrexate, and for a short period of time leflunomide. During the periods of disease flare, bridge therapy with intraarticular and/or systemic GC was used, and soon she was dependent on a daily dose of GC. Eventually, this led to the development of iatrogenic Cushing syndrome with characteristic appearance, growth retardation and low bone mineral density, regardless of the vitamin D and ibandronic acid therapy. Since every attempt to wean off GC inevitably led to disease flare, from June to December 2016 she received cyclophosphamide (6x) and rituximab (3x), again without achieving a sustained remission. Afterwards, for a short period of time she was given metformin but without an appropriate improvement in musculoskeletal symptoms (Fig. 1).
Fig. 1 Schematic representation of treatment modalities during the time. 2007 – 2020 - the period of treatment, NSAID - nonsteroidal anti-inflammatory drug, IFX - infliximab, ADA - adalimumab, TOC - tocilizumab, ETC - etanercept, DMARD - disease modifying anti-rheumatic drug, MTX - methotrexate, CFM - cyclophosphamide, RTX - rituximab, MTF - metformin, MMF - mycophenolate mofetil, CYC - cyclosporine, TFA - tofacitinib, p.o. - per os, i.a. - intraarticular, i.v. - intravenous, GC - glucocorticoids
During the 2017, at the age of 13, the trial of mycophenolate mofetil (MMF) followed by the trial of cyclosporin was initiated, but the patient nevertheless remained GC dependent. Both shoulders, elbows, radiocarpal joints, metacarpophalangeal (MCP), proximal interphalangeal (PIP), distal interphalangeal (DIP) joints and both knees had restricted range of movement, and repeated IAGI were necessary to alleviate the symptoms. Finally, in 2018, the treatment with Janus kinase (JAK) inhibitor tofacitinib was initiated, which lead to gradual amelioration of musculoskeletal symptoms and improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic GC. Moreover, as the swelling of the wrists subsided for the first time in many years, Madelung deformity was noticed by clinical examination. Interestingly, it was only then, in 2019, that the deformity was for the first time described on x-ray (Fig. 2), although x-ray and MRI imaging of both hands were previously performed on many occasions in order to assess the inflammation (Figs. 3 and 4). Nevertheless, subsequent analysis by experienced musculoskeletal radiologist revealed characteristic bilateral signs of Madelung deformity dating back in 2015 and 2017 (Fig. 3), with the MRI showing the Vickers and radiotriquetral ligament (Fig. 4). The finding of those two ligaments allowed the distinguishing between Madelung deformity and pseudo-Madelung deformity, which includes post-traumatic and post-infective forms, forms associated with Turner syndrome, multiple hereditary exostoses and Ollier disease [23]. Unfortunately, due to the parent’s refusal, no further radiological assessment was performed, so we have not documented the other important aspects of Madelung deformity, such as radial shortening and diaphysis bowing, nor the mesolimbic shortening of limbs characteristic for Leri Weill syndrome.
Fig. 2 The anteroposterior radiograph of left hand at the age of 14. Note the increased volar angulation of distal radius, wedge shaped carpus with proximally positioned lunate and a characteristic notch on the distal radius (white arrow), which are the features of the Madelung deformity [12]
Fig. 3 The anteroposterior radiograph of both hands at the age of 10 (a) and 13 (b), and of the left hand at the age of 14 (c). Note the bowing of the distal radius, an increased radial inclination (~ 30°) with the deformation of the carpus that acquired a triangular appearance and widening of the distal radial-ulnar joint bilaterally, which are the typical features of Madelung deformity. Dorsal subluxation of the ulnar head is not seen as lateral images of the wrist were not taken. Osteopenia of carpal bones and periarticular osteopenia of MCP, PIP and DIP joints related to JIA are present. No relevant changes are observed during the time
Fig. 4 MRI coronal T1-weighted (a), proton density BLADE fluid sensitive sequence (b), post contrast T1-weighted coronal fat sat sequence (c) and post contrast T1-weighted axial fat sat sequence (d) images of both hands at the age of 13. Note the radiotriquetral ligament (red arrow) and Vickers ligament (green arrow) (a, b). Note the inflammatory changes characterized by postcontrast imbibition in carpal joints and MCP joints (red circle), as well as tenosynovitis of flexor tendons related to JIA, more prominent on the left hand (c, d)
Although our patient was simultaneously followed by pediatric endocrinologist from age of 11, her short stature, along with delayed menarche, and Cushingoid appearance, was attributed to the prolonged use of GC. It was only after the Madelung’s deformity was observed that genetic causes, primarily Leri Weill syndrome, were taken into consideration. Genetic analysis was performed by commercially available SALSA MLPA Probemix P018 SHOX (MRC-Holland, Amsterdam, The Netherland) according to the manufacturer’s recommendations. The MLPA mix included probes for each exon of SHOX, one probe just before the promoter region as well as probes covering a region downstream of the gene. The results revealed one copy of sixteen probes (10 probes for Xp22-PAR1 from CNE2 to CNE9, 4 probes for SHOX area downstream, 1 probe for CRLF2 in PAR1 region and 1 probe for CSF2RA in PAR1 region), with the size of the smallest deletion of 766,5 kb. Based on the genetic testing and imaging findings of Madelung deformity, the diagnosis of Leri Weill syndrome was established, and parents were advised to undergo further genetic testing of both the patient and themselves, which they rejected.
Currently, our patient has many consequences of the adverse course of the disease and prolonged GC treatment, such as joint contractures of elbows, wrists, DIPs, PIPs, hips, knees and MCPs and low bone density, respectively. She developed secondary sex characteristics only after the therapy with estradiol was initiated at the age of 14. Nevertheless, after the discontinuation of GC and subsequent discontinuation of estradiol, she finally had a menarche at the age of 15, along with a long-awaited growth spurt.
Discussion and Conclusion
Children with rheumatic diseases, their families, as well as their treating physicians are dealt with numerous issues and dilemmas regarding either the disease itself or ongoing treatment modalities. Besides, the diagnosis of rheumatic diseases in children is regularly made by excluding wide range of other diseases, with no pathognomonic tests and/or criteria. Therefore, even after the classification criteria are fulfilled, the diagnosis should be revised if new symptoms emerge or if the recommended treatment options are failing.
In our patient, a variety of steroid-sparing agents with different mechanisms of action have been employed with limited or no clinical success. Some of these agents were used in line with current treatment recommendations, but many were used based on anecdotal reports [24–28]. Finally, due to signs of systemic inflammation characterized by increased inflammatory markers (CRP and ESR) and cytokines (IL-6 and TNF-alfa), which is indicative for the activation of JAK/STAT pathway, treatment with tofacitinib, a first generation JAK inhibitor, was initiated with a good clinical response. Several clinical trials in adults with rheumatoid and psoriatic arthritis have given solid evidence about the use of tofacitinib, while the results of a phase 3 randomized double blind placebo controlled withdrawal study in patients with polyarticular JIA showed improvement in symptoms, less disease flares and improved functional ability, together with a clinical amelioration of disease activity [29, 30]. Moreover, tofacitinib is an oral agent, and the challenge of using biologics requiring injection or infusion for an extended length of time, especially in children, should not be overlooked.
Along with the various treatment modalities, the different diagnosis was constantly being considered in our patient. Firstly, due to persistent contracture in some joints with little or no signs of swelling, LSDs such as mucopolysaccharidosis type I, Gaucher disease type I and Fabry disease were investigated. Besides, other inflammatory causes like systemic lupus erythematosus were also excluded. Lastly, the diagnosis of Leri Weill syndrome characterized by deletions in SHOX gene and Madelung deformity was established. This painful deformity of the wrist was first described in 1878 by the German surgeon Otto Madelung in adolescents between the ages 8 and 14 [12]. Although initially asymptomatic, the patients often went on to develop pain, loss of grip strength and reduced mobility, which were the symptoms present in our patient even after the inflammation was tackled with tofacitinib. Moreover, the features of Leri Weill syndrome include the short stature, which was also one of the dominant finding in the presented patient. Yet, the growth deficit caused by SHOX haploinsufficiency in Leri Weill syndrome is around 2 standard deviation scores (SDS) [31], while our patient had a SDS of -5,5. Besides, due to a prolonged use of GC, our patient had a full blown Cushingoid appearance, low bone density, delayed puberty and growth retardation. Therefore, the possible explanation for the short stature and growth delay in our patient includes multifactorial aetiology. Firstly, it is well known that extended GC treatment leads to a defect in bone turnover (and formation) due to impaired osteoblastogenesis and osteoclastogenesis, and may have direct effects on the growth plate [32]. Additionally, higher prepubertal glucocorticoid level appears to delay early and late pubertal timing of healthy girls, particularly the onset of pubertal growth spurt and menarche [33]. Moreover, it has been shown that girls with polyarticular juvenile idiopathic arthritis are significantly more likely to present with short stature even 6 months after stopping the steroid therapy [34]. Finally, the product of SHOX gene is implicated in bone development and regulation of chondrocyte differentiation, which clarifies the association of SHOX gene haploinsufficiency with idiopathic short stature, as well as short stature in Turner syndrome and Leri Weill dyschondrosteosis [31].
In the presented case, the diagnosis of the Madelung deformity and Leri Weill syndrome was delayed due to the concomitant active inflammation caused by JIA taking the focus from other possible causes of pain in the wrists. However, as subsequent analysis by experienced musculoskeletal radiologist has shown, the characteristic signs of the Madelung deformity were present few years before the final diagnosis was reached, emphasizing once again the importance of multidisciplinary approach and close collaboration of many subspecialists in the care of children with rheumatic diseases. Nevertheless, this lag probably did not influence the therapeutic management in our particular patient; although positive effect on final height was observed with growth hormone therapy in patients with Leri Weill syndrome, due to the matching influence of GC and lack of agreement with her parents, this treatment option was avoided in our patient [35].
In conclusion, this case report emphasizes the difficulties and challenges in management of patient with long-standing polyarticular JIA refractory to wide range of treatment modalities. Although many high-quality guidelines are available for treatment of JIA patients, there is still need for individual reports of difficult to treat cases, especially when additional diagnosis are involved. While Leri Weill syndrome is extensively reported in the literature, to the best of our knowledge, our case report describes it for the first time along with JIA. Taking all these into account, we strongly encourage the aggregation of similar patients and establishment of the common ground that will help clinician to decide upon the introduction of treatment options outside of the contemporary guidelines.
Abbreviations
JIAJuvenile idiopathic arthritis
LSDLysosomal storage disease
MPSMucopolysaccharidosis
NSAIDNonsteroidal anti-inflammatory drug
cDMARDConventional disease modifying anti-rheumatic drug
bDMARDBiologic disease modifying anti-rheumatic drug
IAGIIntraarticular glucocorticoid injection
GCGlucocorticoids
MASMacrophage activation syndrome
TNFiTumor necrosis factor inhibitor
T2TTreat-to-target
RFRheumatoid factor
ESRErythrocyte sedimentation rate
CRPC-reactive protein
ANAAntinuclear antibody
MTXMethotrexate
SLESystemic lupus erythematosus
TNFαTumor necrosis factor alpha
anti-IL-6Anti-interleukin-6
MMFMycophenolate mofetil
MCPMetacarpophalangeal
PIPProximal interphalangeal
DIPDistal interphalangeal
JAKJanus kinase
MRIMagnetic resonance imaging
SHOXShort-stature homeobox
JAK/STATJanus kinase/signal transducer and activator of transcription proteins
SDSStandard deviation score
GnRHGonadotropin-releasing hormone
HPGHypothalamic-pituitary-gonadal
IFXInfliximab
ADAAdalimumab
TOCTocilizumab
ETCEtanercept
CFMCyclophosphamide
RTXRituximab
MTFMetformin
CYCCyclosporine
TFATofacitinib
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank parents for availability of publishing medical history of their daughter.
Authors’ contributions
VV and AS have equally contributed to the paper. VV: medical charts review, literature search, creation of figures and tables and manuscript draft preparation. AS: medical charts review, literature search, creation of figures and tables and manuscript draft preparation RV: radiographic images interpretation, manuscript draft preparation. MV: clinical care and the final revision of the manuscript. MH: clinical care and the final revision of the manuscript. LL: clinical care, medical charts review, literature search, creation of figures and tables, manuscript draft preparation, final revision of the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. / Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the parents for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | Recovering | ReactionOutcome | CC BY | 33451288 | 18,970,451 | 2021-01-15 |
What was the outcome of reaction 'Growth retardation'? | Beyond the guidelines management of juvenile idiopathic arthritis: a case report of a girl with polyarticular disease refractory to multiple treatment options and Leri Weill syndrome.
The last two decades brought new treatment options and high quality guidelines into the paediatric rheumatologic practice. Nevertheless, a number of patients still present a diagnostic and therapeutic challenge due to combination of vague symptoms and unresponsiveness to available treatment modalities.
We report a case of sixteen years old girl suffering from polyarticular type of juvenile idiopathic arthritis refractory to multiple treatment options. She first presented at the age of 4 with swelling and contractures of both knees. Her symptoms were initially unresponsive to nonsteroidal anti-inflammatory drugs and progressed despite treatment with intraarticular and systemic glucocorticoids and methotrexate. Throughout the years, she received several biologics together with continuous administration of nonsteroidal anti-inflammatory drugs and disease modifying anti-rheumatic drugs as well as intraarticular and systemic glucocorticoids in disease flares. However, none of this options provided a permanent remission, so various other modalities, as well as other possible diagnoses were constantly being considered. Eventually she became dependent on a daily dose of systemic glucocorticoids. In 2018, the treatment with Janus kinase inhibitor tofacitinib was initiated, which led to gradual amelioration of musculoskeletal symptoms, improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic glucocorticoids. As the swelling of the wrists subsided for the first time in many years, Madelung's deformity was noticed, first clinically, and later radiographically as well. Genetic analysis revealed short-stature homeobox gene deficiency and confirmed the diagnosis of Leri Weill syndrome.
This case report emphasizes the need for reporting refractory, complicated cases from everyday clinical practice in order to build-up the overall knowledge and share experience which is complementary to available guidelines. Individual reports of difficult to treat cases, especially when additional diagnoses are involved, can be helpful for physicians treating patients with common rheumatological diseases such as juvenile idiopathic arthritis.
Background
Joint pain and/or swelling with limited range of motion is a common manifestation of many paediatric diseases, most notably wide range of rheumatic conditions. If both of these symptoms are present for longer than 6 weeks in a patient younger than 16 years of age, a diagnosis of juvenile idiopathic arthritis (JIA), the most common childhood rheumatic disease, should be considered [1]. JIA is heterogenous disease that encompasses different subtypes of childhood arthritis defined depending on the number of affected joints and/or presence of the enthesitis and/or sacroiliitis. Nevertheless, alongside JIA, there is a wide range of loosely related noninflammatory causes of a swollen joint in children, especially in the absence of clinical signs of inflammation. Lysosomal storage diseases (LSD) such as mucopolysaccharidosis type I (MPS I), Gaucher disease type I and Fabry disease all have prominent musculoskeletal symptoms early in the course of the disease, and are often first seen by a pediatric rheumatologist [2–8]. However, the underlying mechanism of those disorders does not directly involve the immune mediated inflammatory response, but rather an inflammation caused by genetic defects and subsequent perturbations at the protein level. More specifically, in Gaucher disease, bone marrow infiltration with histiocytes causes acute attacks of pain, which may be mistaken for arthritis in the vicinity of a joint [5, 8]. In Fabry disease, episodes of neuropathic pain in hands, feet, wrists, ankles (acroparesthesias), often associated with fever, malaise and elevated inflammation markers, can mimic a rheumatic condition, such as an inflammatory arthritis [3, 9]. Finally, joint stiffness and contractures are characteristic for some types of MPS, the so called „attenuated“ forms like Hurler-Scheie syndrome, which have a less severe presentation and progress silently over the years, making the diagnosis a challenge [3, 10, 11]. On the other hand, some congenital conditions, such as Madelung and Madelung-type deformities resulting from the premature closure of the medial volar aspect of the distal radial physis, might cause similar symptoms [12]. Hence, it is not a rarity that some of the children with LSD and congenital deformities are treated for prolonged periods of time as having an inflammatory arthritis, despite the lack of appropriate response [13].
With regard to the treatment of JIA, various modalities emerged over the last two decades, revolutionizing the pediatric rheumatology practice [14]. Majority of the presently available guidelines recommend a step-up approach, starting with nonsteroidal anti-inflammatory drugs (NSAID) and intraarticular glucocorticoid injections (IAGI), followed by conventional and biologic disease modifying anti-rheumatic drugs (cDMARD and bDMARD), respectively [15]. Moreover, despite many known adverse effects, systemic glucocorticoids (GC) are still being used as an important therapeutic option for wide range of complications associated with JIA (e.g., macrophage activation syndrome, myocarditis, pericarditis, pleuritis, peritonitis, uveitis and severe anaemia), as well as a bridge therapy in severe forms of JIA before the full effect of other treatment modalities has been achieved [16]. Those modalities nowadays primarily involve tumor necrosis factor alpha (TNFα) inhibitors (TNFi), such as etanercept, adalimumab and infliximab, and non-TNFi, such as anti-interleukin-6 (anti-IL-6) agent tocilizumab and a selective T-cell co-stimulation modulator abatacept [17, 18]. Furthermore, new medications are continuously being investigated [19, 20].
Together with the expansion of new treatment modalities, efforts have been made to introduce the treat-to-target (T2T) model in pediatric rheumatologic practice [21]. Signs and symptoms control, prevention of structural damage of joints and optimization of linear growth and pubertal development, as well as abolition of inflammation, have all been set as treatment goals. Essentially, this model advocates that therapy should be revised and adjusted based on regular disease activity assessments to reach and maintain the treatment target. Special attention should be paid to preventing or minimizing the side effects of systemic GC given their negative effect on growth and pubertal development. Consequently, their long-term use to maintain treatment target should be avoided, especially considering that GC dependence demonstrates the inadequacy of chosen treatment. The shared decision making, as well as multidisciplinary approach, have been recognized as exceptionally valuable for assurance of better adherence to treatment and subsequently improvement of outcome and overall prognosis.
Unfortunately, despite all these achievements, only 14 % of patients with rheumatoid factor (RF) negative and 0 % with RF positive polyarticular JIA achieves the remission off medications within five years, implying that JIA treatment requires a long-lasting commitment [22]. Hence, it comes as no surprise that every clinician involved in the care of children with JIA patients eventually sees one with disease not responding to acclaimed treatment options (i.e. NSAIDs, cDMARDS, bDMARDS) [15]. At that point, the consideration of additional treatment modalities seems like a valid course of action, but sometimes alternative diagnosis should be considered as well. Here, we present one such case, a girl with long standing polyarticular JIA refractory to many standard treatment modalities, with symptoms suggestive of other diseases.
Case presentation
A four-year-old first came to our attention in February 2008 due to painful swelling and contractures of both knees. Her symptoms started a year earlier and were not associated with any discernible trigger such as infection or trauma. Moreover, the symptoms were not responding to NSAIDs and she soon developed a severe morning stiffness lasting for up to three hours. Her birth history as well as psychomotor development prior to disease evolution was unremarkable. She was born as a first child into a family of non-consanguine parents, with no relatives having the similar symptoms.
The initial laboratory findings showed persistently elevated inflammatory markers (erythrocyte sedimentation rate (ESR) up to 100 mm/h and C-reactive protein (CRP) up to 100 mg/dL), with negative RF and antinuclear antibody (ANA) screen, and normal immunoglobulin levels. Despite the initial treatment with GC and methotrexate (MTX), her symptoms progressed affecting elbows, wrists, ankles and small joints of both hands. Moreover, she developed a severe uveitis of the left eye. In November 2008 biologic therapy with infliximab was started, with initially good response. Unfortunately, this lasted only for a few months and frequent relapses necessitated switching to adalimumab in April 2011. Again, there was an initial period of remission followed by progressive exacerbation characterized by swelling and pain in some joints, and persistent contracture of others. Other diagnosis, such as mucopolysaccharidosis and systemic lupus erythematosus (SLE) were suspected, but metabolic and immunological screening were negative, respectively. Beside ESR and CRP, the increased values of IL-6 (up to 75 pg/mL) and TNF-alfa (up to 20 pg/mL) were measured.
In November 2012 therapy was cycled to non-TNFi, tocilizumab, which led only to a short period of remission. Finally, in September 2014, etanercept was introduced, again with the lack of permanent response. Along with four different bDMARDs she continuously received cDMARD methotrexate, and for a short period of time leflunomide. During the periods of disease flare, bridge therapy with intraarticular and/or systemic GC was used, and soon she was dependent on a daily dose of GC. Eventually, this led to the development of iatrogenic Cushing syndrome with characteristic appearance, growth retardation and low bone mineral density, regardless of the vitamin D and ibandronic acid therapy. Since every attempt to wean off GC inevitably led to disease flare, from June to December 2016 she received cyclophosphamide (6x) and rituximab (3x), again without achieving a sustained remission. Afterwards, for a short period of time she was given metformin but without an appropriate improvement in musculoskeletal symptoms (Fig. 1).
Fig. 1 Schematic representation of treatment modalities during the time. 2007 – 2020 - the period of treatment, NSAID - nonsteroidal anti-inflammatory drug, IFX - infliximab, ADA - adalimumab, TOC - tocilizumab, ETC - etanercept, DMARD - disease modifying anti-rheumatic drug, MTX - methotrexate, CFM - cyclophosphamide, RTX - rituximab, MTF - metformin, MMF - mycophenolate mofetil, CYC - cyclosporine, TFA - tofacitinib, p.o. - per os, i.a. - intraarticular, i.v. - intravenous, GC - glucocorticoids
During the 2017, at the age of 13, the trial of mycophenolate mofetil (MMF) followed by the trial of cyclosporin was initiated, but the patient nevertheless remained GC dependent. Both shoulders, elbows, radiocarpal joints, metacarpophalangeal (MCP), proximal interphalangeal (PIP), distal interphalangeal (DIP) joints and both knees had restricted range of movement, and repeated IAGI were necessary to alleviate the symptoms. Finally, in 2018, the treatment with Janus kinase (JAK) inhibitor tofacitinib was initiated, which lead to gradual amelioration of musculoskeletal symptoms and improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic GC. Moreover, as the swelling of the wrists subsided for the first time in many years, Madelung deformity was noticed by clinical examination. Interestingly, it was only then, in 2019, that the deformity was for the first time described on x-ray (Fig. 2), although x-ray and MRI imaging of both hands were previously performed on many occasions in order to assess the inflammation (Figs. 3 and 4). Nevertheless, subsequent analysis by experienced musculoskeletal radiologist revealed characteristic bilateral signs of Madelung deformity dating back in 2015 and 2017 (Fig. 3), with the MRI showing the Vickers and radiotriquetral ligament (Fig. 4). The finding of those two ligaments allowed the distinguishing between Madelung deformity and pseudo-Madelung deformity, which includes post-traumatic and post-infective forms, forms associated with Turner syndrome, multiple hereditary exostoses and Ollier disease [23]. Unfortunately, due to the parent’s refusal, no further radiological assessment was performed, so we have not documented the other important aspects of Madelung deformity, such as radial shortening and diaphysis bowing, nor the mesolimbic shortening of limbs characteristic for Leri Weill syndrome.
Fig. 2 The anteroposterior radiograph of left hand at the age of 14. Note the increased volar angulation of distal radius, wedge shaped carpus with proximally positioned lunate and a characteristic notch on the distal radius (white arrow), which are the features of the Madelung deformity [12]
Fig. 3 The anteroposterior radiograph of both hands at the age of 10 (a) and 13 (b), and of the left hand at the age of 14 (c). Note the bowing of the distal radius, an increased radial inclination (~ 30°) with the deformation of the carpus that acquired a triangular appearance and widening of the distal radial-ulnar joint bilaterally, which are the typical features of Madelung deformity. Dorsal subluxation of the ulnar head is not seen as lateral images of the wrist were not taken. Osteopenia of carpal bones and periarticular osteopenia of MCP, PIP and DIP joints related to JIA are present. No relevant changes are observed during the time
Fig. 4 MRI coronal T1-weighted (a), proton density BLADE fluid sensitive sequence (b), post contrast T1-weighted coronal fat sat sequence (c) and post contrast T1-weighted axial fat sat sequence (d) images of both hands at the age of 13. Note the radiotriquetral ligament (red arrow) and Vickers ligament (green arrow) (a, b). Note the inflammatory changes characterized by postcontrast imbibition in carpal joints and MCP joints (red circle), as well as tenosynovitis of flexor tendons related to JIA, more prominent on the left hand (c, d)
Although our patient was simultaneously followed by pediatric endocrinologist from age of 11, her short stature, along with delayed menarche, and Cushingoid appearance, was attributed to the prolonged use of GC. It was only after the Madelung’s deformity was observed that genetic causes, primarily Leri Weill syndrome, were taken into consideration. Genetic analysis was performed by commercially available SALSA MLPA Probemix P018 SHOX (MRC-Holland, Amsterdam, The Netherland) according to the manufacturer’s recommendations. The MLPA mix included probes for each exon of SHOX, one probe just before the promoter region as well as probes covering a region downstream of the gene. The results revealed one copy of sixteen probes (10 probes for Xp22-PAR1 from CNE2 to CNE9, 4 probes for SHOX area downstream, 1 probe for CRLF2 in PAR1 region and 1 probe for CSF2RA in PAR1 region), with the size of the smallest deletion of 766,5 kb. Based on the genetic testing and imaging findings of Madelung deformity, the diagnosis of Leri Weill syndrome was established, and parents were advised to undergo further genetic testing of both the patient and themselves, which they rejected.
Currently, our patient has many consequences of the adverse course of the disease and prolonged GC treatment, such as joint contractures of elbows, wrists, DIPs, PIPs, hips, knees and MCPs and low bone density, respectively. She developed secondary sex characteristics only after the therapy with estradiol was initiated at the age of 14. Nevertheless, after the discontinuation of GC and subsequent discontinuation of estradiol, she finally had a menarche at the age of 15, along with a long-awaited growth spurt.
Discussion and Conclusion
Children with rheumatic diseases, their families, as well as their treating physicians are dealt with numerous issues and dilemmas regarding either the disease itself or ongoing treatment modalities. Besides, the diagnosis of rheumatic diseases in children is regularly made by excluding wide range of other diseases, with no pathognomonic tests and/or criteria. Therefore, even after the classification criteria are fulfilled, the diagnosis should be revised if new symptoms emerge or if the recommended treatment options are failing.
In our patient, a variety of steroid-sparing agents with different mechanisms of action have been employed with limited or no clinical success. Some of these agents were used in line with current treatment recommendations, but many were used based on anecdotal reports [24–28]. Finally, due to signs of systemic inflammation characterized by increased inflammatory markers (CRP and ESR) and cytokines (IL-6 and TNF-alfa), which is indicative for the activation of JAK/STAT pathway, treatment with tofacitinib, a first generation JAK inhibitor, was initiated with a good clinical response. Several clinical trials in adults with rheumatoid and psoriatic arthritis have given solid evidence about the use of tofacitinib, while the results of a phase 3 randomized double blind placebo controlled withdrawal study in patients with polyarticular JIA showed improvement in symptoms, less disease flares and improved functional ability, together with a clinical amelioration of disease activity [29, 30]. Moreover, tofacitinib is an oral agent, and the challenge of using biologics requiring injection or infusion for an extended length of time, especially in children, should not be overlooked.
Along with the various treatment modalities, the different diagnosis was constantly being considered in our patient. Firstly, due to persistent contracture in some joints with little or no signs of swelling, LSDs such as mucopolysaccharidosis type I, Gaucher disease type I and Fabry disease were investigated. Besides, other inflammatory causes like systemic lupus erythematosus were also excluded. Lastly, the diagnosis of Leri Weill syndrome characterized by deletions in SHOX gene and Madelung deformity was established. This painful deformity of the wrist was first described in 1878 by the German surgeon Otto Madelung in adolescents between the ages 8 and 14 [12]. Although initially asymptomatic, the patients often went on to develop pain, loss of grip strength and reduced mobility, which were the symptoms present in our patient even after the inflammation was tackled with tofacitinib. Moreover, the features of Leri Weill syndrome include the short stature, which was also one of the dominant finding in the presented patient. Yet, the growth deficit caused by SHOX haploinsufficiency in Leri Weill syndrome is around 2 standard deviation scores (SDS) [31], while our patient had a SDS of -5,5. Besides, due to a prolonged use of GC, our patient had a full blown Cushingoid appearance, low bone density, delayed puberty and growth retardation. Therefore, the possible explanation for the short stature and growth delay in our patient includes multifactorial aetiology. Firstly, it is well known that extended GC treatment leads to a defect in bone turnover (and formation) due to impaired osteoblastogenesis and osteoclastogenesis, and may have direct effects on the growth plate [32]. Additionally, higher prepubertal glucocorticoid level appears to delay early and late pubertal timing of healthy girls, particularly the onset of pubertal growth spurt and menarche [33]. Moreover, it has been shown that girls with polyarticular juvenile idiopathic arthritis are significantly more likely to present with short stature even 6 months after stopping the steroid therapy [34]. Finally, the product of SHOX gene is implicated in bone development and regulation of chondrocyte differentiation, which clarifies the association of SHOX gene haploinsufficiency with idiopathic short stature, as well as short stature in Turner syndrome and Leri Weill dyschondrosteosis [31].
In the presented case, the diagnosis of the Madelung deformity and Leri Weill syndrome was delayed due to the concomitant active inflammation caused by JIA taking the focus from other possible causes of pain in the wrists. However, as subsequent analysis by experienced musculoskeletal radiologist has shown, the characteristic signs of the Madelung deformity were present few years before the final diagnosis was reached, emphasizing once again the importance of multidisciplinary approach and close collaboration of many subspecialists in the care of children with rheumatic diseases. Nevertheless, this lag probably did not influence the therapeutic management in our particular patient; although positive effect on final height was observed with growth hormone therapy in patients with Leri Weill syndrome, due to the matching influence of GC and lack of agreement with her parents, this treatment option was avoided in our patient [35].
In conclusion, this case report emphasizes the difficulties and challenges in management of patient with long-standing polyarticular JIA refractory to wide range of treatment modalities. Although many high-quality guidelines are available for treatment of JIA patients, there is still need for individual reports of difficult to treat cases, especially when additional diagnosis are involved. While Leri Weill syndrome is extensively reported in the literature, to the best of our knowledge, our case report describes it for the first time along with JIA. Taking all these into account, we strongly encourage the aggregation of similar patients and establishment of the common ground that will help clinician to decide upon the introduction of treatment options outside of the contemporary guidelines.
Abbreviations
JIAJuvenile idiopathic arthritis
LSDLysosomal storage disease
MPSMucopolysaccharidosis
NSAIDNonsteroidal anti-inflammatory drug
cDMARDConventional disease modifying anti-rheumatic drug
bDMARDBiologic disease modifying anti-rheumatic drug
IAGIIntraarticular glucocorticoid injection
GCGlucocorticoids
MASMacrophage activation syndrome
TNFiTumor necrosis factor inhibitor
T2TTreat-to-target
RFRheumatoid factor
ESRErythrocyte sedimentation rate
CRPC-reactive protein
ANAAntinuclear antibody
MTXMethotrexate
SLESystemic lupus erythematosus
TNFαTumor necrosis factor alpha
anti-IL-6Anti-interleukin-6
MMFMycophenolate mofetil
MCPMetacarpophalangeal
PIPProximal interphalangeal
DIPDistal interphalangeal
JAKJanus kinase
MRIMagnetic resonance imaging
SHOXShort-stature homeobox
JAK/STATJanus kinase/signal transducer and activator of transcription proteins
SDSStandard deviation score
GnRHGonadotropin-releasing hormone
HPGHypothalamic-pituitary-gonadal
IFXInfliximab
ADAAdalimumab
TOCTocilizumab
ETCEtanercept
CFMCyclophosphamide
RTXRituximab
MTFMetformin
CYCCyclosporine
TFATofacitinib
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Acknowledgements
We thank parents for availability of publishing medical history of their daughter.
Authors’ contributions
VV and AS have equally contributed to the paper. VV: medical charts review, literature search, creation of figures and tables and manuscript draft preparation. AS: medical charts review, literature search, creation of figures and tables and manuscript draft preparation RV: radiographic images interpretation, manuscript draft preparation. MV: clinical care and the final revision of the manuscript. MH: clinical care and the final revision of the manuscript. LL: clinical care, medical charts review, literature search, creation of figures and tables, manuscript draft preparation, final revision of the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. / Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the parents for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | Recovering | ReactionOutcome | CC BY | 33451288 | 18,970,451 | 2021-01-15 |
What was the outcome of reaction 'Short stature'? | Beyond the guidelines management of juvenile idiopathic arthritis: a case report of a girl with polyarticular disease refractory to multiple treatment options and Leri Weill syndrome.
The last two decades brought new treatment options and high quality guidelines into the paediatric rheumatologic practice. Nevertheless, a number of patients still present a diagnostic and therapeutic challenge due to combination of vague symptoms and unresponsiveness to available treatment modalities.
We report a case of sixteen years old girl suffering from polyarticular type of juvenile idiopathic arthritis refractory to multiple treatment options. She first presented at the age of 4 with swelling and contractures of both knees. Her symptoms were initially unresponsive to nonsteroidal anti-inflammatory drugs and progressed despite treatment with intraarticular and systemic glucocorticoids and methotrexate. Throughout the years, she received several biologics together with continuous administration of nonsteroidal anti-inflammatory drugs and disease modifying anti-rheumatic drugs as well as intraarticular and systemic glucocorticoids in disease flares. However, none of this options provided a permanent remission, so various other modalities, as well as other possible diagnoses were constantly being considered. Eventually she became dependent on a daily dose of systemic glucocorticoids. In 2018, the treatment with Janus kinase inhibitor tofacitinib was initiated, which led to gradual amelioration of musculoskeletal symptoms, improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic glucocorticoids. As the swelling of the wrists subsided for the first time in many years, Madelung's deformity was noticed, first clinically, and later radiographically as well. Genetic analysis revealed short-stature homeobox gene deficiency and confirmed the diagnosis of Leri Weill syndrome.
This case report emphasizes the need for reporting refractory, complicated cases from everyday clinical practice in order to build-up the overall knowledge and share experience which is complementary to available guidelines. Individual reports of difficult to treat cases, especially when additional diagnoses are involved, can be helpful for physicians treating patients with common rheumatological diseases such as juvenile idiopathic arthritis.
Background
Joint pain and/or swelling with limited range of motion is a common manifestation of many paediatric diseases, most notably wide range of rheumatic conditions. If both of these symptoms are present for longer than 6 weeks in a patient younger than 16 years of age, a diagnosis of juvenile idiopathic arthritis (JIA), the most common childhood rheumatic disease, should be considered [1]. JIA is heterogenous disease that encompasses different subtypes of childhood arthritis defined depending on the number of affected joints and/or presence of the enthesitis and/or sacroiliitis. Nevertheless, alongside JIA, there is a wide range of loosely related noninflammatory causes of a swollen joint in children, especially in the absence of clinical signs of inflammation. Lysosomal storage diseases (LSD) such as mucopolysaccharidosis type I (MPS I), Gaucher disease type I and Fabry disease all have prominent musculoskeletal symptoms early in the course of the disease, and are often first seen by a pediatric rheumatologist [2–8]. However, the underlying mechanism of those disorders does not directly involve the immune mediated inflammatory response, but rather an inflammation caused by genetic defects and subsequent perturbations at the protein level. More specifically, in Gaucher disease, bone marrow infiltration with histiocytes causes acute attacks of pain, which may be mistaken for arthritis in the vicinity of a joint [5, 8]. In Fabry disease, episodes of neuropathic pain in hands, feet, wrists, ankles (acroparesthesias), often associated with fever, malaise and elevated inflammation markers, can mimic a rheumatic condition, such as an inflammatory arthritis [3, 9]. Finally, joint stiffness and contractures are characteristic for some types of MPS, the so called „attenuated“ forms like Hurler-Scheie syndrome, which have a less severe presentation and progress silently over the years, making the diagnosis a challenge [3, 10, 11]. On the other hand, some congenital conditions, such as Madelung and Madelung-type deformities resulting from the premature closure of the medial volar aspect of the distal radial physis, might cause similar symptoms [12]. Hence, it is not a rarity that some of the children with LSD and congenital deformities are treated for prolonged periods of time as having an inflammatory arthritis, despite the lack of appropriate response [13].
With regard to the treatment of JIA, various modalities emerged over the last two decades, revolutionizing the pediatric rheumatology practice [14]. Majority of the presently available guidelines recommend a step-up approach, starting with nonsteroidal anti-inflammatory drugs (NSAID) and intraarticular glucocorticoid injections (IAGI), followed by conventional and biologic disease modifying anti-rheumatic drugs (cDMARD and bDMARD), respectively [15]. Moreover, despite many known adverse effects, systemic glucocorticoids (GC) are still being used as an important therapeutic option for wide range of complications associated with JIA (e.g., macrophage activation syndrome, myocarditis, pericarditis, pleuritis, peritonitis, uveitis and severe anaemia), as well as a bridge therapy in severe forms of JIA before the full effect of other treatment modalities has been achieved [16]. Those modalities nowadays primarily involve tumor necrosis factor alpha (TNFα) inhibitors (TNFi), such as etanercept, adalimumab and infliximab, and non-TNFi, such as anti-interleukin-6 (anti-IL-6) agent tocilizumab and a selective T-cell co-stimulation modulator abatacept [17, 18]. Furthermore, new medications are continuously being investigated [19, 20].
Together with the expansion of new treatment modalities, efforts have been made to introduce the treat-to-target (T2T) model in pediatric rheumatologic practice [21]. Signs and symptoms control, prevention of structural damage of joints and optimization of linear growth and pubertal development, as well as abolition of inflammation, have all been set as treatment goals. Essentially, this model advocates that therapy should be revised and adjusted based on regular disease activity assessments to reach and maintain the treatment target. Special attention should be paid to preventing or minimizing the side effects of systemic GC given their negative effect on growth and pubertal development. Consequently, their long-term use to maintain treatment target should be avoided, especially considering that GC dependence demonstrates the inadequacy of chosen treatment. The shared decision making, as well as multidisciplinary approach, have been recognized as exceptionally valuable for assurance of better adherence to treatment and subsequently improvement of outcome and overall prognosis.
Unfortunately, despite all these achievements, only 14 % of patients with rheumatoid factor (RF) negative and 0 % with RF positive polyarticular JIA achieves the remission off medications within five years, implying that JIA treatment requires a long-lasting commitment [22]. Hence, it comes as no surprise that every clinician involved in the care of children with JIA patients eventually sees one with disease not responding to acclaimed treatment options (i.e. NSAIDs, cDMARDS, bDMARDS) [15]. At that point, the consideration of additional treatment modalities seems like a valid course of action, but sometimes alternative diagnosis should be considered as well. Here, we present one such case, a girl with long standing polyarticular JIA refractory to many standard treatment modalities, with symptoms suggestive of other diseases.
Case presentation
A four-year-old first came to our attention in February 2008 due to painful swelling and contractures of both knees. Her symptoms started a year earlier and were not associated with any discernible trigger such as infection or trauma. Moreover, the symptoms were not responding to NSAIDs and she soon developed a severe morning stiffness lasting for up to three hours. Her birth history as well as psychomotor development prior to disease evolution was unremarkable. She was born as a first child into a family of non-consanguine parents, with no relatives having the similar symptoms.
The initial laboratory findings showed persistently elevated inflammatory markers (erythrocyte sedimentation rate (ESR) up to 100 mm/h and C-reactive protein (CRP) up to 100 mg/dL), with negative RF and antinuclear antibody (ANA) screen, and normal immunoglobulin levels. Despite the initial treatment with GC and methotrexate (MTX), her symptoms progressed affecting elbows, wrists, ankles and small joints of both hands. Moreover, she developed a severe uveitis of the left eye. In November 2008 biologic therapy with infliximab was started, with initially good response. Unfortunately, this lasted only for a few months and frequent relapses necessitated switching to adalimumab in April 2011. Again, there was an initial period of remission followed by progressive exacerbation characterized by swelling and pain in some joints, and persistent contracture of others. Other diagnosis, such as mucopolysaccharidosis and systemic lupus erythematosus (SLE) were suspected, but metabolic and immunological screening were negative, respectively. Beside ESR and CRP, the increased values of IL-6 (up to 75 pg/mL) and TNF-alfa (up to 20 pg/mL) were measured.
In November 2012 therapy was cycled to non-TNFi, tocilizumab, which led only to a short period of remission. Finally, in September 2014, etanercept was introduced, again with the lack of permanent response. Along with four different bDMARDs she continuously received cDMARD methotrexate, and for a short period of time leflunomide. During the periods of disease flare, bridge therapy with intraarticular and/or systemic GC was used, and soon she was dependent on a daily dose of GC. Eventually, this led to the development of iatrogenic Cushing syndrome with characteristic appearance, growth retardation and low bone mineral density, regardless of the vitamin D and ibandronic acid therapy. Since every attempt to wean off GC inevitably led to disease flare, from June to December 2016 she received cyclophosphamide (6x) and rituximab (3x), again without achieving a sustained remission. Afterwards, for a short period of time she was given metformin but without an appropriate improvement in musculoskeletal symptoms (Fig. 1).
Fig. 1 Schematic representation of treatment modalities during the time. 2007 – 2020 - the period of treatment, NSAID - nonsteroidal anti-inflammatory drug, IFX - infliximab, ADA - adalimumab, TOC - tocilizumab, ETC - etanercept, DMARD - disease modifying anti-rheumatic drug, MTX - methotrexate, CFM - cyclophosphamide, RTX - rituximab, MTF - metformin, MMF - mycophenolate mofetil, CYC - cyclosporine, TFA - tofacitinib, p.o. - per os, i.a. - intraarticular, i.v. - intravenous, GC - glucocorticoids
During the 2017, at the age of 13, the trial of mycophenolate mofetil (MMF) followed by the trial of cyclosporin was initiated, but the patient nevertheless remained GC dependent. Both shoulders, elbows, radiocarpal joints, metacarpophalangeal (MCP), proximal interphalangeal (PIP), distal interphalangeal (DIP) joints and both knees had restricted range of movement, and repeated IAGI were necessary to alleviate the symptoms. Finally, in 2018, the treatment with Janus kinase (JAK) inhibitor tofacitinib was initiated, which lead to gradual amelioration of musculoskeletal symptoms and improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic GC. Moreover, as the swelling of the wrists subsided for the first time in many years, Madelung deformity was noticed by clinical examination. Interestingly, it was only then, in 2019, that the deformity was for the first time described on x-ray (Fig. 2), although x-ray and MRI imaging of both hands were previously performed on many occasions in order to assess the inflammation (Figs. 3 and 4). Nevertheless, subsequent analysis by experienced musculoskeletal radiologist revealed characteristic bilateral signs of Madelung deformity dating back in 2015 and 2017 (Fig. 3), with the MRI showing the Vickers and radiotriquetral ligament (Fig. 4). The finding of those two ligaments allowed the distinguishing between Madelung deformity and pseudo-Madelung deformity, which includes post-traumatic and post-infective forms, forms associated with Turner syndrome, multiple hereditary exostoses and Ollier disease [23]. Unfortunately, due to the parent’s refusal, no further radiological assessment was performed, so we have not documented the other important aspects of Madelung deformity, such as radial shortening and diaphysis bowing, nor the mesolimbic shortening of limbs characteristic for Leri Weill syndrome.
Fig. 2 The anteroposterior radiograph of left hand at the age of 14. Note the increased volar angulation of distal radius, wedge shaped carpus with proximally positioned lunate and a characteristic notch on the distal radius (white arrow), which are the features of the Madelung deformity [12]
Fig. 3 The anteroposterior radiograph of both hands at the age of 10 (a) and 13 (b), and of the left hand at the age of 14 (c). Note the bowing of the distal radius, an increased radial inclination (~ 30°) with the deformation of the carpus that acquired a triangular appearance and widening of the distal radial-ulnar joint bilaterally, which are the typical features of Madelung deformity. Dorsal subluxation of the ulnar head is not seen as lateral images of the wrist were not taken. Osteopenia of carpal bones and periarticular osteopenia of MCP, PIP and DIP joints related to JIA are present. No relevant changes are observed during the time
Fig. 4 MRI coronal T1-weighted (a), proton density BLADE fluid sensitive sequence (b), post contrast T1-weighted coronal fat sat sequence (c) and post contrast T1-weighted axial fat sat sequence (d) images of both hands at the age of 13. Note the radiotriquetral ligament (red arrow) and Vickers ligament (green arrow) (a, b). Note the inflammatory changes characterized by postcontrast imbibition in carpal joints and MCP joints (red circle), as well as tenosynovitis of flexor tendons related to JIA, more prominent on the left hand (c, d)
Although our patient was simultaneously followed by pediatric endocrinologist from age of 11, her short stature, along with delayed menarche, and Cushingoid appearance, was attributed to the prolonged use of GC. It was only after the Madelung’s deformity was observed that genetic causes, primarily Leri Weill syndrome, were taken into consideration. Genetic analysis was performed by commercially available SALSA MLPA Probemix P018 SHOX (MRC-Holland, Amsterdam, The Netherland) according to the manufacturer’s recommendations. The MLPA mix included probes for each exon of SHOX, one probe just before the promoter region as well as probes covering a region downstream of the gene. The results revealed one copy of sixteen probes (10 probes for Xp22-PAR1 from CNE2 to CNE9, 4 probes for SHOX area downstream, 1 probe for CRLF2 in PAR1 region and 1 probe for CSF2RA in PAR1 region), with the size of the smallest deletion of 766,5 kb. Based on the genetic testing and imaging findings of Madelung deformity, the diagnosis of Leri Weill syndrome was established, and parents were advised to undergo further genetic testing of both the patient and themselves, which they rejected.
Currently, our patient has many consequences of the adverse course of the disease and prolonged GC treatment, such as joint contractures of elbows, wrists, DIPs, PIPs, hips, knees and MCPs and low bone density, respectively. She developed secondary sex characteristics only after the therapy with estradiol was initiated at the age of 14. Nevertheless, after the discontinuation of GC and subsequent discontinuation of estradiol, she finally had a menarche at the age of 15, along with a long-awaited growth spurt.
Discussion and Conclusion
Children with rheumatic diseases, their families, as well as their treating physicians are dealt with numerous issues and dilemmas regarding either the disease itself or ongoing treatment modalities. Besides, the diagnosis of rheumatic diseases in children is regularly made by excluding wide range of other diseases, with no pathognomonic tests and/or criteria. Therefore, even after the classification criteria are fulfilled, the diagnosis should be revised if new symptoms emerge or if the recommended treatment options are failing.
In our patient, a variety of steroid-sparing agents with different mechanisms of action have been employed with limited or no clinical success. Some of these agents were used in line with current treatment recommendations, but many were used based on anecdotal reports [24–28]. Finally, due to signs of systemic inflammation characterized by increased inflammatory markers (CRP and ESR) and cytokines (IL-6 and TNF-alfa), which is indicative for the activation of JAK/STAT pathway, treatment with tofacitinib, a first generation JAK inhibitor, was initiated with a good clinical response. Several clinical trials in adults with rheumatoid and psoriatic arthritis have given solid evidence about the use of tofacitinib, while the results of a phase 3 randomized double blind placebo controlled withdrawal study in patients with polyarticular JIA showed improvement in symptoms, less disease flares and improved functional ability, together with a clinical amelioration of disease activity [29, 30]. Moreover, tofacitinib is an oral agent, and the challenge of using biologics requiring injection or infusion for an extended length of time, especially in children, should not be overlooked.
Along with the various treatment modalities, the different diagnosis was constantly being considered in our patient. Firstly, due to persistent contracture in some joints with little or no signs of swelling, LSDs such as mucopolysaccharidosis type I, Gaucher disease type I and Fabry disease were investigated. Besides, other inflammatory causes like systemic lupus erythematosus were also excluded. Lastly, the diagnosis of Leri Weill syndrome characterized by deletions in SHOX gene and Madelung deformity was established. This painful deformity of the wrist was first described in 1878 by the German surgeon Otto Madelung in adolescents between the ages 8 and 14 [12]. Although initially asymptomatic, the patients often went on to develop pain, loss of grip strength and reduced mobility, which were the symptoms present in our patient even after the inflammation was tackled with tofacitinib. Moreover, the features of Leri Weill syndrome include the short stature, which was also one of the dominant finding in the presented patient. Yet, the growth deficit caused by SHOX haploinsufficiency in Leri Weill syndrome is around 2 standard deviation scores (SDS) [31], while our patient had a SDS of -5,5. Besides, due to a prolonged use of GC, our patient had a full blown Cushingoid appearance, low bone density, delayed puberty and growth retardation. Therefore, the possible explanation for the short stature and growth delay in our patient includes multifactorial aetiology. Firstly, it is well known that extended GC treatment leads to a defect in bone turnover (and formation) due to impaired osteoblastogenesis and osteoclastogenesis, and may have direct effects on the growth plate [32]. Additionally, higher prepubertal glucocorticoid level appears to delay early and late pubertal timing of healthy girls, particularly the onset of pubertal growth spurt and menarche [33]. Moreover, it has been shown that girls with polyarticular juvenile idiopathic arthritis are significantly more likely to present with short stature even 6 months after stopping the steroid therapy [34]. Finally, the product of SHOX gene is implicated in bone development and regulation of chondrocyte differentiation, which clarifies the association of SHOX gene haploinsufficiency with idiopathic short stature, as well as short stature in Turner syndrome and Leri Weill dyschondrosteosis [31].
In the presented case, the diagnosis of the Madelung deformity and Leri Weill syndrome was delayed due to the concomitant active inflammation caused by JIA taking the focus from other possible causes of pain in the wrists. However, as subsequent analysis by experienced musculoskeletal radiologist has shown, the characteristic signs of the Madelung deformity were present few years before the final diagnosis was reached, emphasizing once again the importance of multidisciplinary approach and close collaboration of many subspecialists in the care of children with rheumatic diseases. Nevertheless, this lag probably did not influence the therapeutic management in our particular patient; although positive effect on final height was observed with growth hormone therapy in patients with Leri Weill syndrome, due to the matching influence of GC and lack of agreement with her parents, this treatment option was avoided in our patient [35].
In conclusion, this case report emphasizes the difficulties and challenges in management of patient with long-standing polyarticular JIA refractory to wide range of treatment modalities. Although many high-quality guidelines are available for treatment of JIA patients, there is still need for individual reports of difficult to treat cases, especially when additional diagnosis are involved. While Leri Weill syndrome is extensively reported in the literature, to the best of our knowledge, our case report describes it for the first time along with JIA. Taking all these into account, we strongly encourage the aggregation of similar patients and establishment of the common ground that will help clinician to decide upon the introduction of treatment options outside of the contemporary guidelines.
Abbreviations
JIAJuvenile idiopathic arthritis
LSDLysosomal storage disease
MPSMucopolysaccharidosis
NSAIDNonsteroidal anti-inflammatory drug
cDMARDConventional disease modifying anti-rheumatic drug
bDMARDBiologic disease modifying anti-rheumatic drug
IAGIIntraarticular glucocorticoid injection
GCGlucocorticoids
MASMacrophage activation syndrome
TNFiTumor necrosis factor inhibitor
T2TTreat-to-target
RFRheumatoid factor
ESRErythrocyte sedimentation rate
CRPC-reactive protein
ANAAntinuclear antibody
MTXMethotrexate
SLESystemic lupus erythematosus
TNFαTumor necrosis factor alpha
anti-IL-6Anti-interleukin-6
MMFMycophenolate mofetil
MCPMetacarpophalangeal
PIPProximal interphalangeal
DIPDistal interphalangeal
JAKJanus kinase
MRIMagnetic resonance imaging
SHOXShort-stature homeobox
JAK/STATJanus kinase/signal transducer and activator of transcription proteins
SDSStandard deviation score
GnRHGonadotropin-releasing hormone
HPGHypothalamic-pituitary-gonadal
IFXInfliximab
ADAAdalimumab
TOCTocilizumab
ETCEtanercept
CFMCyclophosphamide
RTXRituximab
MTFMetformin
CYCCyclosporine
TFATofacitinib
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Acknowledgements
We thank parents for availability of publishing medical history of their daughter.
Authors’ contributions
VV and AS have equally contributed to the paper. VV: medical charts review, literature search, creation of figures and tables and manuscript draft preparation. AS: medical charts review, literature search, creation of figures and tables and manuscript draft preparation RV: radiographic images interpretation, manuscript draft preparation. MV: clinical care and the final revision of the manuscript. MH: clinical care and the final revision of the manuscript. LL: clinical care, medical charts review, literature search, creation of figures and tables, manuscript draft preparation, final revision of the manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. / Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the parents for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | Recovering | ReactionOutcome | CC BY | 33451288 | 18,970,451 | 2021-01-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lactic acidosis'. | Clinical and molecular findings in 37 Turkish patients with isolated methylmalonic acidemia
Isolated methylmalonic acidemia (MMA) is caused by complete or partial deficiency of the enzyme methylmalonyl- CoA mutase (mut0 or mut– enzymatic subtype), a defect of its cofactor adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. While onset of the disease ranges from the neonatal period to adulthood, most cases present with lethargy, vomiting and ketoacidosis in the early infancy. Major secondary complications are; growth failure, developmental delay, interstitial nephritis with progressive renal failure, basal ganglia injury and cardiomyopathy. We aimed to demonstrate clinical and molecular findings based on long-term follow up in our patient cohort.
The study includes 37 Turkish patients with isolated MMA who were followed up for long term complications 1 to 14 years. All patients were followed up regularly with clinical, biochemical and dietary monitoring to determine long term complications. Next Generation Sequencing technique was used for mutation screening in five disease-causing genes including; MUT, MMAA, MMAB, MMADHC, MCEE genes. Mutation screening identified 30 different types of mutations.
While 28 of these mutations were previously reported, one novel MMAA mutation p.H382Pfs*24 (c.1145delA) and one novel MUT mutation IVS3+1G>T(c.752+1G>T) has been reported. The most common clinical complications were growth retardation, renal involvement, mental motor retardation and developmental delay. Furthermore, one of our patients developed cardiomyopathy, another one died because of hepatic failure and one presented with lactic acidosis after linezolid exposure.
We have detected two novel mutations, including one splice-site mutation in the MUT gene and one frame shift mutation in the MMAA gene in 37 Turkish patients. We confirm the genotype-phenotype correlation in the study population according to the long-term complications.
1. Introduction
Isolated methylmalonic acidemia (MMA, OMIM 251000) consists of a group of genetically heterogeneous inborn errors of metabolism characterized by abnormal accumulation of methylmalonyl-CoA and methylmalonic acid (MA) in body fluids without hyperhomocysteinemia [1]. MMA is an autosomal recessive error of organic acid metabolism caused by the impaired isomerization of L-methylmalonyl-CoA to succinylCoA during the oxidation of propionate towards the Krebs cycle [2]. Isolated MMA is caused by complete or partial deficiency of the mitochondrial enzyme L-methylmalonylCoA mutase (MCM, EC 5.4.99.2) (mut 0 enzymatic subtype or mut– enzymatic subtype, respectively), a defect in the handling of its cofactor, AdoCbl (cblA (OMIM607481), cblB (OMIM607568), or cblD2 variant-MMA (OMIM 606169), or deficiency of the enzyme methylmalonyl-CoA epimerase (MCE) [3]. The five genes known to cause isolated MMA include MUT , MMAA , MMAB , MMADHC , MCEE genes, which are responsible for the MCM, cblA, cblB, and cblD2 variant, MCE deficiency, respectively [4–7].
The disease typically presents in the first weeks or months of life and is clinically characterized by recurrent vomiting, poor feeding, failure to thrive, respiratory distress, and neurological deficit from progressive alteration of consciousness to deep coma and death [8]. Ketoacidosis, hypo/hyperglycemia, hyperammonemia, anemia/pancytopenia are the main laboratory findings [8]. Lethal ketoacidosis attacks can follow intercurrent illnesses and it can even mimic diabetic ketoacidosis [9,10]. The mut 0 type, is characterized by significantly low apoenzyme activity, which is not more than 0.1 %, often presents with metabolic acidosis within the first week after birth, frequently resulting in death in early childhood. The mut 0 type usually presents with repeated attacks of ketoacidosis which are triggered by infection and high protein intake during the weaning period after the age of 1 year [11].
Methylmalonyl-CoA accumulates in the mitochondrial matrix as a result of MCM deficiency, thus it is subsequently hydrolyzed to CoA and MA, resulting in elevated blood and urine levels of MA [12]. The excessive accumulation of methylmalonic acid and its CoA esters may inhibit mitochondrial enzymes [13,14]. Even with the dietary treatment, affected patients experience various life-threatening metabolic crises, and most patients have problems with growth and motor skills [15]. Although there is a significant improvement in the therapeutic opportunities over the last 20-year-period, the overall outcome of patients with MMA remained almost stable as the number of long-term complications such as failure to thrive, developmental delay, neurologic disorders by degeneration of the basal ganglia, progressive renal failure, and cardiomyopathy has been increasing [16–19]. It is predicted that some mediators like 2-methylcitrate, MA, and other propionate derived mediators inhibit some of the mitochondrial enzymes. 2-methylcitrate inhibits the tricarboxylic acid (TCA) cycle enzymes citrate synthase, aconitase, and isocitrate dehydrogenase.MA inhibits pyruvate carboxylase and propionyl-CoA inhibits CoA dependent enzymes, such as pyruvate dehydrogenase, succinyl-CoA synthetase, and ATP citrate lyase [20]. Furthermore, some studies provided data about the increased levels of lactate particularly in globi pallidi, which indicates a secondary respiratory chain deficiency [14,21].
In this study, we report the clinical features, long term complications, and genetic defects in the MUT , MMAA , and MMAB genes of 37 Turkish patients affected with isolated MMA.
2. Materials and methods
This is a retrospective cohort study between June 2013 and June 2016. Patient data extracted from previous medical records. Written informed consent obtained from all participants during their clinical visits and conducted according to the Declaration of Helsinki.
2.1. Patients
The study includes 37 Turkish patients with isolated MMA, who were diagnosed and have been followed up at the Department of Pediatric Metabolism and Nutrition, Çukurova University, Adana, Turkey between June 2013 and June 2016. Unfortunately, none of the patients were diagnosed through neonatal screening, all patients were diagnosed by urine organic acid analysis and the blood carnitine acylcarnitine profile after presenting clinical symptoms and/or developing complications. Enzyme activity assay cannot be performed. Metabolic treatments, including protein restriction (with administration of isoleucine-, methionine-, threonine-, and valine-free special formulas), oral carnitine supplementation, intermittent eradication of gut flora by metronidazole or neomycin, and cobalamin (either oral or intramuscular administration) were given to all patients. They were all followed up for long-term complications 1 to 14 years. Emergency treatment was performed during acute metabolic crises.
2.2. Chronic management and follow-up
Neurological examination with detailed history of developmental milestones was a routine part of evaluation in every visit to the metabolic clinic. All patients were screened with laboratory markers of renal function including urinary electrolytes and protein loss, blood urea nitrogen (BUN,) and creatinine. Creatinine clearances were calculated according to the Schwartz formula annually in all patients to assess the glomerular filtration rates [22]. A glomerular filtration rate under 80ml/min/1.73 m2 was defined as renal failure. All patients were routinely screened with echocardiography and electrocardiography (ECG) yearly for cardiac complications.
2.3. Mutation analysis
Mutation analysis performed for all participants and results were obtained from medical records, retrospectively. Genomic DNA was isolated from 2 mL EDTA blood samples obtained by venipuncture on antecubital vein. Next generation sequencing (NGS) technique was used for mutation screening in five disease-causing genes by Illumina-Miseq (Illumina, San Diego, CA, USA) by using in-house designed primers. Mutation analysis was done directly to the gene in question in case there is a preliminary clinical diagnosis. In cases without a differential diagnosis within these five, all five genes were sequenced. The integrative genomics viewer (IGV) software of Broad Institute was used for analysis and comparison with reference sequence. All variations were evaluated by and checked in HGMD-Public version, ClinVar, specific databases, 1000 genome database, EXAC and 2000 exome data of Intergen Genetics Center, Google search for the mutations and all mutations, both previously published and unpublished ones were evaluated with ACMG criterias, DANN, GERP, dbNSFP. FATHMM, FATHMM-MKL, LRT, MetaLR, MetaSVM, Mutation Assessor, Mutation Taster, SIFT, PROVEAN, and Polyphen2. For the splicing defects, we also used Human Splicing Finder program for the prediction. Family screening studies were done for the variants predicted as variant of uncertain significance (VUS) for segregation studies.
3. Results
A total of 37 patients representing 36 Turkish families (patients 4 and 5 are siblings) are included in this study. Nineteen of 37 (51.4%) patients were male and 18 of 37 (48.6) were female. The clinical features and complementation groups of all patients are summarized in Table 1. Nineteen of 37 patients (51%) presented in the neonatal period (between the ages of 1 and 30 days), while the remaining 18 patients presented in the later infancy period (between the ages of 3 and 24 months). Consanguinity was noted in 33 out of 36 families (92%). The interval from the age of onset to the age at diagnosis was between 2 days and 7 months, except for patient 14, who had an older sibling (patient 13) known to have MMA and was diagnosed at the age of 4 days. Three patients died during subsequent metabolic crises and one of them died because of severe hepatic coma. 32 patients are alive (ages range from 12 months to 14 years), and they were all followed up regularly in the interim period. The most common clinical and biochemical features described were acute episodes of vomiting, poor feeding, failure to thrive, lethargy, hypotonia, and neurological abnormalities with metabolic acidosis, hyperammonemia and methylmalonic aciduria. Other frequently reported features are neurological complications such as developmental delay and mental and motor retardation and renal involvement. 12 out of 37 patients (32%) have some degree of renal involvement. Patient 3 had early-onset and rapidly progressive renal complications, specifically renal tubular acidosis (RTA) type 4 and chronic kidney disease (CKD) stage 3, despite good metabolic control. Patient 10 developed dilated cardiomyopathy with decreased left ventricular ejection fraction (LVEF) of 31% (normal>55%) during a severe metabolic episode at the age of 14 months. When she was 19 months old, she had a severe pneumonia, and she was transferred to the intensive care unit on day 10 of the hospital admission due to the respiratory failure. The antibiotic therapy was advanced to vancomycin. Because of decreased renal function (estimated renal clearance was under 30 mL/min), intravenous linezolid (600 mg q/12 h) was given as an alternative treatment to vancomycin. After the administration of the third dose of linezolid, her blood lactate levels had increased to 10.0 mmol/L. As linezolid was suspected as a potential cause of the lactic acidosis, the agent was stopped. The patient required mechanical ventilation because of respiratory failure and continuous renal replacement therapy was started to normalize her blood pH and clear linezolid from her plasma.
Table 1 Clinical characterization of the isolated MMA patients.
Patientno Sex Consan-guinity Age of onset Outcome/Current age (years) Long-term complications Zygosity Mutation
1 M Yes 6 m Alive/6 DD, GR H MMAA gene p.E773* (c.1117G>T)
2 M Yes 1 m Alive/8 GR, MMR H MUT gene p.R532H (c.1595G>A)
3 M No 10 m Alive/15 RI, Liver-renaltransplantation, GR H MUT gene p.I671V (c.2011A>G)
4 F Yes 8 m Alive/11 DD, MMR, GR H MUT gene p.T387I (c.1160C>T)
5 M Yes 10 m Alive/6 NA H MUT gene p.T387I (c.1160C>T)
6 M No 12 m Alive/5 RI, GR CH MUT gene c.2055_2056insCTC /p.R727* (c.2179C>T)
7 F Yes 6 m Died MMR, contractures, GR H MUT gene p.M1T (c.2T>C)
8 M Yes 3 d Alive/6 RI, GR H MUT gene p.G454E (c.1361G>A)
9 F Yes 10 m Alive/6 DD,RI H MMAA gene p.H382Pfs*24 (c.1145delA)
10 F Yes 3 d Alive/5 RI,CMP, GR LA H MUT gene p.G454E (c.1361G>A)
11 M Yes 6 m Alive/12 DD, MMR, RI, GR H MMAB gene p.R191W (c.571C>T)
12 F Yes 20 d Died HF, GR H MUT gene p.N219Y (c.655A>T)
13 F Yes 24 m Alive/8 MMR, RI H MMAA gene p.G278D (c.833G>A)
14 F No 25 d Died MMR contractures, GR, RI H MUT gene p.K223R (c.668A>G)
15 M Yes 15 m Died MMR, GR, RI H MUT gene p.R694W (c.2080C>T)
16 M Yes 3 d Alive/3 DD H MUT gene p.N219Y (c.655A>T)
17 F Yes 18 d Alive/6 MR H MMAA gene p.R359Q (c.1076G>A)
18 F Yes 13 d Alive/8 RI, DD, MR GR H MUT gene p.A141Rfs*39 (c.421delG)
19 F Yes 3 d Alive/1 DD H MMAA genep.R196* (c.586C>T)
20 F Yes 22 d Alive/11 MMR, GR H MMAB gene p.E193K (c.577G>A)
21 F Yes 5 d Alive/10 GR H MMAA gene c.1075C>T (p.R359*)
22 M Yes 20 d Alive/1 NA H MMAA gene c.658G>A (p.V220M)
23 M Yes 3 d Alive/7 DD, RI, GR H MUT gene p.347delL(c.1038_1040delTCT)
24 F Yes 2 d Alive/5 NA H MUT gene p.K121* (c.360_361insT)
25 M Yes 3 d Alive/2 NA H MMAA gene p.R330*(c.988C>T )
26 F Yes 4 m Alive/2 DD H MUT gene p.K121* (c.360_361insT)
27 M Yes 6 m Died MMR DystoniaEpilepsy, RI, GR H MUT gene p.K121* (c.360_361insT)
28 F Yes 24 m Alive/5 NA H MMAA gene p.T216P (c.646A>C)
29 F Yes 16 m Alive/5 GR H MUT gene p.P615T(c.1843C>A )
30 M Yes 8 m Alive/4 GR H MMAA gene p.R196* (c.586C>T)
31 M No 1 m Alive/5 NA CH MUT gene p.R108H (c.323G>A)/ IVS3+1G>T (c.752+1G>T)-novel
32 M Yes 18 m Alive/6 GR H MUT gene p.K121* (c.360_361insT)
33 M Yes 2 d Alive/3 NA H MUT gene p.N219Y (c.655A>T)
34 M Yes 2 d Alive/4 NA H MMAB gene p.R186Q (c.557G>A)
35 F Yes 12 m Alive/4 NA H MMAA gene p.H382Pfs*24 (c.1145delA) -novel
36 M Yes 29 m Alive/5 GR H MUT gene p.A137G (c.410C>G)
37 F Yes 2 d Alive/1 DD H MUT genep.R474* (c.1420C>T)
GR: growth retardation; DD: developmental delay; RI: renal involvement; CMP: cardiomyopathy; LA: lactic acidosis; MMR: mental motor retardation; HF: hepatic failure; NA: not available; m:months; d: days; H: homozygous; CH: compound heterozygous.
Eighteen out of thirty-seven patients (49%) had variable neurologic complications, including mental retardation, developmental delay, seizures and metabolic stroke due to the basal ganglia infarction. Growth failure and failure to thrive were identified in 21 out of 37 cases (57%). Overall, 26 out of 37 cases (70%), who are older than 1 year of age, were affected with one of the long-term complications related to isolated MMA.
Thirty-seven isolated MMA patients were classified in 3 complentation groups: mut, cblA, and cblB. 22 were mut (60%), 12 cblA (32%), and 3 cblB (8%) forms (Table 2). Mutation screening identified 30 mutant alleles in all patients diagnosed as isolated MMA. Thirty-five patients were homozygous, and two patients had compound heterozygous mutations. Ninety-four percent (33/35) of the homozygous patients had documented parental consanguinity, only two were nonconsanguineous. Clinical phenotypes were correlated with the genotypes identified.
Table 2 Identified mutations.
Gene/ Reference Seq Protein Change Nucleotid change Exon Mutation type ACMG
MMAA/ NM_172250.2 p.H382Pfs*24 c.1145delA 7 Frame Shift Pathogenic
MMAA/ NM_172250.2 p.G278D c.833G>A 6 Missense VUS
MMAA/ NM_172250.2 p.V220M c.658G>A 4 Missense Pathogenic
MMAA/ NM_172250.2 p.E773* c.1117G>T 7 Nonsense Pathogenic
MMAA/ NM_172250.2 p.R359Q c.1076G>A 7 Missense Pathogenic
MMAA/ NM_172250.2 p.R196* c.586C>T 4 Nonsense Pathogenic
MMAA/ NM_172250.2 p.R359* c.1075C>T 7 Nonsense Pathogenic
MMAA/ NM_172250.2 p.R330* c.988C>T 7 Nonsense Pathogenic
MMAA/ NM_172250.2 p.T216P c.646A>C 4 Missense VUS
MMAB/ NM_052845.3 p.R191W c.571C>T 7 Missense Pathogenic
MMAB/ NM_052845.3 p.R186Q c.557G>A 7 Missense VUS
MMAB/ NM_052845.3 p.E193K c.577G>A 7 Missense VUS
MUT/ NM_000255.3 p.R532H c.1595G>A 9 Missense Benign
MUT/ NM_000255.3 p.I671V c.2011A>G 12 Missense Benign
MUT/ NM_000255.3 p.T387I c.1160C>T 6 Missense VUS
MUT/ NM_000255.3 - c.2055_2056insCTC 12 Deletion-inframe Likely pathogenic
MUT/ NM_000255.3 p.R727* c.2179C>T 13 Nonsense Pathogenic
MUT/ NM_000255.3 p.M1T c.2T>C 2 Missense Likely pathogenic
MUT/ NM_000255.3 p.G454E c.1361G>A 7 Missense VUS
MUT/ NM_000255.3 p.N219Y c.655A>T 3 Missense Likely pathogenic
MUT/ NM_000255.3 p.K223R c.668A>G 3 Missense VUS
MUT/ NM_000255.3 p.R694W c.2080C>T 12 Missense Likely pathogenic
MUT/ NM_000255.3 p.A141Rfs*39 c.421delG 3 Frame Shift Pathogenic
MUT/ NM_000255.3 p.K121* c.360_361insT 2 Nonsense Pathogenic
MUT/ NM_000255.3 p.P615T c.1843C>A 11 Missense Likely pathogenic
MUT/ NM_000255.3 p.R108H c.323G>A 2 Missense Pathogenic
MUT/ NM_000255.3 IVS3+1G>T c.752+1 G>T 3+1 Splicing Pathogenic
MUT/ NM_000255.3 p.347delL (c.1038_1040delTCT) 3 Deletion Likely pathogenic
MUT/ NM_000255.3 p.A137G c.410C>G 3 Missense Pathogenic
MUT/ NM_000255.3 p.R474* c.1420C>T 7 Nonsense Pathogenic
ACMG: American college of medical genetics; VUS: variant of uncertain significance.
Among identified mutant alleles, 9 different MMAA alleles, 3 different MMAB alleles, and 18 different MUT alleles were described. While 28 of these mutant alleles were previously reported, one novel MMAA mutation p.H382Pfs*24 (c.1145delA) and one novel MUT mutation IVS3+1G>T (c.752+1G>T) has been reported. p.H382Pfs*24 (c.1145delA) is a frame shift mutation in exon 7, which is detected in both alleles of patient 35. Patient 31, who does not have consanguinity, had IVS3+1G>T (c.752+1G>T), which is located in splice site sequence along with a heterozygous mutated allele p.R108H (c.323G>A). Novel MUT and MMAA mutations have not been reported in the locus specific databases including, the Human Gene Mutation Database, ClinVar, specific databases, 1000 genome database, EXAC and 2000 exome data of Intergen Genetics Center.
Two previously recognized polymorphisms in MUT gene; p.R532H, and p.I671V were reported in patient 2 and 3, respectively. Both patients presented in the first year of life with vomiting, rapid breathing, and restlessness, and was found to have severe metabolic acidosis with an increased anion gap. Tandem mass spectrometry analysis showed significant elevation of propionylcarnitine, which may be indicative of organic acidemia. While plasma amino acid levels were found to be within normal limits, urine organic acid analysis indicated marked excretion of methylmalonic acid and methylcitric acid, which confirmed the diagnosis of MMA. They both presented with typical MMA features. Under protein-restricted dietary treatment they both had various subsequent metabolic crisis. While patient 2 who had homozygous p.R532H polymorphism developed growth retardation and mental-motor retardation during the follow-up, patient 3 who had p.I671V in a homozygous state presented with severe renal failure and combined liver-renal transplantation was performed at the age of 16.
4. Discussion
This study expands the mutation spectrum for isolated MMA in the Turkish population particularly highlighting the extent of mutations in the south-eastern part of the country with a large number of patients by using NGS. Moreover, with the classification into the 3 complementation groups, we can slightly anticipate the differences of the phenotypes from the complementation groups and genotypes.
It is obvious to say that among all of the patients presented in early childhood, almost one half of them had their first symptoms in the neonatal period. All patients are characterized by intermittent metabolic decompensation periods triggered by infections, excessive protein intake, and other stressors. MMA has some major complications such as intellectual impairment, tubulointerstitial nephritis with progressive renal failure, “metabolic stroke” (acute and chronic basal ganglia injury) causing a disabling movement disorder with choreoathetosis, dystonia, and para/quadriparesis; pancreatitis, and growth failure [3]. The most common clinical complications of our patients were growth retardation, renal involvement, mental motor retardation, and developmental delay. Furthermore, one of our patients developed cardiomyopathy, and another one died because of hepatic failure. None of our patients presented with pancreatitis. Moreover, patient 10 presented with life-threatening lactic acidosis after 3 doses of linezolid exposure. While linezolid is increasingly used as a multidrug-resistant antibacterial agent, linezolid-induced lactic acidosis has been frequently reported as a serious side effect [23]. On the other hand, it is commonly believed that MMA causes mitochondrial dysfunction by different mechanisms. While elevated metabolites 2-methylcitrate, methylmalonic acid (MA), and propionyl-CoA inhibit some mitochondrial enzymes, secondary respiratory chain deficiency has also been identified in MMA patients [14]. 2-methylcitrate inhibits citrate synthase, aconitase, and isocitrate dehydrogenase, which are the key enzymes of the tricarboxylic acid cycle (TCA); MA inhibits pyruvate carboxylase, and propionyl-CoA inhibits CoA-dependent enzymes pyruvate dehydrogenase, succinyl-CoA synthetase, and ATP citrate lyase [20]. Thus, neurotoxic metabolites, which inhibit the energy metabolism in various different steps and respiratory chain deficiencies detected in many tissues like liver, muscle, and proximale tubule cells may enhance the formation of lactic acidosis induced by linezolid.
The MUT gene mutations contribute to the majority of the mutant alleles in the Turkish patients, similar to the data from other populations [1,24,25]. We identified a novel splicing mutation c. 752+1G>T (IVS3+1G>T) in one patient in the compound heterozygote state. The second allele was a missense mutation in exon 3;
c.323G>A (p.R108H) [26]. This patient was presented with metabolic decompensation at the age of 1 month. He is currently alive and 5 years old without any complications under the treatment.
The frameshift mutation c.360_361insT (p.K121*) was detected in four patients. This single nucleotide insertion causes an immediate stop codon in exon 2. This mutation was first described as a homozygous change in a mut 0 patient who had consanguineous parents [26]. Four of our patients who have this change in a homozygous state presented to the hospital before the age of 2. While three of them are still alive with milder complications, one of them died after developing severe neurological complications and renal failure.
A missense mutation of c.1160C>T (p.T387I) located in exon 6 was found as a homozygous change in two siblings; patient 4 and 5. Although the older one has renal involvement, developmental delay, and mental retardation as long-term complications, younger one has developed none of these. This mutation has been firstly identified in a 5-year-old Turkish patient who has only mental retardation as a complication [15]. Another missense mutation of c.1361G>A (p.G454E), which is located in the linker region, has been found in two of our patients. Both of them were presented at the third day of life. One of them developed cardiomyopathy and linezolid-induced lactic acidosis besides renal involvement. This missense mutation has been found first in an Italian patient as a heterozygous change with accompanying c.427C>T (p.H143Y) mutation [27]. c.655A>T (p.219Y) mutation is a common missense mutation reported in the Caucasian population particularly in French and Turkish patients [28]. We found this mutation in 3 patients; one of them died because of hepatic failure.
From presumed missense mutations, we identified two single nucleotide polymorphisms (SNP) p. R532H and p.I69V in the MUT gene. Although these changes have been determined as benign, which has not been accepted as a disease-causing variant, both patients had significant clinical and laboratory features of MMA [26]. The functional analysis of this mutant allele bearing both changes will provide insight about the real functional consequences of these sequence variants. Also, while there is no commercial multiplex ligation-dependent probe amplification (MLPA) kit, we could not perform deletion and duplication analysis in these cases. Further molecular analysis should be performed in these patients.
c.2179C>T (p.R727*), c.2T>C (p.M1T), c. 2055_2056insCTC, c.668A>G (p.K223R), c.2080C>T (p.R694W), c.421delG (p.A141Rfs*39), c.1843C>A (p.P615T),
c.1038_1040delTCT (p.347delL), c.410C>G (p.A137G) and c.1420C>T (p.R474*) are the other MUT mutations, which have been previously reported [15, 26, 27, 29, 30] .
9 different MMAA gene mutations have been described. While c.1145delA (p.H382Pfs*24) is a novel frameshift mutation, other 8 mutations have been reported previously. Four of them were missense mutations. c.833G>A (p.G278D) was identified firstly in an Indian infant who presented at 18 months-old with a typical presentation including ketoacidosis and hyperammonemia [31]. c.658G>A (p.V220M), c.1076G>A (p.R359Q) and c.646A>C (p.T216P) are the other missense MMAA gene mutations which were identified in our patients in a homozygous state.
4 nonsense previously reported MMAA mutations have been identified in our patients. c.586C>T (p.R196*) mutation in exon 4 is a nonsense mutation predicted an amino acid change from arginine to a premature stop codon at position 196 in the mature protein. This nonsense mutation has previously been reported in a compound heterozygote patient with B12-responsive cblA-type methylmalonic academia [32]. It has been also reported in a homozygous state in a Turkish infant mimicking diabetic ketoacidosis [33]. c.1075C>T (p.R359*) is another nonsense mutation in exon 7, which has been previously identified with a high-resolution melting analysis technique [34].
c.988C>T (p.R330*) is the other nonsense mutation at codon 330. The mutation is 37 amino acids downstream of a predicted GTP binding site [35]. c.1117G>T (p.E773*) is the fourth nonsense mutation in exon 7, which was found in our patients.
We have identified 3 missense mutations, which were all previously reported as missense mutations: c.571C>T (p.R191W), c.557G>A (p.R186Q) and c.577G>A (p.E193K) in the MMAB gene [4, 36, 37].
In conclusion, we have detected two novel mutations, including one splice-site mutation in the MUT gene and one frame shift mutation in the MMAA gene in 37 Turkish patients. In summary, we have reported the genetic basis of three genes causing isolated MMA in Turkey providing clinical data to explain the phenotypic differences of these disorders.
Informed Consent
Written informed consent was taken from the families of participating patients. Çukurova University Medical Faculty Institutional review ethical board approvals for the research project were obtained. Çukurova University Clinical Research Ethics Committee stated that ethical approval was not required as patients were not exposed to a nonroutine practice and an IRB number was not given. The study complied with the World Medical Association Declaration of Helsinki regarding the ethical conduct of research involving human subjects and/or animals. | LINEZOLID | DrugsGivenReaction | CC BY | 33453710 | 18,910,655 | 2021-06-28 |
What was the administration route of drug 'LINEZOLID'? | Clinical and molecular findings in 37 Turkish patients with isolated methylmalonic acidemia
Isolated methylmalonic acidemia (MMA) is caused by complete or partial deficiency of the enzyme methylmalonyl- CoA mutase (mut0 or mut– enzymatic subtype), a defect of its cofactor adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. While onset of the disease ranges from the neonatal period to adulthood, most cases present with lethargy, vomiting and ketoacidosis in the early infancy. Major secondary complications are; growth failure, developmental delay, interstitial nephritis with progressive renal failure, basal ganglia injury and cardiomyopathy. We aimed to demonstrate clinical and molecular findings based on long-term follow up in our patient cohort.
The study includes 37 Turkish patients with isolated MMA who were followed up for long term complications 1 to 14 years. All patients were followed up regularly with clinical, biochemical and dietary monitoring to determine long term complications. Next Generation Sequencing technique was used for mutation screening in five disease-causing genes including; MUT, MMAA, MMAB, MMADHC, MCEE genes. Mutation screening identified 30 different types of mutations.
While 28 of these mutations were previously reported, one novel MMAA mutation p.H382Pfs*24 (c.1145delA) and one novel MUT mutation IVS3+1G>T(c.752+1G>T) has been reported. The most common clinical complications were growth retardation, renal involvement, mental motor retardation and developmental delay. Furthermore, one of our patients developed cardiomyopathy, another one died because of hepatic failure and one presented with lactic acidosis after linezolid exposure.
We have detected two novel mutations, including one splice-site mutation in the MUT gene and one frame shift mutation in the MMAA gene in 37 Turkish patients. We confirm the genotype-phenotype correlation in the study population according to the long-term complications.
1. Introduction
Isolated methylmalonic acidemia (MMA, OMIM 251000) consists of a group of genetically heterogeneous inborn errors of metabolism characterized by abnormal accumulation of methylmalonyl-CoA and methylmalonic acid (MA) in body fluids without hyperhomocysteinemia [1]. MMA is an autosomal recessive error of organic acid metabolism caused by the impaired isomerization of L-methylmalonyl-CoA to succinylCoA during the oxidation of propionate towards the Krebs cycle [2]. Isolated MMA is caused by complete or partial deficiency of the mitochondrial enzyme L-methylmalonylCoA mutase (MCM, EC 5.4.99.2) (mut 0 enzymatic subtype or mut– enzymatic subtype, respectively), a defect in the handling of its cofactor, AdoCbl (cblA (OMIM607481), cblB (OMIM607568), or cblD2 variant-MMA (OMIM 606169), or deficiency of the enzyme methylmalonyl-CoA epimerase (MCE) [3]. The five genes known to cause isolated MMA include MUT , MMAA , MMAB , MMADHC , MCEE genes, which are responsible for the MCM, cblA, cblB, and cblD2 variant, MCE deficiency, respectively [4–7].
The disease typically presents in the first weeks or months of life and is clinically characterized by recurrent vomiting, poor feeding, failure to thrive, respiratory distress, and neurological deficit from progressive alteration of consciousness to deep coma and death [8]. Ketoacidosis, hypo/hyperglycemia, hyperammonemia, anemia/pancytopenia are the main laboratory findings [8]. Lethal ketoacidosis attacks can follow intercurrent illnesses and it can even mimic diabetic ketoacidosis [9,10]. The mut 0 type, is characterized by significantly low apoenzyme activity, which is not more than 0.1 %, often presents with metabolic acidosis within the first week after birth, frequently resulting in death in early childhood. The mut 0 type usually presents with repeated attacks of ketoacidosis which are triggered by infection and high protein intake during the weaning period after the age of 1 year [11].
Methylmalonyl-CoA accumulates in the mitochondrial matrix as a result of MCM deficiency, thus it is subsequently hydrolyzed to CoA and MA, resulting in elevated blood and urine levels of MA [12]. The excessive accumulation of methylmalonic acid and its CoA esters may inhibit mitochondrial enzymes [13,14]. Even with the dietary treatment, affected patients experience various life-threatening metabolic crises, and most patients have problems with growth and motor skills [15]. Although there is a significant improvement in the therapeutic opportunities over the last 20-year-period, the overall outcome of patients with MMA remained almost stable as the number of long-term complications such as failure to thrive, developmental delay, neurologic disorders by degeneration of the basal ganglia, progressive renal failure, and cardiomyopathy has been increasing [16–19]. It is predicted that some mediators like 2-methylcitrate, MA, and other propionate derived mediators inhibit some of the mitochondrial enzymes. 2-methylcitrate inhibits the tricarboxylic acid (TCA) cycle enzymes citrate synthase, aconitase, and isocitrate dehydrogenase.MA inhibits pyruvate carboxylase and propionyl-CoA inhibits CoA dependent enzymes, such as pyruvate dehydrogenase, succinyl-CoA synthetase, and ATP citrate lyase [20]. Furthermore, some studies provided data about the increased levels of lactate particularly in globi pallidi, which indicates a secondary respiratory chain deficiency [14,21].
In this study, we report the clinical features, long term complications, and genetic defects in the MUT , MMAA , and MMAB genes of 37 Turkish patients affected with isolated MMA.
2. Materials and methods
This is a retrospective cohort study between June 2013 and June 2016. Patient data extracted from previous medical records. Written informed consent obtained from all participants during their clinical visits and conducted according to the Declaration of Helsinki.
2.1. Patients
The study includes 37 Turkish patients with isolated MMA, who were diagnosed and have been followed up at the Department of Pediatric Metabolism and Nutrition, Çukurova University, Adana, Turkey between June 2013 and June 2016. Unfortunately, none of the patients were diagnosed through neonatal screening, all patients were diagnosed by urine organic acid analysis and the blood carnitine acylcarnitine profile after presenting clinical symptoms and/or developing complications. Enzyme activity assay cannot be performed. Metabolic treatments, including protein restriction (with administration of isoleucine-, methionine-, threonine-, and valine-free special formulas), oral carnitine supplementation, intermittent eradication of gut flora by metronidazole or neomycin, and cobalamin (either oral or intramuscular administration) were given to all patients. They were all followed up for long-term complications 1 to 14 years. Emergency treatment was performed during acute metabolic crises.
2.2. Chronic management and follow-up
Neurological examination with detailed history of developmental milestones was a routine part of evaluation in every visit to the metabolic clinic. All patients were screened with laboratory markers of renal function including urinary electrolytes and protein loss, blood urea nitrogen (BUN,) and creatinine. Creatinine clearances were calculated according to the Schwartz formula annually in all patients to assess the glomerular filtration rates [22]. A glomerular filtration rate under 80ml/min/1.73 m2 was defined as renal failure. All patients were routinely screened with echocardiography and electrocardiography (ECG) yearly for cardiac complications.
2.3. Mutation analysis
Mutation analysis performed for all participants and results were obtained from medical records, retrospectively. Genomic DNA was isolated from 2 mL EDTA blood samples obtained by venipuncture on antecubital vein. Next generation sequencing (NGS) technique was used for mutation screening in five disease-causing genes by Illumina-Miseq (Illumina, San Diego, CA, USA) by using in-house designed primers. Mutation analysis was done directly to the gene in question in case there is a preliminary clinical diagnosis. In cases without a differential diagnosis within these five, all five genes were sequenced. The integrative genomics viewer (IGV) software of Broad Institute was used for analysis and comparison with reference sequence. All variations were evaluated by and checked in HGMD-Public version, ClinVar, specific databases, 1000 genome database, EXAC and 2000 exome data of Intergen Genetics Center, Google search for the mutations and all mutations, both previously published and unpublished ones were evaluated with ACMG criterias, DANN, GERP, dbNSFP. FATHMM, FATHMM-MKL, LRT, MetaLR, MetaSVM, Mutation Assessor, Mutation Taster, SIFT, PROVEAN, and Polyphen2. For the splicing defects, we also used Human Splicing Finder program for the prediction. Family screening studies were done for the variants predicted as variant of uncertain significance (VUS) for segregation studies.
3. Results
A total of 37 patients representing 36 Turkish families (patients 4 and 5 are siblings) are included in this study. Nineteen of 37 (51.4%) patients were male and 18 of 37 (48.6) were female. The clinical features and complementation groups of all patients are summarized in Table 1. Nineteen of 37 patients (51%) presented in the neonatal period (between the ages of 1 and 30 days), while the remaining 18 patients presented in the later infancy period (between the ages of 3 and 24 months). Consanguinity was noted in 33 out of 36 families (92%). The interval from the age of onset to the age at diagnosis was between 2 days and 7 months, except for patient 14, who had an older sibling (patient 13) known to have MMA and was diagnosed at the age of 4 days. Three patients died during subsequent metabolic crises and one of them died because of severe hepatic coma. 32 patients are alive (ages range from 12 months to 14 years), and they were all followed up regularly in the interim period. The most common clinical and biochemical features described were acute episodes of vomiting, poor feeding, failure to thrive, lethargy, hypotonia, and neurological abnormalities with metabolic acidosis, hyperammonemia and methylmalonic aciduria. Other frequently reported features are neurological complications such as developmental delay and mental and motor retardation and renal involvement. 12 out of 37 patients (32%) have some degree of renal involvement. Patient 3 had early-onset and rapidly progressive renal complications, specifically renal tubular acidosis (RTA) type 4 and chronic kidney disease (CKD) stage 3, despite good metabolic control. Patient 10 developed dilated cardiomyopathy with decreased left ventricular ejection fraction (LVEF) of 31% (normal>55%) during a severe metabolic episode at the age of 14 months. When she was 19 months old, she had a severe pneumonia, and she was transferred to the intensive care unit on day 10 of the hospital admission due to the respiratory failure. The antibiotic therapy was advanced to vancomycin. Because of decreased renal function (estimated renal clearance was under 30 mL/min), intravenous linezolid (600 mg q/12 h) was given as an alternative treatment to vancomycin. After the administration of the third dose of linezolid, her blood lactate levels had increased to 10.0 mmol/L. As linezolid was suspected as a potential cause of the lactic acidosis, the agent was stopped. The patient required mechanical ventilation because of respiratory failure and continuous renal replacement therapy was started to normalize her blood pH and clear linezolid from her plasma.
Table 1 Clinical characterization of the isolated MMA patients.
Patientno Sex Consan-guinity Age of onset Outcome/Current age (years) Long-term complications Zygosity Mutation
1 M Yes 6 m Alive/6 DD, GR H MMAA gene p.E773* (c.1117G>T)
2 M Yes 1 m Alive/8 GR, MMR H MUT gene p.R532H (c.1595G>A)
3 M No 10 m Alive/15 RI, Liver-renaltransplantation, GR H MUT gene p.I671V (c.2011A>G)
4 F Yes 8 m Alive/11 DD, MMR, GR H MUT gene p.T387I (c.1160C>T)
5 M Yes 10 m Alive/6 NA H MUT gene p.T387I (c.1160C>T)
6 M No 12 m Alive/5 RI, GR CH MUT gene c.2055_2056insCTC /p.R727* (c.2179C>T)
7 F Yes 6 m Died MMR, contractures, GR H MUT gene p.M1T (c.2T>C)
8 M Yes 3 d Alive/6 RI, GR H MUT gene p.G454E (c.1361G>A)
9 F Yes 10 m Alive/6 DD,RI H MMAA gene p.H382Pfs*24 (c.1145delA)
10 F Yes 3 d Alive/5 RI,CMP, GR LA H MUT gene p.G454E (c.1361G>A)
11 M Yes 6 m Alive/12 DD, MMR, RI, GR H MMAB gene p.R191W (c.571C>T)
12 F Yes 20 d Died HF, GR H MUT gene p.N219Y (c.655A>T)
13 F Yes 24 m Alive/8 MMR, RI H MMAA gene p.G278D (c.833G>A)
14 F No 25 d Died MMR contractures, GR, RI H MUT gene p.K223R (c.668A>G)
15 M Yes 15 m Died MMR, GR, RI H MUT gene p.R694W (c.2080C>T)
16 M Yes 3 d Alive/3 DD H MUT gene p.N219Y (c.655A>T)
17 F Yes 18 d Alive/6 MR H MMAA gene p.R359Q (c.1076G>A)
18 F Yes 13 d Alive/8 RI, DD, MR GR H MUT gene p.A141Rfs*39 (c.421delG)
19 F Yes 3 d Alive/1 DD H MMAA genep.R196* (c.586C>T)
20 F Yes 22 d Alive/11 MMR, GR H MMAB gene p.E193K (c.577G>A)
21 F Yes 5 d Alive/10 GR H MMAA gene c.1075C>T (p.R359*)
22 M Yes 20 d Alive/1 NA H MMAA gene c.658G>A (p.V220M)
23 M Yes 3 d Alive/7 DD, RI, GR H MUT gene p.347delL(c.1038_1040delTCT)
24 F Yes 2 d Alive/5 NA H MUT gene p.K121* (c.360_361insT)
25 M Yes 3 d Alive/2 NA H MMAA gene p.R330*(c.988C>T )
26 F Yes 4 m Alive/2 DD H MUT gene p.K121* (c.360_361insT)
27 M Yes 6 m Died MMR DystoniaEpilepsy, RI, GR H MUT gene p.K121* (c.360_361insT)
28 F Yes 24 m Alive/5 NA H MMAA gene p.T216P (c.646A>C)
29 F Yes 16 m Alive/5 GR H MUT gene p.P615T(c.1843C>A )
30 M Yes 8 m Alive/4 GR H MMAA gene p.R196* (c.586C>T)
31 M No 1 m Alive/5 NA CH MUT gene p.R108H (c.323G>A)/ IVS3+1G>T (c.752+1G>T)-novel
32 M Yes 18 m Alive/6 GR H MUT gene p.K121* (c.360_361insT)
33 M Yes 2 d Alive/3 NA H MUT gene p.N219Y (c.655A>T)
34 M Yes 2 d Alive/4 NA H MMAB gene p.R186Q (c.557G>A)
35 F Yes 12 m Alive/4 NA H MMAA gene p.H382Pfs*24 (c.1145delA) -novel
36 M Yes 29 m Alive/5 GR H MUT gene p.A137G (c.410C>G)
37 F Yes 2 d Alive/1 DD H MUT genep.R474* (c.1420C>T)
GR: growth retardation; DD: developmental delay; RI: renal involvement; CMP: cardiomyopathy; LA: lactic acidosis; MMR: mental motor retardation; HF: hepatic failure; NA: not available; m:months; d: days; H: homozygous; CH: compound heterozygous.
Eighteen out of thirty-seven patients (49%) had variable neurologic complications, including mental retardation, developmental delay, seizures and metabolic stroke due to the basal ganglia infarction. Growth failure and failure to thrive were identified in 21 out of 37 cases (57%). Overall, 26 out of 37 cases (70%), who are older than 1 year of age, were affected with one of the long-term complications related to isolated MMA.
Thirty-seven isolated MMA patients were classified in 3 complentation groups: mut, cblA, and cblB. 22 were mut (60%), 12 cblA (32%), and 3 cblB (8%) forms (Table 2). Mutation screening identified 30 mutant alleles in all patients diagnosed as isolated MMA. Thirty-five patients were homozygous, and two patients had compound heterozygous mutations. Ninety-four percent (33/35) of the homozygous patients had documented parental consanguinity, only two were nonconsanguineous. Clinical phenotypes were correlated with the genotypes identified.
Table 2 Identified mutations.
Gene/ Reference Seq Protein Change Nucleotid change Exon Mutation type ACMG
MMAA/ NM_172250.2 p.H382Pfs*24 c.1145delA 7 Frame Shift Pathogenic
MMAA/ NM_172250.2 p.G278D c.833G>A 6 Missense VUS
MMAA/ NM_172250.2 p.V220M c.658G>A 4 Missense Pathogenic
MMAA/ NM_172250.2 p.E773* c.1117G>T 7 Nonsense Pathogenic
MMAA/ NM_172250.2 p.R359Q c.1076G>A 7 Missense Pathogenic
MMAA/ NM_172250.2 p.R196* c.586C>T 4 Nonsense Pathogenic
MMAA/ NM_172250.2 p.R359* c.1075C>T 7 Nonsense Pathogenic
MMAA/ NM_172250.2 p.R330* c.988C>T 7 Nonsense Pathogenic
MMAA/ NM_172250.2 p.T216P c.646A>C 4 Missense VUS
MMAB/ NM_052845.3 p.R191W c.571C>T 7 Missense Pathogenic
MMAB/ NM_052845.3 p.R186Q c.557G>A 7 Missense VUS
MMAB/ NM_052845.3 p.E193K c.577G>A 7 Missense VUS
MUT/ NM_000255.3 p.R532H c.1595G>A 9 Missense Benign
MUT/ NM_000255.3 p.I671V c.2011A>G 12 Missense Benign
MUT/ NM_000255.3 p.T387I c.1160C>T 6 Missense VUS
MUT/ NM_000255.3 - c.2055_2056insCTC 12 Deletion-inframe Likely pathogenic
MUT/ NM_000255.3 p.R727* c.2179C>T 13 Nonsense Pathogenic
MUT/ NM_000255.3 p.M1T c.2T>C 2 Missense Likely pathogenic
MUT/ NM_000255.3 p.G454E c.1361G>A 7 Missense VUS
MUT/ NM_000255.3 p.N219Y c.655A>T 3 Missense Likely pathogenic
MUT/ NM_000255.3 p.K223R c.668A>G 3 Missense VUS
MUT/ NM_000255.3 p.R694W c.2080C>T 12 Missense Likely pathogenic
MUT/ NM_000255.3 p.A141Rfs*39 c.421delG 3 Frame Shift Pathogenic
MUT/ NM_000255.3 p.K121* c.360_361insT 2 Nonsense Pathogenic
MUT/ NM_000255.3 p.P615T c.1843C>A 11 Missense Likely pathogenic
MUT/ NM_000255.3 p.R108H c.323G>A 2 Missense Pathogenic
MUT/ NM_000255.3 IVS3+1G>T c.752+1 G>T 3+1 Splicing Pathogenic
MUT/ NM_000255.3 p.347delL (c.1038_1040delTCT) 3 Deletion Likely pathogenic
MUT/ NM_000255.3 p.A137G c.410C>G 3 Missense Pathogenic
MUT/ NM_000255.3 p.R474* c.1420C>T 7 Nonsense Pathogenic
ACMG: American college of medical genetics; VUS: variant of uncertain significance.
Among identified mutant alleles, 9 different MMAA alleles, 3 different MMAB alleles, and 18 different MUT alleles were described. While 28 of these mutant alleles were previously reported, one novel MMAA mutation p.H382Pfs*24 (c.1145delA) and one novel MUT mutation IVS3+1G>T (c.752+1G>T) has been reported. p.H382Pfs*24 (c.1145delA) is a frame shift mutation in exon 7, which is detected in both alleles of patient 35. Patient 31, who does not have consanguinity, had IVS3+1G>T (c.752+1G>T), which is located in splice site sequence along with a heterozygous mutated allele p.R108H (c.323G>A). Novel MUT and MMAA mutations have not been reported in the locus specific databases including, the Human Gene Mutation Database, ClinVar, specific databases, 1000 genome database, EXAC and 2000 exome data of Intergen Genetics Center.
Two previously recognized polymorphisms in MUT gene; p.R532H, and p.I671V were reported in patient 2 and 3, respectively. Both patients presented in the first year of life with vomiting, rapid breathing, and restlessness, and was found to have severe metabolic acidosis with an increased anion gap. Tandem mass spectrometry analysis showed significant elevation of propionylcarnitine, which may be indicative of organic acidemia. While plasma amino acid levels were found to be within normal limits, urine organic acid analysis indicated marked excretion of methylmalonic acid and methylcitric acid, which confirmed the diagnosis of MMA. They both presented with typical MMA features. Under protein-restricted dietary treatment they both had various subsequent metabolic crisis. While patient 2 who had homozygous p.R532H polymorphism developed growth retardation and mental-motor retardation during the follow-up, patient 3 who had p.I671V in a homozygous state presented with severe renal failure and combined liver-renal transplantation was performed at the age of 16.
4. Discussion
This study expands the mutation spectrum for isolated MMA in the Turkish population particularly highlighting the extent of mutations in the south-eastern part of the country with a large number of patients by using NGS. Moreover, with the classification into the 3 complementation groups, we can slightly anticipate the differences of the phenotypes from the complementation groups and genotypes.
It is obvious to say that among all of the patients presented in early childhood, almost one half of them had their first symptoms in the neonatal period. All patients are characterized by intermittent metabolic decompensation periods triggered by infections, excessive protein intake, and other stressors. MMA has some major complications such as intellectual impairment, tubulointerstitial nephritis with progressive renal failure, “metabolic stroke” (acute and chronic basal ganglia injury) causing a disabling movement disorder with choreoathetosis, dystonia, and para/quadriparesis; pancreatitis, and growth failure [3]. The most common clinical complications of our patients were growth retardation, renal involvement, mental motor retardation, and developmental delay. Furthermore, one of our patients developed cardiomyopathy, and another one died because of hepatic failure. None of our patients presented with pancreatitis. Moreover, patient 10 presented with life-threatening lactic acidosis after 3 doses of linezolid exposure. While linezolid is increasingly used as a multidrug-resistant antibacterial agent, linezolid-induced lactic acidosis has been frequently reported as a serious side effect [23]. On the other hand, it is commonly believed that MMA causes mitochondrial dysfunction by different mechanisms. While elevated metabolites 2-methylcitrate, methylmalonic acid (MA), and propionyl-CoA inhibit some mitochondrial enzymes, secondary respiratory chain deficiency has also been identified in MMA patients [14]. 2-methylcitrate inhibits citrate synthase, aconitase, and isocitrate dehydrogenase, which are the key enzymes of the tricarboxylic acid cycle (TCA); MA inhibits pyruvate carboxylase, and propionyl-CoA inhibits CoA-dependent enzymes pyruvate dehydrogenase, succinyl-CoA synthetase, and ATP citrate lyase [20]. Thus, neurotoxic metabolites, which inhibit the energy metabolism in various different steps and respiratory chain deficiencies detected in many tissues like liver, muscle, and proximale tubule cells may enhance the formation of lactic acidosis induced by linezolid.
The MUT gene mutations contribute to the majority of the mutant alleles in the Turkish patients, similar to the data from other populations [1,24,25]. We identified a novel splicing mutation c. 752+1G>T (IVS3+1G>T) in one patient in the compound heterozygote state. The second allele was a missense mutation in exon 3;
c.323G>A (p.R108H) [26]. This patient was presented with metabolic decompensation at the age of 1 month. He is currently alive and 5 years old without any complications under the treatment.
The frameshift mutation c.360_361insT (p.K121*) was detected in four patients. This single nucleotide insertion causes an immediate stop codon in exon 2. This mutation was first described as a homozygous change in a mut 0 patient who had consanguineous parents [26]. Four of our patients who have this change in a homozygous state presented to the hospital before the age of 2. While three of them are still alive with milder complications, one of them died after developing severe neurological complications and renal failure.
A missense mutation of c.1160C>T (p.T387I) located in exon 6 was found as a homozygous change in two siblings; patient 4 and 5. Although the older one has renal involvement, developmental delay, and mental retardation as long-term complications, younger one has developed none of these. This mutation has been firstly identified in a 5-year-old Turkish patient who has only mental retardation as a complication [15]. Another missense mutation of c.1361G>A (p.G454E), which is located in the linker region, has been found in two of our patients. Both of them were presented at the third day of life. One of them developed cardiomyopathy and linezolid-induced lactic acidosis besides renal involvement. This missense mutation has been found first in an Italian patient as a heterozygous change with accompanying c.427C>T (p.H143Y) mutation [27]. c.655A>T (p.219Y) mutation is a common missense mutation reported in the Caucasian population particularly in French and Turkish patients [28]. We found this mutation in 3 patients; one of them died because of hepatic failure.
From presumed missense mutations, we identified two single nucleotide polymorphisms (SNP) p. R532H and p.I69V in the MUT gene. Although these changes have been determined as benign, which has not been accepted as a disease-causing variant, both patients had significant clinical and laboratory features of MMA [26]. The functional analysis of this mutant allele bearing both changes will provide insight about the real functional consequences of these sequence variants. Also, while there is no commercial multiplex ligation-dependent probe amplification (MLPA) kit, we could not perform deletion and duplication analysis in these cases. Further molecular analysis should be performed in these patients.
c.2179C>T (p.R727*), c.2T>C (p.M1T), c. 2055_2056insCTC, c.668A>G (p.K223R), c.2080C>T (p.R694W), c.421delG (p.A141Rfs*39), c.1843C>A (p.P615T),
c.1038_1040delTCT (p.347delL), c.410C>G (p.A137G) and c.1420C>T (p.R474*) are the other MUT mutations, which have been previously reported [15, 26, 27, 29, 30] .
9 different MMAA gene mutations have been described. While c.1145delA (p.H382Pfs*24) is a novel frameshift mutation, other 8 mutations have been reported previously. Four of them were missense mutations. c.833G>A (p.G278D) was identified firstly in an Indian infant who presented at 18 months-old with a typical presentation including ketoacidosis and hyperammonemia [31]. c.658G>A (p.V220M), c.1076G>A (p.R359Q) and c.646A>C (p.T216P) are the other missense MMAA gene mutations which were identified in our patients in a homozygous state.
4 nonsense previously reported MMAA mutations have been identified in our patients. c.586C>T (p.R196*) mutation in exon 4 is a nonsense mutation predicted an amino acid change from arginine to a premature stop codon at position 196 in the mature protein. This nonsense mutation has previously been reported in a compound heterozygote patient with B12-responsive cblA-type methylmalonic academia [32]. It has been also reported in a homozygous state in a Turkish infant mimicking diabetic ketoacidosis [33]. c.1075C>T (p.R359*) is another nonsense mutation in exon 7, which has been previously identified with a high-resolution melting analysis technique [34].
c.988C>T (p.R330*) is the other nonsense mutation at codon 330. The mutation is 37 amino acids downstream of a predicted GTP binding site [35]. c.1117G>T (p.E773*) is the fourth nonsense mutation in exon 7, which was found in our patients.
We have identified 3 missense mutations, which were all previously reported as missense mutations: c.571C>T (p.R191W), c.557G>A (p.R186Q) and c.577G>A (p.E193K) in the MMAB gene [4, 36, 37].
In conclusion, we have detected two novel mutations, including one splice-site mutation in the MUT gene and one frame shift mutation in the MMAA gene in 37 Turkish patients. In summary, we have reported the genetic basis of three genes causing isolated MMA in Turkey providing clinical data to explain the phenotypic differences of these disorders.
Informed Consent
Written informed consent was taken from the families of participating patients. Çukurova University Medical Faculty Institutional review ethical board approvals for the research project were obtained. Çukurova University Clinical Research Ethics Committee stated that ethical approval was not required as patients were not exposed to a nonroutine practice and an IRB number was not given. The study complied with the World Medical Association Declaration of Helsinki regarding the ethical conduct of research involving human subjects and/or animals. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33453710 | 18,910,655 | 2021-06-28 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Inappropriate schedule of product administration'. | Chemoimmunotherapy-related enteritis resulting in a mechanical small bowel obstruction - A case report.
Mechanical small bowel obstruction (SBO) is amongst the commonest diagnoses encountered in surgical departments. Although the aetiology is frequently post-surgical adhesions, the condition can arise in a virgin abdomen and we now know several of these cases do not require acute operative management. Here we report one such case where a small bowel obstruction transpired due to enteritis in the setting of chemoimmunotherapy with no prior abdominal surgery.
METHODS
A 62 year old male presented to our department with 2 days of vomiting and obstipation. This is on a background of metastatic non-small cell lung cancer for which he was due for his 4th cycle of carboplatin, pemetrexed and pembrolizumab. Computed Tomography (CT) of the abdomen demonstrated a segment of thickened distal small bowel without any mass lesion, along with upstream dilatation. The findings were consistent with a mechanical SBO due to enteritis. Infective causes were excluded. The patient successfully recovered with non-operative intervention in the coming days.
Enteritis is an established adverse effect of various chemoimmunotherapy agents, though a case severe enough to produce a mechanical bowel obstruction is exceptionally rare. We demonstrate through this case that the condition may resolve through conservative measures.
CONCLUSIONS
The diagnosis of chemoimmunotherapy-related enteritis producing an SBO although uncommon, should be considered in the relevant population. A non-operative approach may be appropriate under some circumstances.
1 Introduction
Mechanical small bowel obstruction (SBO) is one of the more common diagnoses encountered in surgical units globally. The causes are diverse and can be classified as those extrinsic, intrinsic or within the intestinal lumen. Up to 75% of cases are attributable to post-surgical adhesions [1]. Under these circumstances, treatment usually encompasses a trial of conservative therapy in the form of nasogastric decompression and gut rest prior to considering surgical intervention [2]. Although the traditional doctrine dictated an SBO in a virgin abdomen mandates operative intervention, a shift in practice has occurred in recent years [3]. Management is guided by the underlying aetiology, and a non-operative approach is appropriate in some circumstances. We present an unusual case encountered at a tertiary hospital whereby a mechanical SBO ensued due to chemoimmunotherapy-related enteritis, without a prior history of surgery. Although the enterotoxicity of these agents is well established, a case severe enough to disrupt gastrointestinal (GI) continuity is atypical [4]. This case has been reported in line with the SCARE 2020 criteria [5].
2 Presentation of case
A 62 year old male self-presented to his local emergency department with a 2-day history of anorexia, vomiting, lower abdominal pain and obstipation. This is on a background of stage IV metastatic non-small cell lung cancer diagnosed 4-months previously. At the time of his initial diagnosis, there was evidence of bilateral hilar disease alongside skeletal and adrenal metastatic deposits, but sparing the alimentary tract (Fig. 1). He had completed 3-cycles of systemic therapy in the form of 3-weekly carboplatin, pemetrexed and pembrolizumab; with the 4th cycle scheduled on the day of presentation. Imaging performed 2-weeks prior demonstrated a good response to treatment with a reduction in the burden of disease. The patient’s additional systemic comorbidities included coronary artery disease, dyslipidaemia, hypertension and a 35 pack-year ex-smoking history. His medications included low dose aspirin, telmisartan and rosuvastatin. Background was also relevant for no prior intraabdominal surgery or pelvic radiotherapy. There was no personal or family history of inflammatory bowel disease and surveillance colonoscopy performed 16-months prior demonstrated normal ileocolonic mucosa (Fig. 2).Fig. 1 Positron Emission Tomography (PET) scan at the time of initial diagnosis. There is evidence of uptake at the left upper lobe primary lesion along with hilar, cervical node and musculoskeletal metastatic deposits. Note sparing of the alimentary tract throughout.
Fig. 1Fig. 2 Surveillance lower gastrointestinal endoscopy 16 months prior to presentation. Image is of the caecum with the ileocaecal valve visible. The ileocolonic mucosa appears normal.
Fig. 2
On arrival, his temperature was 37.5 degrees Celsius and he was tachycardic to a heart rate of 140. The latter normalised quickly with intravenous fluid resuscitation. On examination his abdomen was distended and tender in the lower regions without signs of peritonism. No masses or cough impulses were palpated in the inguinal regions. Haematology and biochemistry showed a white cell count of 7 × 109/L, neutrophils of 5 × 109/L and C-reactive protein (CRP) of 294 mg/L. A computed tomography (CT) scan of the abdomen was performed demonstrating a long segment of thickened distal small bowel with surrounding induration of the mesentery (Fig. 3A). Small bowel dilatation was evident upstream to this point and was collapsed distally (Fig. 3B). Notably, no obstructing mass was visualised and there was sparing of the entire colon. The findings were consistent with a distal mechanical small bowel obstruction due to enteritis and were new when compared to the most recent imaging 2 weeks prior. On further questioning, the patient described alternating constipation and diarrhoea in the week preceding his presentation. There were no known sick contacts, no recent travel history and no notable exposure to undercooked foods.Fig. 3 Computed tomography (CT) scan of the abdomen performed at the time of presentation to hospital (left column) when compared to the patient’s most recent surveillance imaging two weeks prior (right column). A: Axial CT slice at the level of the S1 vertebra demonstrating a thickened segment of small bowel with surrounding induration of the mesentery. A narrowed transition point is evident (red arrow). Collapsed small bowel distally is seen in the right lower quadrant (white arrows). B: Axial CT slice at the level of L4 with evidence of dilated loops of small bowel upstream to the segment of enteritis. The findings are new when compared to baseline imaging two weeks prior.
Fig. 3
He was admitted under the care of the surgical team, kept fasted and a nasogastric tube was inserted. As the working diagnosis was enteritis related to chemoimmunotherapy, the medical oncology team was consulted with a view to consider directed treatment options. Upon their review less than 24 h later, he began to show signs of improvement in the form of improved pain, reduced nasogastric output, passage of small amounts of flatus and a CRP that was down-trending. The scheduled treatment cycle for his malignancy was delayed. He continued to improve in the coming days, with his diet gradually upgraded and eventuated in the passage of stool. Faeces culture and PCR returned negative for viral, bacterial and parasitic causes. He was discharged 72 h into his admission tolerating a full diet. At 2 weeks follow up in the outpatient oncology department, his symptoms remained improved and CRP was down to 10 mg/L. In light of his clinical stability, the 4th cycle of chemoimmunotherapy was administered a week later although unfortunately he experienced a recurrence of intermittent abdominal pain, eventuating in a small bowel perforation the following month. All antineoplastic agents were subsequently withheld to allow for his recovery.
3 Discussion
Despite recent advancements, enterotoxicity remains a challenging adverse effect to manage amongst antineoplastic agents used in a variety of cancers [4]. Chemotherapy and immunotherapy related enteritis usually manifests as abdominal pain, diarrhoea and paradoxically constipation under some circumstances. Its severity is graded according to the frequency of stools and the presence of alarm signs such as fevers or bloody diarrhoea, which ultimately guides treatment and the requirement for inpatient management [6,7]. In some cases, the condition can progress to severe surgical complications such as a spontaneous small bowel perforation [8]. Although it is not uncommonly associated with the presence of a paralytic ileus, chemoimmunotherapy-induced enteritis severe enough to result in a mechanical bowel obstruction is an extremely rare occurrence [9]. To our knowledge, only one such case has previously been described related to capecitabine in metastatic colorectal cancer [10].
Some of the more commonly described culprits of this phenomenon are 5-fluorouracil and ironectan, both used in combination in colorectal cancer. With regards to our patient’s regimen, selected reports have implicated pemetrexed [11]. Although, it should be noted that cases of pemetrexed-related enterocolitis are more frequently accompanied by neutropenia. In the KEYNOTE-189 phase III trial, there were notably higher rates of GI toxicity in the Pembrolizumab-chemotherapy arm compared with chemotherapy alone in the absence of an increased risk of neutropenia [12]. This raises the possibility of Pembrolizumab as the potential causative agent in the setting of concurrent chemotherapy.
The mechanism in which chemo- and immunotherapeutic agents induce intestinal inflammation can be explained through first principles. One of the biggest challenges in antineoplastic therapy has been to selectively halt proliferation of rapidly dividing tumour cells. Adverse effects frequently stem from their non-selective effects on high turnover host cells, which includes elements of the GI mucosa [4,7]. A mucositis may subsequently develop, characterised by lymphocytic infiltrate and bowel wall oedema. This may manifest as mouth ulcers, enteritis or colitis depending on the region of GI tract involved. Histological features in the small bowel include villous atrophy and glandular destruction [10]. In the case we describe, it is likely that wall oedema was to the extent such that the intestinal lumen was obscured, ultimately preventing passage of gastrointestinal contents.
We recognise that the diagnosis of chemoimmunotherapy-related enteritis producing a SBO is difficult to make in the absence of histological sampling at the time of the obstruction. The segment of bowel affected in our patient was not accessible endoscopically, and a surgical resection could not be justified given the patient initially improved with conservative measures. Accordingly, we considered other plausible causes under the given circumstances. The rapid evolution of the bowel wall changes on imaging, absence of a mass lesion together with the spontaneous resolution of symptoms effectively excluded a malignant cause of SBO. Negative faeces culture/virology and lack of epidemiological risk factors meant that a communicable cause was unlikely. Additionally, in a study that looked to differentiate chemotherapy-related enterocolitis from an infective cause, radiological evidence of small bowel involvement favoured the former [13]. Absence of a strong family history alongside a normal recent colonoscopy study rendered inflammatory bowel disease less likely. Thus the clinical and radiological features are most in keeping with a drug-induced enteritis with a resultant SBO.
In addition to the usual supportive measures with any SBO, management in this case involved withholding the suspected offending agents. Thereafter, treatment is directed depending on the nature, duration and severity of symptoms [7]. Severe cases of chemotherapy related gastrointestinal toxicity have been managed with octreotide alongside fluid resuscitation and antimotility agents, though the latter is evidently inappropriate in the presence of obstructive features as in this case [14]. Antibiotics are usually reserved where there is accompanying neutropenia or fevers [7,14]. Where immunotherapy is believed to be the causative agent, corticosteroids and anti-TNF alpha therapy have proven successful in refractory cases [6]. However, little information is available on the best practice when a mechanical SBO ensues as a result of enteritis owing to the rarity of the condition. Our patients symptoms initially resolved with supportive measures and he was referred on for ongoing management of his malignancy. It should be noted that acute toxicity does not preclude reinstating chemoimmunotherapy at a later point and there have been cases were this was implemented with a successful outcome [6,8].
4 Conclusion
Chemoimmunotherapy-related enteritis is an unfortunate adverse effect of various antineoplastic agents. In the rare event that this progresses to a mechanical SBO, we demonstrate through this case that withholding the offending agents alongside the appropriate supportive care can effectively resolve the condition. Despite its rarity, the diagnosis should be considered in the appropriate population as the condition can be successfully managed without operative intervention.
Declaration of Competing Interest
The authors Ali P. Mourad and Marie Shella De Robles declare no conflict of interest.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethical approval
Ethics approval is not required for the writing of case reports at our facility.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Registration of research studies
researchregistry 6307 available at: https://www.researchregistry.com/browse-the-registry#home/registrationdetails/5fc2f6df704425001b6e41ca/.
Guarantor
Ali P. Mourad.
Patient perspective
The patient was grateful of the care he received during his time in our unit. He was strongly supportive of the writing of this case if it could help others in a similar scenario.
Provenance and peer review
Not commissioned, externally peer-reviewed.
CRediT authorship contribution statement
Ali P. Mourad: Conceptualization, Investigation, Resources, Writing - original draft, Writing - review & editing. Marie Shella De Robles: Conceptualization, Writing - original draft, Writing - review & editing. | ASPIRIN, CARBOPLATIN, PEMBROLIZUMAB, PEMETREXED DISODIUM, ROSUVASTATIN, TELMISARTAN | DrugsGivenReaction | CC BY-NC-ND | 33454633 | 18,826,979 | 2021-02 |
What was the dosage of drug 'ASPIRIN'? | Chemoimmunotherapy-related enteritis resulting in a mechanical small bowel obstruction - A case report.
Mechanical small bowel obstruction (SBO) is amongst the commonest diagnoses encountered in surgical departments. Although the aetiology is frequently post-surgical adhesions, the condition can arise in a virgin abdomen and we now know several of these cases do not require acute operative management. Here we report one such case where a small bowel obstruction transpired due to enteritis in the setting of chemoimmunotherapy with no prior abdominal surgery.
METHODS
A 62 year old male presented to our department with 2 days of vomiting and obstipation. This is on a background of metastatic non-small cell lung cancer for which he was due for his 4th cycle of carboplatin, pemetrexed and pembrolizumab. Computed Tomography (CT) of the abdomen demonstrated a segment of thickened distal small bowel without any mass lesion, along with upstream dilatation. The findings were consistent with a mechanical SBO due to enteritis. Infective causes were excluded. The patient successfully recovered with non-operative intervention in the coming days.
Enteritis is an established adverse effect of various chemoimmunotherapy agents, though a case severe enough to produce a mechanical bowel obstruction is exceptionally rare. We demonstrate through this case that the condition may resolve through conservative measures.
CONCLUSIONS
The diagnosis of chemoimmunotherapy-related enteritis producing an SBO although uncommon, should be considered in the relevant population. A non-operative approach may be appropriate under some circumstances.
1 Introduction
Mechanical small bowel obstruction (SBO) is one of the more common diagnoses encountered in surgical units globally. The causes are diverse and can be classified as those extrinsic, intrinsic or within the intestinal lumen. Up to 75% of cases are attributable to post-surgical adhesions [1]. Under these circumstances, treatment usually encompasses a trial of conservative therapy in the form of nasogastric decompression and gut rest prior to considering surgical intervention [2]. Although the traditional doctrine dictated an SBO in a virgin abdomen mandates operative intervention, a shift in practice has occurred in recent years [3]. Management is guided by the underlying aetiology, and a non-operative approach is appropriate in some circumstances. We present an unusual case encountered at a tertiary hospital whereby a mechanical SBO ensued due to chemoimmunotherapy-related enteritis, without a prior history of surgery. Although the enterotoxicity of these agents is well established, a case severe enough to disrupt gastrointestinal (GI) continuity is atypical [4]. This case has been reported in line with the SCARE 2020 criteria [5].
2 Presentation of case
A 62 year old male self-presented to his local emergency department with a 2-day history of anorexia, vomiting, lower abdominal pain and obstipation. This is on a background of stage IV metastatic non-small cell lung cancer diagnosed 4-months previously. At the time of his initial diagnosis, there was evidence of bilateral hilar disease alongside skeletal and adrenal metastatic deposits, but sparing the alimentary tract (Fig. 1). He had completed 3-cycles of systemic therapy in the form of 3-weekly carboplatin, pemetrexed and pembrolizumab; with the 4th cycle scheduled on the day of presentation. Imaging performed 2-weeks prior demonstrated a good response to treatment with a reduction in the burden of disease. The patient’s additional systemic comorbidities included coronary artery disease, dyslipidaemia, hypertension and a 35 pack-year ex-smoking history. His medications included low dose aspirin, telmisartan and rosuvastatin. Background was also relevant for no prior intraabdominal surgery or pelvic radiotherapy. There was no personal or family history of inflammatory bowel disease and surveillance colonoscopy performed 16-months prior demonstrated normal ileocolonic mucosa (Fig. 2).Fig. 1 Positron Emission Tomography (PET) scan at the time of initial diagnosis. There is evidence of uptake at the left upper lobe primary lesion along with hilar, cervical node and musculoskeletal metastatic deposits. Note sparing of the alimentary tract throughout.
Fig. 1Fig. 2 Surveillance lower gastrointestinal endoscopy 16 months prior to presentation. Image is of the caecum with the ileocaecal valve visible. The ileocolonic mucosa appears normal.
Fig. 2
On arrival, his temperature was 37.5 degrees Celsius and he was tachycardic to a heart rate of 140. The latter normalised quickly with intravenous fluid resuscitation. On examination his abdomen was distended and tender in the lower regions without signs of peritonism. No masses or cough impulses were palpated in the inguinal regions. Haematology and biochemistry showed a white cell count of 7 × 109/L, neutrophils of 5 × 109/L and C-reactive protein (CRP) of 294 mg/L. A computed tomography (CT) scan of the abdomen was performed demonstrating a long segment of thickened distal small bowel with surrounding induration of the mesentery (Fig. 3A). Small bowel dilatation was evident upstream to this point and was collapsed distally (Fig. 3B). Notably, no obstructing mass was visualised and there was sparing of the entire colon. The findings were consistent with a distal mechanical small bowel obstruction due to enteritis and were new when compared to the most recent imaging 2 weeks prior. On further questioning, the patient described alternating constipation and diarrhoea in the week preceding his presentation. There were no known sick contacts, no recent travel history and no notable exposure to undercooked foods.Fig. 3 Computed tomography (CT) scan of the abdomen performed at the time of presentation to hospital (left column) when compared to the patient’s most recent surveillance imaging two weeks prior (right column). A: Axial CT slice at the level of the S1 vertebra demonstrating a thickened segment of small bowel with surrounding induration of the mesentery. A narrowed transition point is evident (red arrow). Collapsed small bowel distally is seen in the right lower quadrant (white arrows). B: Axial CT slice at the level of L4 with evidence of dilated loops of small bowel upstream to the segment of enteritis. The findings are new when compared to baseline imaging two weeks prior.
Fig. 3
He was admitted under the care of the surgical team, kept fasted and a nasogastric tube was inserted. As the working diagnosis was enteritis related to chemoimmunotherapy, the medical oncology team was consulted with a view to consider directed treatment options. Upon their review less than 24 h later, he began to show signs of improvement in the form of improved pain, reduced nasogastric output, passage of small amounts of flatus and a CRP that was down-trending. The scheduled treatment cycle for his malignancy was delayed. He continued to improve in the coming days, with his diet gradually upgraded and eventuated in the passage of stool. Faeces culture and PCR returned negative for viral, bacterial and parasitic causes. He was discharged 72 h into his admission tolerating a full diet. At 2 weeks follow up in the outpatient oncology department, his symptoms remained improved and CRP was down to 10 mg/L. In light of his clinical stability, the 4th cycle of chemoimmunotherapy was administered a week later although unfortunately he experienced a recurrence of intermittent abdominal pain, eventuating in a small bowel perforation the following month. All antineoplastic agents were subsequently withheld to allow for his recovery.
3 Discussion
Despite recent advancements, enterotoxicity remains a challenging adverse effect to manage amongst antineoplastic agents used in a variety of cancers [4]. Chemotherapy and immunotherapy related enteritis usually manifests as abdominal pain, diarrhoea and paradoxically constipation under some circumstances. Its severity is graded according to the frequency of stools and the presence of alarm signs such as fevers or bloody diarrhoea, which ultimately guides treatment and the requirement for inpatient management [6,7]. In some cases, the condition can progress to severe surgical complications such as a spontaneous small bowel perforation [8]. Although it is not uncommonly associated with the presence of a paralytic ileus, chemoimmunotherapy-induced enteritis severe enough to result in a mechanical bowel obstruction is an extremely rare occurrence [9]. To our knowledge, only one such case has previously been described related to capecitabine in metastatic colorectal cancer [10].
Some of the more commonly described culprits of this phenomenon are 5-fluorouracil and ironectan, both used in combination in colorectal cancer. With regards to our patient’s regimen, selected reports have implicated pemetrexed [11]. Although, it should be noted that cases of pemetrexed-related enterocolitis are more frequently accompanied by neutropenia. In the KEYNOTE-189 phase III trial, there were notably higher rates of GI toxicity in the Pembrolizumab-chemotherapy arm compared with chemotherapy alone in the absence of an increased risk of neutropenia [12]. This raises the possibility of Pembrolizumab as the potential causative agent in the setting of concurrent chemotherapy.
The mechanism in which chemo- and immunotherapeutic agents induce intestinal inflammation can be explained through first principles. One of the biggest challenges in antineoplastic therapy has been to selectively halt proliferation of rapidly dividing tumour cells. Adverse effects frequently stem from their non-selective effects on high turnover host cells, which includes elements of the GI mucosa [4,7]. A mucositis may subsequently develop, characterised by lymphocytic infiltrate and bowel wall oedema. This may manifest as mouth ulcers, enteritis or colitis depending on the region of GI tract involved. Histological features in the small bowel include villous atrophy and glandular destruction [10]. In the case we describe, it is likely that wall oedema was to the extent such that the intestinal lumen was obscured, ultimately preventing passage of gastrointestinal contents.
We recognise that the diagnosis of chemoimmunotherapy-related enteritis producing a SBO is difficult to make in the absence of histological sampling at the time of the obstruction. The segment of bowel affected in our patient was not accessible endoscopically, and a surgical resection could not be justified given the patient initially improved with conservative measures. Accordingly, we considered other plausible causes under the given circumstances. The rapid evolution of the bowel wall changes on imaging, absence of a mass lesion together with the spontaneous resolution of symptoms effectively excluded a malignant cause of SBO. Negative faeces culture/virology and lack of epidemiological risk factors meant that a communicable cause was unlikely. Additionally, in a study that looked to differentiate chemotherapy-related enterocolitis from an infective cause, radiological evidence of small bowel involvement favoured the former [13]. Absence of a strong family history alongside a normal recent colonoscopy study rendered inflammatory bowel disease less likely. Thus the clinical and radiological features are most in keeping with a drug-induced enteritis with a resultant SBO.
In addition to the usual supportive measures with any SBO, management in this case involved withholding the suspected offending agents. Thereafter, treatment is directed depending on the nature, duration and severity of symptoms [7]. Severe cases of chemotherapy related gastrointestinal toxicity have been managed with octreotide alongside fluid resuscitation and antimotility agents, though the latter is evidently inappropriate in the presence of obstructive features as in this case [14]. Antibiotics are usually reserved where there is accompanying neutropenia or fevers [7,14]. Where immunotherapy is believed to be the causative agent, corticosteroids and anti-TNF alpha therapy have proven successful in refractory cases [6]. However, little information is available on the best practice when a mechanical SBO ensues as a result of enteritis owing to the rarity of the condition. Our patients symptoms initially resolved with supportive measures and he was referred on for ongoing management of his malignancy. It should be noted that acute toxicity does not preclude reinstating chemoimmunotherapy at a later point and there have been cases were this was implemented with a successful outcome [6,8].
4 Conclusion
Chemoimmunotherapy-related enteritis is an unfortunate adverse effect of various antineoplastic agents. In the rare event that this progresses to a mechanical SBO, we demonstrate through this case that withholding the offending agents alongside the appropriate supportive care can effectively resolve the condition. Despite its rarity, the diagnosis should be considered in the appropriate population as the condition can be successfully managed without operative intervention.
Declaration of Competing Interest
The authors Ali P. Mourad and Marie Shella De Robles declare no conflict of interest.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethical approval
Ethics approval is not required for the writing of case reports at our facility.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Registration of research studies
researchregistry 6307 available at: https://www.researchregistry.com/browse-the-registry#home/registrationdetails/5fc2f6df704425001b6e41ca/.
Guarantor
Ali P. Mourad.
Patient perspective
The patient was grateful of the care he received during his time in our unit. He was strongly supportive of the writing of this case if it could help others in a similar scenario.
Provenance and peer review
Not commissioned, externally peer-reviewed.
CRediT authorship contribution statement
Ali P. Mourad: Conceptualization, Investigation, Resources, Writing - original draft, Writing - review & editing. Marie Shella De Robles: Conceptualization, Writing - original draft, Writing - review & editing. | LOW DOSE | DrugDosageText | CC BY-NC-ND | 33454633 | 18,826,979 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug-induced liver injury'. | Pralatrexate for refractory mycosis fungoides in two Japanese patients.
Pralatrexate has been approved for the treatment of relapsed/refractory peripheral T cell lymphomas. Studies in the U.S. also support the clinical efficacy of pralatrexate to treat advanced-stage cutaneous T-cell lymphomas, but outcomes in Japanese patients have not yet been reported. We herein describe two Japanese patients with heavily-pretreated relapsed/refractory mycosis fungoides that were successfully controlled by pralatrexate.
1 INTRODUCTION
Mycosis fungoides (MF) is the most prevalent form of cutaneous T‐cell lymphoma (CTCL). 1 Advanced‐stage MF has a poor prognosis 2 and requires systemic therapies. 1 Pralatrexate, a folic acid analog metabolic inhibitor, has been approved in the U.S.A. since 2009 for the treatment of relapsed/refractory peripheral T‐cell lymphoma (PTCL), but was launched in Japan in 2017. 3 In patients with advanced‐stage CTCL, U.S. studies with pralatrexate showed clinical response rates up to 58%, 4 , 5 but outcomes in Japanese patients have not yet been reported. We describe the clinical outcomes of two Japanese patients with relapsed/refractory MF who were treated with pralatrexate.
2 CASE REPORT
2.1 Case 1
A 58‐year‐old Japanese man was diagnosed with MF 6 years ago, and was classified as stage IIB (T3N0M0B0) 6 3 years later. Although some erythema and tumors were resolved with mogamulizumab (1 mg/kg/week, 8 cycles), new tumors appeared after the treatment ended. Histopathological findings revealed CD30+ large‐cell transformation, and brentuximab vedotin (BV; 1.8 mg/kg/3 weeks, 8 cycles) was started. After three cycles of BV, the tumors reduced but the erythema remained. Subsequent courses of therapy included vorinostat (400 mg/day), which led to drug‐induced liver injury, oral bexarotene (225 mg/day), a second course of BV (1.8 mg/kg/3 weeks, 8 cycles) and mogamulizumab (1 mg/kg/week, 5 cycles), each providing an inadequate response. A third course of BV (2 cycles) with ionizing radiation therapy (36 Gy, left cheek tumor), which resulted in drug eruption, oral etoposide monotherapy (50 mg/day) and interferon‐gamma (2 million IU, 7 doses), followed but none of those led to an adequate response. Treatment with ionizing radiation (34 Gy, right cheek) with etoposide (25 mg/day) combined with sobuzoxane (400 mg/day) partially reduced his erythema and lesions, but new tumors appeared that required further ionizing radiation therapy (34 Gy, left hand).
He then began intravenous treatment with pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles). He also received a mucositis prophylactic regimen of intramuscular vitamin B12 (0.5 mg every 4 weeks), oral folic acid (1.25 mg daily), oral cryotherapy prior to and for 30 minutes after pralatrexate, and dental care provided by a dentist. Before and after three cycles of pralatrexate treatment, the modified severity weighted assessment tool (mSWAT) score improved from 53.5 to 31.5 and the soluble IL‐2 receptor value decreased from 4,608 U/mL to 2,731 U/mL. Adverse reactions included mild anemia (hemoglobin 11.7 g/dL), nausea and some mucositis lesions, but none of them were particularly severe. However, his treatment was changed from pralatrexate to oral forodesine due to general fatigue. At 2.5 months after the discontinuation of pralatrexate, his mSWAT score worsened to 69.7 (Figure 1). He resumed pralatrexate treatment and radiation therapy, and after two cycles of treatment, most of the tumors and erythema disappeared. He had a partial response for 5 months, but then the erythema and plaques flared up (mSWAT score, 34), and he changed to BV therapy.
Figure 1 Response to pralatrexate in patient 1. (a, d) Before treatment with pralatrexate. (b, e) After three cycles of treatment with pralatrexate. (c, f) At 2.5 months after the discontinuation of pralatrexate. Most erythema had resolved with pralatrexate, but after discontinuation, erythema flare‐ups and rapid tumor formation/enlargement were observed (arrows)
2.2 Case 2
A 60‐year‐old Japanese man was diagnosed with MF 14 years ago, and was classified as stage IIB (T3N0M0B0) 6 7 years later. Previous therapies included interferon‐gamma (1 million IU, 2 doses), etoposide (50 mg/day), methotrexate (10 mg/week) and oral prednisone (approximately 20 mg/day), but he had inadequate responses to all of them. Although vorinostat (400 mg/day) reduced some of the erythema and plaques, it led to anorexia and general fatigue. His atypical lymphocytes were positive for CCR4, and treatment with mogamulizumab (1 mg/kg/week, 8 cycles) was initiated. Mogamulizumab led to partial remission for 10 months, but new tumors gradually developed on his legs. A skin biopsy revealed CD30+ large‐cell transformation. BV (1.8 mg/kg/3 weeks, 4 cycles) led to normalization of soluble IL‐2 receptor levels and some tumors disappeared, but the tumor on his buttocks remained and required ionizing radiation therapy (36 Gy). Sobuzoxane (400 mg/day) and etoposide (25 mg/day) led to a partial reduction of the tumors but did not suppress new tumor formation.
He began treatment with intravenous pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles) together with the same mucositis prophylaxis as described for Case 1. After two cycles of treatment, the erythema, which was recalcitrant to previous therapies, resolved and the mSWAT score decreased from 49.2 to 17.5 (Figure 2). Although the tumor on his left foot remained, no new tumors emerged, and a partial response was maintained for 15 months with continued pralatrexate therapy. The patient experienced mild nausea and general fatigue, but mucositis and severe adverse events were not observed. 16 months later, some erythema and plaques appeared on his trunk and extremities. Bexarotene (300 mg/day) was added at 17 months, but erythema and tumors became more frequent rapidly and mSWAT worsened to 87. At present, he has been changed to gemcitabine therapy.
Figure 2 Response to pralatrexate in patient 2. (a–c) Before beginning treatment with pralatrexate. (d–f) After two cycles of treatment with pralatrexate
3 DISCUSSION/CONCLUSION
In Japan, about 90% of malignant lymphomas involving the skin are CTCLs, with MF being the most prevalent. 1 Although most patients with MF present with early‐stage disease, about one‐third of them experience disease progression, and 26% of them die due to MF. 2 Patients with advanced stages have a poor prognosis, with a median survival of 3.4 (stage III) to 4.7 years (stage IIB). 2 The chronic and recurrent nature of MF progression necessitates repeated systemic treatment for disease control. Although various treatment options exist, comparative trials and evidence‐based treatment algorithms to guide treatment prioritization have not yet been established. 7
Pralatrexate is a folate analog metabolic inhibitor that blocks dihydrofolate reductase, thereby preventing thymidylate and purine synthesis, which results in cell cycle arrest in the S phase. 8 Pralatrexate has a higher affinity for reduced folate carrier type 1 (RFC‐1) compared to MTX, and therefore it is preferentially taken up by many tumor cells that overexpress RFC‐1 and has a markedly greater activity than MTX. 8 , 9 Pralatrexate has been approved for relapsed/refractory PTCL in the U.S. (2009) based on results from a PROPEL study. 10 Pralatrexate was subsequently approved in Japan (in 2017) for treating relapsed/refractory PTCL after a phase I/II study in Japan demonstrated its efficacy and tolerability. 11 In the PROPEL study, pralatrexate (30 mg/m2/week intravenously for 6 weeks in 7‐week cycles) had a response rate of 58% in 12 patients with transformed MF. 4 Subsequently, in a prospective dose‐finding study in heavily‐pretreated U.S. patients, including relapsed/refractory MF, pralatrexate (15 mg/m2/week for 3 of 4 weeks) resulted in a 45% response rate after a median of four cycles. 12 The most common treatment‐related adverse events were mucosal inflammation (48%), fatigue (38%) and nausea (31%). 12 Foss et al. reported a study of 27 U.S. patients with relapsed/refractory MF or Sézary syndrome treated with pralatrexate (10 to 30 mg/m2 weekly for 3 of 4 weeks, or every other week) and partial or complete clinical responses were observed in 57% of patients. 5 These results suggest that pralatrexate has a clinical efficacy and confirms a high overall response rate at doses even less than 15 mg/m2 in the treatment of advanced CTCL. In addition, pralatrexate has been investigated in combination with bexarotene 13 , 14 and romidepsin. 15 These combination therapies have been reported to have high overall response rates of more than 50%, and can be efficient and well‐tolerated treatments for advanced‐stage MF.
Although some preceding therapies provided temporary partial remission, our patients experienced relapses. We used pralatrexate at a dose of 30 mg/m2/week for 6 weeks in 7‐week cycles, which is the approved regimen for relapsed/refractory PTCL based on clinical trials. 10 , 11 Pralatrexate suppressed new tumor formation within two to three cycles of treatment and led to a partial response. As adverse events, mucositis was controlled by prophylactic measures, but moderate general fatigue and nausea were observed, so that treatment was temporarily discontinued in Case 1. If intolerable side effects with pralatrexate are encountered, a lower‐dose regimen should be considered. 5 , 12 In Case 2, the patient experienced a long‐term partial response and then relapsed, but the patient did not want to change to another therapy or combination therapy with other drugs, resulting in a rapid progression. It may be reasonable to combine pralatrexate with other agents or treatment modalities if the disease has progressed. 7
CONFLICT OF INTEREST
The authors have no conflict of interest to declare.
ACKNOWLEDGEMENTS
The authors thank Phillips‐Gilmore Oncology Communications and Annie Kai I. Cheang, PharmD, MS, for professional assistance with manuscript preparation. Preparation of the manuscript was funded by Mundipharma. The funder had no role in data collection, interpretation, decision to publish or preparation of the manuscript. | BEXAROTENE, BRENTUXIMAB VEDOTIN, CANDESARTAN, DAPAGLIFLOZIN, METFORMIN HYDROCHLORIDE, MOGAMULIZUMAB-KPKC, PIOGLITAZONE, PRAVASTATIN SODIUM, SITAGLIPTIN PHOSPHATE, VORINOSTAT | DrugsGivenReaction | CC BY-NC-ND | 33454985 | 19,326,681 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatic function abnormal'. | Pralatrexate for refractory mycosis fungoides in two Japanese patients.
Pralatrexate has been approved for the treatment of relapsed/refractory peripheral T cell lymphomas. Studies in the U.S. also support the clinical efficacy of pralatrexate to treat advanced-stage cutaneous T-cell lymphomas, but outcomes in Japanese patients have not yet been reported. We herein describe two Japanese patients with heavily-pretreated relapsed/refractory mycosis fungoides that were successfully controlled by pralatrexate.
1 INTRODUCTION
Mycosis fungoides (MF) is the most prevalent form of cutaneous T‐cell lymphoma (CTCL). 1 Advanced‐stage MF has a poor prognosis 2 and requires systemic therapies. 1 Pralatrexate, a folic acid analog metabolic inhibitor, has been approved in the U.S.A. since 2009 for the treatment of relapsed/refractory peripheral T‐cell lymphoma (PTCL), but was launched in Japan in 2017. 3 In patients with advanced‐stage CTCL, U.S. studies with pralatrexate showed clinical response rates up to 58%, 4 , 5 but outcomes in Japanese patients have not yet been reported. We describe the clinical outcomes of two Japanese patients with relapsed/refractory MF who were treated with pralatrexate.
2 CASE REPORT
2.1 Case 1
A 58‐year‐old Japanese man was diagnosed with MF 6 years ago, and was classified as stage IIB (T3N0M0B0) 6 3 years later. Although some erythema and tumors were resolved with mogamulizumab (1 mg/kg/week, 8 cycles), new tumors appeared after the treatment ended. Histopathological findings revealed CD30+ large‐cell transformation, and brentuximab vedotin (BV; 1.8 mg/kg/3 weeks, 8 cycles) was started. After three cycles of BV, the tumors reduced but the erythema remained. Subsequent courses of therapy included vorinostat (400 mg/day), which led to drug‐induced liver injury, oral bexarotene (225 mg/day), a second course of BV (1.8 mg/kg/3 weeks, 8 cycles) and mogamulizumab (1 mg/kg/week, 5 cycles), each providing an inadequate response. A third course of BV (2 cycles) with ionizing radiation therapy (36 Gy, left cheek tumor), which resulted in drug eruption, oral etoposide monotherapy (50 mg/day) and interferon‐gamma (2 million IU, 7 doses), followed but none of those led to an adequate response. Treatment with ionizing radiation (34 Gy, right cheek) with etoposide (25 mg/day) combined with sobuzoxane (400 mg/day) partially reduced his erythema and lesions, but new tumors appeared that required further ionizing radiation therapy (34 Gy, left hand).
He then began intravenous treatment with pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles). He also received a mucositis prophylactic regimen of intramuscular vitamin B12 (0.5 mg every 4 weeks), oral folic acid (1.25 mg daily), oral cryotherapy prior to and for 30 minutes after pralatrexate, and dental care provided by a dentist. Before and after three cycles of pralatrexate treatment, the modified severity weighted assessment tool (mSWAT) score improved from 53.5 to 31.5 and the soluble IL‐2 receptor value decreased from 4,608 U/mL to 2,731 U/mL. Adverse reactions included mild anemia (hemoglobin 11.7 g/dL), nausea and some mucositis lesions, but none of them were particularly severe. However, his treatment was changed from pralatrexate to oral forodesine due to general fatigue. At 2.5 months after the discontinuation of pralatrexate, his mSWAT score worsened to 69.7 (Figure 1). He resumed pralatrexate treatment and radiation therapy, and after two cycles of treatment, most of the tumors and erythema disappeared. He had a partial response for 5 months, but then the erythema and plaques flared up (mSWAT score, 34), and he changed to BV therapy.
Figure 1 Response to pralatrexate in patient 1. (a, d) Before treatment with pralatrexate. (b, e) After three cycles of treatment with pralatrexate. (c, f) At 2.5 months after the discontinuation of pralatrexate. Most erythema had resolved with pralatrexate, but after discontinuation, erythema flare‐ups and rapid tumor formation/enlargement were observed (arrows)
2.2 Case 2
A 60‐year‐old Japanese man was diagnosed with MF 14 years ago, and was classified as stage IIB (T3N0M0B0) 6 7 years later. Previous therapies included interferon‐gamma (1 million IU, 2 doses), etoposide (50 mg/day), methotrexate (10 mg/week) and oral prednisone (approximately 20 mg/day), but he had inadequate responses to all of them. Although vorinostat (400 mg/day) reduced some of the erythema and plaques, it led to anorexia and general fatigue. His atypical lymphocytes were positive for CCR4, and treatment with mogamulizumab (1 mg/kg/week, 8 cycles) was initiated. Mogamulizumab led to partial remission for 10 months, but new tumors gradually developed on his legs. A skin biopsy revealed CD30+ large‐cell transformation. BV (1.8 mg/kg/3 weeks, 4 cycles) led to normalization of soluble IL‐2 receptor levels and some tumors disappeared, but the tumor on his buttocks remained and required ionizing radiation therapy (36 Gy). Sobuzoxane (400 mg/day) and etoposide (25 mg/day) led to a partial reduction of the tumors but did not suppress new tumor formation.
He began treatment with intravenous pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles) together with the same mucositis prophylaxis as described for Case 1. After two cycles of treatment, the erythema, which was recalcitrant to previous therapies, resolved and the mSWAT score decreased from 49.2 to 17.5 (Figure 2). Although the tumor on his left foot remained, no new tumors emerged, and a partial response was maintained for 15 months with continued pralatrexate therapy. The patient experienced mild nausea and general fatigue, but mucositis and severe adverse events were not observed. 16 months later, some erythema and plaques appeared on his trunk and extremities. Bexarotene (300 mg/day) was added at 17 months, but erythema and tumors became more frequent rapidly and mSWAT worsened to 87. At present, he has been changed to gemcitabine therapy.
Figure 2 Response to pralatrexate in patient 2. (a–c) Before beginning treatment with pralatrexate. (d–f) After two cycles of treatment with pralatrexate
3 DISCUSSION/CONCLUSION
In Japan, about 90% of malignant lymphomas involving the skin are CTCLs, with MF being the most prevalent. 1 Although most patients with MF present with early‐stage disease, about one‐third of them experience disease progression, and 26% of them die due to MF. 2 Patients with advanced stages have a poor prognosis, with a median survival of 3.4 (stage III) to 4.7 years (stage IIB). 2 The chronic and recurrent nature of MF progression necessitates repeated systemic treatment for disease control. Although various treatment options exist, comparative trials and evidence‐based treatment algorithms to guide treatment prioritization have not yet been established. 7
Pralatrexate is a folate analog metabolic inhibitor that blocks dihydrofolate reductase, thereby preventing thymidylate and purine synthesis, which results in cell cycle arrest in the S phase. 8 Pralatrexate has a higher affinity for reduced folate carrier type 1 (RFC‐1) compared to MTX, and therefore it is preferentially taken up by many tumor cells that overexpress RFC‐1 and has a markedly greater activity than MTX. 8 , 9 Pralatrexate has been approved for relapsed/refractory PTCL in the U.S. (2009) based on results from a PROPEL study. 10 Pralatrexate was subsequently approved in Japan (in 2017) for treating relapsed/refractory PTCL after a phase I/II study in Japan demonstrated its efficacy and tolerability. 11 In the PROPEL study, pralatrexate (30 mg/m2/week intravenously for 6 weeks in 7‐week cycles) had a response rate of 58% in 12 patients with transformed MF. 4 Subsequently, in a prospective dose‐finding study in heavily‐pretreated U.S. patients, including relapsed/refractory MF, pralatrexate (15 mg/m2/week for 3 of 4 weeks) resulted in a 45% response rate after a median of four cycles. 12 The most common treatment‐related adverse events were mucosal inflammation (48%), fatigue (38%) and nausea (31%). 12 Foss et al. reported a study of 27 U.S. patients with relapsed/refractory MF or Sézary syndrome treated with pralatrexate (10 to 30 mg/m2 weekly for 3 of 4 weeks, or every other week) and partial or complete clinical responses were observed in 57% of patients. 5 These results suggest that pralatrexate has a clinical efficacy and confirms a high overall response rate at doses even less than 15 mg/m2 in the treatment of advanced CTCL. In addition, pralatrexate has been investigated in combination with bexarotene 13 , 14 and romidepsin. 15 These combination therapies have been reported to have high overall response rates of more than 50%, and can be efficient and well‐tolerated treatments for advanced‐stage MF.
Although some preceding therapies provided temporary partial remission, our patients experienced relapses. We used pralatrexate at a dose of 30 mg/m2/week for 6 weeks in 7‐week cycles, which is the approved regimen for relapsed/refractory PTCL based on clinical trials. 10 , 11 Pralatrexate suppressed new tumor formation within two to three cycles of treatment and led to a partial response. As adverse events, mucositis was controlled by prophylactic measures, but moderate general fatigue and nausea were observed, so that treatment was temporarily discontinued in Case 1. If intolerable side effects with pralatrexate are encountered, a lower‐dose regimen should be considered. 5 , 12 In Case 2, the patient experienced a long‐term partial response and then relapsed, but the patient did not want to change to another therapy or combination therapy with other drugs, resulting in a rapid progression. It may be reasonable to combine pralatrexate with other agents or treatment modalities if the disease has progressed. 7
CONFLICT OF INTEREST
The authors have no conflict of interest to declare.
ACKNOWLEDGEMENTS
The authors thank Phillips‐Gilmore Oncology Communications and Annie Kai I. Cheang, PharmD, MS, for professional assistance with manuscript preparation. Preparation of the manuscript was funded by Mundipharma. The funder had no role in data collection, interpretation, decision to publish or preparation of the manuscript. | BEXAROTENE, BRENTUXIMAB VEDOTIN, CANDESARTAN, DAPAGLIFLOZIN, METFORMIN HYDROCHLORIDE, MOGAMULIZUMAB-KPKC, PIOGLITAZONE, PRAVASTATIN SODIUM, SITAGLIPTIN PHOSPHATE, VORINOSTAT | DrugsGivenReaction | CC BY-NC-ND | 33454985 | 19,326,681 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapeutic product effect incomplete'. | Pralatrexate for refractory mycosis fungoides in two Japanese patients.
Pralatrexate has been approved for the treatment of relapsed/refractory peripheral T cell lymphomas. Studies in the U.S. also support the clinical efficacy of pralatrexate to treat advanced-stage cutaneous T-cell lymphomas, but outcomes in Japanese patients have not yet been reported. We herein describe two Japanese patients with heavily-pretreated relapsed/refractory mycosis fungoides that were successfully controlled by pralatrexate.
1 INTRODUCTION
Mycosis fungoides (MF) is the most prevalent form of cutaneous T‐cell lymphoma (CTCL). 1 Advanced‐stage MF has a poor prognosis 2 and requires systemic therapies. 1 Pralatrexate, a folic acid analog metabolic inhibitor, has been approved in the U.S.A. since 2009 for the treatment of relapsed/refractory peripheral T‐cell lymphoma (PTCL), but was launched in Japan in 2017. 3 In patients with advanced‐stage CTCL, U.S. studies with pralatrexate showed clinical response rates up to 58%, 4 , 5 but outcomes in Japanese patients have not yet been reported. We describe the clinical outcomes of two Japanese patients with relapsed/refractory MF who were treated with pralatrexate.
2 CASE REPORT
2.1 Case 1
A 58‐year‐old Japanese man was diagnosed with MF 6 years ago, and was classified as stage IIB (T3N0M0B0) 6 3 years later. Although some erythema and tumors were resolved with mogamulizumab (1 mg/kg/week, 8 cycles), new tumors appeared after the treatment ended. Histopathological findings revealed CD30+ large‐cell transformation, and brentuximab vedotin (BV; 1.8 mg/kg/3 weeks, 8 cycles) was started. After three cycles of BV, the tumors reduced but the erythema remained. Subsequent courses of therapy included vorinostat (400 mg/day), which led to drug‐induced liver injury, oral bexarotene (225 mg/day), a second course of BV (1.8 mg/kg/3 weeks, 8 cycles) and mogamulizumab (1 mg/kg/week, 5 cycles), each providing an inadequate response. A third course of BV (2 cycles) with ionizing radiation therapy (36 Gy, left cheek tumor), which resulted in drug eruption, oral etoposide monotherapy (50 mg/day) and interferon‐gamma (2 million IU, 7 doses), followed but none of those led to an adequate response. Treatment with ionizing radiation (34 Gy, right cheek) with etoposide (25 mg/day) combined with sobuzoxane (400 mg/day) partially reduced his erythema and lesions, but new tumors appeared that required further ionizing radiation therapy (34 Gy, left hand).
He then began intravenous treatment with pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles). He also received a mucositis prophylactic regimen of intramuscular vitamin B12 (0.5 mg every 4 weeks), oral folic acid (1.25 mg daily), oral cryotherapy prior to and for 30 minutes after pralatrexate, and dental care provided by a dentist. Before and after three cycles of pralatrexate treatment, the modified severity weighted assessment tool (mSWAT) score improved from 53.5 to 31.5 and the soluble IL‐2 receptor value decreased from 4,608 U/mL to 2,731 U/mL. Adverse reactions included mild anemia (hemoglobin 11.7 g/dL), nausea and some mucositis lesions, but none of them were particularly severe. However, his treatment was changed from pralatrexate to oral forodesine due to general fatigue. At 2.5 months after the discontinuation of pralatrexate, his mSWAT score worsened to 69.7 (Figure 1). He resumed pralatrexate treatment and radiation therapy, and after two cycles of treatment, most of the tumors and erythema disappeared. He had a partial response for 5 months, but then the erythema and plaques flared up (mSWAT score, 34), and he changed to BV therapy.
Figure 1 Response to pralatrexate in patient 1. (a, d) Before treatment with pralatrexate. (b, e) After three cycles of treatment with pralatrexate. (c, f) At 2.5 months after the discontinuation of pralatrexate. Most erythema had resolved with pralatrexate, but after discontinuation, erythema flare‐ups and rapid tumor formation/enlargement were observed (arrows)
2.2 Case 2
A 60‐year‐old Japanese man was diagnosed with MF 14 years ago, and was classified as stage IIB (T3N0M0B0) 6 7 years later. Previous therapies included interferon‐gamma (1 million IU, 2 doses), etoposide (50 mg/day), methotrexate (10 mg/week) and oral prednisone (approximately 20 mg/day), but he had inadequate responses to all of them. Although vorinostat (400 mg/day) reduced some of the erythema and plaques, it led to anorexia and general fatigue. His atypical lymphocytes were positive for CCR4, and treatment with mogamulizumab (1 mg/kg/week, 8 cycles) was initiated. Mogamulizumab led to partial remission for 10 months, but new tumors gradually developed on his legs. A skin biopsy revealed CD30+ large‐cell transformation. BV (1.8 mg/kg/3 weeks, 4 cycles) led to normalization of soluble IL‐2 receptor levels and some tumors disappeared, but the tumor on his buttocks remained and required ionizing radiation therapy (36 Gy). Sobuzoxane (400 mg/day) and etoposide (25 mg/day) led to a partial reduction of the tumors but did not suppress new tumor formation.
He began treatment with intravenous pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles) together with the same mucositis prophylaxis as described for Case 1. After two cycles of treatment, the erythema, which was recalcitrant to previous therapies, resolved and the mSWAT score decreased from 49.2 to 17.5 (Figure 2). Although the tumor on his left foot remained, no new tumors emerged, and a partial response was maintained for 15 months with continued pralatrexate therapy. The patient experienced mild nausea and general fatigue, but mucositis and severe adverse events were not observed. 16 months later, some erythema and plaques appeared on his trunk and extremities. Bexarotene (300 mg/day) was added at 17 months, but erythema and tumors became more frequent rapidly and mSWAT worsened to 87. At present, he has been changed to gemcitabine therapy.
Figure 2 Response to pralatrexate in patient 2. (a–c) Before beginning treatment with pralatrexate. (d–f) After two cycles of treatment with pralatrexate
3 DISCUSSION/CONCLUSION
In Japan, about 90% of malignant lymphomas involving the skin are CTCLs, with MF being the most prevalent. 1 Although most patients with MF present with early‐stage disease, about one‐third of them experience disease progression, and 26% of them die due to MF. 2 Patients with advanced stages have a poor prognosis, with a median survival of 3.4 (stage III) to 4.7 years (stage IIB). 2 The chronic and recurrent nature of MF progression necessitates repeated systemic treatment for disease control. Although various treatment options exist, comparative trials and evidence‐based treatment algorithms to guide treatment prioritization have not yet been established. 7
Pralatrexate is a folate analog metabolic inhibitor that blocks dihydrofolate reductase, thereby preventing thymidylate and purine synthesis, which results in cell cycle arrest in the S phase. 8 Pralatrexate has a higher affinity for reduced folate carrier type 1 (RFC‐1) compared to MTX, and therefore it is preferentially taken up by many tumor cells that overexpress RFC‐1 and has a markedly greater activity than MTX. 8 , 9 Pralatrexate has been approved for relapsed/refractory PTCL in the U.S. (2009) based on results from a PROPEL study. 10 Pralatrexate was subsequently approved in Japan (in 2017) for treating relapsed/refractory PTCL after a phase I/II study in Japan demonstrated its efficacy and tolerability. 11 In the PROPEL study, pralatrexate (30 mg/m2/week intravenously for 6 weeks in 7‐week cycles) had a response rate of 58% in 12 patients with transformed MF. 4 Subsequently, in a prospective dose‐finding study in heavily‐pretreated U.S. patients, including relapsed/refractory MF, pralatrexate (15 mg/m2/week for 3 of 4 weeks) resulted in a 45% response rate after a median of four cycles. 12 The most common treatment‐related adverse events were mucosal inflammation (48%), fatigue (38%) and nausea (31%). 12 Foss et al. reported a study of 27 U.S. patients with relapsed/refractory MF or Sézary syndrome treated with pralatrexate (10 to 30 mg/m2 weekly for 3 of 4 weeks, or every other week) and partial or complete clinical responses were observed in 57% of patients. 5 These results suggest that pralatrexate has a clinical efficacy and confirms a high overall response rate at doses even less than 15 mg/m2 in the treatment of advanced CTCL. In addition, pralatrexate has been investigated in combination with bexarotene 13 , 14 and romidepsin. 15 These combination therapies have been reported to have high overall response rates of more than 50%, and can be efficient and well‐tolerated treatments for advanced‐stage MF.
Although some preceding therapies provided temporary partial remission, our patients experienced relapses. We used pralatrexate at a dose of 30 mg/m2/week for 6 weeks in 7‐week cycles, which is the approved regimen for relapsed/refractory PTCL based on clinical trials. 10 , 11 Pralatrexate suppressed new tumor formation within two to three cycles of treatment and led to a partial response. As adverse events, mucositis was controlled by prophylactic measures, but moderate general fatigue and nausea were observed, so that treatment was temporarily discontinued in Case 1. If intolerable side effects with pralatrexate are encountered, a lower‐dose regimen should be considered. 5 , 12 In Case 2, the patient experienced a long‐term partial response and then relapsed, but the patient did not want to change to another therapy or combination therapy with other drugs, resulting in a rapid progression. It may be reasonable to combine pralatrexate with other agents or treatment modalities if the disease has progressed. 7
CONFLICT OF INTEREST
The authors have no conflict of interest to declare.
ACKNOWLEDGEMENTS
The authors thank Phillips‐Gilmore Oncology Communications and Annie Kai I. Cheang, PharmD, MS, for professional assistance with manuscript preparation. Preparation of the manuscript was funded by Mundipharma. The funder had no role in data collection, interpretation, decision to publish or preparation of the manuscript. | BEXAROTENE, BRENTUXIMAB VEDOTIN, CANDESARTAN, DAPAGLIFLOZIN, METFORMIN HYDROCHLORIDE, MOGAMULIZUMAB-KPKC, PIOGLITAZONE, PRAVASTATIN SODIUM, SITAGLIPTIN PHOSPHATE, VORINOSTAT | DrugsGivenReaction | CC BY-NC-ND | 33454985 | 19,326,681 | 2021-05 |
What is the weight of the patient? | Pralatrexate for refractory mycosis fungoides in two Japanese patients.
Pralatrexate has been approved for the treatment of relapsed/refractory peripheral T cell lymphomas. Studies in the U.S. also support the clinical efficacy of pralatrexate to treat advanced-stage cutaneous T-cell lymphomas, but outcomes in Japanese patients have not yet been reported. We herein describe two Japanese patients with heavily-pretreated relapsed/refractory mycosis fungoides that were successfully controlled by pralatrexate.
1 INTRODUCTION
Mycosis fungoides (MF) is the most prevalent form of cutaneous T‐cell lymphoma (CTCL). 1 Advanced‐stage MF has a poor prognosis 2 and requires systemic therapies. 1 Pralatrexate, a folic acid analog metabolic inhibitor, has been approved in the U.S.A. since 2009 for the treatment of relapsed/refractory peripheral T‐cell lymphoma (PTCL), but was launched in Japan in 2017. 3 In patients with advanced‐stage CTCL, U.S. studies with pralatrexate showed clinical response rates up to 58%, 4 , 5 but outcomes in Japanese patients have not yet been reported. We describe the clinical outcomes of two Japanese patients with relapsed/refractory MF who were treated with pralatrexate.
2 CASE REPORT
2.1 Case 1
A 58‐year‐old Japanese man was diagnosed with MF 6 years ago, and was classified as stage IIB (T3N0M0B0) 6 3 years later. Although some erythema and tumors were resolved with mogamulizumab (1 mg/kg/week, 8 cycles), new tumors appeared after the treatment ended. Histopathological findings revealed CD30+ large‐cell transformation, and brentuximab vedotin (BV; 1.8 mg/kg/3 weeks, 8 cycles) was started. After three cycles of BV, the tumors reduced but the erythema remained. Subsequent courses of therapy included vorinostat (400 mg/day), which led to drug‐induced liver injury, oral bexarotene (225 mg/day), a second course of BV (1.8 mg/kg/3 weeks, 8 cycles) and mogamulizumab (1 mg/kg/week, 5 cycles), each providing an inadequate response. A third course of BV (2 cycles) with ionizing radiation therapy (36 Gy, left cheek tumor), which resulted in drug eruption, oral etoposide monotherapy (50 mg/day) and interferon‐gamma (2 million IU, 7 doses), followed but none of those led to an adequate response. Treatment with ionizing radiation (34 Gy, right cheek) with etoposide (25 mg/day) combined with sobuzoxane (400 mg/day) partially reduced his erythema and lesions, but new tumors appeared that required further ionizing radiation therapy (34 Gy, left hand).
He then began intravenous treatment with pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles). He also received a mucositis prophylactic regimen of intramuscular vitamin B12 (0.5 mg every 4 weeks), oral folic acid (1.25 mg daily), oral cryotherapy prior to and for 30 minutes after pralatrexate, and dental care provided by a dentist. Before and after three cycles of pralatrexate treatment, the modified severity weighted assessment tool (mSWAT) score improved from 53.5 to 31.5 and the soluble IL‐2 receptor value decreased from 4,608 U/mL to 2,731 U/mL. Adverse reactions included mild anemia (hemoglobin 11.7 g/dL), nausea and some mucositis lesions, but none of them were particularly severe. However, his treatment was changed from pralatrexate to oral forodesine due to general fatigue. At 2.5 months after the discontinuation of pralatrexate, his mSWAT score worsened to 69.7 (Figure 1). He resumed pralatrexate treatment and radiation therapy, and after two cycles of treatment, most of the tumors and erythema disappeared. He had a partial response for 5 months, but then the erythema and plaques flared up (mSWAT score, 34), and he changed to BV therapy.
Figure 1 Response to pralatrexate in patient 1. (a, d) Before treatment with pralatrexate. (b, e) After three cycles of treatment with pralatrexate. (c, f) At 2.5 months after the discontinuation of pralatrexate. Most erythema had resolved with pralatrexate, but after discontinuation, erythema flare‐ups and rapid tumor formation/enlargement were observed (arrows)
2.2 Case 2
A 60‐year‐old Japanese man was diagnosed with MF 14 years ago, and was classified as stage IIB (T3N0M0B0) 6 7 years later. Previous therapies included interferon‐gamma (1 million IU, 2 doses), etoposide (50 mg/day), methotrexate (10 mg/week) and oral prednisone (approximately 20 mg/day), but he had inadequate responses to all of them. Although vorinostat (400 mg/day) reduced some of the erythema and plaques, it led to anorexia and general fatigue. His atypical lymphocytes were positive for CCR4, and treatment with mogamulizumab (1 mg/kg/week, 8 cycles) was initiated. Mogamulizumab led to partial remission for 10 months, but new tumors gradually developed on his legs. A skin biopsy revealed CD30+ large‐cell transformation. BV (1.8 mg/kg/3 weeks, 4 cycles) led to normalization of soluble IL‐2 receptor levels and some tumors disappeared, but the tumor on his buttocks remained and required ionizing radiation therapy (36 Gy). Sobuzoxane (400 mg/day) and etoposide (25 mg/day) led to a partial reduction of the tumors but did not suppress new tumor formation.
He began treatment with intravenous pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles) together with the same mucositis prophylaxis as described for Case 1. After two cycles of treatment, the erythema, which was recalcitrant to previous therapies, resolved and the mSWAT score decreased from 49.2 to 17.5 (Figure 2). Although the tumor on his left foot remained, no new tumors emerged, and a partial response was maintained for 15 months with continued pralatrexate therapy. The patient experienced mild nausea and general fatigue, but mucositis and severe adverse events were not observed. 16 months later, some erythema and plaques appeared on his trunk and extremities. Bexarotene (300 mg/day) was added at 17 months, but erythema and tumors became more frequent rapidly and mSWAT worsened to 87. At present, he has been changed to gemcitabine therapy.
Figure 2 Response to pralatrexate in patient 2. (a–c) Before beginning treatment with pralatrexate. (d–f) After two cycles of treatment with pralatrexate
3 DISCUSSION/CONCLUSION
In Japan, about 90% of malignant lymphomas involving the skin are CTCLs, with MF being the most prevalent. 1 Although most patients with MF present with early‐stage disease, about one‐third of them experience disease progression, and 26% of them die due to MF. 2 Patients with advanced stages have a poor prognosis, with a median survival of 3.4 (stage III) to 4.7 years (stage IIB). 2 The chronic and recurrent nature of MF progression necessitates repeated systemic treatment for disease control. Although various treatment options exist, comparative trials and evidence‐based treatment algorithms to guide treatment prioritization have not yet been established. 7
Pralatrexate is a folate analog metabolic inhibitor that blocks dihydrofolate reductase, thereby preventing thymidylate and purine synthesis, which results in cell cycle arrest in the S phase. 8 Pralatrexate has a higher affinity for reduced folate carrier type 1 (RFC‐1) compared to MTX, and therefore it is preferentially taken up by many tumor cells that overexpress RFC‐1 and has a markedly greater activity than MTX. 8 , 9 Pralatrexate has been approved for relapsed/refractory PTCL in the U.S. (2009) based on results from a PROPEL study. 10 Pralatrexate was subsequently approved in Japan (in 2017) for treating relapsed/refractory PTCL after a phase I/II study in Japan demonstrated its efficacy and tolerability. 11 In the PROPEL study, pralatrexate (30 mg/m2/week intravenously for 6 weeks in 7‐week cycles) had a response rate of 58% in 12 patients with transformed MF. 4 Subsequently, in a prospective dose‐finding study in heavily‐pretreated U.S. patients, including relapsed/refractory MF, pralatrexate (15 mg/m2/week for 3 of 4 weeks) resulted in a 45% response rate after a median of four cycles. 12 The most common treatment‐related adverse events were mucosal inflammation (48%), fatigue (38%) and nausea (31%). 12 Foss et al. reported a study of 27 U.S. patients with relapsed/refractory MF or Sézary syndrome treated with pralatrexate (10 to 30 mg/m2 weekly for 3 of 4 weeks, or every other week) and partial or complete clinical responses were observed in 57% of patients. 5 These results suggest that pralatrexate has a clinical efficacy and confirms a high overall response rate at doses even less than 15 mg/m2 in the treatment of advanced CTCL. In addition, pralatrexate has been investigated in combination with bexarotene 13 , 14 and romidepsin. 15 These combination therapies have been reported to have high overall response rates of more than 50%, and can be efficient and well‐tolerated treatments for advanced‐stage MF.
Although some preceding therapies provided temporary partial remission, our patients experienced relapses. We used pralatrexate at a dose of 30 mg/m2/week for 6 weeks in 7‐week cycles, which is the approved regimen for relapsed/refractory PTCL based on clinical trials. 10 , 11 Pralatrexate suppressed new tumor formation within two to three cycles of treatment and led to a partial response. As adverse events, mucositis was controlled by prophylactic measures, but moderate general fatigue and nausea were observed, so that treatment was temporarily discontinued in Case 1. If intolerable side effects with pralatrexate are encountered, a lower‐dose regimen should be considered. 5 , 12 In Case 2, the patient experienced a long‐term partial response and then relapsed, but the patient did not want to change to another therapy or combination therapy with other drugs, resulting in a rapid progression. It may be reasonable to combine pralatrexate with other agents or treatment modalities if the disease has progressed. 7
CONFLICT OF INTEREST
The authors have no conflict of interest to declare.
ACKNOWLEDGEMENTS
The authors thank Phillips‐Gilmore Oncology Communications and Annie Kai I. Cheang, PharmD, MS, for professional assistance with manuscript preparation. Preparation of the manuscript was funded by Mundipharma. The funder had no role in data collection, interpretation, decision to publish or preparation of the manuscript. | 49 kg. | Weight | CC BY-NC-ND | 33454985 | 19,326,681 | 2021-05 |
What was the administration route of drug 'BEXAROTENE'? | Pralatrexate for refractory mycosis fungoides in two Japanese patients.
Pralatrexate has been approved for the treatment of relapsed/refractory peripheral T cell lymphomas. Studies in the U.S. also support the clinical efficacy of pralatrexate to treat advanced-stage cutaneous T-cell lymphomas, but outcomes in Japanese patients have not yet been reported. We herein describe two Japanese patients with heavily-pretreated relapsed/refractory mycosis fungoides that were successfully controlled by pralatrexate.
1 INTRODUCTION
Mycosis fungoides (MF) is the most prevalent form of cutaneous T‐cell lymphoma (CTCL). 1 Advanced‐stage MF has a poor prognosis 2 and requires systemic therapies. 1 Pralatrexate, a folic acid analog metabolic inhibitor, has been approved in the U.S.A. since 2009 for the treatment of relapsed/refractory peripheral T‐cell lymphoma (PTCL), but was launched in Japan in 2017. 3 In patients with advanced‐stage CTCL, U.S. studies with pralatrexate showed clinical response rates up to 58%, 4 , 5 but outcomes in Japanese patients have not yet been reported. We describe the clinical outcomes of two Japanese patients with relapsed/refractory MF who were treated with pralatrexate.
2 CASE REPORT
2.1 Case 1
A 58‐year‐old Japanese man was diagnosed with MF 6 years ago, and was classified as stage IIB (T3N0M0B0) 6 3 years later. Although some erythema and tumors were resolved with mogamulizumab (1 mg/kg/week, 8 cycles), new tumors appeared after the treatment ended. Histopathological findings revealed CD30+ large‐cell transformation, and brentuximab vedotin (BV; 1.8 mg/kg/3 weeks, 8 cycles) was started. After three cycles of BV, the tumors reduced but the erythema remained. Subsequent courses of therapy included vorinostat (400 mg/day), which led to drug‐induced liver injury, oral bexarotene (225 mg/day), a second course of BV (1.8 mg/kg/3 weeks, 8 cycles) and mogamulizumab (1 mg/kg/week, 5 cycles), each providing an inadequate response. A third course of BV (2 cycles) with ionizing radiation therapy (36 Gy, left cheek tumor), which resulted in drug eruption, oral etoposide monotherapy (50 mg/day) and interferon‐gamma (2 million IU, 7 doses), followed but none of those led to an adequate response. Treatment with ionizing radiation (34 Gy, right cheek) with etoposide (25 mg/day) combined with sobuzoxane (400 mg/day) partially reduced his erythema and lesions, but new tumors appeared that required further ionizing radiation therapy (34 Gy, left hand).
He then began intravenous treatment with pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles). He also received a mucositis prophylactic regimen of intramuscular vitamin B12 (0.5 mg every 4 weeks), oral folic acid (1.25 mg daily), oral cryotherapy prior to and for 30 minutes after pralatrexate, and dental care provided by a dentist. Before and after three cycles of pralatrexate treatment, the modified severity weighted assessment tool (mSWAT) score improved from 53.5 to 31.5 and the soluble IL‐2 receptor value decreased from 4,608 U/mL to 2,731 U/mL. Adverse reactions included mild anemia (hemoglobin 11.7 g/dL), nausea and some mucositis lesions, but none of them were particularly severe. However, his treatment was changed from pralatrexate to oral forodesine due to general fatigue. At 2.5 months after the discontinuation of pralatrexate, his mSWAT score worsened to 69.7 (Figure 1). He resumed pralatrexate treatment and radiation therapy, and after two cycles of treatment, most of the tumors and erythema disappeared. He had a partial response for 5 months, but then the erythema and plaques flared up (mSWAT score, 34), and he changed to BV therapy.
Figure 1 Response to pralatrexate in patient 1. (a, d) Before treatment with pralatrexate. (b, e) After three cycles of treatment with pralatrexate. (c, f) At 2.5 months after the discontinuation of pralatrexate. Most erythema had resolved with pralatrexate, but after discontinuation, erythema flare‐ups and rapid tumor formation/enlargement were observed (arrows)
2.2 Case 2
A 60‐year‐old Japanese man was diagnosed with MF 14 years ago, and was classified as stage IIB (T3N0M0B0) 6 7 years later. Previous therapies included interferon‐gamma (1 million IU, 2 doses), etoposide (50 mg/day), methotrexate (10 mg/week) and oral prednisone (approximately 20 mg/day), but he had inadequate responses to all of them. Although vorinostat (400 mg/day) reduced some of the erythema and plaques, it led to anorexia and general fatigue. His atypical lymphocytes were positive for CCR4, and treatment with mogamulizumab (1 mg/kg/week, 8 cycles) was initiated. Mogamulizumab led to partial remission for 10 months, but new tumors gradually developed on his legs. A skin biopsy revealed CD30+ large‐cell transformation. BV (1.8 mg/kg/3 weeks, 4 cycles) led to normalization of soluble IL‐2 receptor levels and some tumors disappeared, but the tumor on his buttocks remained and required ionizing radiation therapy (36 Gy). Sobuzoxane (400 mg/day) and etoposide (25 mg/day) led to a partial reduction of the tumors but did not suppress new tumor formation.
He began treatment with intravenous pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles) together with the same mucositis prophylaxis as described for Case 1. After two cycles of treatment, the erythema, which was recalcitrant to previous therapies, resolved and the mSWAT score decreased from 49.2 to 17.5 (Figure 2). Although the tumor on his left foot remained, no new tumors emerged, and a partial response was maintained for 15 months with continued pralatrexate therapy. The patient experienced mild nausea and general fatigue, but mucositis and severe adverse events were not observed. 16 months later, some erythema and plaques appeared on his trunk and extremities. Bexarotene (300 mg/day) was added at 17 months, but erythema and tumors became more frequent rapidly and mSWAT worsened to 87. At present, he has been changed to gemcitabine therapy.
Figure 2 Response to pralatrexate in patient 2. (a–c) Before beginning treatment with pralatrexate. (d–f) After two cycles of treatment with pralatrexate
3 DISCUSSION/CONCLUSION
In Japan, about 90% of malignant lymphomas involving the skin are CTCLs, with MF being the most prevalent. 1 Although most patients with MF present with early‐stage disease, about one‐third of them experience disease progression, and 26% of them die due to MF. 2 Patients with advanced stages have a poor prognosis, with a median survival of 3.4 (stage III) to 4.7 years (stage IIB). 2 The chronic and recurrent nature of MF progression necessitates repeated systemic treatment for disease control. Although various treatment options exist, comparative trials and evidence‐based treatment algorithms to guide treatment prioritization have not yet been established. 7
Pralatrexate is a folate analog metabolic inhibitor that blocks dihydrofolate reductase, thereby preventing thymidylate and purine synthesis, which results in cell cycle arrest in the S phase. 8 Pralatrexate has a higher affinity for reduced folate carrier type 1 (RFC‐1) compared to MTX, and therefore it is preferentially taken up by many tumor cells that overexpress RFC‐1 and has a markedly greater activity than MTX. 8 , 9 Pralatrexate has been approved for relapsed/refractory PTCL in the U.S. (2009) based on results from a PROPEL study. 10 Pralatrexate was subsequently approved in Japan (in 2017) for treating relapsed/refractory PTCL after a phase I/II study in Japan demonstrated its efficacy and tolerability. 11 In the PROPEL study, pralatrexate (30 mg/m2/week intravenously for 6 weeks in 7‐week cycles) had a response rate of 58% in 12 patients with transformed MF. 4 Subsequently, in a prospective dose‐finding study in heavily‐pretreated U.S. patients, including relapsed/refractory MF, pralatrexate (15 mg/m2/week for 3 of 4 weeks) resulted in a 45% response rate after a median of four cycles. 12 The most common treatment‐related adverse events were mucosal inflammation (48%), fatigue (38%) and nausea (31%). 12 Foss et al. reported a study of 27 U.S. patients with relapsed/refractory MF or Sézary syndrome treated with pralatrexate (10 to 30 mg/m2 weekly for 3 of 4 weeks, or every other week) and partial or complete clinical responses were observed in 57% of patients. 5 These results suggest that pralatrexate has a clinical efficacy and confirms a high overall response rate at doses even less than 15 mg/m2 in the treatment of advanced CTCL. In addition, pralatrexate has been investigated in combination with bexarotene 13 , 14 and romidepsin. 15 These combination therapies have been reported to have high overall response rates of more than 50%, and can be efficient and well‐tolerated treatments for advanced‐stage MF.
Although some preceding therapies provided temporary partial remission, our patients experienced relapses. We used pralatrexate at a dose of 30 mg/m2/week for 6 weeks in 7‐week cycles, which is the approved regimen for relapsed/refractory PTCL based on clinical trials. 10 , 11 Pralatrexate suppressed new tumor formation within two to three cycles of treatment and led to a partial response. As adverse events, mucositis was controlled by prophylactic measures, but moderate general fatigue and nausea were observed, so that treatment was temporarily discontinued in Case 1. If intolerable side effects with pralatrexate are encountered, a lower‐dose regimen should be considered. 5 , 12 In Case 2, the patient experienced a long‐term partial response and then relapsed, but the patient did not want to change to another therapy or combination therapy with other drugs, resulting in a rapid progression. It may be reasonable to combine pralatrexate with other agents or treatment modalities if the disease has progressed. 7
CONFLICT OF INTEREST
The authors have no conflict of interest to declare.
ACKNOWLEDGEMENTS
The authors thank Phillips‐Gilmore Oncology Communications and Annie Kai I. Cheang, PharmD, MS, for professional assistance with manuscript preparation. Preparation of the manuscript was funded by Mundipharma. The funder had no role in data collection, interpretation, decision to publish or preparation of the manuscript. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33454985 | 19,326,681 | 2021-05 |
What was the administration route of drug 'VORINOSTAT'? | Pralatrexate for refractory mycosis fungoides in two Japanese patients.
Pralatrexate has been approved for the treatment of relapsed/refractory peripheral T cell lymphomas. Studies in the U.S. also support the clinical efficacy of pralatrexate to treat advanced-stage cutaneous T-cell lymphomas, but outcomes in Japanese patients have not yet been reported. We herein describe two Japanese patients with heavily-pretreated relapsed/refractory mycosis fungoides that were successfully controlled by pralatrexate.
1 INTRODUCTION
Mycosis fungoides (MF) is the most prevalent form of cutaneous T‐cell lymphoma (CTCL). 1 Advanced‐stage MF has a poor prognosis 2 and requires systemic therapies. 1 Pralatrexate, a folic acid analog metabolic inhibitor, has been approved in the U.S.A. since 2009 for the treatment of relapsed/refractory peripheral T‐cell lymphoma (PTCL), but was launched in Japan in 2017. 3 In patients with advanced‐stage CTCL, U.S. studies with pralatrexate showed clinical response rates up to 58%, 4 , 5 but outcomes in Japanese patients have not yet been reported. We describe the clinical outcomes of two Japanese patients with relapsed/refractory MF who were treated with pralatrexate.
2 CASE REPORT
2.1 Case 1
A 58‐year‐old Japanese man was diagnosed with MF 6 years ago, and was classified as stage IIB (T3N0M0B0) 6 3 years later. Although some erythema and tumors were resolved with mogamulizumab (1 mg/kg/week, 8 cycles), new tumors appeared after the treatment ended. Histopathological findings revealed CD30+ large‐cell transformation, and brentuximab vedotin (BV; 1.8 mg/kg/3 weeks, 8 cycles) was started. After three cycles of BV, the tumors reduced but the erythema remained. Subsequent courses of therapy included vorinostat (400 mg/day), which led to drug‐induced liver injury, oral bexarotene (225 mg/day), a second course of BV (1.8 mg/kg/3 weeks, 8 cycles) and mogamulizumab (1 mg/kg/week, 5 cycles), each providing an inadequate response. A third course of BV (2 cycles) with ionizing radiation therapy (36 Gy, left cheek tumor), which resulted in drug eruption, oral etoposide monotherapy (50 mg/day) and interferon‐gamma (2 million IU, 7 doses), followed but none of those led to an adequate response. Treatment with ionizing radiation (34 Gy, right cheek) with etoposide (25 mg/day) combined with sobuzoxane (400 mg/day) partially reduced his erythema and lesions, but new tumors appeared that required further ionizing radiation therapy (34 Gy, left hand).
He then began intravenous treatment with pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles). He also received a mucositis prophylactic regimen of intramuscular vitamin B12 (0.5 mg every 4 weeks), oral folic acid (1.25 mg daily), oral cryotherapy prior to and for 30 minutes after pralatrexate, and dental care provided by a dentist. Before and after three cycles of pralatrexate treatment, the modified severity weighted assessment tool (mSWAT) score improved from 53.5 to 31.5 and the soluble IL‐2 receptor value decreased from 4,608 U/mL to 2,731 U/mL. Adverse reactions included mild anemia (hemoglobin 11.7 g/dL), nausea and some mucositis lesions, but none of them were particularly severe. However, his treatment was changed from pralatrexate to oral forodesine due to general fatigue. At 2.5 months after the discontinuation of pralatrexate, his mSWAT score worsened to 69.7 (Figure 1). He resumed pralatrexate treatment and radiation therapy, and after two cycles of treatment, most of the tumors and erythema disappeared. He had a partial response for 5 months, but then the erythema and plaques flared up (mSWAT score, 34), and he changed to BV therapy.
Figure 1 Response to pralatrexate in patient 1. (a, d) Before treatment with pralatrexate. (b, e) After three cycles of treatment with pralatrexate. (c, f) At 2.5 months after the discontinuation of pralatrexate. Most erythema had resolved with pralatrexate, but after discontinuation, erythema flare‐ups and rapid tumor formation/enlargement were observed (arrows)
2.2 Case 2
A 60‐year‐old Japanese man was diagnosed with MF 14 years ago, and was classified as stage IIB (T3N0M0B0) 6 7 years later. Previous therapies included interferon‐gamma (1 million IU, 2 doses), etoposide (50 mg/day), methotrexate (10 mg/week) and oral prednisone (approximately 20 mg/day), but he had inadequate responses to all of them. Although vorinostat (400 mg/day) reduced some of the erythema and plaques, it led to anorexia and general fatigue. His atypical lymphocytes were positive for CCR4, and treatment with mogamulizumab (1 mg/kg/week, 8 cycles) was initiated. Mogamulizumab led to partial remission for 10 months, but new tumors gradually developed on his legs. A skin biopsy revealed CD30+ large‐cell transformation. BV (1.8 mg/kg/3 weeks, 4 cycles) led to normalization of soluble IL‐2 receptor levels and some tumors disappeared, but the tumor on his buttocks remained and required ionizing radiation therapy (36 Gy). Sobuzoxane (400 mg/day) and etoposide (25 mg/day) led to a partial reduction of the tumors but did not suppress new tumor formation.
He began treatment with intravenous pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles) together with the same mucositis prophylaxis as described for Case 1. After two cycles of treatment, the erythema, which was recalcitrant to previous therapies, resolved and the mSWAT score decreased from 49.2 to 17.5 (Figure 2). Although the tumor on his left foot remained, no new tumors emerged, and a partial response was maintained for 15 months with continued pralatrexate therapy. The patient experienced mild nausea and general fatigue, but mucositis and severe adverse events were not observed. 16 months later, some erythema and plaques appeared on his trunk and extremities. Bexarotene (300 mg/day) was added at 17 months, but erythema and tumors became more frequent rapidly and mSWAT worsened to 87. At present, he has been changed to gemcitabine therapy.
Figure 2 Response to pralatrexate in patient 2. (a–c) Before beginning treatment with pralatrexate. (d–f) After two cycles of treatment with pralatrexate
3 DISCUSSION/CONCLUSION
In Japan, about 90% of malignant lymphomas involving the skin are CTCLs, with MF being the most prevalent. 1 Although most patients with MF present with early‐stage disease, about one‐third of them experience disease progression, and 26% of them die due to MF. 2 Patients with advanced stages have a poor prognosis, with a median survival of 3.4 (stage III) to 4.7 years (stage IIB). 2 The chronic and recurrent nature of MF progression necessitates repeated systemic treatment for disease control. Although various treatment options exist, comparative trials and evidence‐based treatment algorithms to guide treatment prioritization have not yet been established. 7
Pralatrexate is a folate analog metabolic inhibitor that blocks dihydrofolate reductase, thereby preventing thymidylate and purine synthesis, which results in cell cycle arrest in the S phase. 8 Pralatrexate has a higher affinity for reduced folate carrier type 1 (RFC‐1) compared to MTX, and therefore it is preferentially taken up by many tumor cells that overexpress RFC‐1 and has a markedly greater activity than MTX. 8 , 9 Pralatrexate has been approved for relapsed/refractory PTCL in the U.S. (2009) based on results from a PROPEL study. 10 Pralatrexate was subsequently approved in Japan (in 2017) for treating relapsed/refractory PTCL after a phase I/II study in Japan demonstrated its efficacy and tolerability. 11 In the PROPEL study, pralatrexate (30 mg/m2/week intravenously for 6 weeks in 7‐week cycles) had a response rate of 58% in 12 patients with transformed MF. 4 Subsequently, in a prospective dose‐finding study in heavily‐pretreated U.S. patients, including relapsed/refractory MF, pralatrexate (15 mg/m2/week for 3 of 4 weeks) resulted in a 45% response rate after a median of four cycles. 12 The most common treatment‐related adverse events were mucosal inflammation (48%), fatigue (38%) and nausea (31%). 12 Foss et al. reported a study of 27 U.S. patients with relapsed/refractory MF or Sézary syndrome treated with pralatrexate (10 to 30 mg/m2 weekly for 3 of 4 weeks, or every other week) and partial or complete clinical responses were observed in 57% of patients. 5 These results suggest that pralatrexate has a clinical efficacy and confirms a high overall response rate at doses even less than 15 mg/m2 in the treatment of advanced CTCL. In addition, pralatrexate has been investigated in combination with bexarotene 13 , 14 and romidepsin. 15 These combination therapies have been reported to have high overall response rates of more than 50%, and can be efficient and well‐tolerated treatments for advanced‐stage MF.
Although some preceding therapies provided temporary partial remission, our patients experienced relapses. We used pralatrexate at a dose of 30 mg/m2/week for 6 weeks in 7‐week cycles, which is the approved regimen for relapsed/refractory PTCL based on clinical trials. 10 , 11 Pralatrexate suppressed new tumor formation within two to three cycles of treatment and led to a partial response. As adverse events, mucositis was controlled by prophylactic measures, but moderate general fatigue and nausea were observed, so that treatment was temporarily discontinued in Case 1. If intolerable side effects with pralatrexate are encountered, a lower‐dose regimen should be considered. 5 , 12 In Case 2, the patient experienced a long‐term partial response and then relapsed, but the patient did not want to change to another therapy or combination therapy with other drugs, resulting in a rapid progression. It may be reasonable to combine pralatrexate with other agents or treatment modalities if the disease has progressed. 7
CONFLICT OF INTEREST
The authors have no conflict of interest to declare.
ACKNOWLEDGEMENTS
The authors thank Phillips‐Gilmore Oncology Communications and Annie Kai I. Cheang, PharmD, MS, for professional assistance with manuscript preparation. Preparation of the manuscript was funded by Mundipharma. The funder had no role in data collection, interpretation, decision to publish or preparation of the manuscript. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33454985 | 19,326,681 | 2021-05 |
What was the dosage of drug 'BEXAROTENE'? | Pralatrexate for refractory mycosis fungoides in two Japanese patients.
Pralatrexate has been approved for the treatment of relapsed/refractory peripheral T cell lymphomas. Studies in the U.S. also support the clinical efficacy of pralatrexate to treat advanced-stage cutaneous T-cell lymphomas, but outcomes in Japanese patients have not yet been reported. We herein describe two Japanese patients with heavily-pretreated relapsed/refractory mycosis fungoides that were successfully controlled by pralatrexate.
1 INTRODUCTION
Mycosis fungoides (MF) is the most prevalent form of cutaneous T‐cell lymphoma (CTCL). 1 Advanced‐stage MF has a poor prognosis 2 and requires systemic therapies. 1 Pralatrexate, a folic acid analog metabolic inhibitor, has been approved in the U.S.A. since 2009 for the treatment of relapsed/refractory peripheral T‐cell lymphoma (PTCL), but was launched in Japan in 2017. 3 In patients with advanced‐stage CTCL, U.S. studies with pralatrexate showed clinical response rates up to 58%, 4 , 5 but outcomes in Japanese patients have not yet been reported. We describe the clinical outcomes of two Japanese patients with relapsed/refractory MF who were treated with pralatrexate.
2 CASE REPORT
2.1 Case 1
A 58‐year‐old Japanese man was diagnosed with MF 6 years ago, and was classified as stage IIB (T3N0M0B0) 6 3 years later. Although some erythema and tumors were resolved with mogamulizumab (1 mg/kg/week, 8 cycles), new tumors appeared after the treatment ended. Histopathological findings revealed CD30+ large‐cell transformation, and brentuximab vedotin (BV; 1.8 mg/kg/3 weeks, 8 cycles) was started. After three cycles of BV, the tumors reduced but the erythema remained. Subsequent courses of therapy included vorinostat (400 mg/day), which led to drug‐induced liver injury, oral bexarotene (225 mg/day), a second course of BV (1.8 mg/kg/3 weeks, 8 cycles) and mogamulizumab (1 mg/kg/week, 5 cycles), each providing an inadequate response. A third course of BV (2 cycles) with ionizing radiation therapy (36 Gy, left cheek tumor), which resulted in drug eruption, oral etoposide monotherapy (50 mg/day) and interferon‐gamma (2 million IU, 7 doses), followed but none of those led to an adequate response. Treatment with ionizing radiation (34 Gy, right cheek) with etoposide (25 mg/day) combined with sobuzoxane (400 mg/day) partially reduced his erythema and lesions, but new tumors appeared that required further ionizing radiation therapy (34 Gy, left hand).
He then began intravenous treatment with pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles). He also received a mucositis prophylactic regimen of intramuscular vitamin B12 (0.5 mg every 4 weeks), oral folic acid (1.25 mg daily), oral cryotherapy prior to and for 30 minutes after pralatrexate, and dental care provided by a dentist. Before and after three cycles of pralatrexate treatment, the modified severity weighted assessment tool (mSWAT) score improved from 53.5 to 31.5 and the soluble IL‐2 receptor value decreased from 4,608 U/mL to 2,731 U/mL. Adverse reactions included mild anemia (hemoglobin 11.7 g/dL), nausea and some mucositis lesions, but none of them were particularly severe. However, his treatment was changed from pralatrexate to oral forodesine due to general fatigue. At 2.5 months after the discontinuation of pralatrexate, his mSWAT score worsened to 69.7 (Figure 1). He resumed pralatrexate treatment and radiation therapy, and after two cycles of treatment, most of the tumors and erythema disappeared. He had a partial response for 5 months, but then the erythema and plaques flared up (mSWAT score, 34), and he changed to BV therapy.
Figure 1 Response to pralatrexate in patient 1. (a, d) Before treatment with pralatrexate. (b, e) After three cycles of treatment with pralatrexate. (c, f) At 2.5 months after the discontinuation of pralatrexate. Most erythema had resolved with pralatrexate, but after discontinuation, erythema flare‐ups and rapid tumor formation/enlargement were observed (arrows)
2.2 Case 2
A 60‐year‐old Japanese man was diagnosed with MF 14 years ago, and was classified as stage IIB (T3N0M0B0) 6 7 years later. Previous therapies included interferon‐gamma (1 million IU, 2 doses), etoposide (50 mg/day), methotrexate (10 mg/week) and oral prednisone (approximately 20 mg/day), but he had inadequate responses to all of them. Although vorinostat (400 mg/day) reduced some of the erythema and plaques, it led to anorexia and general fatigue. His atypical lymphocytes were positive for CCR4, and treatment with mogamulizumab (1 mg/kg/week, 8 cycles) was initiated. Mogamulizumab led to partial remission for 10 months, but new tumors gradually developed on his legs. A skin biopsy revealed CD30+ large‐cell transformation. BV (1.8 mg/kg/3 weeks, 4 cycles) led to normalization of soluble IL‐2 receptor levels and some tumors disappeared, but the tumor on his buttocks remained and required ionizing radiation therapy (36 Gy). Sobuzoxane (400 mg/day) and etoposide (25 mg/day) led to a partial reduction of the tumors but did not suppress new tumor formation.
He began treatment with intravenous pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles) together with the same mucositis prophylaxis as described for Case 1. After two cycles of treatment, the erythema, which was recalcitrant to previous therapies, resolved and the mSWAT score decreased from 49.2 to 17.5 (Figure 2). Although the tumor on his left foot remained, no new tumors emerged, and a partial response was maintained for 15 months with continued pralatrexate therapy. The patient experienced mild nausea and general fatigue, but mucositis and severe adverse events were not observed. 16 months later, some erythema and plaques appeared on his trunk and extremities. Bexarotene (300 mg/day) was added at 17 months, but erythema and tumors became more frequent rapidly and mSWAT worsened to 87. At present, he has been changed to gemcitabine therapy.
Figure 2 Response to pralatrexate in patient 2. (a–c) Before beginning treatment with pralatrexate. (d–f) After two cycles of treatment with pralatrexate
3 DISCUSSION/CONCLUSION
In Japan, about 90% of malignant lymphomas involving the skin are CTCLs, with MF being the most prevalent. 1 Although most patients with MF present with early‐stage disease, about one‐third of them experience disease progression, and 26% of them die due to MF. 2 Patients with advanced stages have a poor prognosis, with a median survival of 3.4 (stage III) to 4.7 years (stage IIB). 2 The chronic and recurrent nature of MF progression necessitates repeated systemic treatment for disease control. Although various treatment options exist, comparative trials and evidence‐based treatment algorithms to guide treatment prioritization have not yet been established. 7
Pralatrexate is a folate analog metabolic inhibitor that blocks dihydrofolate reductase, thereby preventing thymidylate and purine synthesis, which results in cell cycle arrest in the S phase. 8 Pralatrexate has a higher affinity for reduced folate carrier type 1 (RFC‐1) compared to MTX, and therefore it is preferentially taken up by many tumor cells that overexpress RFC‐1 and has a markedly greater activity than MTX. 8 , 9 Pralatrexate has been approved for relapsed/refractory PTCL in the U.S. (2009) based on results from a PROPEL study. 10 Pralatrexate was subsequently approved in Japan (in 2017) for treating relapsed/refractory PTCL after a phase I/II study in Japan demonstrated its efficacy and tolerability. 11 In the PROPEL study, pralatrexate (30 mg/m2/week intravenously for 6 weeks in 7‐week cycles) had a response rate of 58% in 12 patients with transformed MF. 4 Subsequently, in a prospective dose‐finding study in heavily‐pretreated U.S. patients, including relapsed/refractory MF, pralatrexate (15 mg/m2/week for 3 of 4 weeks) resulted in a 45% response rate after a median of four cycles. 12 The most common treatment‐related adverse events were mucosal inflammation (48%), fatigue (38%) and nausea (31%). 12 Foss et al. reported a study of 27 U.S. patients with relapsed/refractory MF or Sézary syndrome treated with pralatrexate (10 to 30 mg/m2 weekly for 3 of 4 weeks, or every other week) and partial or complete clinical responses were observed in 57% of patients. 5 These results suggest that pralatrexate has a clinical efficacy and confirms a high overall response rate at doses even less than 15 mg/m2 in the treatment of advanced CTCL. In addition, pralatrexate has been investigated in combination with bexarotene 13 , 14 and romidepsin. 15 These combination therapies have been reported to have high overall response rates of more than 50%, and can be efficient and well‐tolerated treatments for advanced‐stage MF.
Although some preceding therapies provided temporary partial remission, our patients experienced relapses. We used pralatrexate at a dose of 30 mg/m2/week for 6 weeks in 7‐week cycles, which is the approved regimen for relapsed/refractory PTCL based on clinical trials. 10 , 11 Pralatrexate suppressed new tumor formation within two to three cycles of treatment and led to a partial response. As adverse events, mucositis was controlled by prophylactic measures, but moderate general fatigue and nausea were observed, so that treatment was temporarily discontinued in Case 1. If intolerable side effects with pralatrexate are encountered, a lower‐dose regimen should be considered. 5 , 12 In Case 2, the patient experienced a long‐term partial response and then relapsed, but the patient did not want to change to another therapy or combination therapy with other drugs, resulting in a rapid progression. It may be reasonable to combine pralatrexate with other agents or treatment modalities if the disease has progressed. 7
CONFLICT OF INTEREST
The authors have no conflict of interest to declare.
ACKNOWLEDGEMENTS
The authors thank Phillips‐Gilmore Oncology Communications and Annie Kai I. Cheang, PharmD, MS, for professional assistance with manuscript preparation. Preparation of the manuscript was funded by Mundipharma. The funder had no role in data collection, interpretation, decision to publish or preparation of the manuscript. | 225 MILLIGRAM, QD | DrugDosageText | CC BY-NC-ND | 33454985 | 19,326,681 | 2021-05 |
What was the dosage of drug 'CANDESARTAN'? | Pralatrexate for refractory mycosis fungoides in two Japanese patients.
Pralatrexate has been approved for the treatment of relapsed/refractory peripheral T cell lymphomas. Studies in the U.S. also support the clinical efficacy of pralatrexate to treat advanced-stage cutaneous T-cell lymphomas, but outcomes in Japanese patients have not yet been reported. We herein describe two Japanese patients with heavily-pretreated relapsed/refractory mycosis fungoides that were successfully controlled by pralatrexate.
1 INTRODUCTION
Mycosis fungoides (MF) is the most prevalent form of cutaneous T‐cell lymphoma (CTCL). 1 Advanced‐stage MF has a poor prognosis 2 and requires systemic therapies. 1 Pralatrexate, a folic acid analog metabolic inhibitor, has been approved in the U.S.A. since 2009 for the treatment of relapsed/refractory peripheral T‐cell lymphoma (PTCL), but was launched in Japan in 2017. 3 In patients with advanced‐stage CTCL, U.S. studies with pralatrexate showed clinical response rates up to 58%, 4 , 5 but outcomes in Japanese patients have not yet been reported. We describe the clinical outcomes of two Japanese patients with relapsed/refractory MF who were treated with pralatrexate.
2 CASE REPORT
2.1 Case 1
A 58‐year‐old Japanese man was diagnosed with MF 6 years ago, and was classified as stage IIB (T3N0M0B0) 6 3 years later. Although some erythema and tumors were resolved with mogamulizumab (1 mg/kg/week, 8 cycles), new tumors appeared after the treatment ended. Histopathological findings revealed CD30+ large‐cell transformation, and brentuximab vedotin (BV; 1.8 mg/kg/3 weeks, 8 cycles) was started. After three cycles of BV, the tumors reduced but the erythema remained. Subsequent courses of therapy included vorinostat (400 mg/day), which led to drug‐induced liver injury, oral bexarotene (225 mg/day), a second course of BV (1.8 mg/kg/3 weeks, 8 cycles) and mogamulizumab (1 mg/kg/week, 5 cycles), each providing an inadequate response. A third course of BV (2 cycles) with ionizing radiation therapy (36 Gy, left cheek tumor), which resulted in drug eruption, oral etoposide monotherapy (50 mg/day) and interferon‐gamma (2 million IU, 7 doses), followed but none of those led to an adequate response. Treatment with ionizing radiation (34 Gy, right cheek) with etoposide (25 mg/day) combined with sobuzoxane (400 mg/day) partially reduced his erythema and lesions, but new tumors appeared that required further ionizing radiation therapy (34 Gy, left hand).
He then began intravenous treatment with pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles). He also received a mucositis prophylactic regimen of intramuscular vitamin B12 (0.5 mg every 4 weeks), oral folic acid (1.25 mg daily), oral cryotherapy prior to and for 30 minutes after pralatrexate, and dental care provided by a dentist. Before and after three cycles of pralatrexate treatment, the modified severity weighted assessment tool (mSWAT) score improved from 53.5 to 31.5 and the soluble IL‐2 receptor value decreased from 4,608 U/mL to 2,731 U/mL. Adverse reactions included mild anemia (hemoglobin 11.7 g/dL), nausea and some mucositis lesions, but none of them were particularly severe. However, his treatment was changed from pralatrexate to oral forodesine due to general fatigue. At 2.5 months after the discontinuation of pralatrexate, his mSWAT score worsened to 69.7 (Figure 1). He resumed pralatrexate treatment and radiation therapy, and after two cycles of treatment, most of the tumors and erythema disappeared. He had a partial response for 5 months, but then the erythema and plaques flared up (mSWAT score, 34), and he changed to BV therapy.
Figure 1 Response to pralatrexate in patient 1. (a, d) Before treatment with pralatrexate. (b, e) After three cycles of treatment with pralatrexate. (c, f) At 2.5 months after the discontinuation of pralatrexate. Most erythema had resolved with pralatrexate, but after discontinuation, erythema flare‐ups and rapid tumor formation/enlargement were observed (arrows)
2.2 Case 2
A 60‐year‐old Japanese man was diagnosed with MF 14 years ago, and was classified as stage IIB (T3N0M0B0) 6 7 years later. Previous therapies included interferon‐gamma (1 million IU, 2 doses), etoposide (50 mg/day), methotrexate (10 mg/week) and oral prednisone (approximately 20 mg/day), but he had inadequate responses to all of them. Although vorinostat (400 mg/day) reduced some of the erythema and plaques, it led to anorexia and general fatigue. His atypical lymphocytes were positive for CCR4, and treatment with mogamulizumab (1 mg/kg/week, 8 cycles) was initiated. Mogamulizumab led to partial remission for 10 months, but new tumors gradually developed on his legs. A skin biopsy revealed CD30+ large‐cell transformation. BV (1.8 mg/kg/3 weeks, 4 cycles) led to normalization of soluble IL‐2 receptor levels and some tumors disappeared, but the tumor on his buttocks remained and required ionizing radiation therapy (36 Gy). Sobuzoxane (400 mg/day) and etoposide (25 mg/day) led to a partial reduction of the tumors but did not suppress new tumor formation.
He began treatment with intravenous pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles) together with the same mucositis prophylaxis as described for Case 1. After two cycles of treatment, the erythema, which was recalcitrant to previous therapies, resolved and the mSWAT score decreased from 49.2 to 17.5 (Figure 2). Although the tumor on his left foot remained, no new tumors emerged, and a partial response was maintained for 15 months with continued pralatrexate therapy. The patient experienced mild nausea and general fatigue, but mucositis and severe adverse events were not observed. 16 months later, some erythema and plaques appeared on his trunk and extremities. Bexarotene (300 mg/day) was added at 17 months, but erythema and tumors became more frequent rapidly and mSWAT worsened to 87. At present, he has been changed to gemcitabine therapy.
Figure 2 Response to pralatrexate in patient 2. (a–c) Before beginning treatment with pralatrexate. (d–f) After two cycles of treatment with pralatrexate
3 DISCUSSION/CONCLUSION
In Japan, about 90% of malignant lymphomas involving the skin are CTCLs, with MF being the most prevalent. 1 Although most patients with MF present with early‐stage disease, about one‐third of them experience disease progression, and 26% of them die due to MF. 2 Patients with advanced stages have a poor prognosis, with a median survival of 3.4 (stage III) to 4.7 years (stage IIB). 2 The chronic and recurrent nature of MF progression necessitates repeated systemic treatment for disease control. Although various treatment options exist, comparative trials and evidence‐based treatment algorithms to guide treatment prioritization have not yet been established. 7
Pralatrexate is a folate analog metabolic inhibitor that blocks dihydrofolate reductase, thereby preventing thymidylate and purine synthesis, which results in cell cycle arrest in the S phase. 8 Pralatrexate has a higher affinity for reduced folate carrier type 1 (RFC‐1) compared to MTX, and therefore it is preferentially taken up by many tumor cells that overexpress RFC‐1 and has a markedly greater activity than MTX. 8 , 9 Pralatrexate has been approved for relapsed/refractory PTCL in the U.S. (2009) based on results from a PROPEL study. 10 Pralatrexate was subsequently approved in Japan (in 2017) for treating relapsed/refractory PTCL after a phase I/II study in Japan demonstrated its efficacy and tolerability. 11 In the PROPEL study, pralatrexate (30 mg/m2/week intravenously for 6 weeks in 7‐week cycles) had a response rate of 58% in 12 patients with transformed MF. 4 Subsequently, in a prospective dose‐finding study in heavily‐pretreated U.S. patients, including relapsed/refractory MF, pralatrexate (15 mg/m2/week for 3 of 4 weeks) resulted in a 45% response rate after a median of four cycles. 12 The most common treatment‐related adverse events were mucosal inflammation (48%), fatigue (38%) and nausea (31%). 12 Foss et al. reported a study of 27 U.S. patients with relapsed/refractory MF or Sézary syndrome treated with pralatrexate (10 to 30 mg/m2 weekly for 3 of 4 weeks, or every other week) and partial or complete clinical responses were observed in 57% of patients. 5 These results suggest that pralatrexate has a clinical efficacy and confirms a high overall response rate at doses even less than 15 mg/m2 in the treatment of advanced CTCL. In addition, pralatrexate has been investigated in combination with bexarotene 13 , 14 and romidepsin. 15 These combination therapies have been reported to have high overall response rates of more than 50%, and can be efficient and well‐tolerated treatments for advanced‐stage MF.
Although some preceding therapies provided temporary partial remission, our patients experienced relapses. We used pralatrexate at a dose of 30 mg/m2/week for 6 weeks in 7‐week cycles, which is the approved regimen for relapsed/refractory PTCL based on clinical trials. 10 , 11 Pralatrexate suppressed new tumor formation within two to three cycles of treatment and led to a partial response. As adverse events, mucositis was controlled by prophylactic measures, but moderate general fatigue and nausea were observed, so that treatment was temporarily discontinued in Case 1. If intolerable side effects with pralatrexate are encountered, a lower‐dose regimen should be considered. 5 , 12 In Case 2, the patient experienced a long‐term partial response and then relapsed, but the patient did not want to change to another therapy or combination therapy with other drugs, resulting in a rapid progression. It may be reasonable to combine pralatrexate with other agents or treatment modalities if the disease has progressed. 7
CONFLICT OF INTEREST
The authors have no conflict of interest to declare.
ACKNOWLEDGEMENTS
The authors thank Phillips‐Gilmore Oncology Communications and Annie Kai I. Cheang, PharmD, MS, for professional assistance with manuscript preparation. Preparation of the manuscript was funded by Mundipharma. The funder had no role in data collection, interpretation, decision to publish or preparation of the manuscript. | 8MG *1/DAY | DrugDosageText | CC BY-NC-ND | 33454985 | 19,326,681 | 2021-05 |
What was the dosage of drug 'DAPAGLIFLOZIN'? | Pralatrexate for refractory mycosis fungoides in two Japanese patients.
Pralatrexate has been approved for the treatment of relapsed/refractory peripheral T cell lymphomas. Studies in the U.S. also support the clinical efficacy of pralatrexate to treat advanced-stage cutaneous T-cell lymphomas, but outcomes in Japanese patients have not yet been reported. We herein describe two Japanese patients with heavily-pretreated relapsed/refractory mycosis fungoides that were successfully controlled by pralatrexate.
1 INTRODUCTION
Mycosis fungoides (MF) is the most prevalent form of cutaneous T‐cell lymphoma (CTCL). 1 Advanced‐stage MF has a poor prognosis 2 and requires systemic therapies. 1 Pralatrexate, a folic acid analog metabolic inhibitor, has been approved in the U.S.A. since 2009 for the treatment of relapsed/refractory peripheral T‐cell lymphoma (PTCL), but was launched in Japan in 2017. 3 In patients with advanced‐stage CTCL, U.S. studies with pralatrexate showed clinical response rates up to 58%, 4 , 5 but outcomes in Japanese patients have not yet been reported. We describe the clinical outcomes of two Japanese patients with relapsed/refractory MF who were treated with pralatrexate.
2 CASE REPORT
2.1 Case 1
A 58‐year‐old Japanese man was diagnosed with MF 6 years ago, and was classified as stage IIB (T3N0M0B0) 6 3 years later. Although some erythema and tumors were resolved with mogamulizumab (1 mg/kg/week, 8 cycles), new tumors appeared after the treatment ended. Histopathological findings revealed CD30+ large‐cell transformation, and brentuximab vedotin (BV; 1.8 mg/kg/3 weeks, 8 cycles) was started. After three cycles of BV, the tumors reduced but the erythema remained. Subsequent courses of therapy included vorinostat (400 mg/day), which led to drug‐induced liver injury, oral bexarotene (225 mg/day), a second course of BV (1.8 mg/kg/3 weeks, 8 cycles) and mogamulizumab (1 mg/kg/week, 5 cycles), each providing an inadequate response. A third course of BV (2 cycles) with ionizing radiation therapy (36 Gy, left cheek tumor), which resulted in drug eruption, oral etoposide monotherapy (50 mg/day) and interferon‐gamma (2 million IU, 7 doses), followed but none of those led to an adequate response. Treatment with ionizing radiation (34 Gy, right cheek) with etoposide (25 mg/day) combined with sobuzoxane (400 mg/day) partially reduced his erythema and lesions, but new tumors appeared that required further ionizing radiation therapy (34 Gy, left hand).
He then began intravenous treatment with pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles). He also received a mucositis prophylactic regimen of intramuscular vitamin B12 (0.5 mg every 4 weeks), oral folic acid (1.25 mg daily), oral cryotherapy prior to and for 30 minutes after pralatrexate, and dental care provided by a dentist. Before and after three cycles of pralatrexate treatment, the modified severity weighted assessment tool (mSWAT) score improved from 53.5 to 31.5 and the soluble IL‐2 receptor value decreased from 4,608 U/mL to 2,731 U/mL. Adverse reactions included mild anemia (hemoglobin 11.7 g/dL), nausea and some mucositis lesions, but none of them were particularly severe. However, his treatment was changed from pralatrexate to oral forodesine due to general fatigue. At 2.5 months after the discontinuation of pralatrexate, his mSWAT score worsened to 69.7 (Figure 1). He resumed pralatrexate treatment and radiation therapy, and after two cycles of treatment, most of the tumors and erythema disappeared. He had a partial response for 5 months, but then the erythema and plaques flared up (mSWAT score, 34), and he changed to BV therapy.
Figure 1 Response to pralatrexate in patient 1. (a, d) Before treatment with pralatrexate. (b, e) After three cycles of treatment with pralatrexate. (c, f) At 2.5 months after the discontinuation of pralatrexate. Most erythema had resolved with pralatrexate, but after discontinuation, erythema flare‐ups and rapid tumor formation/enlargement were observed (arrows)
2.2 Case 2
A 60‐year‐old Japanese man was diagnosed with MF 14 years ago, and was classified as stage IIB (T3N0M0B0) 6 7 years later. Previous therapies included interferon‐gamma (1 million IU, 2 doses), etoposide (50 mg/day), methotrexate (10 mg/week) and oral prednisone (approximately 20 mg/day), but he had inadequate responses to all of them. Although vorinostat (400 mg/day) reduced some of the erythema and plaques, it led to anorexia and general fatigue. His atypical lymphocytes were positive for CCR4, and treatment with mogamulizumab (1 mg/kg/week, 8 cycles) was initiated. Mogamulizumab led to partial remission for 10 months, but new tumors gradually developed on his legs. A skin biopsy revealed CD30+ large‐cell transformation. BV (1.8 mg/kg/3 weeks, 4 cycles) led to normalization of soluble IL‐2 receptor levels and some tumors disappeared, but the tumor on his buttocks remained and required ionizing radiation therapy (36 Gy). Sobuzoxane (400 mg/day) and etoposide (25 mg/day) led to a partial reduction of the tumors but did not suppress new tumor formation.
He began treatment with intravenous pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles) together with the same mucositis prophylaxis as described for Case 1. After two cycles of treatment, the erythema, which was recalcitrant to previous therapies, resolved and the mSWAT score decreased from 49.2 to 17.5 (Figure 2). Although the tumor on his left foot remained, no new tumors emerged, and a partial response was maintained for 15 months with continued pralatrexate therapy. The patient experienced mild nausea and general fatigue, but mucositis and severe adverse events were not observed. 16 months later, some erythema and plaques appeared on his trunk and extremities. Bexarotene (300 mg/day) was added at 17 months, but erythema and tumors became more frequent rapidly and mSWAT worsened to 87. At present, he has been changed to gemcitabine therapy.
Figure 2 Response to pralatrexate in patient 2. (a–c) Before beginning treatment with pralatrexate. (d–f) After two cycles of treatment with pralatrexate
3 DISCUSSION/CONCLUSION
In Japan, about 90% of malignant lymphomas involving the skin are CTCLs, with MF being the most prevalent. 1 Although most patients with MF present with early‐stage disease, about one‐third of them experience disease progression, and 26% of them die due to MF. 2 Patients with advanced stages have a poor prognosis, with a median survival of 3.4 (stage III) to 4.7 years (stage IIB). 2 The chronic and recurrent nature of MF progression necessitates repeated systemic treatment for disease control. Although various treatment options exist, comparative trials and evidence‐based treatment algorithms to guide treatment prioritization have not yet been established. 7
Pralatrexate is a folate analog metabolic inhibitor that blocks dihydrofolate reductase, thereby preventing thymidylate and purine synthesis, which results in cell cycle arrest in the S phase. 8 Pralatrexate has a higher affinity for reduced folate carrier type 1 (RFC‐1) compared to MTX, and therefore it is preferentially taken up by many tumor cells that overexpress RFC‐1 and has a markedly greater activity than MTX. 8 , 9 Pralatrexate has been approved for relapsed/refractory PTCL in the U.S. (2009) based on results from a PROPEL study. 10 Pralatrexate was subsequently approved in Japan (in 2017) for treating relapsed/refractory PTCL after a phase I/II study in Japan demonstrated its efficacy and tolerability. 11 In the PROPEL study, pralatrexate (30 mg/m2/week intravenously for 6 weeks in 7‐week cycles) had a response rate of 58% in 12 patients with transformed MF. 4 Subsequently, in a prospective dose‐finding study in heavily‐pretreated U.S. patients, including relapsed/refractory MF, pralatrexate (15 mg/m2/week for 3 of 4 weeks) resulted in a 45% response rate after a median of four cycles. 12 The most common treatment‐related adverse events were mucosal inflammation (48%), fatigue (38%) and nausea (31%). 12 Foss et al. reported a study of 27 U.S. patients with relapsed/refractory MF or Sézary syndrome treated with pralatrexate (10 to 30 mg/m2 weekly for 3 of 4 weeks, or every other week) and partial or complete clinical responses were observed in 57% of patients. 5 These results suggest that pralatrexate has a clinical efficacy and confirms a high overall response rate at doses even less than 15 mg/m2 in the treatment of advanced CTCL. In addition, pralatrexate has been investigated in combination with bexarotene 13 , 14 and romidepsin. 15 These combination therapies have been reported to have high overall response rates of more than 50%, and can be efficient and well‐tolerated treatments for advanced‐stage MF.
Although some preceding therapies provided temporary partial remission, our patients experienced relapses. We used pralatrexate at a dose of 30 mg/m2/week for 6 weeks in 7‐week cycles, which is the approved regimen for relapsed/refractory PTCL based on clinical trials. 10 , 11 Pralatrexate suppressed new tumor formation within two to three cycles of treatment and led to a partial response. As adverse events, mucositis was controlled by prophylactic measures, but moderate general fatigue and nausea were observed, so that treatment was temporarily discontinued in Case 1. If intolerable side effects with pralatrexate are encountered, a lower‐dose regimen should be considered. 5 , 12 In Case 2, the patient experienced a long‐term partial response and then relapsed, but the patient did not want to change to another therapy or combination therapy with other drugs, resulting in a rapid progression. It may be reasonable to combine pralatrexate with other agents or treatment modalities if the disease has progressed. 7
CONFLICT OF INTEREST
The authors have no conflict of interest to declare.
ACKNOWLEDGEMENTS
The authors thank Phillips‐Gilmore Oncology Communications and Annie Kai I. Cheang, PharmD, MS, for professional assistance with manuscript preparation. Preparation of the manuscript was funded by Mundipharma. The funder had no role in data collection, interpretation, decision to publish or preparation of the manuscript. | 5MG *1/DAY | DrugDosageText | CC BY-NC-ND | 33454985 | 19,326,681 | 2021-05 |
What was the dosage of drug 'METFORMIN HYDROCHLORIDE'? | Pralatrexate for refractory mycosis fungoides in two Japanese patients.
Pralatrexate has been approved for the treatment of relapsed/refractory peripheral T cell lymphomas. Studies in the U.S. also support the clinical efficacy of pralatrexate to treat advanced-stage cutaneous T-cell lymphomas, but outcomes in Japanese patients have not yet been reported. We herein describe two Japanese patients with heavily-pretreated relapsed/refractory mycosis fungoides that were successfully controlled by pralatrexate.
1 INTRODUCTION
Mycosis fungoides (MF) is the most prevalent form of cutaneous T‐cell lymphoma (CTCL). 1 Advanced‐stage MF has a poor prognosis 2 and requires systemic therapies. 1 Pralatrexate, a folic acid analog metabolic inhibitor, has been approved in the U.S.A. since 2009 for the treatment of relapsed/refractory peripheral T‐cell lymphoma (PTCL), but was launched in Japan in 2017. 3 In patients with advanced‐stage CTCL, U.S. studies with pralatrexate showed clinical response rates up to 58%, 4 , 5 but outcomes in Japanese patients have not yet been reported. We describe the clinical outcomes of two Japanese patients with relapsed/refractory MF who were treated with pralatrexate.
2 CASE REPORT
2.1 Case 1
A 58‐year‐old Japanese man was diagnosed with MF 6 years ago, and was classified as stage IIB (T3N0M0B0) 6 3 years later. Although some erythema and tumors were resolved with mogamulizumab (1 mg/kg/week, 8 cycles), new tumors appeared after the treatment ended. Histopathological findings revealed CD30+ large‐cell transformation, and brentuximab vedotin (BV; 1.8 mg/kg/3 weeks, 8 cycles) was started. After three cycles of BV, the tumors reduced but the erythema remained. Subsequent courses of therapy included vorinostat (400 mg/day), which led to drug‐induced liver injury, oral bexarotene (225 mg/day), a second course of BV (1.8 mg/kg/3 weeks, 8 cycles) and mogamulizumab (1 mg/kg/week, 5 cycles), each providing an inadequate response. A third course of BV (2 cycles) with ionizing radiation therapy (36 Gy, left cheek tumor), which resulted in drug eruption, oral etoposide monotherapy (50 mg/day) and interferon‐gamma (2 million IU, 7 doses), followed but none of those led to an adequate response. Treatment with ionizing radiation (34 Gy, right cheek) with etoposide (25 mg/day) combined with sobuzoxane (400 mg/day) partially reduced his erythema and lesions, but new tumors appeared that required further ionizing radiation therapy (34 Gy, left hand).
He then began intravenous treatment with pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles). He also received a mucositis prophylactic regimen of intramuscular vitamin B12 (0.5 mg every 4 weeks), oral folic acid (1.25 mg daily), oral cryotherapy prior to and for 30 minutes after pralatrexate, and dental care provided by a dentist. Before and after three cycles of pralatrexate treatment, the modified severity weighted assessment tool (mSWAT) score improved from 53.5 to 31.5 and the soluble IL‐2 receptor value decreased from 4,608 U/mL to 2,731 U/mL. Adverse reactions included mild anemia (hemoglobin 11.7 g/dL), nausea and some mucositis lesions, but none of them were particularly severe. However, his treatment was changed from pralatrexate to oral forodesine due to general fatigue. At 2.5 months after the discontinuation of pralatrexate, his mSWAT score worsened to 69.7 (Figure 1). He resumed pralatrexate treatment and radiation therapy, and after two cycles of treatment, most of the tumors and erythema disappeared. He had a partial response for 5 months, but then the erythema and plaques flared up (mSWAT score, 34), and he changed to BV therapy.
Figure 1 Response to pralatrexate in patient 1. (a, d) Before treatment with pralatrexate. (b, e) After three cycles of treatment with pralatrexate. (c, f) At 2.5 months after the discontinuation of pralatrexate. Most erythema had resolved with pralatrexate, but after discontinuation, erythema flare‐ups and rapid tumor formation/enlargement were observed (arrows)
2.2 Case 2
A 60‐year‐old Japanese man was diagnosed with MF 14 years ago, and was classified as stage IIB (T3N0M0B0) 6 7 years later. Previous therapies included interferon‐gamma (1 million IU, 2 doses), etoposide (50 mg/day), methotrexate (10 mg/week) and oral prednisone (approximately 20 mg/day), but he had inadequate responses to all of them. Although vorinostat (400 mg/day) reduced some of the erythema and plaques, it led to anorexia and general fatigue. His atypical lymphocytes were positive for CCR4, and treatment with mogamulizumab (1 mg/kg/week, 8 cycles) was initiated. Mogamulizumab led to partial remission for 10 months, but new tumors gradually developed on his legs. A skin biopsy revealed CD30+ large‐cell transformation. BV (1.8 mg/kg/3 weeks, 4 cycles) led to normalization of soluble IL‐2 receptor levels and some tumors disappeared, but the tumor on his buttocks remained and required ionizing radiation therapy (36 Gy). Sobuzoxane (400 mg/day) and etoposide (25 mg/day) led to a partial reduction of the tumors but did not suppress new tumor formation.
He began treatment with intravenous pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles) together with the same mucositis prophylaxis as described for Case 1. After two cycles of treatment, the erythema, which was recalcitrant to previous therapies, resolved and the mSWAT score decreased from 49.2 to 17.5 (Figure 2). Although the tumor on his left foot remained, no new tumors emerged, and a partial response was maintained for 15 months with continued pralatrexate therapy. The patient experienced mild nausea and general fatigue, but mucositis and severe adverse events were not observed. 16 months later, some erythema and plaques appeared on his trunk and extremities. Bexarotene (300 mg/day) was added at 17 months, but erythema and tumors became more frequent rapidly and mSWAT worsened to 87. At present, he has been changed to gemcitabine therapy.
Figure 2 Response to pralatrexate in patient 2. (a–c) Before beginning treatment with pralatrexate. (d–f) After two cycles of treatment with pralatrexate
3 DISCUSSION/CONCLUSION
In Japan, about 90% of malignant lymphomas involving the skin are CTCLs, with MF being the most prevalent. 1 Although most patients with MF present with early‐stage disease, about one‐third of them experience disease progression, and 26% of them die due to MF. 2 Patients with advanced stages have a poor prognosis, with a median survival of 3.4 (stage III) to 4.7 years (stage IIB). 2 The chronic and recurrent nature of MF progression necessitates repeated systemic treatment for disease control. Although various treatment options exist, comparative trials and evidence‐based treatment algorithms to guide treatment prioritization have not yet been established. 7
Pralatrexate is a folate analog metabolic inhibitor that blocks dihydrofolate reductase, thereby preventing thymidylate and purine synthesis, which results in cell cycle arrest in the S phase. 8 Pralatrexate has a higher affinity for reduced folate carrier type 1 (RFC‐1) compared to MTX, and therefore it is preferentially taken up by many tumor cells that overexpress RFC‐1 and has a markedly greater activity than MTX. 8 , 9 Pralatrexate has been approved for relapsed/refractory PTCL in the U.S. (2009) based on results from a PROPEL study. 10 Pralatrexate was subsequently approved in Japan (in 2017) for treating relapsed/refractory PTCL after a phase I/II study in Japan demonstrated its efficacy and tolerability. 11 In the PROPEL study, pralatrexate (30 mg/m2/week intravenously for 6 weeks in 7‐week cycles) had a response rate of 58% in 12 patients with transformed MF. 4 Subsequently, in a prospective dose‐finding study in heavily‐pretreated U.S. patients, including relapsed/refractory MF, pralatrexate (15 mg/m2/week for 3 of 4 weeks) resulted in a 45% response rate after a median of four cycles. 12 The most common treatment‐related adverse events were mucosal inflammation (48%), fatigue (38%) and nausea (31%). 12 Foss et al. reported a study of 27 U.S. patients with relapsed/refractory MF or Sézary syndrome treated with pralatrexate (10 to 30 mg/m2 weekly for 3 of 4 weeks, or every other week) and partial or complete clinical responses were observed in 57% of patients. 5 These results suggest that pralatrexate has a clinical efficacy and confirms a high overall response rate at doses even less than 15 mg/m2 in the treatment of advanced CTCL. In addition, pralatrexate has been investigated in combination with bexarotene 13 , 14 and romidepsin. 15 These combination therapies have been reported to have high overall response rates of more than 50%, and can be efficient and well‐tolerated treatments for advanced‐stage MF.
Although some preceding therapies provided temporary partial remission, our patients experienced relapses. We used pralatrexate at a dose of 30 mg/m2/week for 6 weeks in 7‐week cycles, which is the approved regimen for relapsed/refractory PTCL based on clinical trials. 10 , 11 Pralatrexate suppressed new tumor formation within two to three cycles of treatment and led to a partial response. As adverse events, mucositis was controlled by prophylactic measures, but moderate general fatigue and nausea were observed, so that treatment was temporarily discontinued in Case 1. If intolerable side effects with pralatrexate are encountered, a lower‐dose regimen should be considered. 5 , 12 In Case 2, the patient experienced a long‐term partial response and then relapsed, but the patient did not want to change to another therapy or combination therapy with other drugs, resulting in a rapid progression. It may be reasonable to combine pralatrexate with other agents or treatment modalities if the disease has progressed. 7
CONFLICT OF INTEREST
The authors have no conflict of interest to declare.
ACKNOWLEDGEMENTS
The authors thank Phillips‐Gilmore Oncology Communications and Annie Kai I. Cheang, PharmD, MS, for professional assistance with manuscript preparation. Preparation of the manuscript was funded by Mundipharma. The funder had no role in data collection, interpretation, decision to publish or preparation of the manuscript. | 500MG *3/DAY | DrugDosageText | CC BY-NC-ND | 33454985 | 19,326,681 | 2021-05 |
What was the dosage of drug 'PIOGLITAZONE'? | Pralatrexate for refractory mycosis fungoides in two Japanese patients.
Pralatrexate has been approved for the treatment of relapsed/refractory peripheral T cell lymphomas. Studies in the U.S. also support the clinical efficacy of pralatrexate to treat advanced-stage cutaneous T-cell lymphomas, but outcomes in Japanese patients have not yet been reported. We herein describe two Japanese patients with heavily-pretreated relapsed/refractory mycosis fungoides that were successfully controlled by pralatrexate.
1 INTRODUCTION
Mycosis fungoides (MF) is the most prevalent form of cutaneous T‐cell lymphoma (CTCL). 1 Advanced‐stage MF has a poor prognosis 2 and requires systemic therapies. 1 Pralatrexate, a folic acid analog metabolic inhibitor, has been approved in the U.S.A. since 2009 for the treatment of relapsed/refractory peripheral T‐cell lymphoma (PTCL), but was launched in Japan in 2017. 3 In patients with advanced‐stage CTCL, U.S. studies with pralatrexate showed clinical response rates up to 58%, 4 , 5 but outcomes in Japanese patients have not yet been reported. We describe the clinical outcomes of two Japanese patients with relapsed/refractory MF who were treated with pralatrexate.
2 CASE REPORT
2.1 Case 1
A 58‐year‐old Japanese man was diagnosed with MF 6 years ago, and was classified as stage IIB (T3N0M0B0) 6 3 years later. Although some erythema and tumors were resolved with mogamulizumab (1 mg/kg/week, 8 cycles), new tumors appeared after the treatment ended. Histopathological findings revealed CD30+ large‐cell transformation, and brentuximab vedotin (BV; 1.8 mg/kg/3 weeks, 8 cycles) was started. After three cycles of BV, the tumors reduced but the erythema remained. Subsequent courses of therapy included vorinostat (400 mg/day), which led to drug‐induced liver injury, oral bexarotene (225 mg/day), a second course of BV (1.8 mg/kg/3 weeks, 8 cycles) and mogamulizumab (1 mg/kg/week, 5 cycles), each providing an inadequate response. A third course of BV (2 cycles) with ionizing radiation therapy (36 Gy, left cheek tumor), which resulted in drug eruption, oral etoposide monotherapy (50 mg/day) and interferon‐gamma (2 million IU, 7 doses), followed but none of those led to an adequate response. Treatment with ionizing radiation (34 Gy, right cheek) with etoposide (25 mg/day) combined with sobuzoxane (400 mg/day) partially reduced his erythema and lesions, but new tumors appeared that required further ionizing radiation therapy (34 Gy, left hand).
He then began intravenous treatment with pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles). He also received a mucositis prophylactic regimen of intramuscular vitamin B12 (0.5 mg every 4 weeks), oral folic acid (1.25 mg daily), oral cryotherapy prior to and for 30 minutes after pralatrexate, and dental care provided by a dentist. Before and after three cycles of pralatrexate treatment, the modified severity weighted assessment tool (mSWAT) score improved from 53.5 to 31.5 and the soluble IL‐2 receptor value decreased from 4,608 U/mL to 2,731 U/mL. Adverse reactions included mild anemia (hemoglobin 11.7 g/dL), nausea and some mucositis lesions, but none of them were particularly severe. However, his treatment was changed from pralatrexate to oral forodesine due to general fatigue. At 2.5 months after the discontinuation of pralatrexate, his mSWAT score worsened to 69.7 (Figure 1). He resumed pralatrexate treatment and radiation therapy, and after two cycles of treatment, most of the tumors and erythema disappeared. He had a partial response for 5 months, but then the erythema and plaques flared up (mSWAT score, 34), and he changed to BV therapy.
Figure 1 Response to pralatrexate in patient 1. (a, d) Before treatment with pralatrexate. (b, e) After three cycles of treatment with pralatrexate. (c, f) At 2.5 months after the discontinuation of pralatrexate. Most erythema had resolved with pralatrexate, but after discontinuation, erythema flare‐ups and rapid tumor formation/enlargement were observed (arrows)
2.2 Case 2
A 60‐year‐old Japanese man was diagnosed with MF 14 years ago, and was classified as stage IIB (T3N0M0B0) 6 7 years later. Previous therapies included interferon‐gamma (1 million IU, 2 doses), etoposide (50 mg/day), methotrexate (10 mg/week) and oral prednisone (approximately 20 mg/day), but he had inadequate responses to all of them. Although vorinostat (400 mg/day) reduced some of the erythema and plaques, it led to anorexia and general fatigue. His atypical lymphocytes were positive for CCR4, and treatment with mogamulizumab (1 mg/kg/week, 8 cycles) was initiated. Mogamulizumab led to partial remission for 10 months, but new tumors gradually developed on his legs. A skin biopsy revealed CD30+ large‐cell transformation. BV (1.8 mg/kg/3 weeks, 4 cycles) led to normalization of soluble IL‐2 receptor levels and some tumors disappeared, but the tumor on his buttocks remained and required ionizing radiation therapy (36 Gy). Sobuzoxane (400 mg/day) and etoposide (25 mg/day) led to a partial reduction of the tumors but did not suppress new tumor formation.
He began treatment with intravenous pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles) together with the same mucositis prophylaxis as described for Case 1. After two cycles of treatment, the erythema, which was recalcitrant to previous therapies, resolved and the mSWAT score decreased from 49.2 to 17.5 (Figure 2). Although the tumor on his left foot remained, no new tumors emerged, and a partial response was maintained for 15 months with continued pralatrexate therapy. The patient experienced mild nausea and general fatigue, but mucositis and severe adverse events were not observed. 16 months later, some erythema and plaques appeared on his trunk and extremities. Bexarotene (300 mg/day) was added at 17 months, but erythema and tumors became more frequent rapidly and mSWAT worsened to 87. At present, he has been changed to gemcitabine therapy.
Figure 2 Response to pralatrexate in patient 2. (a–c) Before beginning treatment with pralatrexate. (d–f) After two cycles of treatment with pralatrexate
3 DISCUSSION/CONCLUSION
In Japan, about 90% of malignant lymphomas involving the skin are CTCLs, with MF being the most prevalent. 1 Although most patients with MF present with early‐stage disease, about one‐third of them experience disease progression, and 26% of them die due to MF. 2 Patients with advanced stages have a poor prognosis, with a median survival of 3.4 (stage III) to 4.7 years (stage IIB). 2 The chronic and recurrent nature of MF progression necessitates repeated systemic treatment for disease control. Although various treatment options exist, comparative trials and evidence‐based treatment algorithms to guide treatment prioritization have not yet been established. 7
Pralatrexate is a folate analog metabolic inhibitor that blocks dihydrofolate reductase, thereby preventing thymidylate and purine synthesis, which results in cell cycle arrest in the S phase. 8 Pralatrexate has a higher affinity for reduced folate carrier type 1 (RFC‐1) compared to MTX, and therefore it is preferentially taken up by many tumor cells that overexpress RFC‐1 and has a markedly greater activity than MTX. 8 , 9 Pralatrexate has been approved for relapsed/refractory PTCL in the U.S. (2009) based on results from a PROPEL study. 10 Pralatrexate was subsequently approved in Japan (in 2017) for treating relapsed/refractory PTCL after a phase I/II study in Japan demonstrated its efficacy and tolerability. 11 In the PROPEL study, pralatrexate (30 mg/m2/week intravenously for 6 weeks in 7‐week cycles) had a response rate of 58% in 12 patients with transformed MF. 4 Subsequently, in a prospective dose‐finding study in heavily‐pretreated U.S. patients, including relapsed/refractory MF, pralatrexate (15 mg/m2/week for 3 of 4 weeks) resulted in a 45% response rate after a median of four cycles. 12 The most common treatment‐related adverse events were mucosal inflammation (48%), fatigue (38%) and nausea (31%). 12 Foss et al. reported a study of 27 U.S. patients with relapsed/refractory MF or Sézary syndrome treated with pralatrexate (10 to 30 mg/m2 weekly for 3 of 4 weeks, or every other week) and partial or complete clinical responses were observed in 57% of patients. 5 These results suggest that pralatrexate has a clinical efficacy and confirms a high overall response rate at doses even less than 15 mg/m2 in the treatment of advanced CTCL. In addition, pralatrexate has been investigated in combination with bexarotene 13 , 14 and romidepsin. 15 These combination therapies have been reported to have high overall response rates of more than 50%, and can be efficient and well‐tolerated treatments for advanced‐stage MF.
Although some preceding therapies provided temporary partial remission, our patients experienced relapses. We used pralatrexate at a dose of 30 mg/m2/week for 6 weeks in 7‐week cycles, which is the approved regimen for relapsed/refractory PTCL based on clinical trials. 10 , 11 Pralatrexate suppressed new tumor formation within two to three cycles of treatment and led to a partial response. As adverse events, mucositis was controlled by prophylactic measures, but moderate general fatigue and nausea were observed, so that treatment was temporarily discontinued in Case 1. If intolerable side effects with pralatrexate are encountered, a lower‐dose regimen should be considered. 5 , 12 In Case 2, the patient experienced a long‐term partial response and then relapsed, but the patient did not want to change to another therapy or combination therapy with other drugs, resulting in a rapid progression. It may be reasonable to combine pralatrexate with other agents or treatment modalities if the disease has progressed. 7
CONFLICT OF INTEREST
The authors have no conflict of interest to declare.
ACKNOWLEDGEMENTS
The authors thank Phillips‐Gilmore Oncology Communications and Annie Kai I. Cheang, PharmD, MS, for professional assistance with manuscript preparation. Preparation of the manuscript was funded by Mundipharma. The funder had no role in data collection, interpretation, decision to publish or preparation of the manuscript. | 15MG *1/DAY | DrugDosageText | CC BY-NC-ND | 33454985 | 19,326,681 | 2021-05 |
What was the dosage of drug 'PRAVASTATIN SODIUM'? | Pralatrexate for refractory mycosis fungoides in two Japanese patients.
Pralatrexate has been approved for the treatment of relapsed/refractory peripheral T cell lymphomas. Studies in the U.S. also support the clinical efficacy of pralatrexate to treat advanced-stage cutaneous T-cell lymphomas, but outcomes in Japanese patients have not yet been reported. We herein describe two Japanese patients with heavily-pretreated relapsed/refractory mycosis fungoides that were successfully controlled by pralatrexate.
1 INTRODUCTION
Mycosis fungoides (MF) is the most prevalent form of cutaneous T‐cell lymphoma (CTCL). 1 Advanced‐stage MF has a poor prognosis 2 and requires systemic therapies. 1 Pralatrexate, a folic acid analog metabolic inhibitor, has been approved in the U.S.A. since 2009 for the treatment of relapsed/refractory peripheral T‐cell lymphoma (PTCL), but was launched in Japan in 2017. 3 In patients with advanced‐stage CTCL, U.S. studies with pralatrexate showed clinical response rates up to 58%, 4 , 5 but outcomes in Japanese patients have not yet been reported. We describe the clinical outcomes of two Japanese patients with relapsed/refractory MF who were treated with pralatrexate.
2 CASE REPORT
2.1 Case 1
A 58‐year‐old Japanese man was diagnosed with MF 6 years ago, and was classified as stage IIB (T3N0M0B0) 6 3 years later. Although some erythema and tumors were resolved with mogamulizumab (1 mg/kg/week, 8 cycles), new tumors appeared after the treatment ended. Histopathological findings revealed CD30+ large‐cell transformation, and brentuximab vedotin (BV; 1.8 mg/kg/3 weeks, 8 cycles) was started. After three cycles of BV, the tumors reduced but the erythema remained. Subsequent courses of therapy included vorinostat (400 mg/day), which led to drug‐induced liver injury, oral bexarotene (225 mg/day), a second course of BV (1.8 mg/kg/3 weeks, 8 cycles) and mogamulizumab (1 mg/kg/week, 5 cycles), each providing an inadequate response. A third course of BV (2 cycles) with ionizing radiation therapy (36 Gy, left cheek tumor), which resulted in drug eruption, oral etoposide monotherapy (50 mg/day) and interferon‐gamma (2 million IU, 7 doses), followed but none of those led to an adequate response. Treatment with ionizing radiation (34 Gy, right cheek) with etoposide (25 mg/day) combined with sobuzoxane (400 mg/day) partially reduced his erythema and lesions, but new tumors appeared that required further ionizing radiation therapy (34 Gy, left hand).
He then began intravenous treatment with pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles). He also received a mucositis prophylactic regimen of intramuscular vitamin B12 (0.5 mg every 4 weeks), oral folic acid (1.25 mg daily), oral cryotherapy prior to and for 30 minutes after pralatrexate, and dental care provided by a dentist. Before and after three cycles of pralatrexate treatment, the modified severity weighted assessment tool (mSWAT) score improved from 53.5 to 31.5 and the soluble IL‐2 receptor value decreased from 4,608 U/mL to 2,731 U/mL. Adverse reactions included mild anemia (hemoglobin 11.7 g/dL), nausea and some mucositis lesions, but none of them were particularly severe. However, his treatment was changed from pralatrexate to oral forodesine due to general fatigue. At 2.5 months after the discontinuation of pralatrexate, his mSWAT score worsened to 69.7 (Figure 1). He resumed pralatrexate treatment and radiation therapy, and after two cycles of treatment, most of the tumors and erythema disappeared. He had a partial response for 5 months, but then the erythema and plaques flared up (mSWAT score, 34), and he changed to BV therapy.
Figure 1 Response to pralatrexate in patient 1. (a, d) Before treatment with pralatrexate. (b, e) After three cycles of treatment with pralatrexate. (c, f) At 2.5 months after the discontinuation of pralatrexate. Most erythema had resolved with pralatrexate, but after discontinuation, erythema flare‐ups and rapid tumor formation/enlargement were observed (arrows)
2.2 Case 2
A 60‐year‐old Japanese man was diagnosed with MF 14 years ago, and was classified as stage IIB (T3N0M0B0) 6 7 years later. Previous therapies included interferon‐gamma (1 million IU, 2 doses), etoposide (50 mg/day), methotrexate (10 mg/week) and oral prednisone (approximately 20 mg/day), but he had inadequate responses to all of them. Although vorinostat (400 mg/day) reduced some of the erythema and plaques, it led to anorexia and general fatigue. His atypical lymphocytes were positive for CCR4, and treatment with mogamulizumab (1 mg/kg/week, 8 cycles) was initiated. Mogamulizumab led to partial remission for 10 months, but new tumors gradually developed on his legs. A skin biopsy revealed CD30+ large‐cell transformation. BV (1.8 mg/kg/3 weeks, 4 cycles) led to normalization of soluble IL‐2 receptor levels and some tumors disappeared, but the tumor on his buttocks remained and required ionizing radiation therapy (36 Gy). Sobuzoxane (400 mg/day) and etoposide (25 mg/day) led to a partial reduction of the tumors but did not suppress new tumor formation.
He began treatment with intravenous pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles) together with the same mucositis prophylaxis as described for Case 1. After two cycles of treatment, the erythema, which was recalcitrant to previous therapies, resolved and the mSWAT score decreased from 49.2 to 17.5 (Figure 2). Although the tumor on his left foot remained, no new tumors emerged, and a partial response was maintained for 15 months with continued pralatrexate therapy. The patient experienced mild nausea and general fatigue, but mucositis and severe adverse events were not observed. 16 months later, some erythema and plaques appeared on his trunk and extremities. Bexarotene (300 mg/day) was added at 17 months, but erythema and tumors became more frequent rapidly and mSWAT worsened to 87. At present, he has been changed to gemcitabine therapy.
Figure 2 Response to pralatrexate in patient 2. (a–c) Before beginning treatment with pralatrexate. (d–f) After two cycles of treatment with pralatrexate
3 DISCUSSION/CONCLUSION
In Japan, about 90% of malignant lymphomas involving the skin are CTCLs, with MF being the most prevalent. 1 Although most patients with MF present with early‐stage disease, about one‐third of them experience disease progression, and 26% of them die due to MF. 2 Patients with advanced stages have a poor prognosis, with a median survival of 3.4 (stage III) to 4.7 years (stage IIB). 2 The chronic and recurrent nature of MF progression necessitates repeated systemic treatment for disease control. Although various treatment options exist, comparative trials and evidence‐based treatment algorithms to guide treatment prioritization have not yet been established. 7
Pralatrexate is a folate analog metabolic inhibitor that blocks dihydrofolate reductase, thereby preventing thymidylate and purine synthesis, which results in cell cycle arrest in the S phase. 8 Pralatrexate has a higher affinity for reduced folate carrier type 1 (RFC‐1) compared to MTX, and therefore it is preferentially taken up by many tumor cells that overexpress RFC‐1 and has a markedly greater activity than MTX. 8 , 9 Pralatrexate has been approved for relapsed/refractory PTCL in the U.S. (2009) based on results from a PROPEL study. 10 Pralatrexate was subsequently approved in Japan (in 2017) for treating relapsed/refractory PTCL after a phase I/II study in Japan demonstrated its efficacy and tolerability. 11 In the PROPEL study, pralatrexate (30 mg/m2/week intravenously for 6 weeks in 7‐week cycles) had a response rate of 58% in 12 patients with transformed MF. 4 Subsequently, in a prospective dose‐finding study in heavily‐pretreated U.S. patients, including relapsed/refractory MF, pralatrexate (15 mg/m2/week for 3 of 4 weeks) resulted in a 45% response rate after a median of four cycles. 12 The most common treatment‐related adverse events were mucosal inflammation (48%), fatigue (38%) and nausea (31%). 12 Foss et al. reported a study of 27 U.S. patients with relapsed/refractory MF or Sézary syndrome treated with pralatrexate (10 to 30 mg/m2 weekly for 3 of 4 weeks, or every other week) and partial or complete clinical responses were observed in 57% of patients. 5 These results suggest that pralatrexate has a clinical efficacy and confirms a high overall response rate at doses even less than 15 mg/m2 in the treatment of advanced CTCL. In addition, pralatrexate has been investigated in combination with bexarotene 13 , 14 and romidepsin. 15 These combination therapies have been reported to have high overall response rates of more than 50%, and can be efficient and well‐tolerated treatments for advanced‐stage MF.
Although some preceding therapies provided temporary partial remission, our patients experienced relapses. We used pralatrexate at a dose of 30 mg/m2/week for 6 weeks in 7‐week cycles, which is the approved regimen for relapsed/refractory PTCL based on clinical trials. 10 , 11 Pralatrexate suppressed new tumor formation within two to three cycles of treatment and led to a partial response. As adverse events, mucositis was controlled by prophylactic measures, but moderate general fatigue and nausea were observed, so that treatment was temporarily discontinued in Case 1. If intolerable side effects with pralatrexate are encountered, a lower‐dose regimen should be considered. 5 , 12 In Case 2, the patient experienced a long‐term partial response and then relapsed, but the patient did not want to change to another therapy or combination therapy with other drugs, resulting in a rapid progression. It may be reasonable to combine pralatrexate with other agents or treatment modalities if the disease has progressed. 7
CONFLICT OF INTEREST
The authors have no conflict of interest to declare.
ACKNOWLEDGEMENTS
The authors thank Phillips‐Gilmore Oncology Communications and Annie Kai I. Cheang, PharmD, MS, for professional assistance with manuscript preparation. Preparation of the manuscript was funded by Mundipharma. The funder had no role in data collection, interpretation, decision to publish or preparation of the manuscript. | 10MG *1/DAY | DrugDosageText | CC BY-NC-ND | 33454985 | 19,326,681 | 2021-05 |
What was the dosage of drug 'SITAGLIPTIN PHOSPHATE'? | Pralatrexate for refractory mycosis fungoides in two Japanese patients.
Pralatrexate has been approved for the treatment of relapsed/refractory peripheral T cell lymphomas. Studies in the U.S. also support the clinical efficacy of pralatrexate to treat advanced-stage cutaneous T-cell lymphomas, but outcomes in Japanese patients have not yet been reported. We herein describe two Japanese patients with heavily-pretreated relapsed/refractory mycosis fungoides that were successfully controlled by pralatrexate.
1 INTRODUCTION
Mycosis fungoides (MF) is the most prevalent form of cutaneous T‐cell lymphoma (CTCL). 1 Advanced‐stage MF has a poor prognosis 2 and requires systemic therapies. 1 Pralatrexate, a folic acid analog metabolic inhibitor, has been approved in the U.S.A. since 2009 for the treatment of relapsed/refractory peripheral T‐cell lymphoma (PTCL), but was launched in Japan in 2017. 3 In patients with advanced‐stage CTCL, U.S. studies with pralatrexate showed clinical response rates up to 58%, 4 , 5 but outcomes in Japanese patients have not yet been reported. We describe the clinical outcomes of two Japanese patients with relapsed/refractory MF who were treated with pralatrexate.
2 CASE REPORT
2.1 Case 1
A 58‐year‐old Japanese man was diagnosed with MF 6 years ago, and was classified as stage IIB (T3N0M0B0) 6 3 years later. Although some erythema and tumors were resolved with mogamulizumab (1 mg/kg/week, 8 cycles), new tumors appeared after the treatment ended. Histopathological findings revealed CD30+ large‐cell transformation, and brentuximab vedotin (BV; 1.8 mg/kg/3 weeks, 8 cycles) was started. After three cycles of BV, the tumors reduced but the erythema remained. Subsequent courses of therapy included vorinostat (400 mg/day), which led to drug‐induced liver injury, oral bexarotene (225 mg/day), a second course of BV (1.8 mg/kg/3 weeks, 8 cycles) and mogamulizumab (1 mg/kg/week, 5 cycles), each providing an inadequate response. A third course of BV (2 cycles) with ionizing radiation therapy (36 Gy, left cheek tumor), which resulted in drug eruption, oral etoposide monotherapy (50 mg/day) and interferon‐gamma (2 million IU, 7 doses), followed but none of those led to an adequate response. Treatment with ionizing radiation (34 Gy, right cheek) with etoposide (25 mg/day) combined with sobuzoxane (400 mg/day) partially reduced his erythema and lesions, but new tumors appeared that required further ionizing radiation therapy (34 Gy, left hand).
He then began intravenous treatment with pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles). He also received a mucositis prophylactic regimen of intramuscular vitamin B12 (0.5 mg every 4 weeks), oral folic acid (1.25 mg daily), oral cryotherapy prior to and for 30 minutes after pralatrexate, and dental care provided by a dentist. Before and after three cycles of pralatrexate treatment, the modified severity weighted assessment tool (mSWAT) score improved from 53.5 to 31.5 and the soluble IL‐2 receptor value decreased from 4,608 U/mL to 2,731 U/mL. Adverse reactions included mild anemia (hemoglobin 11.7 g/dL), nausea and some mucositis lesions, but none of them were particularly severe. However, his treatment was changed from pralatrexate to oral forodesine due to general fatigue. At 2.5 months after the discontinuation of pralatrexate, his mSWAT score worsened to 69.7 (Figure 1). He resumed pralatrexate treatment and radiation therapy, and after two cycles of treatment, most of the tumors and erythema disappeared. He had a partial response for 5 months, but then the erythema and plaques flared up (mSWAT score, 34), and he changed to BV therapy.
Figure 1 Response to pralatrexate in patient 1. (a, d) Before treatment with pralatrexate. (b, e) After three cycles of treatment with pralatrexate. (c, f) At 2.5 months after the discontinuation of pralatrexate. Most erythema had resolved with pralatrexate, but after discontinuation, erythema flare‐ups and rapid tumor formation/enlargement were observed (arrows)
2.2 Case 2
A 60‐year‐old Japanese man was diagnosed with MF 14 years ago, and was classified as stage IIB (T3N0M0B0) 6 7 years later. Previous therapies included interferon‐gamma (1 million IU, 2 doses), etoposide (50 mg/day), methotrexate (10 mg/week) and oral prednisone (approximately 20 mg/day), but he had inadequate responses to all of them. Although vorinostat (400 mg/day) reduced some of the erythema and plaques, it led to anorexia and general fatigue. His atypical lymphocytes were positive for CCR4, and treatment with mogamulizumab (1 mg/kg/week, 8 cycles) was initiated. Mogamulizumab led to partial remission for 10 months, but new tumors gradually developed on his legs. A skin biopsy revealed CD30+ large‐cell transformation. BV (1.8 mg/kg/3 weeks, 4 cycles) led to normalization of soluble IL‐2 receptor levels and some tumors disappeared, but the tumor on his buttocks remained and required ionizing radiation therapy (36 Gy). Sobuzoxane (400 mg/day) and etoposide (25 mg/day) led to a partial reduction of the tumors but did not suppress new tumor formation.
He began treatment with intravenous pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles) together with the same mucositis prophylaxis as described for Case 1. After two cycles of treatment, the erythema, which was recalcitrant to previous therapies, resolved and the mSWAT score decreased from 49.2 to 17.5 (Figure 2). Although the tumor on his left foot remained, no new tumors emerged, and a partial response was maintained for 15 months with continued pralatrexate therapy. The patient experienced mild nausea and general fatigue, but mucositis and severe adverse events were not observed. 16 months later, some erythema and plaques appeared on his trunk and extremities. Bexarotene (300 mg/day) was added at 17 months, but erythema and tumors became more frequent rapidly and mSWAT worsened to 87. At present, he has been changed to gemcitabine therapy.
Figure 2 Response to pralatrexate in patient 2. (a–c) Before beginning treatment with pralatrexate. (d–f) After two cycles of treatment with pralatrexate
3 DISCUSSION/CONCLUSION
In Japan, about 90% of malignant lymphomas involving the skin are CTCLs, with MF being the most prevalent. 1 Although most patients with MF present with early‐stage disease, about one‐third of them experience disease progression, and 26% of them die due to MF. 2 Patients with advanced stages have a poor prognosis, with a median survival of 3.4 (stage III) to 4.7 years (stage IIB). 2 The chronic and recurrent nature of MF progression necessitates repeated systemic treatment for disease control. Although various treatment options exist, comparative trials and evidence‐based treatment algorithms to guide treatment prioritization have not yet been established. 7
Pralatrexate is a folate analog metabolic inhibitor that blocks dihydrofolate reductase, thereby preventing thymidylate and purine synthesis, which results in cell cycle arrest in the S phase. 8 Pralatrexate has a higher affinity for reduced folate carrier type 1 (RFC‐1) compared to MTX, and therefore it is preferentially taken up by many tumor cells that overexpress RFC‐1 and has a markedly greater activity than MTX. 8 , 9 Pralatrexate has been approved for relapsed/refractory PTCL in the U.S. (2009) based on results from a PROPEL study. 10 Pralatrexate was subsequently approved in Japan (in 2017) for treating relapsed/refractory PTCL after a phase I/II study in Japan demonstrated its efficacy and tolerability. 11 In the PROPEL study, pralatrexate (30 mg/m2/week intravenously for 6 weeks in 7‐week cycles) had a response rate of 58% in 12 patients with transformed MF. 4 Subsequently, in a prospective dose‐finding study in heavily‐pretreated U.S. patients, including relapsed/refractory MF, pralatrexate (15 mg/m2/week for 3 of 4 weeks) resulted in a 45% response rate after a median of four cycles. 12 The most common treatment‐related adverse events were mucosal inflammation (48%), fatigue (38%) and nausea (31%). 12 Foss et al. reported a study of 27 U.S. patients with relapsed/refractory MF or Sézary syndrome treated with pralatrexate (10 to 30 mg/m2 weekly for 3 of 4 weeks, or every other week) and partial or complete clinical responses were observed in 57% of patients. 5 These results suggest that pralatrexate has a clinical efficacy and confirms a high overall response rate at doses even less than 15 mg/m2 in the treatment of advanced CTCL. In addition, pralatrexate has been investigated in combination with bexarotene 13 , 14 and romidepsin. 15 These combination therapies have been reported to have high overall response rates of more than 50%, and can be efficient and well‐tolerated treatments for advanced‐stage MF.
Although some preceding therapies provided temporary partial remission, our patients experienced relapses. We used pralatrexate at a dose of 30 mg/m2/week for 6 weeks in 7‐week cycles, which is the approved regimen for relapsed/refractory PTCL based on clinical trials. 10 , 11 Pralatrexate suppressed new tumor formation within two to three cycles of treatment and led to a partial response. As adverse events, mucositis was controlled by prophylactic measures, but moderate general fatigue and nausea were observed, so that treatment was temporarily discontinued in Case 1. If intolerable side effects with pralatrexate are encountered, a lower‐dose regimen should be considered. 5 , 12 In Case 2, the patient experienced a long‐term partial response and then relapsed, but the patient did not want to change to another therapy or combination therapy with other drugs, resulting in a rapid progression. It may be reasonable to combine pralatrexate with other agents or treatment modalities if the disease has progressed. 7
CONFLICT OF INTEREST
The authors have no conflict of interest to declare.
ACKNOWLEDGEMENTS
The authors thank Phillips‐Gilmore Oncology Communications and Annie Kai I. Cheang, PharmD, MS, for professional assistance with manuscript preparation. Preparation of the manuscript was funded by Mundipharma. The funder had no role in data collection, interpretation, decision to publish or preparation of the manuscript. | 50MG *1/DAY | DrugDosageText | CC BY-NC-ND | 33454985 | 19,326,681 | 2021-05 |
What was the dosage of drug 'VORINOSTAT'? | Pralatrexate for refractory mycosis fungoides in two Japanese patients.
Pralatrexate has been approved for the treatment of relapsed/refractory peripheral T cell lymphomas. Studies in the U.S. also support the clinical efficacy of pralatrexate to treat advanced-stage cutaneous T-cell lymphomas, but outcomes in Japanese patients have not yet been reported. We herein describe two Japanese patients with heavily-pretreated relapsed/refractory mycosis fungoides that were successfully controlled by pralatrexate.
1 INTRODUCTION
Mycosis fungoides (MF) is the most prevalent form of cutaneous T‐cell lymphoma (CTCL). 1 Advanced‐stage MF has a poor prognosis 2 and requires systemic therapies. 1 Pralatrexate, a folic acid analog metabolic inhibitor, has been approved in the U.S.A. since 2009 for the treatment of relapsed/refractory peripheral T‐cell lymphoma (PTCL), but was launched in Japan in 2017. 3 In patients with advanced‐stage CTCL, U.S. studies with pralatrexate showed clinical response rates up to 58%, 4 , 5 but outcomes in Japanese patients have not yet been reported. We describe the clinical outcomes of two Japanese patients with relapsed/refractory MF who were treated with pralatrexate.
2 CASE REPORT
2.1 Case 1
A 58‐year‐old Japanese man was diagnosed with MF 6 years ago, and was classified as stage IIB (T3N0M0B0) 6 3 years later. Although some erythema and tumors were resolved with mogamulizumab (1 mg/kg/week, 8 cycles), new tumors appeared after the treatment ended. Histopathological findings revealed CD30+ large‐cell transformation, and brentuximab vedotin (BV; 1.8 mg/kg/3 weeks, 8 cycles) was started. After three cycles of BV, the tumors reduced but the erythema remained. Subsequent courses of therapy included vorinostat (400 mg/day), which led to drug‐induced liver injury, oral bexarotene (225 mg/day), a second course of BV (1.8 mg/kg/3 weeks, 8 cycles) and mogamulizumab (1 mg/kg/week, 5 cycles), each providing an inadequate response. A third course of BV (2 cycles) with ionizing radiation therapy (36 Gy, left cheek tumor), which resulted in drug eruption, oral etoposide monotherapy (50 mg/day) and interferon‐gamma (2 million IU, 7 doses), followed but none of those led to an adequate response. Treatment with ionizing radiation (34 Gy, right cheek) with etoposide (25 mg/day) combined with sobuzoxane (400 mg/day) partially reduced his erythema and lesions, but new tumors appeared that required further ionizing radiation therapy (34 Gy, left hand).
He then began intravenous treatment with pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles). He also received a mucositis prophylactic regimen of intramuscular vitamin B12 (0.5 mg every 4 weeks), oral folic acid (1.25 mg daily), oral cryotherapy prior to and for 30 minutes after pralatrexate, and dental care provided by a dentist. Before and after three cycles of pralatrexate treatment, the modified severity weighted assessment tool (mSWAT) score improved from 53.5 to 31.5 and the soluble IL‐2 receptor value decreased from 4,608 U/mL to 2,731 U/mL. Adverse reactions included mild anemia (hemoglobin 11.7 g/dL), nausea and some mucositis lesions, but none of them were particularly severe. However, his treatment was changed from pralatrexate to oral forodesine due to general fatigue. At 2.5 months after the discontinuation of pralatrexate, his mSWAT score worsened to 69.7 (Figure 1). He resumed pralatrexate treatment and radiation therapy, and after two cycles of treatment, most of the tumors and erythema disappeared. He had a partial response for 5 months, but then the erythema and plaques flared up (mSWAT score, 34), and he changed to BV therapy.
Figure 1 Response to pralatrexate in patient 1. (a, d) Before treatment with pralatrexate. (b, e) After three cycles of treatment with pralatrexate. (c, f) At 2.5 months after the discontinuation of pralatrexate. Most erythema had resolved with pralatrexate, but after discontinuation, erythema flare‐ups and rapid tumor formation/enlargement were observed (arrows)
2.2 Case 2
A 60‐year‐old Japanese man was diagnosed with MF 14 years ago, and was classified as stage IIB (T3N0M0B0) 6 7 years later. Previous therapies included interferon‐gamma (1 million IU, 2 doses), etoposide (50 mg/day), methotrexate (10 mg/week) and oral prednisone (approximately 20 mg/day), but he had inadequate responses to all of them. Although vorinostat (400 mg/day) reduced some of the erythema and plaques, it led to anorexia and general fatigue. His atypical lymphocytes were positive for CCR4, and treatment with mogamulizumab (1 mg/kg/week, 8 cycles) was initiated. Mogamulizumab led to partial remission for 10 months, but new tumors gradually developed on his legs. A skin biopsy revealed CD30+ large‐cell transformation. BV (1.8 mg/kg/3 weeks, 4 cycles) led to normalization of soluble IL‐2 receptor levels and some tumors disappeared, but the tumor on his buttocks remained and required ionizing radiation therapy (36 Gy). Sobuzoxane (400 mg/day) and etoposide (25 mg/day) led to a partial reduction of the tumors but did not suppress new tumor formation.
He began treatment with intravenous pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles) together with the same mucositis prophylaxis as described for Case 1. After two cycles of treatment, the erythema, which was recalcitrant to previous therapies, resolved and the mSWAT score decreased from 49.2 to 17.5 (Figure 2). Although the tumor on his left foot remained, no new tumors emerged, and a partial response was maintained for 15 months with continued pralatrexate therapy. The patient experienced mild nausea and general fatigue, but mucositis and severe adverse events were not observed. 16 months later, some erythema and plaques appeared on his trunk and extremities. Bexarotene (300 mg/day) was added at 17 months, but erythema and tumors became more frequent rapidly and mSWAT worsened to 87. At present, he has been changed to gemcitabine therapy.
Figure 2 Response to pralatrexate in patient 2. (a–c) Before beginning treatment with pralatrexate. (d–f) After two cycles of treatment with pralatrexate
3 DISCUSSION/CONCLUSION
In Japan, about 90% of malignant lymphomas involving the skin are CTCLs, with MF being the most prevalent. 1 Although most patients with MF present with early‐stage disease, about one‐third of them experience disease progression, and 26% of them die due to MF. 2 Patients with advanced stages have a poor prognosis, with a median survival of 3.4 (stage III) to 4.7 years (stage IIB). 2 The chronic and recurrent nature of MF progression necessitates repeated systemic treatment for disease control. Although various treatment options exist, comparative trials and evidence‐based treatment algorithms to guide treatment prioritization have not yet been established. 7
Pralatrexate is a folate analog metabolic inhibitor that blocks dihydrofolate reductase, thereby preventing thymidylate and purine synthesis, which results in cell cycle arrest in the S phase. 8 Pralatrexate has a higher affinity for reduced folate carrier type 1 (RFC‐1) compared to MTX, and therefore it is preferentially taken up by many tumor cells that overexpress RFC‐1 and has a markedly greater activity than MTX. 8 , 9 Pralatrexate has been approved for relapsed/refractory PTCL in the U.S. (2009) based on results from a PROPEL study. 10 Pralatrexate was subsequently approved in Japan (in 2017) for treating relapsed/refractory PTCL after a phase I/II study in Japan demonstrated its efficacy and tolerability. 11 In the PROPEL study, pralatrexate (30 mg/m2/week intravenously for 6 weeks in 7‐week cycles) had a response rate of 58% in 12 patients with transformed MF. 4 Subsequently, in a prospective dose‐finding study in heavily‐pretreated U.S. patients, including relapsed/refractory MF, pralatrexate (15 mg/m2/week for 3 of 4 weeks) resulted in a 45% response rate after a median of four cycles. 12 The most common treatment‐related adverse events were mucosal inflammation (48%), fatigue (38%) and nausea (31%). 12 Foss et al. reported a study of 27 U.S. patients with relapsed/refractory MF or Sézary syndrome treated with pralatrexate (10 to 30 mg/m2 weekly for 3 of 4 weeks, or every other week) and partial or complete clinical responses were observed in 57% of patients. 5 These results suggest that pralatrexate has a clinical efficacy and confirms a high overall response rate at doses even less than 15 mg/m2 in the treatment of advanced CTCL. In addition, pralatrexate has been investigated in combination with bexarotene 13 , 14 and romidepsin. 15 These combination therapies have been reported to have high overall response rates of more than 50%, and can be efficient and well‐tolerated treatments for advanced‐stage MF.
Although some preceding therapies provided temporary partial remission, our patients experienced relapses. We used pralatrexate at a dose of 30 mg/m2/week for 6 weeks in 7‐week cycles, which is the approved regimen for relapsed/refractory PTCL based on clinical trials. 10 , 11 Pralatrexate suppressed new tumor formation within two to three cycles of treatment and led to a partial response. As adverse events, mucositis was controlled by prophylactic measures, but moderate general fatigue and nausea were observed, so that treatment was temporarily discontinued in Case 1. If intolerable side effects with pralatrexate are encountered, a lower‐dose regimen should be considered. 5 , 12 In Case 2, the patient experienced a long‐term partial response and then relapsed, but the patient did not want to change to another therapy or combination therapy with other drugs, resulting in a rapid progression. It may be reasonable to combine pralatrexate with other agents or treatment modalities if the disease has progressed. 7
CONFLICT OF INTEREST
The authors have no conflict of interest to declare.
ACKNOWLEDGEMENTS
The authors thank Phillips‐Gilmore Oncology Communications and Annie Kai I. Cheang, PharmD, MS, for professional assistance with manuscript preparation. Preparation of the manuscript was funded by Mundipharma. The funder had no role in data collection, interpretation, decision to publish or preparation of the manuscript. | 400 MILLIGRAM, QD | DrugDosageText | CC BY-NC-ND | 33454985 | 19,326,681 | 2021-05 |
What was the outcome of reaction 'Hepatic function abnormal'? | Pralatrexate for refractory mycosis fungoides in two Japanese patients.
Pralatrexate has been approved for the treatment of relapsed/refractory peripheral T cell lymphomas. Studies in the U.S. also support the clinical efficacy of pralatrexate to treat advanced-stage cutaneous T-cell lymphomas, but outcomes in Japanese patients have not yet been reported. We herein describe two Japanese patients with heavily-pretreated relapsed/refractory mycosis fungoides that were successfully controlled by pralatrexate.
1 INTRODUCTION
Mycosis fungoides (MF) is the most prevalent form of cutaneous T‐cell lymphoma (CTCL). 1 Advanced‐stage MF has a poor prognosis 2 and requires systemic therapies. 1 Pralatrexate, a folic acid analog metabolic inhibitor, has been approved in the U.S.A. since 2009 for the treatment of relapsed/refractory peripheral T‐cell lymphoma (PTCL), but was launched in Japan in 2017. 3 In patients with advanced‐stage CTCL, U.S. studies with pralatrexate showed clinical response rates up to 58%, 4 , 5 but outcomes in Japanese patients have not yet been reported. We describe the clinical outcomes of two Japanese patients with relapsed/refractory MF who were treated with pralatrexate.
2 CASE REPORT
2.1 Case 1
A 58‐year‐old Japanese man was diagnosed with MF 6 years ago, and was classified as stage IIB (T3N0M0B0) 6 3 years later. Although some erythema and tumors were resolved with mogamulizumab (1 mg/kg/week, 8 cycles), new tumors appeared after the treatment ended. Histopathological findings revealed CD30+ large‐cell transformation, and brentuximab vedotin (BV; 1.8 mg/kg/3 weeks, 8 cycles) was started. After three cycles of BV, the tumors reduced but the erythema remained. Subsequent courses of therapy included vorinostat (400 mg/day), which led to drug‐induced liver injury, oral bexarotene (225 mg/day), a second course of BV (1.8 mg/kg/3 weeks, 8 cycles) and mogamulizumab (1 mg/kg/week, 5 cycles), each providing an inadequate response. A third course of BV (2 cycles) with ionizing radiation therapy (36 Gy, left cheek tumor), which resulted in drug eruption, oral etoposide monotherapy (50 mg/day) and interferon‐gamma (2 million IU, 7 doses), followed but none of those led to an adequate response. Treatment with ionizing radiation (34 Gy, right cheek) with etoposide (25 mg/day) combined with sobuzoxane (400 mg/day) partially reduced his erythema and lesions, but new tumors appeared that required further ionizing radiation therapy (34 Gy, left hand).
He then began intravenous treatment with pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles). He also received a mucositis prophylactic regimen of intramuscular vitamin B12 (0.5 mg every 4 weeks), oral folic acid (1.25 mg daily), oral cryotherapy prior to and for 30 minutes after pralatrexate, and dental care provided by a dentist. Before and after three cycles of pralatrexate treatment, the modified severity weighted assessment tool (mSWAT) score improved from 53.5 to 31.5 and the soluble IL‐2 receptor value decreased from 4,608 U/mL to 2,731 U/mL. Adverse reactions included mild anemia (hemoglobin 11.7 g/dL), nausea and some mucositis lesions, but none of them were particularly severe. However, his treatment was changed from pralatrexate to oral forodesine due to general fatigue. At 2.5 months after the discontinuation of pralatrexate, his mSWAT score worsened to 69.7 (Figure 1). He resumed pralatrexate treatment and radiation therapy, and after two cycles of treatment, most of the tumors and erythema disappeared. He had a partial response for 5 months, but then the erythema and plaques flared up (mSWAT score, 34), and he changed to BV therapy.
Figure 1 Response to pralatrexate in patient 1. (a, d) Before treatment with pralatrexate. (b, e) After three cycles of treatment with pralatrexate. (c, f) At 2.5 months after the discontinuation of pralatrexate. Most erythema had resolved with pralatrexate, but after discontinuation, erythema flare‐ups and rapid tumor formation/enlargement were observed (arrows)
2.2 Case 2
A 60‐year‐old Japanese man was diagnosed with MF 14 years ago, and was classified as stage IIB (T3N0M0B0) 6 7 years later. Previous therapies included interferon‐gamma (1 million IU, 2 doses), etoposide (50 mg/day), methotrexate (10 mg/week) and oral prednisone (approximately 20 mg/day), but he had inadequate responses to all of them. Although vorinostat (400 mg/day) reduced some of the erythema and plaques, it led to anorexia and general fatigue. His atypical lymphocytes were positive for CCR4, and treatment with mogamulizumab (1 mg/kg/week, 8 cycles) was initiated. Mogamulizumab led to partial remission for 10 months, but new tumors gradually developed on his legs. A skin biopsy revealed CD30+ large‐cell transformation. BV (1.8 mg/kg/3 weeks, 4 cycles) led to normalization of soluble IL‐2 receptor levels and some tumors disappeared, but the tumor on his buttocks remained and required ionizing radiation therapy (36 Gy). Sobuzoxane (400 mg/day) and etoposide (25 mg/day) led to a partial reduction of the tumors but did not suppress new tumor formation.
He began treatment with intravenous pralatrexate (30 mg/m2 once weekly for 6 weeks in 7‐week cycles) together with the same mucositis prophylaxis as described for Case 1. After two cycles of treatment, the erythema, which was recalcitrant to previous therapies, resolved and the mSWAT score decreased from 49.2 to 17.5 (Figure 2). Although the tumor on his left foot remained, no new tumors emerged, and a partial response was maintained for 15 months with continued pralatrexate therapy. The patient experienced mild nausea and general fatigue, but mucositis and severe adverse events were not observed. 16 months later, some erythema and plaques appeared on his trunk and extremities. Bexarotene (300 mg/day) was added at 17 months, but erythema and tumors became more frequent rapidly and mSWAT worsened to 87. At present, he has been changed to gemcitabine therapy.
Figure 2 Response to pralatrexate in patient 2. (a–c) Before beginning treatment with pralatrexate. (d–f) After two cycles of treatment with pralatrexate
3 DISCUSSION/CONCLUSION
In Japan, about 90% of malignant lymphomas involving the skin are CTCLs, with MF being the most prevalent. 1 Although most patients with MF present with early‐stage disease, about one‐third of them experience disease progression, and 26% of them die due to MF. 2 Patients with advanced stages have a poor prognosis, with a median survival of 3.4 (stage III) to 4.7 years (stage IIB). 2 The chronic and recurrent nature of MF progression necessitates repeated systemic treatment for disease control. Although various treatment options exist, comparative trials and evidence‐based treatment algorithms to guide treatment prioritization have not yet been established. 7
Pralatrexate is a folate analog metabolic inhibitor that blocks dihydrofolate reductase, thereby preventing thymidylate and purine synthesis, which results in cell cycle arrest in the S phase. 8 Pralatrexate has a higher affinity for reduced folate carrier type 1 (RFC‐1) compared to MTX, and therefore it is preferentially taken up by many tumor cells that overexpress RFC‐1 and has a markedly greater activity than MTX. 8 , 9 Pralatrexate has been approved for relapsed/refractory PTCL in the U.S. (2009) based on results from a PROPEL study. 10 Pralatrexate was subsequently approved in Japan (in 2017) for treating relapsed/refractory PTCL after a phase I/II study in Japan demonstrated its efficacy and tolerability. 11 In the PROPEL study, pralatrexate (30 mg/m2/week intravenously for 6 weeks in 7‐week cycles) had a response rate of 58% in 12 patients with transformed MF. 4 Subsequently, in a prospective dose‐finding study in heavily‐pretreated U.S. patients, including relapsed/refractory MF, pralatrexate (15 mg/m2/week for 3 of 4 weeks) resulted in a 45% response rate after a median of four cycles. 12 The most common treatment‐related adverse events were mucosal inflammation (48%), fatigue (38%) and nausea (31%). 12 Foss et al. reported a study of 27 U.S. patients with relapsed/refractory MF or Sézary syndrome treated with pralatrexate (10 to 30 mg/m2 weekly for 3 of 4 weeks, or every other week) and partial or complete clinical responses were observed in 57% of patients. 5 These results suggest that pralatrexate has a clinical efficacy and confirms a high overall response rate at doses even less than 15 mg/m2 in the treatment of advanced CTCL. In addition, pralatrexate has been investigated in combination with bexarotene 13 , 14 and romidepsin. 15 These combination therapies have been reported to have high overall response rates of more than 50%, and can be efficient and well‐tolerated treatments for advanced‐stage MF.
Although some preceding therapies provided temporary partial remission, our patients experienced relapses. We used pralatrexate at a dose of 30 mg/m2/week for 6 weeks in 7‐week cycles, which is the approved regimen for relapsed/refractory PTCL based on clinical trials. 10 , 11 Pralatrexate suppressed new tumor formation within two to three cycles of treatment and led to a partial response. As adverse events, mucositis was controlled by prophylactic measures, but moderate general fatigue and nausea were observed, so that treatment was temporarily discontinued in Case 1. If intolerable side effects with pralatrexate are encountered, a lower‐dose regimen should be considered. 5 , 12 In Case 2, the patient experienced a long‐term partial response and then relapsed, but the patient did not want to change to another therapy or combination therapy with other drugs, resulting in a rapid progression. It may be reasonable to combine pralatrexate with other agents or treatment modalities if the disease has progressed. 7
CONFLICT OF INTEREST
The authors have no conflict of interest to declare.
ACKNOWLEDGEMENTS
The authors thank Phillips‐Gilmore Oncology Communications and Annie Kai I. Cheang, PharmD, MS, for professional assistance with manuscript preparation. Preparation of the manuscript was funded by Mundipharma. The funder had no role in data collection, interpretation, decision to publish or preparation of the manuscript. | Recovering | ReactionOutcome | CC BY-NC-ND | 33454985 | 19,326,681 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pathogen resistance'. | Peg-IFNα-2a Contributed to HBs Antigen Seroclearance in a Patient with Chronic Hepatitis B Administered Nucleic Acid Analogs: A Three-year Follow-up.
We treated a 51-year-old Japanese man with chronic hepatitis B (viral load 7.6 LC/mL, genotype C). Hepatitis B virus DNA and HBe antigen were undetectable during the administration of the nucleic acid analogs (NUCs) lamivudine and adefovir, although the concentration of HBs antigen (HBsAg) was 851.2 IU/mL. The HBsAg levels were reduced 150-fold when pegylated-interferon (Peg-IFN) α-2a was administered weekly for 48 weeks and did not increase during the rest period. Therefore, Peg-IFNα-2a was administered twice each week. During this time, HBsAg reached undetectable concentrations, and HBs antibody was detected and continued to be detectable during the three-year follow-up. These unprecedented findings suggest that IFN may contribute to the seroclearance of HBsAg in patients treated with NUCs.
Introduction
In chronic hepatitis B, the levels of hepatitis B virus (HBV) DNA and the viral HBs antigen (HBsAg) serve as risk factors for liver carcinogenesis, and increases in their levels are significantly associated with a higher incidence of hepatocellular carcinoma (HCC) (1,2). Reductions in the levels of HBV DNA are readily achieved when patients are treated with nucleic acid analogs (NUCs). Furthermore, the inhibition of the production of HBV-DNA by NUCs significantly reduces the frequency of HCC (3-6). However, when levels of HBV-DNA are low, the residual levels of HBsAg are significantly associated with the occurrence of HCC (7). As such, the continued detection of HBsAg may be significantly associated with hepatocarcinogenesis. The goal of treating HBV hepatitis is thus the seroclearance of HBsAg (8).
Clearance of HBsAg significantly decreases the risk of HCC for patients with chronic hepatitis (other than those with liver cirrhosis) or patients ＜50 years old (9). However, specific treatment guidelines for reducing the serum levels of HBsAg are unavailable, and our understanding of the patient characteristics associated with beneficial responses to therapy is insufficient.
Short-term treatment with pegylated-interferon (Peg-IFN) aims to achieve a sustained effect (10). Unlike NUCs, IFN acts by binding to type I IFN receptors on target cell membranes but does not directly inhibit the HBV life cycle (10). IFNα-induced activation of the Janus kinase (JAK)/Signal Transducers and Activator of transcription (STAT) signal transduction pathway leads to increased expression of IFN-stimulated genes, which is required for antiviral activity and closely associated with the efficacy of IFN treatment (11). As described above, the activation of innate or adaptive immunity, or both, of the host may be achieved using IFN but not NUCs.
IFN has been used to treat virus infections in Japan since 1987, and Peg-IFNα-2a has been available since 2011 (8). However, only Peg-IFNα-2a is used to treat hepatitis B in Japan (8).
We herein report a case of HBsAg seroclearance induced by supplemental Peg-IFNα-2a treatment of a patient with chronic hepatitis B who was being concurrently administered NUCs.
Case Report
A 51-year-old Japanese man with a history of chronic hepatitis B had an HBV (genotype C) load of 7.6 log copies (LC)/mL. There was no special mention of this in the patient's or family's medical history. He had been our patient since being admitted to our hospital with chronic hepatitis B in 2001. Lamivudine administration began in October 2001, and resistance was detected in April 2005, at which time combination therapy with adefovir was started. HBV-DNA subsequently reached undetectable levels, although HBsAg tests were positive. Therefore, we started by adding Peg-IFNα-2a to the NUCs (lamivudine and adefovir).
Table 1 shows the laboratory data before Peg-IFNα-2a was administered. The AST and ALT levels were within the normal range, HBV DNA was undetectable, and the HBsAg concentration was 851.2 UI/mL. A liver biopsy was performed before the first Peg-IFNα-2a treatment. The histopathological findings of liver tissue were equivalent to A1F1, according to the New Inuyama classification (12) (Fig. 1). HBV-DNA remained undetectable while NUCs were administered, but seroclearance of HBsAg was not achieved. We informed the patient of the effectiveness of Peg-IFN therapy for seroclearance of HBsAg to reduce the chance of carcinogenesis and explained the potential adverse effects of treatment. The patient then granted his consent for further treatment.
Table 1. Laboratory Data before Administering Peg-IFNα-2a Together with NUCs.
Metric Value Unit Reference
TP 7.0 g/dL 6.5-8.2
Alb 4.8 g/dL 3.5-5.5
BUN 11.6 mg/dL 7-20
Cr 0.7 mg/dL 0.5-1
T-bil 1.3 mg/dL 0.1-1.2
D-bil 0.4 mg/dL 0.1-0.6
AST 25 U/L 10-35
ALT 27 U/L 5-40
ALP 196 U/L 100-340
LDH 204 U/L 110-220
γ-GTP 19 U/L 0-30
Na 142 mmol/L 135-146
K 4 mmol/L 3.5-4.6
Cl 106 mmol/L 96-110
WBC 3,530 /µL 4,700-8,700
RBC 494×104 /µL 370-490
Hb 15.9 g/dL 11-15
Ht 45.5 % 35-45
Plt 12.9×104 /µL 15-35
Neut 42 % 38-71.9
Eos 1.7 % 0.2-6.8
Baso 0.3 % 0-1
Lym 51.8 % 26-46.6
Mono 4.2 % 2.3-7.7
PT 100 % 80-100
HBV-DNA - LIU/mL -
HBs Antigen 851.2 IU/mL 0-0.05
HBs Antibody - mIU/mL 0-10
HBe Antigen - ng/mL -
HBe Antibody - -
HBcr Antigen 4.2 Log U/mL 0-3
AFP 5 ng/mL
DCP 17 mAU/mL
Hyaluronic acid 87.8 ng/mL 0-50
Figure 1. Liver tissue before Peg-IFN treatment. Hematoxylin and Eosin staining, ×20 magnification. In the portal area, there was slight infiltration of inflammatory lymphocytes, piecemeal necrosis was present around the portal area, and fibrosis was present around Gleason’s sheath and the central vein (confirmed using azan stain). The histopathological grade of liver tissue was equivalent to A1F1, according to the New Inuyama classification. Peg-IFN: pegylated-interferon
From the start of this modified treatment (Peg-IFNα-2a once weekly for 48 weeks), the HBsAg concentration was markedly reduced from 851.2 IU/mL to 5.64 IU/mL. The ALT levels, which had been mildly elevated during IFN administration, returned to normal upon completion of Peg-IFNα-2a treatment. No serious side effects were observed during treatment.
The HBsAg levels were not elevated during the resting period (Fig. 2). When HBV-DNA or HBsAg is low, HBsAg clearance by IFN can be expected (13). We therefore administered Peg-IFNα-2a biweekly for 24 weeks. HBsAg was subsequently undetectable, and interestingly, anti-HBs antibodies (HBsAbs) were detected 28 months after the start of treatment. When we simultaneously discontinued the administration of NUCs and Peg-IFNα-2a, HBsAg and HBV-DNA were undetectable, and anti-HBsAb was still positive (Fig. 2). Hyaluronic acid levels decreased after treatment, and other fibrotic markers were undetectable at the end of treatment. HBe antigen and antibody were unexpectedly undetectable before and after treatment (Table 2).
Figure 2. The patient with chronic hepatitis B infection has been treated with the nucleic acid analogs (NUCs) lamivudine and adefovir since 2000. Although the HBV-DNA levels were undetectable, the test for HBs antigen (HBsAg) was positive. Peg-interferon (IFN) administered once weekly for 48 weeks together with the NUCs reduced the levels of HBsAg from 851.2 to 5.64 IU/mL. Although the HBsAg levels were not reduced during the resting period, resuming biweekly treatment with Peg-IFNα-2a biweekly reduced the levels of HBsAg below the limit of detection, and tests for anti-HBsAbs were positive. Upon completion of Peg-IFNα-2a therapy, the ALT levels normalized.
Table 2. Laboratory Data for the Patient after Administering Peg-IFNα-2a.
Variable Value Unit Reference
TP 6.8 g/dL 6.5-8.2
Alb 4.4 g/dL 3.5-5.5
A/G 1.83 1-1.8
BUN 17.3 mg/dL 7-20
Cr 0.72 mg/dL 0.5-1
T-bil 0.8 mg/dL 0.1-1.2
D-bil 0.2 mg/dL 0.1-0.6
AST 21 U/L 10-35
ALT 22 U/L 5-40
ALP 219 U/L 100-340
LDH 201 U/L 110-220
γ-GTP 19 U/L 0-30
Na 142 mmol/L 135-146
K 4.1 mmol/L 3.5-4.6
Cl 110 mmol/L 96-110
WBC 5,190 /µL 4,700-8,700
RBC 419×104 /µL 370-490
Hb 14 g/dL 11-15
Ht 40.9 % 35-45
Plt 14.7×104 /µL 15-35
Neut 53.2 % 38-71.9
Eos 1.7 % 0.2-6.8
Baso 0.6 % 0-1
Lym 39.7 % 26-46.6
Mono 4.8 % 2.3-7.7
PT 100 % 80-100
HBV-DNA - LIU/mL -
HBs Antigen - IU/mL 0-0.05
HBs Antibody 49 mIU/mL 0-10
HBe Antigen - ng/mL -
HBe Antibody - -
HBcr Antigen 3.1 logU/mL 0-3
AFP 2 ng/mL
DCP 16 mAU/mL
M2BPGi - -
7S domain of type IV collagen 3.7 ng/mL 0-6
Hyaluronic acid 30.9 ng/mL 0-50
When this manuscript was submitted, the patient's AST and ALT levels were within normal limits.
Discussion
NUCs are frequently administered to patients with chronic HBV infection to prevent the induction of HCC and the progression of liver fibrosis. However, few cases (0.6-8%) become HBsAg-negative, even after long-term administration of NUCs (9). The incidence of HCC is significantly decreased in patients with undetectable levels of HBsAg. Furthermore, low levels of detected HBsAg at treatment initiation are associated with an increased frequency of a subsequent response (14). When the HBsAg level is low after IFN therapy, it may be possible to consider readministering IFN while paying attention to the adverse as well as therapeutic effects.
The present patient was first treated with NUCs and then subsequently and simultaneously treated with Peg-IFN, which resulted in significant seroclearance of HBsAg. Notably, anti-HBsAbs were detected subsequent to the seroclearance of HBsAg. This finding indicates that, although infrequent (9), Peg-IFN contributes to an immune response against HBV.
We previously reported that reduced serum levels of miR-6126 are associated with a sustained reduction of HBsAg at 48 weeks after the initiation of Peg-IFN therapy (15). MiR-6126 may therefore serve as a marker for selecting patients likely to respond to Peg-IFN therapy, which may reduce the levels of HBsAg (15). However, the present patient exhibited a low miR-6126 signal, similar to the findings in non-responders (15). Although the reason for this is unclear, we hypothesized that it was due to the administration of lamivudine and adefovir. Nucleoside analogs (lamivudine or entecavir) differ from nucleotide analogs (adefovir or tenofovir) in that their mechanism of antiviral activity involves the induction of IFN-λ3 expression (16). However, the potential association with miR-6126 levels requires further study.
Although the present case is rare, our findings suggest that NUCs may be discontinued when Peg-IFN contributes to a reduction in HBsAg levels, which will improve treatment outcomes and thus reduce costs.
The authors state that they have no Conflict of Interest (COI). | LAMIVUDINE | DrugsGivenReaction | CC BY-NC-ND | 33456036 | 18,820,957 | 2021-06-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abscess soft tissue'. | Nocardia veterana infections: case report and systematic review.
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments. In 2001, the species Nocardia veterana was first isolated, and it predominantly causes pulmonary infections in immunocompromised hosts. We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease. After failing to improve with empirical treatment, two incision and drainage procedures were required. She subsequently completed a 1-year course of oral antibiotic therapy consisting of trimethoprim-sulfamethoxazole then azithromycin. No relapse occurred over the next 5 years of follow up. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases. Overall, the rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Introduction
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments [1,2]. They classically lead to infections in immunocompromised hosts [1], but 15% of patients in a large series had no predisposing conditions [3]. In 2001, the species Nocardia veterana was first isolated at a veterans' hospital in Australia, from which its name is derived [4]. It has been demonstrated to predominantly cause pulmonary infections in immunocompromised hosts [[5], [6], [7]], and only two reports have identified N. veterana as the cause of abscesses [8,9].
Materials and methods
We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease (GVHD). Review of medical records was approved by our institution's institutional review board. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases.
Case presentation
A 59-year-old woman with a history of acute lymphoblastic leukaemia—status post-haematopoietic stem cell transplantation—presented to the emergency department for evaluation of a right shoulder cutaneous abscess. Her post-transplant course had been complicated by multiple episodes of gastrointestinal and cutaneous GVHD. At this time, she was receiving phototherapy for chronic cutaneous GVHD and had started taking prednisone (30 mg daily) 6 months before presentation. Her medications included tacrolimus, acyclovir, fluconazole and monthly pentamidine. Two weeks before presentation, she had been evaluated by her oncologist for a 5 × 7 cm erythematous, indurated region on her right shoulder, and empiric treatment with oral minocycline (100 mg twice a day) was initiated. Continued pain prompted an outpatient ultrasound, which demonstrated a fluid collection. Her referring provider then sent her to the emergency department for further evaluation.
Incision and drainage were performed in the emergency department and yielded copious, purulent drainage that was sent for culture. Antibiotic therapy was empirically switched to oral clindamycin (600 mg three times a day). She was afebrile and discharged shortly thereafter. Two days later, she was admitted after a wound check showed increasing erythema around the incision and drainage site. Laboratory studies were notable for leucocytosis (15 200/μL; reference range 4000–10 000/μL), but she remained afebrile. Magnetic resonance imaging of her right upper extremity demonstrated a 2-cm soft-tissue abscess involving superficial fascia of the lateral deltoid and focal myositis (Fig. 1). Antibiotic therapy was broadened to intravenous vancomycin and piperacillin-tazobactam.Fig. 1 Nocardia veterana abscess: T2-weighted magnetic resonance imaging demonstrates 2-cm abscess involving the superficial fascia of the right lateral deltoid muscle.
Fig. 1
On day 2 of hospitalization, the abscess was incised and drained by general surgery. The following day, the culture from her initial presentation to the emergency department grew 4+ Gram-positive rods, prompting Nocardia spp. to be suspected. Antibiotic therapy was switched to oral trimethoprim-sulfamethoxazole (800 mg-160–mg twice a day). Magnetic resonance imaging of the brain and a CT scan of the chest showed no evidence of involvement, and she was discharged on day 4.
Four days after discharge, the isolate from her initial presentation was identified as N. veterana. The MicroSEQ® 500bp 16S rRNA Sequencing Kit (Applied Biosystems, Foster City, CA, USA) was used. Samples were processed and analysed consistent with the manufacturer's instructions. Data were assembled with MicroSEQ software, and amplicons were compared against the MicroSEQ database. Clinical and Laboratory Standards Institute MM18 criteria were used for making an identification. The aligned sequence was 409 bp, with no mixed bases. The isolate was 100% match to N. veterana in the MicroSEQ database; however, the National Center for Biotechnology Information BLAST database has been updated since the time of the isolate's processing, and a Nocardia elegans strain was retrospectively identified as a 100% match during the preparation of this report. Notably, three strains of N. veterana were 100% matches.
Susceptibility testing was sent out to the University of Texas Health Center's Department of Microbiology Research in Tyler, Texas. The isolate's susceptibility profile is summarized in Table 1. Two weeks later, the woman was seen as an outpatient and had been tolerating trimethoprim-sulfamethoxazole therapy. Seventy-three days after discharge, elevated creatinine (3.1 mg/dL, baseline 1.9 mg/dL; reference range 0.6–1.2 mg/dL) was attributed to the use of trimethoprim-sulfamethoxazole in combination with tacrolimus, and antibiotic therapy was switched to oral azithromycin (500 mg daily). This decision was informed by the isolate's susceptibility profile and discussion with the reference laboratory.Table 1 Nocardia veterana isolate susceptibility profilea
Table 1Susceptible Intermediate Resistant No standardized breakpoint for Nocardia spp.
Amikacin (MIC ≤1 μg/mL) Ceftriaxone (MIC 16 μg/mL) Amoxicillin-clavulanate (MIC 32–16 μg/mL) Ertapenem (MIC unavailable; susceptible by bacterial breakpoint)
Clarithromycin (MIC ≤0.06 μg/mL) Kanamycin (MIC unavailable) Ciprofloxacin (MIC >4 μg/mL) Meropenem (MIC unavailable; susceptible by rapidly growing mycobacteria breakpoint)
Imipenem (MIC ≤2 μg/mL) Minocycline (MIC 2 μg/mL) Doxycycline (MIC 16 μg/mL) Tigecycline (MIC 4 μg/mL)
Linezolid (MIC 2 μg/mL) Moxifloxacin (MIC 4 μg/mL)
Trimethoprim-sulfamethoxazole (MIC 1–19 μg/mL) Tobramycin (MIC >16 μg/mL)
a Susceptibility results are reported with reference to their MICs and respective, standardized breakpoints.
Roughly 1.5 months later, her creatinine had returned to baseline (1.7 mg/dL), and she had been tolerating azithromycin without adverse events. In the absence of symptoms attributable to her N. veterana infection, azithromycin therapy was discontinued 289 days after its initiation. She continued to receive phototherapy for GVHD and remained on prednisone (20 mg daily), acyclovir, fluconazole and monthly pentamidine. She was seen 6 months after completing her 1-year course of therapy and displayed no signs of relapse. More than 5 years since completing therapy, no relapse has occurred.
Literature review and discussion
Our case concerned an N. veterana infection in a 59-year-old woman who had been receiving immunosuppressive therapy for chronic cutaneous GVHD. She failed to respond to empiric minocycline, and an abscess was incised and drained twice before resolving. Fortunately, oral antibiotic therapy was capable of treating the infection then serving as prophylaxis against relapse. Acute kidney injury complicated her course, but azithromycin therapy ultimately proved tolerable and successful. The isolate was resistant to several antibiotic choices, and susceptibility testing was integral to her management.
To better characterize N. veterana infections, we searched PubMed with the following operators: (‘Nocardia veterana’ OR ‘N. veterana’) AND (infection OR infections). Articles' citation lists were also reviewed to identify cases. We excluded one abridged report of a mycetoma [10] whose full details were published in a later manuscript [11]. Table 2 summarizes our case and all reported cases of N. veterana infections.Table 2 Nocardia veterana infections
Table 2Age/sex Clinical syndrome Immunocompromising co-morbidities Initial anti-nocardial regimen Length of treatment Outcome Ref.
83/F bowel abscess malignancy TMP-SMX >3 months success [8]
73/M brain abscess diabetes mellitus meropenem 1 year success [9]
66/M endophthalmitis heart transplant, diabetes mellitus meropenem, linezolid planned length of 12 months success [12]
42/F mycetoma SLE amoxicillin >6 years success [11]
72/M nodular lymphangitis immunosuppressive therapy for interstitial pneumonitis TMP-SMX planned length of 3 months stable at time of report [13]
40/M peritoneal infection AIDS, chronic hepatitis B, malignancy died before treatment initiation not applicable died before treatment initiation [14]
24/M pulmonary infection chronic granulomatous disease amikacin, ceftriaxone, trimethoprim >3 months stable at time of report [15]
40/F pulmonary infection HIV TMP-SMX 6 months success [16]
43/F pulmonary infection immunosuppressive therapy for SLE TMP-SMX 6 months success [17]
47/M pulmonary infection liver transplant TMP-SMX 6 months success [17]
52/M pulmonary infection not specified not reported not reported not reported [18]
52/M pulmonary infection HSCT recipient treated for GVHD TMP-SMX 397 days success [19]
52/F pulmonary infection HSCT recipient treated for GVHD TMP-SMX 154 days success [19]
54/M pulmonary infection heart transplant TMP-SMX 15 days success [16]
59/M pulmonary infection liver transplant imipenem >6 months success [16]
63/M pulmonary infection lung transplant, immunosuppressive therapy for bronchiolitis obliterans TMP-SMX 16 weeks died after discontinuing immunosuppression [15]
65/M pulmonary infection HSCT recipient treated for GVHD imipenem/cilastatin, amikacin 722 days died from encephalitis of unknown aetiology [6]
67/F pulmonary infection recurrent pneumonias and bronchiectasis minocycline >7 weeks symptomatic improvement at time of report [17]
78/M pulmonary infection history of tuberculosis not reported not reported not reported [4]
not reported pulmonary infection lung transplant TMP-SMX 30 days success [7]
58/M pulmonary infection with bacteraemia malignancy, recent prednisone course for autoimmune haemolytic anaemia TMP-SMX, azithromycin, piperacillin-tazobactam 3 weeks success [20]
30/M pulmonary infection with bacteraemia HIV, chronic hepatitis B, history of tuberculosis TMP-SMX <1 month died from multi-organ failure [5]
51/M pulmonary and urinary tract infections with bacteraemia malignancy, peritoneal dialysis TMP-SMX <2 months died from underlying malignancy [21]
59/F soft-tissue abscess HSCT recipient treated for GVHD TMP-SMX 1 year success our case
Abbreviations: AIDS, acquired immunodeficiency syndrome; GVHD, graft-versus-host disease; HIV, human immunodeficiency virus; HSCT, haematopoietic stem cell transplantation; SLE, systemic lupus erythematosus; TMP-SMX, trimethoprim-sulfamethoxazole.
Mean age was 55 years, and 29% were women. Pulmonary infections accounted for 17 of 24 infections, with abscesses being the second most common (3 of 24). In total, 25% had previous solid organ transplantations, 17% of patients had undergone haematopoietic stem cell transplantation and were undergoing treatment for GVHD, and 13% were people living with human immunodeficiency virus. The duration of treatment ranged from 3 weeks to >6 years. Trimethoprim-sulfamethoxazole monotherapy was used as initial anti-nocardial therapy for 13 of 24 individuals and led to treatment success in 9 of 13 (69%) of them. Combination therapy or other monotherapy (e.g. amoxicillin) was successful for six of eight (75%) individuals. The number of patients was too small to determine whether the difference in outcome is statistically significant.
Overall, N. veterana has a predilection for causing pulmonary infections in individuals with immunocompromising conditions [[4], [5], [6], [7],[15], [16], [17], [18], [19], [20]], and trimethoprim-sulfamethoxazole is commonly used to treat infections caused by Nocardia spp. [1]. When planning management for an immunocompromised host, a prolonged treatment duration is recommended. For our patient, the concurrent use of immunosuppressive therapy to manage GVHD heightened her susceptibility to N. veterana infection, and disseminated disease was fortunately averted by extended antibiotic therapy. The rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Conflict of interest
The authors declare no conflicts of interest. | ACYCLOVIR, FLUCONAZOLE, MINOCYCLINE HYDROCHLORIDE, PENTAMIDINE, PREDNISONE, SULFAMETHOXAZOLE\TRIMETHOPRIM, TACROLIMUS | DrugsGivenReaction | CC BY-NC-ND | 33456780 | 18,799,519 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abscess'. | Nocardia veterana infections: case report and systematic review.
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments. In 2001, the species Nocardia veterana was first isolated, and it predominantly causes pulmonary infections in immunocompromised hosts. We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease. After failing to improve with empirical treatment, two incision and drainage procedures were required. She subsequently completed a 1-year course of oral antibiotic therapy consisting of trimethoprim-sulfamethoxazole then azithromycin. No relapse occurred over the next 5 years of follow up. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases. Overall, the rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Introduction
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments [1,2]. They classically lead to infections in immunocompromised hosts [1], but 15% of patients in a large series had no predisposing conditions [3]. In 2001, the species Nocardia veterana was first isolated at a veterans' hospital in Australia, from which its name is derived [4]. It has been demonstrated to predominantly cause pulmonary infections in immunocompromised hosts [[5], [6], [7]], and only two reports have identified N. veterana as the cause of abscesses [8,9].
Materials and methods
We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease (GVHD). Review of medical records was approved by our institution's institutional review board. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases.
Case presentation
A 59-year-old woman with a history of acute lymphoblastic leukaemia—status post-haematopoietic stem cell transplantation—presented to the emergency department for evaluation of a right shoulder cutaneous abscess. Her post-transplant course had been complicated by multiple episodes of gastrointestinal and cutaneous GVHD. At this time, she was receiving phototherapy for chronic cutaneous GVHD and had started taking prednisone (30 mg daily) 6 months before presentation. Her medications included tacrolimus, acyclovir, fluconazole and monthly pentamidine. Two weeks before presentation, she had been evaluated by her oncologist for a 5 × 7 cm erythematous, indurated region on her right shoulder, and empiric treatment with oral minocycline (100 mg twice a day) was initiated. Continued pain prompted an outpatient ultrasound, which demonstrated a fluid collection. Her referring provider then sent her to the emergency department for further evaluation.
Incision and drainage were performed in the emergency department and yielded copious, purulent drainage that was sent for culture. Antibiotic therapy was empirically switched to oral clindamycin (600 mg three times a day). She was afebrile and discharged shortly thereafter. Two days later, she was admitted after a wound check showed increasing erythema around the incision and drainage site. Laboratory studies were notable for leucocytosis (15 200/μL; reference range 4000–10 000/μL), but she remained afebrile. Magnetic resonance imaging of her right upper extremity demonstrated a 2-cm soft-tissue abscess involving superficial fascia of the lateral deltoid and focal myositis (Fig. 1). Antibiotic therapy was broadened to intravenous vancomycin and piperacillin-tazobactam.Fig. 1 Nocardia veterana abscess: T2-weighted magnetic resonance imaging demonstrates 2-cm abscess involving the superficial fascia of the right lateral deltoid muscle.
Fig. 1
On day 2 of hospitalization, the abscess was incised and drained by general surgery. The following day, the culture from her initial presentation to the emergency department grew 4+ Gram-positive rods, prompting Nocardia spp. to be suspected. Antibiotic therapy was switched to oral trimethoprim-sulfamethoxazole (800 mg-160–mg twice a day). Magnetic resonance imaging of the brain and a CT scan of the chest showed no evidence of involvement, and she was discharged on day 4.
Four days after discharge, the isolate from her initial presentation was identified as N. veterana. The MicroSEQ® 500bp 16S rRNA Sequencing Kit (Applied Biosystems, Foster City, CA, USA) was used. Samples were processed and analysed consistent with the manufacturer's instructions. Data were assembled with MicroSEQ software, and amplicons were compared against the MicroSEQ database. Clinical and Laboratory Standards Institute MM18 criteria were used for making an identification. The aligned sequence was 409 bp, with no mixed bases. The isolate was 100% match to N. veterana in the MicroSEQ database; however, the National Center for Biotechnology Information BLAST database has been updated since the time of the isolate's processing, and a Nocardia elegans strain was retrospectively identified as a 100% match during the preparation of this report. Notably, three strains of N. veterana were 100% matches.
Susceptibility testing was sent out to the University of Texas Health Center's Department of Microbiology Research in Tyler, Texas. The isolate's susceptibility profile is summarized in Table 1. Two weeks later, the woman was seen as an outpatient and had been tolerating trimethoprim-sulfamethoxazole therapy. Seventy-three days after discharge, elevated creatinine (3.1 mg/dL, baseline 1.9 mg/dL; reference range 0.6–1.2 mg/dL) was attributed to the use of trimethoprim-sulfamethoxazole in combination with tacrolimus, and antibiotic therapy was switched to oral azithromycin (500 mg daily). This decision was informed by the isolate's susceptibility profile and discussion with the reference laboratory.Table 1 Nocardia veterana isolate susceptibility profilea
Table 1Susceptible Intermediate Resistant No standardized breakpoint for Nocardia spp.
Amikacin (MIC ≤1 μg/mL) Ceftriaxone (MIC 16 μg/mL) Amoxicillin-clavulanate (MIC 32–16 μg/mL) Ertapenem (MIC unavailable; susceptible by bacterial breakpoint)
Clarithromycin (MIC ≤0.06 μg/mL) Kanamycin (MIC unavailable) Ciprofloxacin (MIC >4 μg/mL) Meropenem (MIC unavailable; susceptible by rapidly growing mycobacteria breakpoint)
Imipenem (MIC ≤2 μg/mL) Minocycline (MIC 2 μg/mL) Doxycycline (MIC 16 μg/mL) Tigecycline (MIC 4 μg/mL)
Linezolid (MIC 2 μg/mL) Moxifloxacin (MIC 4 μg/mL)
Trimethoprim-sulfamethoxazole (MIC 1–19 μg/mL) Tobramycin (MIC >16 μg/mL)
a Susceptibility results are reported with reference to their MICs and respective, standardized breakpoints.
Roughly 1.5 months later, her creatinine had returned to baseline (1.7 mg/dL), and she had been tolerating azithromycin without adverse events. In the absence of symptoms attributable to her N. veterana infection, azithromycin therapy was discontinued 289 days after its initiation. She continued to receive phototherapy for GVHD and remained on prednisone (20 mg daily), acyclovir, fluconazole and monthly pentamidine. She was seen 6 months after completing her 1-year course of therapy and displayed no signs of relapse. More than 5 years since completing therapy, no relapse has occurred.
Literature review and discussion
Our case concerned an N. veterana infection in a 59-year-old woman who had been receiving immunosuppressive therapy for chronic cutaneous GVHD. She failed to respond to empiric minocycline, and an abscess was incised and drained twice before resolving. Fortunately, oral antibiotic therapy was capable of treating the infection then serving as prophylaxis against relapse. Acute kidney injury complicated her course, but azithromycin therapy ultimately proved tolerable and successful. The isolate was resistant to several antibiotic choices, and susceptibility testing was integral to her management.
To better characterize N. veterana infections, we searched PubMed with the following operators: (‘Nocardia veterana’ OR ‘N. veterana’) AND (infection OR infections). Articles' citation lists were also reviewed to identify cases. We excluded one abridged report of a mycetoma [10] whose full details were published in a later manuscript [11]. Table 2 summarizes our case and all reported cases of N. veterana infections.Table 2 Nocardia veterana infections
Table 2Age/sex Clinical syndrome Immunocompromising co-morbidities Initial anti-nocardial regimen Length of treatment Outcome Ref.
83/F bowel abscess malignancy TMP-SMX >3 months success [8]
73/M brain abscess diabetes mellitus meropenem 1 year success [9]
66/M endophthalmitis heart transplant, diabetes mellitus meropenem, linezolid planned length of 12 months success [12]
42/F mycetoma SLE amoxicillin >6 years success [11]
72/M nodular lymphangitis immunosuppressive therapy for interstitial pneumonitis TMP-SMX planned length of 3 months stable at time of report [13]
40/M peritoneal infection AIDS, chronic hepatitis B, malignancy died before treatment initiation not applicable died before treatment initiation [14]
24/M pulmonary infection chronic granulomatous disease amikacin, ceftriaxone, trimethoprim >3 months stable at time of report [15]
40/F pulmonary infection HIV TMP-SMX 6 months success [16]
43/F pulmonary infection immunosuppressive therapy for SLE TMP-SMX 6 months success [17]
47/M pulmonary infection liver transplant TMP-SMX 6 months success [17]
52/M pulmonary infection not specified not reported not reported not reported [18]
52/M pulmonary infection HSCT recipient treated for GVHD TMP-SMX 397 days success [19]
52/F pulmonary infection HSCT recipient treated for GVHD TMP-SMX 154 days success [19]
54/M pulmonary infection heart transplant TMP-SMX 15 days success [16]
59/M pulmonary infection liver transplant imipenem >6 months success [16]
63/M pulmonary infection lung transplant, immunosuppressive therapy for bronchiolitis obliterans TMP-SMX 16 weeks died after discontinuing immunosuppression [15]
65/M pulmonary infection HSCT recipient treated for GVHD imipenem/cilastatin, amikacin 722 days died from encephalitis of unknown aetiology [6]
67/F pulmonary infection recurrent pneumonias and bronchiectasis minocycline >7 weeks symptomatic improvement at time of report [17]
78/M pulmonary infection history of tuberculosis not reported not reported not reported [4]
not reported pulmonary infection lung transplant TMP-SMX 30 days success [7]
58/M pulmonary infection with bacteraemia malignancy, recent prednisone course for autoimmune haemolytic anaemia TMP-SMX, azithromycin, piperacillin-tazobactam 3 weeks success [20]
30/M pulmonary infection with bacteraemia HIV, chronic hepatitis B, history of tuberculosis TMP-SMX <1 month died from multi-organ failure [5]
51/M pulmonary and urinary tract infections with bacteraemia malignancy, peritoneal dialysis TMP-SMX <2 months died from underlying malignancy [21]
59/F soft-tissue abscess HSCT recipient treated for GVHD TMP-SMX 1 year success our case
Abbreviations: AIDS, acquired immunodeficiency syndrome; GVHD, graft-versus-host disease; HIV, human immunodeficiency virus; HSCT, haematopoietic stem cell transplantation; SLE, systemic lupus erythematosus; TMP-SMX, trimethoprim-sulfamethoxazole.
Mean age was 55 years, and 29% were women. Pulmonary infections accounted for 17 of 24 infections, with abscesses being the second most common (3 of 24). In total, 25% had previous solid organ transplantations, 17% of patients had undergone haematopoietic stem cell transplantation and were undergoing treatment for GVHD, and 13% were people living with human immunodeficiency virus. The duration of treatment ranged from 3 weeks to >6 years. Trimethoprim-sulfamethoxazole monotherapy was used as initial anti-nocardial therapy for 13 of 24 individuals and led to treatment success in 9 of 13 (69%) of them. Combination therapy or other monotherapy (e.g. amoxicillin) was successful for six of eight (75%) individuals. The number of patients was too small to determine whether the difference in outcome is statistically significant.
Overall, N. veterana has a predilection for causing pulmonary infections in individuals with immunocompromising conditions [[4], [5], [6], [7],[15], [16], [17], [18], [19], [20]], and trimethoprim-sulfamethoxazole is commonly used to treat infections caused by Nocardia spp. [1]. When planning management for an immunocompromised host, a prolonged treatment duration is recommended. For our patient, the concurrent use of immunosuppressive therapy to manage GVHD heightened her susceptibility to N. veterana infection, and disseminated disease was fortunately averted by extended antibiotic therapy. The rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Conflict of interest
The authors declare no conflicts of interest. | ACYCLOVIR, FLUCONAZOLE, PENTAMIDINE, PREDNISONE, SULFAMETHOXAZOLE\TRIMETHOPRIM, TACROLIMUS | DrugsGivenReaction | CC BY-NC-ND | 33456780 | 18,797,291 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute kidney injury'. | Nocardia veterana infections: case report and systematic review.
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments. In 2001, the species Nocardia veterana was first isolated, and it predominantly causes pulmonary infections in immunocompromised hosts. We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease. After failing to improve with empirical treatment, two incision and drainage procedures were required. She subsequently completed a 1-year course of oral antibiotic therapy consisting of trimethoprim-sulfamethoxazole then azithromycin. No relapse occurred over the next 5 years of follow up. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases. Overall, the rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Introduction
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments [1,2]. They classically lead to infections in immunocompromised hosts [1], but 15% of patients in a large series had no predisposing conditions [3]. In 2001, the species Nocardia veterana was first isolated at a veterans' hospital in Australia, from which its name is derived [4]. It has been demonstrated to predominantly cause pulmonary infections in immunocompromised hosts [[5], [6], [7]], and only two reports have identified N. veterana as the cause of abscesses [8,9].
Materials and methods
We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease (GVHD). Review of medical records was approved by our institution's institutional review board. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases.
Case presentation
A 59-year-old woman with a history of acute lymphoblastic leukaemia—status post-haematopoietic stem cell transplantation—presented to the emergency department for evaluation of a right shoulder cutaneous abscess. Her post-transplant course had been complicated by multiple episodes of gastrointestinal and cutaneous GVHD. At this time, she was receiving phototherapy for chronic cutaneous GVHD and had started taking prednisone (30 mg daily) 6 months before presentation. Her medications included tacrolimus, acyclovir, fluconazole and monthly pentamidine. Two weeks before presentation, she had been evaluated by her oncologist for a 5 × 7 cm erythematous, indurated region on her right shoulder, and empiric treatment with oral minocycline (100 mg twice a day) was initiated. Continued pain prompted an outpatient ultrasound, which demonstrated a fluid collection. Her referring provider then sent her to the emergency department for further evaluation.
Incision and drainage were performed in the emergency department and yielded copious, purulent drainage that was sent for culture. Antibiotic therapy was empirically switched to oral clindamycin (600 mg three times a day). She was afebrile and discharged shortly thereafter. Two days later, she was admitted after a wound check showed increasing erythema around the incision and drainage site. Laboratory studies were notable for leucocytosis (15 200/μL; reference range 4000–10 000/μL), but she remained afebrile. Magnetic resonance imaging of her right upper extremity demonstrated a 2-cm soft-tissue abscess involving superficial fascia of the lateral deltoid and focal myositis (Fig. 1). Antibiotic therapy was broadened to intravenous vancomycin and piperacillin-tazobactam.Fig. 1 Nocardia veterana abscess: T2-weighted magnetic resonance imaging demonstrates 2-cm abscess involving the superficial fascia of the right lateral deltoid muscle.
Fig. 1
On day 2 of hospitalization, the abscess was incised and drained by general surgery. The following day, the culture from her initial presentation to the emergency department grew 4+ Gram-positive rods, prompting Nocardia spp. to be suspected. Antibiotic therapy was switched to oral trimethoprim-sulfamethoxazole (800 mg-160–mg twice a day). Magnetic resonance imaging of the brain and a CT scan of the chest showed no evidence of involvement, and she was discharged on day 4.
Four days after discharge, the isolate from her initial presentation was identified as N. veterana. The MicroSEQ® 500bp 16S rRNA Sequencing Kit (Applied Biosystems, Foster City, CA, USA) was used. Samples were processed and analysed consistent with the manufacturer's instructions. Data were assembled with MicroSEQ software, and amplicons were compared against the MicroSEQ database. Clinical and Laboratory Standards Institute MM18 criteria were used for making an identification. The aligned sequence was 409 bp, with no mixed bases. The isolate was 100% match to N. veterana in the MicroSEQ database; however, the National Center for Biotechnology Information BLAST database has been updated since the time of the isolate's processing, and a Nocardia elegans strain was retrospectively identified as a 100% match during the preparation of this report. Notably, three strains of N. veterana were 100% matches.
Susceptibility testing was sent out to the University of Texas Health Center's Department of Microbiology Research in Tyler, Texas. The isolate's susceptibility profile is summarized in Table 1. Two weeks later, the woman was seen as an outpatient and had been tolerating trimethoprim-sulfamethoxazole therapy. Seventy-three days after discharge, elevated creatinine (3.1 mg/dL, baseline 1.9 mg/dL; reference range 0.6–1.2 mg/dL) was attributed to the use of trimethoprim-sulfamethoxazole in combination with tacrolimus, and antibiotic therapy was switched to oral azithromycin (500 mg daily). This decision was informed by the isolate's susceptibility profile and discussion with the reference laboratory.Table 1 Nocardia veterana isolate susceptibility profilea
Table 1Susceptible Intermediate Resistant No standardized breakpoint for Nocardia spp.
Amikacin (MIC ≤1 μg/mL) Ceftriaxone (MIC 16 μg/mL) Amoxicillin-clavulanate (MIC 32–16 μg/mL) Ertapenem (MIC unavailable; susceptible by bacterial breakpoint)
Clarithromycin (MIC ≤0.06 μg/mL) Kanamycin (MIC unavailable) Ciprofloxacin (MIC >4 μg/mL) Meropenem (MIC unavailable; susceptible by rapidly growing mycobacteria breakpoint)
Imipenem (MIC ≤2 μg/mL) Minocycline (MIC 2 μg/mL) Doxycycline (MIC 16 μg/mL) Tigecycline (MIC 4 μg/mL)
Linezolid (MIC 2 μg/mL) Moxifloxacin (MIC 4 μg/mL)
Trimethoprim-sulfamethoxazole (MIC 1–19 μg/mL) Tobramycin (MIC >16 μg/mL)
a Susceptibility results are reported with reference to their MICs and respective, standardized breakpoints.
Roughly 1.5 months later, her creatinine had returned to baseline (1.7 mg/dL), and she had been tolerating azithromycin without adverse events. In the absence of symptoms attributable to her N. veterana infection, azithromycin therapy was discontinued 289 days after its initiation. She continued to receive phototherapy for GVHD and remained on prednisone (20 mg daily), acyclovir, fluconazole and monthly pentamidine. She was seen 6 months after completing her 1-year course of therapy and displayed no signs of relapse. More than 5 years since completing therapy, no relapse has occurred.
Literature review and discussion
Our case concerned an N. veterana infection in a 59-year-old woman who had been receiving immunosuppressive therapy for chronic cutaneous GVHD. She failed to respond to empiric minocycline, and an abscess was incised and drained twice before resolving. Fortunately, oral antibiotic therapy was capable of treating the infection then serving as prophylaxis against relapse. Acute kidney injury complicated her course, but azithromycin therapy ultimately proved tolerable and successful. The isolate was resistant to several antibiotic choices, and susceptibility testing was integral to her management.
To better characterize N. veterana infections, we searched PubMed with the following operators: (‘Nocardia veterana’ OR ‘N. veterana’) AND (infection OR infections). Articles' citation lists were also reviewed to identify cases. We excluded one abridged report of a mycetoma [10] whose full details were published in a later manuscript [11]. Table 2 summarizes our case and all reported cases of N. veterana infections.Table 2 Nocardia veterana infections
Table 2Age/sex Clinical syndrome Immunocompromising co-morbidities Initial anti-nocardial regimen Length of treatment Outcome Ref.
83/F bowel abscess malignancy TMP-SMX >3 months success [8]
73/M brain abscess diabetes mellitus meropenem 1 year success [9]
66/M endophthalmitis heart transplant, diabetes mellitus meropenem, linezolid planned length of 12 months success [12]
42/F mycetoma SLE amoxicillin >6 years success [11]
72/M nodular lymphangitis immunosuppressive therapy for interstitial pneumonitis TMP-SMX planned length of 3 months stable at time of report [13]
40/M peritoneal infection AIDS, chronic hepatitis B, malignancy died before treatment initiation not applicable died before treatment initiation [14]
24/M pulmonary infection chronic granulomatous disease amikacin, ceftriaxone, trimethoprim >3 months stable at time of report [15]
40/F pulmonary infection HIV TMP-SMX 6 months success [16]
43/F pulmonary infection immunosuppressive therapy for SLE TMP-SMX 6 months success [17]
47/M pulmonary infection liver transplant TMP-SMX 6 months success [17]
52/M pulmonary infection not specified not reported not reported not reported [18]
52/M pulmonary infection HSCT recipient treated for GVHD TMP-SMX 397 days success [19]
52/F pulmonary infection HSCT recipient treated for GVHD TMP-SMX 154 days success [19]
54/M pulmonary infection heart transplant TMP-SMX 15 days success [16]
59/M pulmonary infection liver transplant imipenem >6 months success [16]
63/M pulmonary infection lung transplant, immunosuppressive therapy for bronchiolitis obliterans TMP-SMX 16 weeks died after discontinuing immunosuppression [15]
65/M pulmonary infection HSCT recipient treated for GVHD imipenem/cilastatin, amikacin 722 days died from encephalitis of unknown aetiology [6]
67/F pulmonary infection recurrent pneumonias and bronchiectasis minocycline >7 weeks symptomatic improvement at time of report [17]
78/M pulmonary infection history of tuberculosis not reported not reported not reported [4]
not reported pulmonary infection lung transplant TMP-SMX 30 days success [7]
58/M pulmonary infection with bacteraemia malignancy, recent prednisone course for autoimmune haemolytic anaemia TMP-SMX, azithromycin, piperacillin-tazobactam 3 weeks success [20]
30/M pulmonary infection with bacteraemia HIV, chronic hepatitis B, history of tuberculosis TMP-SMX <1 month died from multi-organ failure [5]
51/M pulmonary and urinary tract infections with bacteraemia malignancy, peritoneal dialysis TMP-SMX <2 months died from underlying malignancy [21]
59/F soft-tissue abscess HSCT recipient treated for GVHD TMP-SMX 1 year success our case
Abbreviations: AIDS, acquired immunodeficiency syndrome; GVHD, graft-versus-host disease; HIV, human immunodeficiency virus; HSCT, haematopoietic stem cell transplantation; SLE, systemic lupus erythematosus; TMP-SMX, trimethoprim-sulfamethoxazole.
Mean age was 55 years, and 29% were women. Pulmonary infections accounted for 17 of 24 infections, with abscesses being the second most common (3 of 24). In total, 25% had previous solid organ transplantations, 17% of patients had undergone haematopoietic stem cell transplantation and were undergoing treatment for GVHD, and 13% were people living with human immunodeficiency virus. The duration of treatment ranged from 3 weeks to >6 years. Trimethoprim-sulfamethoxazole monotherapy was used as initial anti-nocardial therapy for 13 of 24 individuals and led to treatment success in 9 of 13 (69%) of them. Combination therapy or other monotherapy (e.g. amoxicillin) was successful for six of eight (75%) individuals. The number of patients was too small to determine whether the difference in outcome is statistically significant.
Overall, N. veterana has a predilection for causing pulmonary infections in individuals with immunocompromising conditions [[4], [5], [6], [7],[15], [16], [17], [18], [19], [20]], and trimethoprim-sulfamethoxazole is commonly used to treat infections caused by Nocardia spp. [1]. When planning management for an immunocompromised host, a prolonged treatment duration is recommended. For our patient, the concurrent use of immunosuppressive therapy to manage GVHD heightened her susceptibility to N. veterana infection, and disseminated disease was fortunately averted by extended antibiotic therapy. The rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Conflict of interest
The authors declare no conflicts of interest. | ACYCLOVIR, FLUCONAZOLE, PENTAMIDINE, PREDNISONE, SULFAMETHOXAZOLE\TRIMETHOPRIM, TACROLIMUS | DrugsGivenReaction | CC BY-NC-ND | 33456780 | 18,817,070 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Focal myositis'. | Nocardia veterana infections: case report and systematic review.
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments. In 2001, the species Nocardia veterana was first isolated, and it predominantly causes pulmonary infections in immunocompromised hosts. We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease. After failing to improve with empirical treatment, two incision and drainage procedures were required. She subsequently completed a 1-year course of oral antibiotic therapy consisting of trimethoprim-sulfamethoxazole then azithromycin. No relapse occurred over the next 5 years of follow up. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases. Overall, the rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Introduction
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments [1,2]. They classically lead to infections in immunocompromised hosts [1], but 15% of patients in a large series had no predisposing conditions [3]. In 2001, the species Nocardia veterana was first isolated at a veterans' hospital in Australia, from which its name is derived [4]. It has been demonstrated to predominantly cause pulmonary infections in immunocompromised hosts [[5], [6], [7]], and only two reports have identified N. veterana as the cause of abscesses [8,9].
Materials and methods
We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease (GVHD). Review of medical records was approved by our institution's institutional review board. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases.
Case presentation
A 59-year-old woman with a history of acute lymphoblastic leukaemia—status post-haematopoietic stem cell transplantation—presented to the emergency department for evaluation of a right shoulder cutaneous abscess. Her post-transplant course had been complicated by multiple episodes of gastrointestinal and cutaneous GVHD. At this time, she was receiving phototherapy for chronic cutaneous GVHD and had started taking prednisone (30 mg daily) 6 months before presentation. Her medications included tacrolimus, acyclovir, fluconazole and monthly pentamidine. Two weeks before presentation, she had been evaluated by her oncologist for a 5 × 7 cm erythematous, indurated region on her right shoulder, and empiric treatment with oral minocycline (100 mg twice a day) was initiated. Continued pain prompted an outpatient ultrasound, which demonstrated a fluid collection. Her referring provider then sent her to the emergency department for further evaluation.
Incision and drainage were performed in the emergency department and yielded copious, purulent drainage that was sent for culture. Antibiotic therapy was empirically switched to oral clindamycin (600 mg three times a day). She was afebrile and discharged shortly thereafter. Two days later, she was admitted after a wound check showed increasing erythema around the incision and drainage site. Laboratory studies were notable for leucocytosis (15 200/μL; reference range 4000–10 000/μL), but she remained afebrile. Magnetic resonance imaging of her right upper extremity demonstrated a 2-cm soft-tissue abscess involving superficial fascia of the lateral deltoid and focal myositis (Fig. 1). Antibiotic therapy was broadened to intravenous vancomycin and piperacillin-tazobactam.Fig. 1 Nocardia veterana abscess: T2-weighted magnetic resonance imaging demonstrates 2-cm abscess involving the superficial fascia of the right lateral deltoid muscle.
Fig. 1
On day 2 of hospitalization, the abscess was incised and drained by general surgery. The following day, the culture from her initial presentation to the emergency department grew 4+ Gram-positive rods, prompting Nocardia spp. to be suspected. Antibiotic therapy was switched to oral trimethoprim-sulfamethoxazole (800 mg-160–mg twice a day). Magnetic resonance imaging of the brain and a CT scan of the chest showed no evidence of involvement, and she was discharged on day 4.
Four days after discharge, the isolate from her initial presentation was identified as N. veterana. The MicroSEQ® 500bp 16S rRNA Sequencing Kit (Applied Biosystems, Foster City, CA, USA) was used. Samples were processed and analysed consistent with the manufacturer's instructions. Data were assembled with MicroSEQ software, and amplicons were compared against the MicroSEQ database. Clinical and Laboratory Standards Institute MM18 criteria were used for making an identification. The aligned sequence was 409 bp, with no mixed bases. The isolate was 100% match to N. veterana in the MicroSEQ database; however, the National Center for Biotechnology Information BLAST database has been updated since the time of the isolate's processing, and a Nocardia elegans strain was retrospectively identified as a 100% match during the preparation of this report. Notably, three strains of N. veterana were 100% matches.
Susceptibility testing was sent out to the University of Texas Health Center's Department of Microbiology Research in Tyler, Texas. The isolate's susceptibility profile is summarized in Table 1. Two weeks later, the woman was seen as an outpatient and had been tolerating trimethoprim-sulfamethoxazole therapy. Seventy-three days after discharge, elevated creatinine (3.1 mg/dL, baseline 1.9 mg/dL; reference range 0.6–1.2 mg/dL) was attributed to the use of trimethoprim-sulfamethoxazole in combination with tacrolimus, and antibiotic therapy was switched to oral azithromycin (500 mg daily). This decision was informed by the isolate's susceptibility profile and discussion with the reference laboratory.Table 1 Nocardia veterana isolate susceptibility profilea
Table 1Susceptible Intermediate Resistant No standardized breakpoint for Nocardia spp.
Amikacin (MIC ≤1 μg/mL) Ceftriaxone (MIC 16 μg/mL) Amoxicillin-clavulanate (MIC 32–16 μg/mL) Ertapenem (MIC unavailable; susceptible by bacterial breakpoint)
Clarithromycin (MIC ≤0.06 μg/mL) Kanamycin (MIC unavailable) Ciprofloxacin (MIC >4 μg/mL) Meropenem (MIC unavailable; susceptible by rapidly growing mycobacteria breakpoint)
Imipenem (MIC ≤2 μg/mL) Minocycline (MIC 2 μg/mL) Doxycycline (MIC 16 μg/mL) Tigecycline (MIC 4 μg/mL)
Linezolid (MIC 2 μg/mL) Moxifloxacin (MIC 4 μg/mL)
Trimethoprim-sulfamethoxazole (MIC 1–19 μg/mL) Tobramycin (MIC >16 μg/mL)
a Susceptibility results are reported with reference to their MICs and respective, standardized breakpoints.
Roughly 1.5 months later, her creatinine had returned to baseline (1.7 mg/dL), and she had been tolerating azithromycin without adverse events. In the absence of symptoms attributable to her N. veterana infection, azithromycin therapy was discontinued 289 days after its initiation. She continued to receive phototherapy for GVHD and remained on prednisone (20 mg daily), acyclovir, fluconazole and monthly pentamidine. She was seen 6 months after completing her 1-year course of therapy and displayed no signs of relapse. More than 5 years since completing therapy, no relapse has occurred.
Literature review and discussion
Our case concerned an N. veterana infection in a 59-year-old woman who had been receiving immunosuppressive therapy for chronic cutaneous GVHD. She failed to respond to empiric minocycline, and an abscess was incised and drained twice before resolving. Fortunately, oral antibiotic therapy was capable of treating the infection then serving as prophylaxis against relapse. Acute kidney injury complicated her course, but azithromycin therapy ultimately proved tolerable and successful. The isolate was resistant to several antibiotic choices, and susceptibility testing was integral to her management.
To better characterize N. veterana infections, we searched PubMed with the following operators: (‘Nocardia veterana’ OR ‘N. veterana’) AND (infection OR infections). Articles' citation lists were also reviewed to identify cases. We excluded one abridged report of a mycetoma [10] whose full details were published in a later manuscript [11]. Table 2 summarizes our case and all reported cases of N. veterana infections.Table 2 Nocardia veterana infections
Table 2Age/sex Clinical syndrome Immunocompromising co-morbidities Initial anti-nocardial regimen Length of treatment Outcome Ref.
83/F bowel abscess malignancy TMP-SMX >3 months success [8]
73/M brain abscess diabetes mellitus meropenem 1 year success [9]
66/M endophthalmitis heart transplant, diabetes mellitus meropenem, linezolid planned length of 12 months success [12]
42/F mycetoma SLE amoxicillin >6 years success [11]
72/M nodular lymphangitis immunosuppressive therapy for interstitial pneumonitis TMP-SMX planned length of 3 months stable at time of report [13]
40/M peritoneal infection AIDS, chronic hepatitis B, malignancy died before treatment initiation not applicable died before treatment initiation [14]
24/M pulmonary infection chronic granulomatous disease amikacin, ceftriaxone, trimethoprim >3 months stable at time of report [15]
40/F pulmonary infection HIV TMP-SMX 6 months success [16]
43/F pulmonary infection immunosuppressive therapy for SLE TMP-SMX 6 months success [17]
47/M pulmonary infection liver transplant TMP-SMX 6 months success [17]
52/M pulmonary infection not specified not reported not reported not reported [18]
52/M pulmonary infection HSCT recipient treated for GVHD TMP-SMX 397 days success [19]
52/F pulmonary infection HSCT recipient treated for GVHD TMP-SMX 154 days success [19]
54/M pulmonary infection heart transplant TMP-SMX 15 days success [16]
59/M pulmonary infection liver transplant imipenem >6 months success [16]
63/M pulmonary infection lung transplant, immunosuppressive therapy for bronchiolitis obliterans TMP-SMX 16 weeks died after discontinuing immunosuppression [15]
65/M pulmonary infection HSCT recipient treated for GVHD imipenem/cilastatin, amikacin 722 days died from encephalitis of unknown aetiology [6]
67/F pulmonary infection recurrent pneumonias and bronchiectasis minocycline >7 weeks symptomatic improvement at time of report [17]
78/M pulmonary infection history of tuberculosis not reported not reported not reported [4]
not reported pulmonary infection lung transplant TMP-SMX 30 days success [7]
58/M pulmonary infection with bacteraemia malignancy, recent prednisone course for autoimmune haemolytic anaemia TMP-SMX, azithromycin, piperacillin-tazobactam 3 weeks success [20]
30/M pulmonary infection with bacteraemia HIV, chronic hepatitis B, history of tuberculosis TMP-SMX <1 month died from multi-organ failure [5]
51/M pulmonary and urinary tract infections with bacteraemia malignancy, peritoneal dialysis TMP-SMX <2 months died from underlying malignancy [21]
59/F soft-tissue abscess HSCT recipient treated for GVHD TMP-SMX 1 year success our case
Abbreviations: AIDS, acquired immunodeficiency syndrome; GVHD, graft-versus-host disease; HIV, human immunodeficiency virus; HSCT, haematopoietic stem cell transplantation; SLE, systemic lupus erythematosus; TMP-SMX, trimethoprim-sulfamethoxazole.
Mean age was 55 years, and 29% were women. Pulmonary infections accounted for 17 of 24 infections, with abscesses being the second most common (3 of 24). In total, 25% had previous solid organ transplantations, 17% of patients had undergone haematopoietic stem cell transplantation and were undergoing treatment for GVHD, and 13% were people living with human immunodeficiency virus. The duration of treatment ranged from 3 weeks to >6 years. Trimethoprim-sulfamethoxazole monotherapy was used as initial anti-nocardial therapy for 13 of 24 individuals and led to treatment success in 9 of 13 (69%) of them. Combination therapy or other monotherapy (e.g. amoxicillin) was successful for six of eight (75%) individuals. The number of patients was too small to determine whether the difference in outcome is statistically significant.
Overall, N. veterana has a predilection for causing pulmonary infections in individuals with immunocompromising conditions [[4], [5], [6], [7],[15], [16], [17], [18], [19], [20]], and trimethoprim-sulfamethoxazole is commonly used to treat infections caused by Nocardia spp. [1]. When planning management for an immunocompromised host, a prolonged treatment duration is recommended. For our patient, the concurrent use of immunosuppressive therapy to manage GVHD heightened her susceptibility to N. veterana infection, and disseminated disease was fortunately averted by extended antibiotic therapy. The rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Conflict of interest
The authors declare no conflicts of interest. | ACYCLOVIR, FLUCONAZOLE, PENTAMIDINE, PREDNISONE, SULFAMETHOXAZOLE\TRIMETHOPRIM, TACROLIMUS | DrugsGivenReaction | CC BY-NC-ND | 33456780 | 18,817,070 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Nocardia veterana infections: case report and systematic review.
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments. In 2001, the species Nocardia veterana was first isolated, and it predominantly causes pulmonary infections in immunocompromised hosts. We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease. After failing to improve with empirical treatment, two incision and drainage procedures were required. She subsequently completed a 1-year course of oral antibiotic therapy consisting of trimethoprim-sulfamethoxazole then azithromycin. No relapse occurred over the next 5 years of follow up. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases. Overall, the rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Introduction
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments [1,2]. They classically lead to infections in immunocompromised hosts [1], but 15% of patients in a large series had no predisposing conditions [3]. In 2001, the species Nocardia veterana was first isolated at a veterans' hospital in Australia, from which its name is derived [4]. It has been demonstrated to predominantly cause pulmonary infections in immunocompromised hosts [[5], [6], [7]], and only two reports have identified N. veterana as the cause of abscesses [8,9].
Materials and methods
We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease (GVHD). Review of medical records was approved by our institution's institutional review board. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases.
Case presentation
A 59-year-old woman with a history of acute lymphoblastic leukaemia—status post-haematopoietic stem cell transplantation—presented to the emergency department for evaluation of a right shoulder cutaneous abscess. Her post-transplant course had been complicated by multiple episodes of gastrointestinal and cutaneous GVHD. At this time, she was receiving phototherapy for chronic cutaneous GVHD and had started taking prednisone (30 mg daily) 6 months before presentation. Her medications included tacrolimus, acyclovir, fluconazole and monthly pentamidine. Two weeks before presentation, she had been evaluated by her oncologist for a 5 × 7 cm erythematous, indurated region on her right shoulder, and empiric treatment with oral minocycline (100 mg twice a day) was initiated. Continued pain prompted an outpatient ultrasound, which demonstrated a fluid collection. Her referring provider then sent her to the emergency department for further evaluation.
Incision and drainage were performed in the emergency department and yielded copious, purulent drainage that was sent for culture. Antibiotic therapy was empirically switched to oral clindamycin (600 mg three times a day). She was afebrile and discharged shortly thereafter. Two days later, she was admitted after a wound check showed increasing erythema around the incision and drainage site. Laboratory studies were notable for leucocytosis (15 200/μL; reference range 4000–10 000/μL), but she remained afebrile. Magnetic resonance imaging of her right upper extremity demonstrated a 2-cm soft-tissue abscess involving superficial fascia of the lateral deltoid and focal myositis (Fig. 1). Antibiotic therapy was broadened to intravenous vancomycin and piperacillin-tazobactam.Fig. 1 Nocardia veterana abscess: T2-weighted magnetic resonance imaging demonstrates 2-cm abscess involving the superficial fascia of the right lateral deltoid muscle.
Fig. 1
On day 2 of hospitalization, the abscess was incised and drained by general surgery. The following day, the culture from her initial presentation to the emergency department grew 4+ Gram-positive rods, prompting Nocardia spp. to be suspected. Antibiotic therapy was switched to oral trimethoprim-sulfamethoxazole (800 mg-160–mg twice a day). Magnetic resonance imaging of the brain and a CT scan of the chest showed no evidence of involvement, and she was discharged on day 4.
Four days after discharge, the isolate from her initial presentation was identified as N. veterana. The MicroSEQ® 500bp 16S rRNA Sequencing Kit (Applied Biosystems, Foster City, CA, USA) was used. Samples were processed and analysed consistent with the manufacturer's instructions. Data were assembled with MicroSEQ software, and amplicons were compared against the MicroSEQ database. Clinical and Laboratory Standards Institute MM18 criteria were used for making an identification. The aligned sequence was 409 bp, with no mixed bases. The isolate was 100% match to N. veterana in the MicroSEQ database; however, the National Center for Biotechnology Information BLAST database has been updated since the time of the isolate's processing, and a Nocardia elegans strain was retrospectively identified as a 100% match during the preparation of this report. Notably, three strains of N. veterana were 100% matches.
Susceptibility testing was sent out to the University of Texas Health Center's Department of Microbiology Research in Tyler, Texas. The isolate's susceptibility profile is summarized in Table 1. Two weeks later, the woman was seen as an outpatient and had been tolerating trimethoprim-sulfamethoxazole therapy. Seventy-three days after discharge, elevated creatinine (3.1 mg/dL, baseline 1.9 mg/dL; reference range 0.6–1.2 mg/dL) was attributed to the use of trimethoprim-sulfamethoxazole in combination with tacrolimus, and antibiotic therapy was switched to oral azithromycin (500 mg daily). This decision was informed by the isolate's susceptibility profile and discussion with the reference laboratory.Table 1 Nocardia veterana isolate susceptibility profilea
Table 1Susceptible Intermediate Resistant No standardized breakpoint for Nocardia spp.
Amikacin (MIC ≤1 μg/mL) Ceftriaxone (MIC 16 μg/mL) Amoxicillin-clavulanate (MIC 32–16 μg/mL) Ertapenem (MIC unavailable; susceptible by bacterial breakpoint)
Clarithromycin (MIC ≤0.06 μg/mL) Kanamycin (MIC unavailable) Ciprofloxacin (MIC >4 μg/mL) Meropenem (MIC unavailable; susceptible by rapidly growing mycobacteria breakpoint)
Imipenem (MIC ≤2 μg/mL) Minocycline (MIC 2 μg/mL) Doxycycline (MIC 16 μg/mL) Tigecycline (MIC 4 μg/mL)
Linezolid (MIC 2 μg/mL) Moxifloxacin (MIC 4 μg/mL)
Trimethoprim-sulfamethoxazole (MIC 1–19 μg/mL) Tobramycin (MIC >16 μg/mL)
a Susceptibility results are reported with reference to their MICs and respective, standardized breakpoints.
Roughly 1.5 months later, her creatinine had returned to baseline (1.7 mg/dL), and she had been tolerating azithromycin without adverse events. In the absence of symptoms attributable to her N. veterana infection, azithromycin therapy was discontinued 289 days after its initiation. She continued to receive phototherapy for GVHD and remained on prednisone (20 mg daily), acyclovir, fluconazole and monthly pentamidine. She was seen 6 months after completing her 1-year course of therapy and displayed no signs of relapse. More than 5 years since completing therapy, no relapse has occurred.
Literature review and discussion
Our case concerned an N. veterana infection in a 59-year-old woman who had been receiving immunosuppressive therapy for chronic cutaneous GVHD. She failed to respond to empiric minocycline, and an abscess was incised and drained twice before resolving. Fortunately, oral antibiotic therapy was capable of treating the infection then serving as prophylaxis against relapse. Acute kidney injury complicated her course, but azithromycin therapy ultimately proved tolerable and successful. The isolate was resistant to several antibiotic choices, and susceptibility testing was integral to her management.
To better characterize N. veterana infections, we searched PubMed with the following operators: (‘Nocardia veterana’ OR ‘N. veterana’) AND (infection OR infections). Articles' citation lists were also reviewed to identify cases. We excluded one abridged report of a mycetoma [10] whose full details were published in a later manuscript [11]. Table 2 summarizes our case and all reported cases of N. veterana infections.Table 2 Nocardia veterana infections
Table 2Age/sex Clinical syndrome Immunocompromising co-morbidities Initial anti-nocardial regimen Length of treatment Outcome Ref.
83/F bowel abscess malignancy TMP-SMX >3 months success [8]
73/M brain abscess diabetes mellitus meropenem 1 year success [9]
66/M endophthalmitis heart transplant, diabetes mellitus meropenem, linezolid planned length of 12 months success [12]
42/F mycetoma SLE amoxicillin >6 years success [11]
72/M nodular lymphangitis immunosuppressive therapy for interstitial pneumonitis TMP-SMX planned length of 3 months stable at time of report [13]
40/M peritoneal infection AIDS, chronic hepatitis B, malignancy died before treatment initiation not applicable died before treatment initiation [14]
24/M pulmonary infection chronic granulomatous disease amikacin, ceftriaxone, trimethoprim >3 months stable at time of report [15]
40/F pulmonary infection HIV TMP-SMX 6 months success [16]
43/F pulmonary infection immunosuppressive therapy for SLE TMP-SMX 6 months success [17]
47/M pulmonary infection liver transplant TMP-SMX 6 months success [17]
52/M pulmonary infection not specified not reported not reported not reported [18]
52/M pulmonary infection HSCT recipient treated for GVHD TMP-SMX 397 days success [19]
52/F pulmonary infection HSCT recipient treated for GVHD TMP-SMX 154 days success [19]
54/M pulmonary infection heart transplant TMP-SMX 15 days success [16]
59/M pulmonary infection liver transplant imipenem >6 months success [16]
63/M pulmonary infection lung transplant, immunosuppressive therapy for bronchiolitis obliterans TMP-SMX 16 weeks died after discontinuing immunosuppression [15]
65/M pulmonary infection HSCT recipient treated for GVHD imipenem/cilastatin, amikacin 722 days died from encephalitis of unknown aetiology [6]
67/F pulmonary infection recurrent pneumonias and bronchiectasis minocycline >7 weeks symptomatic improvement at time of report [17]
78/M pulmonary infection history of tuberculosis not reported not reported not reported [4]
not reported pulmonary infection lung transplant TMP-SMX 30 days success [7]
58/M pulmonary infection with bacteraemia malignancy, recent prednisone course for autoimmune haemolytic anaemia TMP-SMX, azithromycin, piperacillin-tazobactam 3 weeks success [20]
30/M pulmonary infection with bacteraemia HIV, chronic hepatitis B, history of tuberculosis TMP-SMX <1 month died from multi-organ failure [5]
51/M pulmonary and urinary tract infections with bacteraemia malignancy, peritoneal dialysis TMP-SMX <2 months died from underlying malignancy [21]
59/F soft-tissue abscess HSCT recipient treated for GVHD TMP-SMX 1 year success our case
Abbreviations: AIDS, acquired immunodeficiency syndrome; GVHD, graft-versus-host disease; HIV, human immunodeficiency virus; HSCT, haematopoietic stem cell transplantation; SLE, systemic lupus erythematosus; TMP-SMX, trimethoprim-sulfamethoxazole.
Mean age was 55 years, and 29% were women. Pulmonary infections accounted for 17 of 24 infections, with abscesses being the second most common (3 of 24). In total, 25% had previous solid organ transplantations, 17% of patients had undergone haematopoietic stem cell transplantation and were undergoing treatment for GVHD, and 13% were people living with human immunodeficiency virus. The duration of treatment ranged from 3 weeks to >6 years. Trimethoprim-sulfamethoxazole monotherapy was used as initial anti-nocardial therapy for 13 of 24 individuals and led to treatment success in 9 of 13 (69%) of them. Combination therapy or other monotherapy (e.g. amoxicillin) was successful for six of eight (75%) individuals. The number of patients was too small to determine whether the difference in outcome is statistically significant.
Overall, N. veterana has a predilection for causing pulmonary infections in individuals with immunocompromising conditions [[4], [5], [6], [7],[15], [16], [17], [18], [19], [20]], and trimethoprim-sulfamethoxazole is commonly used to treat infections caused by Nocardia spp. [1]. When planning management for an immunocompromised host, a prolonged treatment duration is recommended. For our patient, the concurrent use of immunosuppressive therapy to manage GVHD heightened her susceptibility to N. veterana infection, and disseminated disease was fortunately averted by extended antibiotic therapy. The rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Conflict of interest
The authors declare no conflicts of interest. | ACYCLOVIR, FLUCONAZOLE, PENTAMIDINE, PREDNISONE, SULFAMETHOXAZOLE\TRIMETHOPRIM, TACROLIMUS | DrugsGivenReaction | CC BY-NC-ND | 33456780 | 18,817,070 | 2021-01 |
What was the administration route of drug 'SULFAMETHOXAZOLE\TRIMETHOPRIM'? | Nocardia veterana infections: case report and systematic review.
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments. In 2001, the species Nocardia veterana was first isolated, and it predominantly causes pulmonary infections in immunocompromised hosts. We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease. After failing to improve with empirical treatment, two incision and drainage procedures were required. She subsequently completed a 1-year course of oral antibiotic therapy consisting of trimethoprim-sulfamethoxazole then azithromycin. No relapse occurred over the next 5 years of follow up. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases. Overall, the rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Introduction
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments [1,2]. They classically lead to infections in immunocompromised hosts [1], but 15% of patients in a large series had no predisposing conditions [3]. In 2001, the species Nocardia veterana was first isolated at a veterans' hospital in Australia, from which its name is derived [4]. It has been demonstrated to predominantly cause pulmonary infections in immunocompromised hosts [[5], [6], [7]], and only two reports have identified N. veterana as the cause of abscesses [8,9].
Materials and methods
We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease (GVHD). Review of medical records was approved by our institution's institutional review board. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases.
Case presentation
A 59-year-old woman with a history of acute lymphoblastic leukaemia—status post-haematopoietic stem cell transplantation—presented to the emergency department for evaluation of a right shoulder cutaneous abscess. Her post-transplant course had been complicated by multiple episodes of gastrointestinal and cutaneous GVHD. At this time, she was receiving phototherapy for chronic cutaneous GVHD and had started taking prednisone (30 mg daily) 6 months before presentation. Her medications included tacrolimus, acyclovir, fluconazole and monthly pentamidine. Two weeks before presentation, she had been evaluated by her oncologist for a 5 × 7 cm erythematous, indurated region on her right shoulder, and empiric treatment with oral minocycline (100 mg twice a day) was initiated. Continued pain prompted an outpatient ultrasound, which demonstrated a fluid collection. Her referring provider then sent her to the emergency department for further evaluation.
Incision and drainage were performed in the emergency department and yielded copious, purulent drainage that was sent for culture. Antibiotic therapy was empirically switched to oral clindamycin (600 mg three times a day). She was afebrile and discharged shortly thereafter. Two days later, she was admitted after a wound check showed increasing erythema around the incision and drainage site. Laboratory studies were notable for leucocytosis (15 200/μL; reference range 4000–10 000/μL), but she remained afebrile. Magnetic resonance imaging of her right upper extremity demonstrated a 2-cm soft-tissue abscess involving superficial fascia of the lateral deltoid and focal myositis (Fig. 1). Antibiotic therapy was broadened to intravenous vancomycin and piperacillin-tazobactam.Fig. 1 Nocardia veterana abscess: T2-weighted magnetic resonance imaging demonstrates 2-cm abscess involving the superficial fascia of the right lateral deltoid muscle.
Fig. 1
On day 2 of hospitalization, the abscess was incised and drained by general surgery. The following day, the culture from her initial presentation to the emergency department grew 4+ Gram-positive rods, prompting Nocardia spp. to be suspected. Antibiotic therapy was switched to oral trimethoprim-sulfamethoxazole (800 mg-160–mg twice a day). Magnetic resonance imaging of the brain and a CT scan of the chest showed no evidence of involvement, and she was discharged on day 4.
Four days after discharge, the isolate from her initial presentation was identified as N. veterana. The MicroSEQ® 500bp 16S rRNA Sequencing Kit (Applied Biosystems, Foster City, CA, USA) was used. Samples were processed and analysed consistent with the manufacturer's instructions. Data were assembled with MicroSEQ software, and amplicons were compared against the MicroSEQ database. Clinical and Laboratory Standards Institute MM18 criteria were used for making an identification. The aligned sequence was 409 bp, with no mixed bases. The isolate was 100% match to N. veterana in the MicroSEQ database; however, the National Center for Biotechnology Information BLAST database has been updated since the time of the isolate's processing, and a Nocardia elegans strain was retrospectively identified as a 100% match during the preparation of this report. Notably, three strains of N. veterana were 100% matches.
Susceptibility testing was sent out to the University of Texas Health Center's Department of Microbiology Research in Tyler, Texas. The isolate's susceptibility profile is summarized in Table 1. Two weeks later, the woman was seen as an outpatient and had been tolerating trimethoprim-sulfamethoxazole therapy. Seventy-three days after discharge, elevated creatinine (3.1 mg/dL, baseline 1.9 mg/dL; reference range 0.6–1.2 mg/dL) was attributed to the use of trimethoprim-sulfamethoxazole in combination with tacrolimus, and antibiotic therapy was switched to oral azithromycin (500 mg daily). This decision was informed by the isolate's susceptibility profile and discussion with the reference laboratory.Table 1 Nocardia veterana isolate susceptibility profilea
Table 1Susceptible Intermediate Resistant No standardized breakpoint for Nocardia spp.
Amikacin (MIC ≤1 μg/mL) Ceftriaxone (MIC 16 μg/mL) Amoxicillin-clavulanate (MIC 32–16 μg/mL) Ertapenem (MIC unavailable; susceptible by bacterial breakpoint)
Clarithromycin (MIC ≤0.06 μg/mL) Kanamycin (MIC unavailable) Ciprofloxacin (MIC >4 μg/mL) Meropenem (MIC unavailable; susceptible by rapidly growing mycobacteria breakpoint)
Imipenem (MIC ≤2 μg/mL) Minocycline (MIC 2 μg/mL) Doxycycline (MIC 16 μg/mL) Tigecycline (MIC 4 μg/mL)
Linezolid (MIC 2 μg/mL) Moxifloxacin (MIC 4 μg/mL)
Trimethoprim-sulfamethoxazole (MIC 1–19 μg/mL) Tobramycin (MIC >16 μg/mL)
a Susceptibility results are reported with reference to their MICs and respective, standardized breakpoints.
Roughly 1.5 months later, her creatinine had returned to baseline (1.7 mg/dL), and she had been tolerating azithromycin without adverse events. In the absence of symptoms attributable to her N. veterana infection, azithromycin therapy was discontinued 289 days after its initiation. She continued to receive phototherapy for GVHD and remained on prednisone (20 mg daily), acyclovir, fluconazole and monthly pentamidine. She was seen 6 months after completing her 1-year course of therapy and displayed no signs of relapse. More than 5 years since completing therapy, no relapse has occurred.
Literature review and discussion
Our case concerned an N. veterana infection in a 59-year-old woman who had been receiving immunosuppressive therapy for chronic cutaneous GVHD. She failed to respond to empiric minocycline, and an abscess was incised and drained twice before resolving. Fortunately, oral antibiotic therapy was capable of treating the infection then serving as prophylaxis against relapse. Acute kidney injury complicated her course, but azithromycin therapy ultimately proved tolerable and successful. The isolate was resistant to several antibiotic choices, and susceptibility testing was integral to her management.
To better characterize N. veterana infections, we searched PubMed with the following operators: (‘Nocardia veterana’ OR ‘N. veterana’) AND (infection OR infections). Articles' citation lists were also reviewed to identify cases. We excluded one abridged report of a mycetoma [10] whose full details were published in a later manuscript [11]. Table 2 summarizes our case and all reported cases of N. veterana infections.Table 2 Nocardia veterana infections
Table 2Age/sex Clinical syndrome Immunocompromising co-morbidities Initial anti-nocardial regimen Length of treatment Outcome Ref.
83/F bowel abscess malignancy TMP-SMX >3 months success [8]
73/M brain abscess diabetes mellitus meropenem 1 year success [9]
66/M endophthalmitis heart transplant, diabetes mellitus meropenem, linezolid planned length of 12 months success [12]
42/F mycetoma SLE amoxicillin >6 years success [11]
72/M nodular lymphangitis immunosuppressive therapy for interstitial pneumonitis TMP-SMX planned length of 3 months stable at time of report [13]
40/M peritoneal infection AIDS, chronic hepatitis B, malignancy died before treatment initiation not applicable died before treatment initiation [14]
24/M pulmonary infection chronic granulomatous disease amikacin, ceftriaxone, trimethoprim >3 months stable at time of report [15]
40/F pulmonary infection HIV TMP-SMX 6 months success [16]
43/F pulmonary infection immunosuppressive therapy for SLE TMP-SMX 6 months success [17]
47/M pulmonary infection liver transplant TMP-SMX 6 months success [17]
52/M pulmonary infection not specified not reported not reported not reported [18]
52/M pulmonary infection HSCT recipient treated for GVHD TMP-SMX 397 days success [19]
52/F pulmonary infection HSCT recipient treated for GVHD TMP-SMX 154 days success [19]
54/M pulmonary infection heart transplant TMP-SMX 15 days success [16]
59/M pulmonary infection liver transplant imipenem >6 months success [16]
63/M pulmonary infection lung transplant, immunosuppressive therapy for bronchiolitis obliterans TMP-SMX 16 weeks died after discontinuing immunosuppression [15]
65/M pulmonary infection HSCT recipient treated for GVHD imipenem/cilastatin, amikacin 722 days died from encephalitis of unknown aetiology [6]
67/F pulmonary infection recurrent pneumonias and bronchiectasis minocycline >7 weeks symptomatic improvement at time of report [17]
78/M pulmonary infection history of tuberculosis not reported not reported not reported [4]
not reported pulmonary infection lung transplant TMP-SMX 30 days success [7]
58/M pulmonary infection with bacteraemia malignancy, recent prednisone course for autoimmune haemolytic anaemia TMP-SMX, azithromycin, piperacillin-tazobactam 3 weeks success [20]
30/M pulmonary infection with bacteraemia HIV, chronic hepatitis B, history of tuberculosis TMP-SMX <1 month died from multi-organ failure [5]
51/M pulmonary and urinary tract infections with bacteraemia malignancy, peritoneal dialysis TMP-SMX <2 months died from underlying malignancy [21]
59/F soft-tissue abscess HSCT recipient treated for GVHD TMP-SMX 1 year success our case
Abbreviations: AIDS, acquired immunodeficiency syndrome; GVHD, graft-versus-host disease; HIV, human immunodeficiency virus; HSCT, haematopoietic stem cell transplantation; SLE, systemic lupus erythematosus; TMP-SMX, trimethoprim-sulfamethoxazole.
Mean age was 55 years, and 29% were women. Pulmonary infections accounted for 17 of 24 infections, with abscesses being the second most common (3 of 24). In total, 25% had previous solid organ transplantations, 17% of patients had undergone haematopoietic stem cell transplantation and were undergoing treatment for GVHD, and 13% were people living with human immunodeficiency virus. The duration of treatment ranged from 3 weeks to >6 years. Trimethoprim-sulfamethoxazole monotherapy was used as initial anti-nocardial therapy for 13 of 24 individuals and led to treatment success in 9 of 13 (69%) of them. Combination therapy or other monotherapy (e.g. amoxicillin) was successful for six of eight (75%) individuals. The number of patients was too small to determine whether the difference in outcome is statistically significant.
Overall, N. veterana has a predilection for causing pulmonary infections in individuals with immunocompromising conditions [[4], [5], [6], [7],[15], [16], [17], [18], [19], [20]], and trimethoprim-sulfamethoxazole is commonly used to treat infections caused by Nocardia spp. [1]. When planning management for an immunocompromised host, a prolonged treatment duration is recommended. For our patient, the concurrent use of immunosuppressive therapy to manage GVHD heightened her susceptibility to N. veterana infection, and disseminated disease was fortunately averted by extended antibiotic therapy. The rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Conflict of interest
The authors declare no conflicts of interest. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33456780 | 18,799,519 | 2021-01 |
What was the dosage of drug 'ACYCLOVIR'? | Nocardia veterana infections: case report and systematic review.
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments. In 2001, the species Nocardia veterana was first isolated, and it predominantly causes pulmonary infections in immunocompromised hosts. We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease. After failing to improve with empirical treatment, two incision and drainage procedures were required. She subsequently completed a 1-year course of oral antibiotic therapy consisting of trimethoprim-sulfamethoxazole then azithromycin. No relapse occurred over the next 5 years of follow up. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases. Overall, the rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Introduction
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments [1,2]. They classically lead to infections in immunocompromised hosts [1], but 15% of patients in a large series had no predisposing conditions [3]. In 2001, the species Nocardia veterana was first isolated at a veterans' hospital in Australia, from which its name is derived [4]. It has been demonstrated to predominantly cause pulmonary infections in immunocompromised hosts [[5], [6], [7]], and only two reports have identified N. veterana as the cause of abscesses [8,9].
Materials and methods
We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease (GVHD). Review of medical records was approved by our institution's institutional review board. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases.
Case presentation
A 59-year-old woman with a history of acute lymphoblastic leukaemia—status post-haematopoietic stem cell transplantation—presented to the emergency department for evaluation of a right shoulder cutaneous abscess. Her post-transplant course had been complicated by multiple episodes of gastrointestinal and cutaneous GVHD. At this time, she was receiving phototherapy for chronic cutaneous GVHD and had started taking prednisone (30 mg daily) 6 months before presentation. Her medications included tacrolimus, acyclovir, fluconazole and monthly pentamidine. Two weeks before presentation, she had been evaluated by her oncologist for a 5 × 7 cm erythematous, indurated region on her right shoulder, and empiric treatment with oral minocycline (100 mg twice a day) was initiated. Continued pain prompted an outpatient ultrasound, which demonstrated a fluid collection. Her referring provider then sent her to the emergency department for further evaluation.
Incision and drainage were performed in the emergency department and yielded copious, purulent drainage that was sent for culture. Antibiotic therapy was empirically switched to oral clindamycin (600 mg three times a day). She was afebrile and discharged shortly thereafter. Two days later, she was admitted after a wound check showed increasing erythema around the incision and drainage site. Laboratory studies were notable for leucocytosis (15 200/μL; reference range 4000–10 000/μL), but she remained afebrile. Magnetic resonance imaging of her right upper extremity demonstrated a 2-cm soft-tissue abscess involving superficial fascia of the lateral deltoid and focal myositis (Fig. 1). Antibiotic therapy was broadened to intravenous vancomycin and piperacillin-tazobactam.Fig. 1 Nocardia veterana abscess: T2-weighted magnetic resonance imaging demonstrates 2-cm abscess involving the superficial fascia of the right lateral deltoid muscle.
Fig. 1
On day 2 of hospitalization, the abscess was incised and drained by general surgery. The following day, the culture from her initial presentation to the emergency department grew 4+ Gram-positive rods, prompting Nocardia spp. to be suspected. Antibiotic therapy was switched to oral trimethoprim-sulfamethoxazole (800 mg-160–mg twice a day). Magnetic resonance imaging of the brain and a CT scan of the chest showed no evidence of involvement, and she was discharged on day 4.
Four days after discharge, the isolate from her initial presentation was identified as N. veterana. The MicroSEQ® 500bp 16S rRNA Sequencing Kit (Applied Biosystems, Foster City, CA, USA) was used. Samples were processed and analysed consistent with the manufacturer's instructions. Data were assembled with MicroSEQ software, and amplicons were compared against the MicroSEQ database. Clinical and Laboratory Standards Institute MM18 criteria were used for making an identification. The aligned sequence was 409 bp, with no mixed bases. The isolate was 100% match to N. veterana in the MicroSEQ database; however, the National Center for Biotechnology Information BLAST database has been updated since the time of the isolate's processing, and a Nocardia elegans strain was retrospectively identified as a 100% match during the preparation of this report. Notably, three strains of N. veterana were 100% matches.
Susceptibility testing was sent out to the University of Texas Health Center's Department of Microbiology Research in Tyler, Texas. The isolate's susceptibility profile is summarized in Table 1. Two weeks later, the woman was seen as an outpatient and had been tolerating trimethoprim-sulfamethoxazole therapy. Seventy-three days after discharge, elevated creatinine (3.1 mg/dL, baseline 1.9 mg/dL; reference range 0.6–1.2 mg/dL) was attributed to the use of trimethoprim-sulfamethoxazole in combination with tacrolimus, and antibiotic therapy was switched to oral azithromycin (500 mg daily). This decision was informed by the isolate's susceptibility profile and discussion with the reference laboratory.Table 1 Nocardia veterana isolate susceptibility profilea
Table 1Susceptible Intermediate Resistant No standardized breakpoint for Nocardia spp.
Amikacin (MIC ≤1 μg/mL) Ceftriaxone (MIC 16 μg/mL) Amoxicillin-clavulanate (MIC 32–16 μg/mL) Ertapenem (MIC unavailable; susceptible by bacterial breakpoint)
Clarithromycin (MIC ≤0.06 μg/mL) Kanamycin (MIC unavailable) Ciprofloxacin (MIC >4 μg/mL) Meropenem (MIC unavailable; susceptible by rapidly growing mycobacteria breakpoint)
Imipenem (MIC ≤2 μg/mL) Minocycline (MIC 2 μg/mL) Doxycycline (MIC 16 μg/mL) Tigecycline (MIC 4 μg/mL)
Linezolid (MIC 2 μg/mL) Moxifloxacin (MIC 4 μg/mL)
Trimethoprim-sulfamethoxazole (MIC 1–19 μg/mL) Tobramycin (MIC >16 μg/mL)
a Susceptibility results are reported with reference to their MICs and respective, standardized breakpoints.
Roughly 1.5 months later, her creatinine had returned to baseline (1.7 mg/dL), and she had been tolerating azithromycin without adverse events. In the absence of symptoms attributable to her N. veterana infection, azithromycin therapy was discontinued 289 days after its initiation. She continued to receive phototherapy for GVHD and remained on prednisone (20 mg daily), acyclovir, fluconazole and monthly pentamidine. She was seen 6 months after completing her 1-year course of therapy and displayed no signs of relapse. More than 5 years since completing therapy, no relapse has occurred.
Literature review and discussion
Our case concerned an N. veterana infection in a 59-year-old woman who had been receiving immunosuppressive therapy for chronic cutaneous GVHD. She failed to respond to empiric minocycline, and an abscess was incised and drained twice before resolving. Fortunately, oral antibiotic therapy was capable of treating the infection then serving as prophylaxis against relapse. Acute kidney injury complicated her course, but azithromycin therapy ultimately proved tolerable and successful. The isolate was resistant to several antibiotic choices, and susceptibility testing was integral to her management.
To better characterize N. veterana infections, we searched PubMed with the following operators: (‘Nocardia veterana’ OR ‘N. veterana’) AND (infection OR infections). Articles' citation lists were also reviewed to identify cases. We excluded one abridged report of a mycetoma [10] whose full details were published in a later manuscript [11]. Table 2 summarizes our case and all reported cases of N. veterana infections.Table 2 Nocardia veterana infections
Table 2Age/sex Clinical syndrome Immunocompromising co-morbidities Initial anti-nocardial regimen Length of treatment Outcome Ref.
83/F bowel abscess malignancy TMP-SMX >3 months success [8]
73/M brain abscess diabetes mellitus meropenem 1 year success [9]
66/M endophthalmitis heart transplant, diabetes mellitus meropenem, linezolid planned length of 12 months success [12]
42/F mycetoma SLE amoxicillin >6 years success [11]
72/M nodular lymphangitis immunosuppressive therapy for interstitial pneumonitis TMP-SMX planned length of 3 months stable at time of report [13]
40/M peritoneal infection AIDS, chronic hepatitis B, malignancy died before treatment initiation not applicable died before treatment initiation [14]
24/M pulmonary infection chronic granulomatous disease amikacin, ceftriaxone, trimethoprim >3 months stable at time of report [15]
40/F pulmonary infection HIV TMP-SMX 6 months success [16]
43/F pulmonary infection immunosuppressive therapy for SLE TMP-SMX 6 months success [17]
47/M pulmonary infection liver transplant TMP-SMX 6 months success [17]
52/M pulmonary infection not specified not reported not reported not reported [18]
52/M pulmonary infection HSCT recipient treated for GVHD TMP-SMX 397 days success [19]
52/F pulmonary infection HSCT recipient treated for GVHD TMP-SMX 154 days success [19]
54/M pulmonary infection heart transplant TMP-SMX 15 days success [16]
59/M pulmonary infection liver transplant imipenem >6 months success [16]
63/M pulmonary infection lung transplant, immunosuppressive therapy for bronchiolitis obliterans TMP-SMX 16 weeks died after discontinuing immunosuppression [15]
65/M pulmonary infection HSCT recipient treated for GVHD imipenem/cilastatin, amikacin 722 days died from encephalitis of unknown aetiology [6]
67/F pulmonary infection recurrent pneumonias and bronchiectasis minocycline >7 weeks symptomatic improvement at time of report [17]
78/M pulmonary infection history of tuberculosis not reported not reported not reported [4]
not reported pulmonary infection lung transplant TMP-SMX 30 days success [7]
58/M pulmonary infection with bacteraemia malignancy, recent prednisone course for autoimmune haemolytic anaemia TMP-SMX, azithromycin, piperacillin-tazobactam 3 weeks success [20]
30/M pulmonary infection with bacteraemia HIV, chronic hepatitis B, history of tuberculosis TMP-SMX <1 month died from multi-organ failure [5]
51/M pulmonary and urinary tract infections with bacteraemia malignancy, peritoneal dialysis TMP-SMX <2 months died from underlying malignancy [21]
59/F soft-tissue abscess HSCT recipient treated for GVHD TMP-SMX 1 year success our case
Abbreviations: AIDS, acquired immunodeficiency syndrome; GVHD, graft-versus-host disease; HIV, human immunodeficiency virus; HSCT, haematopoietic stem cell transplantation; SLE, systemic lupus erythematosus; TMP-SMX, trimethoprim-sulfamethoxazole.
Mean age was 55 years, and 29% were women. Pulmonary infections accounted for 17 of 24 infections, with abscesses being the second most common (3 of 24). In total, 25% had previous solid organ transplantations, 17% of patients had undergone haematopoietic stem cell transplantation and were undergoing treatment for GVHD, and 13% were people living with human immunodeficiency virus. The duration of treatment ranged from 3 weeks to >6 years. Trimethoprim-sulfamethoxazole monotherapy was used as initial anti-nocardial therapy for 13 of 24 individuals and led to treatment success in 9 of 13 (69%) of them. Combination therapy or other monotherapy (e.g. amoxicillin) was successful for six of eight (75%) individuals. The number of patients was too small to determine whether the difference in outcome is statistically significant.
Overall, N. veterana has a predilection for causing pulmonary infections in individuals with immunocompromising conditions [[4], [5], [6], [7],[15], [16], [17], [18], [19], [20]], and trimethoprim-sulfamethoxazole is commonly used to treat infections caused by Nocardia spp. [1]. When planning management for an immunocompromised host, a prolonged treatment duration is recommended. For our patient, the concurrent use of immunosuppressive therapy to manage GVHD heightened her susceptibility to N. veterana infection, and disseminated disease was fortunately averted by extended antibiotic therapy. The rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Conflict of interest
The authors declare no conflicts of interest. | UNKNOWN | DrugDosageText | CC BY-NC-ND | 33456780 | 18,820,633 | 2021-01 |
What was the dosage of drug 'FLUCONAZOLE'? | Nocardia veterana infections: case report and systematic review.
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments. In 2001, the species Nocardia veterana was first isolated, and it predominantly causes pulmonary infections in immunocompromised hosts. We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease. After failing to improve with empirical treatment, two incision and drainage procedures were required. She subsequently completed a 1-year course of oral antibiotic therapy consisting of trimethoprim-sulfamethoxazole then azithromycin. No relapse occurred over the next 5 years of follow up. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases. Overall, the rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Introduction
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments [1,2]. They classically lead to infections in immunocompromised hosts [1], but 15% of patients in a large series had no predisposing conditions [3]. In 2001, the species Nocardia veterana was first isolated at a veterans' hospital in Australia, from which its name is derived [4]. It has been demonstrated to predominantly cause pulmonary infections in immunocompromised hosts [[5], [6], [7]], and only two reports have identified N. veterana as the cause of abscesses [8,9].
Materials and methods
We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease (GVHD). Review of medical records was approved by our institution's institutional review board. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases.
Case presentation
A 59-year-old woman with a history of acute lymphoblastic leukaemia—status post-haematopoietic stem cell transplantation—presented to the emergency department for evaluation of a right shoulder cutaneous abscess. Her post-transplant course had been complicated by multiple episodes of gastrointestinal and cutaneous GVHD. At this time, she was receiving phototherapy for chronic cutaneous GVHD and had started taking prednisone (30 mg daily) 6 months before presentation. Her medications included tacrolimus, acyclovir, fluconazole and monthly pentamidine. Two weeks before presentation, she had been evaluated by her oncologist for a 5 × 7 cm erythematous, indurated region on her right shoulder, and empiric treatment with oral minocycline (100 mg twice a day) was initiated. Continued pain prompted an outpatient ultrasound, which demonstrated a fluid collection. Her referring provider then sent her to the emergency department for further evaluation.
Incision and drainage were performed in the emergency department and yielded copious, purulent drainage that was sent for culture. Antibiotic therapy was empirically switched to oral clindamycin (600 mg three times a day). She was afebrile and discharged shortly thereafter. Two days later, she was admitted after a wound check showed increasing erythema around the incision and drainage site. Laboratory studies were notable for leucocytosis (15 200/μL; reference range 4000–10 000/μL), but she remained afebrile. Magnetic resonance imaging of her right upper extremity demonstrated a 2-cm soft-tissue abscess involving superficial fascia of the lateral deltoid and focal myositis (Fig. 1). Antibiotic therapy was broadened to intravenous vancomycin and piperacillin-tazobactam.Fig. 1 Nocardia veterana abscess: T2-weighted magnetic resonance imaging demonstrates 2-cm abscess involving the superficial fascia of the right lateral deltoid muscle.
Fig. 1
On day 2 of hospitalization, the abscess was incised and drained by general surgery. The following day, the culture from her initial presentation to the emergency department grew 4+ Gram-positive rods, prompting Nocardia spp. to be suspected. Antibiotic therapy was switched to oral trimethoprim-sulfamethoxazole (800 mg-160–mg twice a day). Magnetic resonance imaging of the brain and a CT scan of the chest showed no evidence of involvement, and she was discharged on day 4.
Four days after discharge, the isolate from her initial presentation was identified as N. veterana. The MicroSEQ® 500bp 16S rRNA Sequencing Kit (Applied Biosystems, Foster City, CA, USA) was used. Samples were processed and analysed consistent with the manufacturer's instructions. Data were assembled with MicroSEQ software, and amplicons were compared against the MicroSEQ database. Clinical and Laboratory Standards Institute MM18 criteria were used for making an identification. The aligned sequence was 409 bp, with no mixed bases. The isolate was 100% match to N. veterana in the MicroSEQ database; however, the National Center for Biotechnology Information BLAST database has been updated since the time of the isolate's processing, and a Nocardia elegans strain was retrospectively identified as a 100% match during the preparation of this report. Notably, three strains of N. veterana were 100% matches.
Susceptibility testing was sent out to the University of Texas Health Center's Department of Microbiology Research in Tyler, Texas. The isolate's susceptibility profile is summarized in Table 1. Two weeks later, the woman was seen as an outpatient and had been tolerating trimethoprim-sulfamethoxazole therapy. Seventy-three days after discharge, elevated creatinine (3.1 mg/dL, baseline 1.9 mg/dL; reference range 0.6–1.2 mg/dL) was attributed to the use of trimethoprim-sulfamethoxazole in combination with tacrolimus, and antibiotic therapy was switched to oral azithromycin (500 mg daily). This decision was informed by the isolate's susceptibility profile and discussion with the reference laboratory.Table 1 Nocardia veterana isolate susceptibility profilea
Table 1Susceptible Intermediate Resistant No standardized breakpoint for Nocardia spp.
Amikacin (MIC ≤1 μg/mL) Ceftriaxone (MIC 16 μg/mL) Amoxicillin-clavulanate (MIC 32–16 μg/mL) Ertapenem (MIC unavailable; susceptible by bacterial breakpoint)
Clarithromycin (MIC ≤0.06 μg/mL) Kanamycin (MIC unavailable) Ciprofloxacin (MIC >4 μg/mL) Meropenem (MIC unavailable; susceptible by rapidly growing mycobacteria breakpoint)
Imipenem (MIC ≤2 μg/mL) Minocycline (MIC 2 μg/mL) Doxycycline (MIC 16 μg/mL) Tigecycline (MIC 4 μg/mL)
Linezolid (MIC 2 μg/mL) Moxifloxacin (MIC 4 μg/mL)
Trimethoprim-sulfamethoxazole (MIC 1–19 μg/mL) Tobramycin (MIC >16 μg/mL)
a Susceptibility results are reported with reference to their MICs and respective, standardized breakpoints.
Roughly 1.5 months later, her creatinine had returned to baseline (1.7 mg/dL), and she had been tolerating azithromycin without adverse events. In the absence of symptoms attributable to her N. veterana infection, azithromycin therapy was discontinued 289 days after its initiation. She continued to receive phototherapy for GVHD and remained on prednisone (20 mg daily), acyclovir, fluconazole and monthly pentamidine. She was seen 6 months after completing her 1-year course of therapy and displayed no signs of relapse. More than 5 years since completing therapy, no relapse has occurred.
Literature review and discussion
Our case concerned an N. veterana infection in a 59-year-old woman who had been receiving immunosuppressive therapy for chronic cutaneous GVHD. She failed to respond to empiric minocycline, and an abscess was incised and drained twice before resolving. Fortunately, oral antibiotic therapy was capable of treating the infection then serving as prophylaxis against relapse. Acute kidney injury complicated her course, but azithromycin therapy ultimately proved tolerable and successful. The isolate was resistant to several antibiotic choices, and susceptibility testing was integral to her management.
To better characterize N. veterana infections, we searched PubMed with the following operators: (‘Nocardia veterana’ OR ‘N. veterana’) AND (infection OR infections). Articles' citation lists were also reviewed to identify cases. We excluded one abridged report of a mycetoma [10] whose full details were published in a later manuscript [11]. Table 2 summarizes our case and all reported cases of N. veterana infections.Table 2 Nocardia veterana infections
Table 2Age/sex Clinical syndrome Immunocompromising co-morbidities Initial anti-nocardial regimen Length of treatment Outcome Ref.
83/F bowel abscess malignancy TMP-SMX >3 months success [8]
73/M brain abscess diabetes mellitus meropenem 1 year success [9]
66/M endophthalmitis heart transplant, diabetes mellitus meropenem, linezolid planned length of 12 months success [12]
42/F mycetoma SLE amoxicillin >6 years success [11]
72/M nodular lymphangitis immunosuppressive therapy for interstitial pneumonitis TMP-SMX planned length of 3 months stable at time of report [13]
40/M peritoneal infection AIDS, chronic hepatitis B, malignancy died before treatment initiation not applicable died before treatment initiation [14]
24/M pulmonary infection chronic granulomatous disease amikacin, ceftriaxone, trimethoprim >3 months stable at time of report [15]
40/F pulmonary infection HIV TMP-SMX 6 months success [16]
43/F pulmonary infection immunosuppressive therapy for SLE TMP-SMX 6 months success [17]
47/M pulmonary infection liver transplant TMP-SMX 6 months success [17]
52/M pulmonary infection not specified not reported not reported not reported [18]
52/M pulmonary infection HSCT recipient treated for GVHD TMP-SMX 397 days success [19]
52/F pulmonary infection HSCT recipient treated for GVHD TMP-SMX 154 days success [19]
54/M pulmonary infection heart transplant TMP-SMX 15 days success [16]
59/M pulmonary infection liver transplant imipenem >6 months success [16]
63/M pulmonary infection lung transplant, immunosuppressive therapy for bronchiolitis obliterans TMP-SMX 16 weeks died after discontinuing immunosuppression [15]
65/M pulmonary infection HSCT recipient treated for GVHD imipenem/cilastatin, amikacin 722 days died from encephalitis of unknown aetiology [6]
67/F pulmonary infection recurrent pneumonias and bronchiectasis minocycline >7 weeks symptomatic improvement at time of report [17]
78/M pulmonary infection history of tuberculosis not reported not reported not reported [4]
not reported pulmonary infection lung transplant TMP-SMX 30 days success [7]
58/M pulmonary infection with bacteraemia malignancy, recent prednisone course for autoimmune haemolytic anaemia TMP-SMX, azithromycin, piperacillin-tazobactam 3 weeks success [20]
30/M pulmonary infection with bacteraemia HIV, chronic hepatitis B, history of tuberculosis TMP-SMX <1 month died from multi-organ failure [5]
51/M pulmonary and urinary tract infections with bacteraemia malignancy, peritoneal dialysis TMP-SMX <2 months died from underlying malignancy [21]
59/F soft-tissue abscess HSCT recipient treated for GVHD TMP-SMX 1 year success our case
Abbreviations: AIDS, acquired immunodeficiency syndrome; GVHD, graft-versus-host disease; HIV, human immunodeficiency virus; HSCT, haematopoietic stem cell transplantation; SLE, systemic lupus erythematosus; TMP-SMX, trimethoprim-sulfamethoxazole.
Mean age was 55 years, and 29% were women. Pulmonary infections accounted for 17 of 24 infections, with abscesses being the second most common (3 of 24). In total, 25% had previous solid organ transplantations, 17% of patients had undergone haematopoietic stem cell transplantation and were undergoing treatment for GVHD, and 13% were people living with human immunodeficiency virus. The duration of treatment ranged from 3 weeks to >6 years. Trimethoprim-sulfamethoxazole monotherapy was used as initial anti-nocardial therapy for 13 of 24 individuals and led to treatment success in 9 of 13 (69%) of them. Combination therapy or other monotherapy (e.g. amoxicillin) was successful for six of eight (75%) individuals. The number of patients was too small to determine whether the difference in outcome is statistically significant.
Overall, N. veterana has a predilection for causing pulmonary infections in individuals with immunocompromising conditions [[4], [5], [6], [7],[15], [16], [17], [18], [19], [20]], and trimethoprim-sulfamethoxazole is commonly used to treat infections caused by Nocardia spp. [1]. When planning management for an immunocompromised host, a prolonged treatment duration is recommended. For our patient, the concurrent use of immunosuppressive therapy to manage GVHD heightened her susceptibility to N. veterana infection, and disseminated disease was fortunately averted by extended antibiotic therapy. The rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Conflict of interest
The authors declare no conflicts of interest. | UNKNOWN | DrugDosageText | CC BY-NC-ND | 33456780 | 18,820,633 | 2021-01 |
What was the dosage of drug 'TACROLIMUS'? | Nocardia veterana infections: case report and systematic review.
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments. In 2001, the species Nocardia veterana was first isolated, and it predominantly causes pulmonary infections in immunocompromised hosts. We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease. After failing to improve with empirical treatment, two incision and drainage procedures were required. She subsequently completed a 1-year course of oral antibiotic therapy consisting of trimethoprim-sulfamethoxazole then azithromycin. No relapse occurred over the next 5 years of follow up. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases. Overall, the rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Introduction
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments [1,2]. They classically lead to infections in immunocompromised hosts [1], but 15% of patients in a large series had no predisposing conditions [3]. In 2001, the species Nocardia veterana was first isolated at a veterans' hospital in Australia, from which its name is derived [4]. It has been demonstrated to predominantly cause pulmonary infections in immunocompromised hosts [[5], [6], [7]], and only two reports have identified N. veterana as the cause of abscesses [8,9].
Materials and methods
We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease (GVHD). Review of medical records was approved by our institution's institutional review board. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases.
Case presentation
A 59-year-old woman with a history of acute lymphoblastic leukaemia—status post-haematopoietic stem cell transplantation—presented to the emergency department for evaluation of a right shoulder cutaneous abscess. Her post-transplant course had been complicated by multiple episodes of gastrointestinal and cutaneous GVHD. At this time, she was receiving phototherapy for chronic cutaneous GVHD and had started taking prednisone (30 mg daily) 6 months before presentation. Her medications included tacrolimus, acyclovir, fluconazole and monthly pentamidine. Two weeks before presentation, she had been evaluated by her oncologist for a 5 × 7 cm erythematous, indurated region on her right shoulder, and empiric treatment with oral minocycline (100 mg twice a day) was initiated. Continued pain prompted an outpatient ultrasound, which demonstrated a fluid collection. Her referring provider then sent her to the emergency department for further evaluation.
Incision and drainage were performed in the emergency department and yielded copious, purulent drainage that was sent for culture. Antibiotic therapy was empirically switched to oral clindamycin (600 mg three times a day). She was afebrile and discharged shortly thereafter. Two days later, she was admitted after a wound check showed increasing erythema around the incision and drainage site. Laboratory studies were notable for leucocytosis (15 200/μL; reference range 4000–10 000/μL), but she remained afebrile. Magnetic resonance imaging of her right upper extremity demonstrated a 2-cm soft-tissue abscess involving superficial fascia of the lateral deltoid and focal myositis (Fig. 1). Antibiotic therapy was broadened to intravenous vancomycin and piperacillin-tazobactam.Fig. 1 Nocardia veterana abscess: T2-weighted magnetic resonance imaging demonstrates 2-cm abscess involving the superficial fascia of the right lateral deltoid muscle.
Fig. 1
On day 2 of hospitalization, the abscess was incised and drained by general surgery. The following day, the culture from her initial presentation to the emergency department grew 4+ Gram-positive rods, prompting Nocardia spp. to be suspected. Antibiotic therapy was switched to oral trimethoprim-sulfamethoxazole (800 mg-160–mg twice a day). Magnetic resonance imaging of the brain and a CT scan of the chest showed no evidence of involvement, and she was discharged on day 4.
Four days after discharge, the isolate from her initial presentation was identified as N. veterana. The MicroSEQ® 500bp 16S rRNA Sequencing Kit (Applied Biosystems, Foster City, CA, USA) was used. Samples were processed and analysed consistent with the manufacturer's instructions. Data were assembled with MicroSEQ software, and amplicons were compared against the MicroSEQ database. Clinical and Laboratory Standards Institute MM18 criteria were used for making an identification. The aligned sequence was 409 bp, with no mixed bases. The isolate was 100% match to N. veterana in the MicroSEQ database; however, the National Center for Biotechnology Information BLAST database has been updated since the time of the isolate's processing, and a Nocardia elegans strain was retrospectively identified as a 100% match during the preparation of this report. Notably, three strains of N. veterana were 100% matches.
Susceptibility testing was sent out to the University of Texas Health Center's Department of Microbiology Research in Tyler, Texas. The isolate's susceptibility profile is summarized in Table 1. Two weeks later, the woman was seen as an outpatient and had been tolerating trimethoprim-sulfamethoxazole therapy. Seventy-three days after discharge, elevated creatinine (3.1 mg/dL, baseline 1.9 mg/dL; reference range 0.6–1.2 mg/dL) was attributed to the use of trimethoprim-sulfamethoxazole in combination with tacrolimus, and antibiotic therapy was switched to oral azithromycin (500 mg daily). This decision was informed by the isolate's susceptibility profile and discussion with the reference laboratory.Table 1 Nocardia veterana isolate susceptibility profilea
Table 1Susceptible Intermediate Resistant No standardized breakpoint for Nocardia spp.
Amikacin (MIC ≤1 μg/mL) Ceftriaxone (MIC 16 μg/mL) Amoxicillin-clavulanate (MIC 32–16 μg/mL) Ertapenem (MIC unavailable; susceptible by bacterial breakpoint)
Clarithromycin (MIC ≤0.06 μg/mL) Kanamycin (MIC unavailable) Ciprofloxacin (MIC >4 μg/mL) Meropenem (MIC unavailable; susceptible by rapidly growing mycobacteria breakpoint)
Imipenem (MIC ≤2 μg/mL) Minocycline (MIC 2 μg/mL) Doxycycline (MIC 16 μg/mL) Tigecycline (MIC 4 μg/mL)
Linezolid (MIC 2 μg/mL) Moxifloxacin (MIC 4 μg/mL)
Trimethoprim-sulfamethoxazole (MIC 1–19 μg/mL) Tobramycin (MIC >16 μg/mL)
a Susceptibility results are reported with reference to their MICs and respective, standardized breakpoints.
Roughly 1.5 months later, her creatinine had returned to baseline (1.7 mg/dL), and she had been tolerating azithromycin without adverse events. In the absence of symptoms attributable to her N. veterana infection, azithromycin therapy was discontinued 289 days after its initiation. She continued to receive phototherapy for GVHD and remained on prednisone (20 mg daily), acyclovir, fluconazole and monthly pentamidine. She was seen 6 months after completing her 1-year course of therapy and displayed no signs of relapse. More than 5 years since completing therapy, no relapse has occurred.
Literature review and discussion
Our case concerned an N. veterana infection in a 59-year-old woman who had been receiving immunosuppressive therapy for chronic cutaneous GVHD. She failed to respond to empiric minocycline, and an abscess was incised and drained twice before resolving. Fortunately, oral antibiotic therapy was capable of treating the infection then serving as prophylaxis against relapse. Acute kidney injury complicated her course, but azithromycin therapy ultimately proved tolerable and successful. The isolate was resistant to several antibiotic choices, and susceptibility testing was integral to her management.
To better characterize N. veterana infections, we searched PubMed with the following operators: (‘Nocardia veterana’ OR ‘N. veterana’) AND (infection OR infections). Articles' citation lists were also reviewed to identify cases. We excluded one abridged report of a mycetoma [10] whose full details were published in a later manuscript [11]. Table 2 summarizes our case and all reported cases of N. veterana infections.Table 2 Nocardia veterana infections
Table 2Age/sex Clinical syndrome Immunocompromising co-morbidities Initial anti-nocardial regimen Length of treatment Outcome Ref.
83/F bowel abscess malignancy TMP-SMX >3 months success [8]
73/M brain abscess diabetes mellitus meropenem 1 year success [9]
66/M endophthalmitis heart transplant, diabetes mellitus meropenem, linezolid planned length of 12 months success [12]
42/F mycetoma SLE amoxicillin >6 years success [11]
72/M nodular lymphangitis immunosuppressive therapy for interstitial pneumonitis TMP-SMX planned length of 3 months stable at time of report [13]
40/M peritoneal infection AIDS, chronic hepatitis B, malignancy died before treatment initiation not applicable died before treatment initiation [14]
24/M pulmonary infection chronic granulomatous disease amikacin, ceftriaxone, trimethoprim >3 months stable at time of report [15]
40/F pulmonary infection HIV TMP-SMX 6 months success [16]
43/F pulmonary infection immunosuppressive therapy for SLE TMP-SMX 6 months success [17]
47/M pulmonary infection liver transplant TMP-SMX 6 months success [17]
52/M pulmonary infection not specified not reported not reported not reported [18]
52/M pulmonary infection HSCT recipient treated for GVHD TMP-SMX 397 days success [19]
52/F pulmonary infection HSCT recipient treated for GVHD TMP-SMX 154 days success [19]
54/M pulmonary infection heart transplant TMP-SMX 15 days success [16]
59/M pulmonary infection liver transplant imipenem >6 months success [16]
63/M pulmonary infection lung transplant, immunosuppressive therapy for bronchiolitis obliterans TMP-SMX 16 weeks died after discontinuing immunosuppression [15]
65/M pulmonary infection HSCT recipient treated for GVHD imipenem/cilastatin, amikacin 722 days died from encephalitis of unknown aetiology [6]
67/F pulmonary infection recurrent pneumonias and bronchiectasis minocycline >7 weeks symptomatic improvement at time of report [17]
78/M pulmonary infection history of tuberculosis not reported not reported not reported [4]
not reported pulmonary infection lung transplant TMP-SMX 30 days success [7]
58/M pulmonary infection with bacteraemia malignancy, recent prednisone course for autoimmune haemolytic anaemia TMP-SMX, azithromycin, piperacillin-tazobactam 3 weeks success [20]
30/M pulmonary infection with bacteraemia HIV, chronic hepatitis B, history of tuberculosis TMP-SMX <1 month died from multi-organ failure [5]
51/M pulmonary and urinary tract infections with bacteraemia malignancy, peritoneal dialysis TMP-SMX <2 months died from underlying malignancy [21]
59/F soft-tissue abscess HSCT recipient treated for GVHD TMP-SMX 1 year success our case
Abbreviations: AIDS, acquired immunodeficiency syndrome; GVHD, graft-versus-host disease; HIV, human immunodeficiency virus; HSCT, haematopoietic stem cell transplantation; SLE, systemic lupus erythematosus; TMP-SMX, trimethoprim-sulfamethoxazole.
Mean age was 55 years, and 29% were women. Pulmonary infections accounted for 17 of 24 infections, with abscesses being the second most common (3 of 24). In total, 25% had previous solid organ transplantations, 17% of patients had undergone haematopoietic stem cell transplantation and were undergoing treatment for GVHD, and 13% were people living with human immunodeficiency virus. The duration of treatment ranged from 3 weeks to >6 years. Trimethoprim-sulfamethoxazole monotherapy was used as initial anti-nocardial therapy for 13 of 24 individuals and led to treatment success in 9 of 13 (69%) of them. Combination therapy or other monotherapy (e.g. amoxicillin) was successful for six of eight (75%) individuals. The number of patients was too small to determine whether the difference in outcome is statistically significant.
Overall, N. veterana has a predilection for causing pulmonary infections in individuals with immunocompromising conditions [[4], [5], [6], [7],[15], [16], [17], [18], [19], [20]], and trimethoprim-sulfamethoxazole is commonly used to treat infections caused by Nocardia spp. [1]. When planning management for an immunocompromised host, a prolonged treatment duration is recommended. For our patient, the concurrent use of immunosuppressive therapy to manage GVHD heightened her susceptibility to N. veterana infection, and disseminated disease was fortunately averted by extended antibiotic therapy. The rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Conflict of interest
The authors declare no conflicts of interest. | UNKNOWN | DrugDosageText | CC BY-NC-ND | 33456780 | 18,820,633 | 2021-01 |
What was the outcome of reaction 'Abscess soft tissue'? | Nocardia veterana infections: case report and systematic review.
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments. In 2001, the species Nocardia veterana was first isolated, and it predominantly causes pulmonary infections in immunocompromised hosts. We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease. After failing to improve with empirical treatment, two incision and drainage procedures were required. She subsequently completed a 1-year course of oral antibiotic therapy consisting of trimethoprim-sulfamethoxazole then azithromycin. No relapse occurred over the next 5 years of follow up. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases. Overall, the rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Introduction
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments [1,2]. They classically lead to infections in immunocompromised hosts [1], but 15% of patients in a large series had no predisposing conditions [3]. In 2001, the species Nocardia veterana was first isolated at a veterans' hospital in Australia, from which its name is derived [4]. It has been demonstrated to predominantly cause pulmonary infections in immunocompromised hosts [[5], [6], [7]], and only two reports have identified N. veterana as the cause of abscesses [8,9].
Materials and methods
We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease (GVHD). Review of medical records was approved by our institution's institutional review board. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases.
Case presentation
A 59-year-old woman with a history of acute lymphoblastic leukaemia—status post-haematopoietic stem cell transplantation—presented to the emergency department for evaluation of a right shoulder cutaneous abscess. Her post-transplant course had been complicated by multiple episodes of gastrointestinal and cutaneous GVHD. At this time, she was receiving phototherapy for chronic cutaneous GVHD and had started taking prednisone (30 mg daily) 6 months before presentation. Her medications included tacrolimus, acyclovir, fluconazole and monthly pentamidine. Two weeks before presentation, she had been evaluated by her oncologist for a 5 × 7 cm erythematous, indurated region on her right shoulder, and empiric treatment with oral minocycline (100 mg twice a day) was initiated. Continued pain prompted an outpatient ultrasound, which demonstrated a fluid collection. Her referring provider then sent her to the emergency department for further evaluation.
Incision and drainage were performed in the emergency department and yielded copious, purulent drainage that was sent for culture. Antibiotic therapy was empirically switched to oral clindamycin (600 mg three times a day). She was afebrile and discharged shortly thereafter. Two days later, she was admitted after a wound check showed increasing erythema around the incision and drainage site. Laboratory studies were notable for leucocytosis (15 200/μL; reference range 4000–10 000/μL), but she remained afebrile. Magnetic resonance imaging of her right upper extremity demonstrated a 2-cm soft-tissue abscess involving superficial fascia of the lateral deltoid and focal myositis (Fig. 1). Antibiotic therapy was broadened to intravenous vancomycin and piperacillin-tazobactam.Fig. 1 Nocardia veterana abscess: T2-weighted magnetic resonance imaging demonstrates 2-cm abscess involving the superficial fascia of the right lateral deltoid muscle.
Fig. 1
On day 2 of hospitalization, the abscess was incised and drained by general surgery. The following day, the culture from her initial presentation to the emergency department grew 4+ Gram-positive rods, prompting Nocardia spp. to be suspected. Antibiotic therapy was switched to oral trimethoprim-sulfamethoxazole (800 mg-160–mg twice a day). Magnetic resonance imaging of the brain and a CT scan of the chest showed no evidence of involvement, and she was discharged on day 4.
Four days after discharge, the isolate from her initial presentation was identified as N. veterana. The MicroSEQ® 500bp 16S rRNA Sequencing Kit (Applied Biosystems, Foster City, CA, USA) was used. Samples were processed and analysed consistent with the manufacturer's instructions. Data were assembled with MicroSEQ software, and amplicons were compared against the MicroSEQ database. Clinical and Laboratory Standards Institute MM18 criteria were used for making an identification. The aligned sequence was 409 bp, with no mixed bases. The isolate was 100% match to N. veterana in the MicroSEQ database; however, the National Center for Biotechnology Information BLAST database has been updated since the time of the isolate's processing, and a Nocardia elegans strain was retrospectively identified as a 100% match during the preparation of this report. Notably, three strains of N. veterana were 100% matches.
Susceptibility testing was sent out to the University of Texas Health Center's Department of Microbiology Research in Tyler, Texas. The isolate's susceptibility profile is summarized in Table 1. Two weeks later, the woman was seen as an outpatient and had been tolerating trimethoprim-sulfamethoxazole therapy. Seventy-three days after discharge, elevated creatinine (3.1 mg/dL, baseline 1.9 mg/dL; reference range 0.6–1.2 mg/dL) was attributed to the use of trimethoprim-sulfamethoxazole in combination with tacrolimus, and antibiotic therapy was switched to oral azithromycin (500 mg daily). This decision was informed by the isolate's susceptibility profile and discussion with the reference laboratory.Table 1 Nocardia veterana isolate susceptibility profilea
Table 1Susceptible Intermediate Resistant No standardized breakpoint for Nocardia spp.
Amikacin (MIC ≤1 μg/mL) Ceftriaxone (MIC 16 μg/mL) Amoxicillin-clavulanate (MIC 32–16 μg/mL) Ertapenem (MIC unavailable; susceptible by bacterial breakpoint)
Clarithromycin (MIC ≤0.06 μg/mL) Kanamycin (MIC unavailable) Ciprofloxacin (MIC >4 μg/mL) Meropenem (MIC unavailable; susceptible by rapidly growing mycobacteria breakpoint)
Imipenem (MIC ≤2 μg/mL) Minocycline (MIC 2 μg/mL) Doxycycline (MIC 16 μg/mL) Tigecycline (MIC 4 μg/mL)
Linezolid (MIC 2 μg/mL) Moxifloxacin (MIC 4 μg/mL)
Trimethoprim-sulfamethoxazole (MIC 1–19 μg/mL) Tobramycin (MIC >16 μg/mL)
a Susceptibility results are reported with reference to their MICs and respective, standardized breakpoints.
Roughly 1.5 months later, her creatinine had returned to baseline (1.7 mg/dL), and she had been tolerating azithromycin without adverse events. In the absence of symptoms attributable to her N. veterana infection, azithromycin therapy was discontinued 289 days after its initiation. She continued to receive phototherapy for GVHD and remained on prednisone (20 mg daily), acyclovir, fluconazole and monthly pentamidine. She was seen 6 months after completing her 1-year course of therapy and displayed no signs of relapse. More than 5 years since completing therapy, no relapse has occurred.
Literature review and discussion
Our case concerned an N. veterana infection in a 59-year-old woman who had been receiving immunosuppressive therapy for chronic cutaneous GVHD. She failed to respond to empiric minocycline, and an abscess was incised and drained twice before resolving. Fortunately, oral antibiotic therapy was capable of treating the infection then serving as prophylaxis against relapse. Acute kidney injury complicated her course, but azithromycin therapy ultimately proved tolerable and successful. The isolate was resistant to several antibiotic choices, and susceptibility testing was integral to her management.
To better characterize N. veterana infections, we searched PubMed with the following operators: (‘Nocardia veterana’ OR ‘N. veterana’) AND (infection OR infections). Articles' citation lists were also reviewed to identify cases. We excluded one abridged report of a mycetoma [10] whose full details were published in a later manuscript [11]. Table 2 summarizes our case and all reported cases of N. veterana infections.Table 2 Nocardia veterana infections
Table 2Age/sex Clinical syndrome Immunocompromising co-morbidities Initial anti-nocardial regimen Length of treatment Outcome Ref.
83/F bowel abscess malignancy TMP-SMX >3 months success [8]
73/M brain abscess diabetes mellitus meropenem 1 year success [9]
66/M endophthalmitis heart transplant, diabetes mellitus meropenem, linezolid planned length of 12 months success [12]
42/F mycetoma SLE amoxicillin >6 years success [11]
72/M nodular lymphangitis immunosuppressive therapy for interstitial pneumonitis TMP-SMX planned length of 3 months stable at time of report [13]
40/M peritoneal infection AIDS, chronic hepatitis B, malignancy died before treatment initiation not applicable died before treatment initiation [14]
24/M pulmonary infection chronic granulomatous disease amikacin, ceftriaxone, trimethoprim >3 months stable at time of report [15]
40/F pulmonary infection HIV TMP-SMX 6 months success [16]
43/F pulmonary infection immunosuppressive therapy for SLE TMP-SMX 6 months success [17]
47/M pulmonary infection liver transplant TMP-SMX 6 months success [17]
52/M pulmonary infection not specified not reported not reported not reported [18]
52/M pulmonary infection HSCT recipient treated for GVHD TMP-SMX 397 days success [19]
52/F pulmonary infection HSCT recipient treated for GVHD TMP-SMX 154 days success [19]
54/M pulmonary infection heart transplant TMP-SMX 15 days success [16]
59/M pulmonary infection liver transplant imipenem >6 months success [16]
63/M pulmonary infection lung transplant, immunosuppressive therapy for bronchiolitis obliterans TMP-SMX 16 weeks died after discontinuing immunosuppression [15]
65/M pulmonary infection HSCT recipient treated for GVHD imipenem/cilastatin, amikacin 722 days died from encephalitis of unknown aetiology [6]
67/F pulmonary infection recurrent pneumonias and bronchiectasis minocycline >7 weeks symptomatic improvement at time of report [17]
78/M pulmonary infection history of tuberculosis not reported not reported not reported [4]
not reported pulmonary infection lung transplant TMP-SMX 30 days success [7]
58/M pulmonary infection with bacteraemia malignancy, recent prednisone course for autoimmune haemolytic anaemia TMP-SMX, azithromycin, piperacillin-tazobactam 3 weeks success [20]
30/M pulmonary infection with bacteraemia HIV, chronic hepatitis B, history of tuberculosis TMP-SMX <1 month died from multi-organ failure [5]
51/M pulmonary and urinary tract infections with bacteraemia malignancy, peritoneal dialysis TMP-SMX <2 months died from underlying malignancy [21]
59/F soft-tissue abscess HSCT recipient treated for GVHD TMP-SMX 1 year success our case
Abbreviations: AIDS, acquired immunodeficiency syndrome; GVHD, graft-versus-host disease; HIV, human immunodeficiency virus; HSCT, haematopoietic stem cell transplantation; SLE, systemic lupus erythematosus; TMP-SMX, trimethoprim-sulfamethoxazole.
Mean age was 55 years, and 29% were women. Pulmonary infections accounted for 17 of 24 infections, with abscesses being the second most common (3 of 24). In total, 25% had previous solid organ transplantations, 17% of patients had undergone haematopoietic stem cell transplantation and were undergoing treatment for GVHD, and 13% were people living with human immunodeficiency virus. The duration of treatment ranged from 3 weeks to >6 years. Trimethoprim-sulfamethoxazole monotherapy was used as initial anti-nocardial therapy for 13 of 24 individuals and led to treatment success in 9 of 13 (69%) of them. Combination therapy or other monotherapy (e.g. amoxicillin) was successful for six of eight (75%) individuals. The number of patients was too small to determine whether the difference in outcome is statistically significant.
Overall, N. veterana has a predilection for causing pulmonary infections in individuals with immunocompromising conditions [[4], [5], [6], [7],[15], [16], [17], [18], [19], [20]], and trimethoprim-sulfamethoxazole is commonly used to treat infections caused by Nocardia spp. [1]. When planning management for an immunocompromised host, a prolonged treatment duration is recommended. For our patient, the concurrent use of immunosuppressive therapy to manage GVHD heightened her susceptibility to N. veterana infection, and disseminated disease was fortunately averted by extended antibiotic therapy. The rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Conflict of interest
The authors declare no conflicts of interest. | Recovered | ReactionOutcome | CC BY-NC-ND | 33456780 | 18,799,519 | 2021-01 |
What was the outcome of reaction 'Abscess'? | Nocardia veterana infections: case report and systematic review.
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments. In 2001, the species Nocardia veterana was first isolated, and it predominantly causes pulmonary infections in immunocompromised hosts. We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease. After failing to improve with empirical treatment, two incision and drainage procedures were required. She subsequently completed a 1-year course of oral antibiotic therapy consisting of trimethoprim-sulfamethoxazole then azithromycin. No relapse occurred over the next 5 years of follow up. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases. Overall, the rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Introduction
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments [1,2]. They classically lead to infections in immunocompromised hosts [1], but 15% of patients in a large series had no predisposing conditions [3]. In 2001, the species Nocardia veterana was first isolated at a veterans' hospital in Australia, from which its name is derived [4]. It has been demonstrated to predominantly cause pulmonary infections in immunocompromised hosts [[5], [6], [7]], and only two reports have identified N. veterana as the cause of abscesses [8,9].
Materials and methods
We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease (GVHD). Review of medical records was approved by our institution's institutional review board. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases.
Case presentation
A 59-year-old woman with a history of acute lymphoblastic leukaemia—status post-haematopoietic stem cell transplantation—presented to the emergency department for evaluation of a right shoulder cutaneous abscess. Her post-transplant course had been complicated by multiple episodes of gastrointestinal and cutaneous GVHD. At this time, she was receiving phototherapy for chronic cutaneous GVHD and had started taking prednisone (30 mg daily) 6 months before presentation. Her medications included tacrolimus, acyclovir, fluconazole and monthly pentamidine. Two weeks before presentation, she had been evaluated by her oncologist for a 5 × 7 cm erythematous, indurated region on her right shoulder, and empiric treatment with oral minocycline (100 mg twice a day) was initiated. Continued pain prompted an outpatient ultrasound, which demonstrated a fluid collection. Her referring provider then sent her to the emergency department for further evaluation.
Incision and drainage were performed in the emergency department and yielded copious, purulent drainage that was sent for culture. Antibiotic therapy was empirically switched to oral clindamycin (600 mg three times a day). She was afebrile and discharged shortly thereafter. Two days later, she was admitted after a wound check showed increasing erythema around the incision and drainage site. Laboratory studies were notable for leucocytosis (15 200/μL; reference range 4000–10 000/μL), but she remained afebrile. Magnetic resonance imaging of her right upper extremity demonstrated a 2-cm soft-tissue abscess involving superficial fascia of the lateral deltoid and focal myositis (Fig. 1). Antibiotic therapy was broadened to intravenous vancomycin and piperacillin-tazobactam.Fig. 1 Nocardia veterana abscess: T2-weighted magnetic resonance imaging demonstrates 2-cm abscess involving the superficial fascia of the right lateral deltoid muscle.
Fig. 1
On day 2 of hospitalization, the abscess was incised and drained by general surgery. The following day, the culture from her initial presentation to the emergency department grew 4+ Gram-positive rods, prompting Nocardia spp. to be suspected. Antibiotic therapy was switched to oral trimethoprim-sulfamethoxazole (800 mg-160–mg twice a day). Magnetic resonance imaging of the brain and a CT scan of the chest showed no evidence of involvement, and she was discharged on day 4.
Four days after discharge, the isolate from her initial presentation was identified as N. veterana. The MicroSEQ® 500bp 16S rRNA Sequencing Kit (Applied Biosystems, Foster City, CA, USA) was used. Samples were processed and analysed consistent with the manufacturer's instructions. Data were assembled with MicroSEQ software, and amplicons were compared against the MicroSEQ database. Clinical and Laboratory Standards Institute MM18 criteria were used for making an identification. The aligned sequence was 409 bp, with no mixed bases. The isolate was 100% match to N. veterana in the MicroSEQ database; however, the National Center for Biotechnology Information BLAST database has been updated since the time of the isolate's processing, and a Nocardia elegans strain was retrospectively identified as a 100% match during the preparation of this report. Notably, three strains of N. veterana were 100% matches.
Susceptibility testing was sent out to the University of Texas Health Center's Department of Microbiology Research in Tyler, Texas. The isolate's susceptibility profile is summarized in Table 1. Two weeks later, the woman was seen as an outpatient and had been tolerating trimethoprim-sulfamethoxazole therapy. Seventy-three days after discharge, elevated creatinine (3.1 mg/dL, baseline 1.9 mg/dL; reference range 0.6–1.2 mg/dL) was attributed to the use of trimethoprim-sulfamethoxazole in combination with tacrolimus, and antibiotic therapy was switched to oral azithromycin (500 mg daily). This decision was informed by the isolate's susceptibility profile and discussion with the reference laboratory.Table 1 Nocardia veterana isolate susceptibility profilea
Table 1Susceptible Intermediate Resistant No standardized breakpoint for Nocardia spp.
Amikacin (MIC ≤1 μg/mL) Ceftriaxone (MIC 16 μg/mL) Amoxicillin-clavulanate (MIC 32–16 μg/mL) Ertapenem (MIC unavailable; susceptible by bacterial breakpoint)
Clarithromycin (MIC ≤0.06 μg/mL) Kanamycin (MIC unavailable) Ciprofloxacin (MIC >4 μg/mL) Meropenem (MIC unavailable; susceptible by rapidly growing mycobacteria breakpoint)
Imipenem (MIC ≤2 μg/mL) Minocycline (MIC 2 μg/mL) Doxycycline (MIC 16 μg/mL) Tigecycline (MIC 4 μg/mL)
Linezolid (MIC 2 μg/mL) Moxifloxacin (MIC 4 μg/mL)
Trimethoprim-sulfamethoxazole (MIC 1–19 μg/mL) Tobramycin (MIC >16 μg/mL)
a Susceptibility results are reported with reference to their MICs and respective, standardized breakpoints.
Roughly 1.5 months later, her creatinine had returned to baseline (1.7 mg/dL), and she had been tolerating azithromycin without adverse events. In the absence of symptoms attributable to her N. veterana infection, azithromycin therapy was discontinued 289 days after its initiation. She continued to receive phototherapy for GVHD and remained on prednisone (20 mg daily), acyclovir, fluconazole and monthly pentamidine. She was seen 6 months after completing her 1-year course of therapy and displayed no signs of relapse. More than 5 years since completing therapy, no relapse has occurred.
Literature review and discussion
Our case concerned an N. veterana infection in a 59-year-old woman who had been receiving immunosuppressive therapy for chronic cutaneous GVHD. She failed to respond to empiric minocycline, and an abscess was incised and drained twice before resolving. Fortunately, oral antibiotic therapy was capable of treating the infection then serving as prophylaxis against relapse. Acute kidney injury complicated her course, but azithromycin therapy ultimately proved tolerable and successful. The isolate was resistant to several antibiotic choices, and susceptibility testing was integral to her management.
To better characterize N. veterana infections, we searched PubMed with the following operators: (‘Nocardia veterana’ OR ‘N. veterana’) AND (infection OR infections). Articles' citation lists were also reviewed to identify cases. We excluded one abridged report of a mycetoma [10] whose full details were published in a later manuscript [11]. Table 2 summarizes our case and all reported cases of N. veterana infections.Table 2 Nocardia veterana infections
Table 2Age/sex Clinical syndrome Immunocompromising co-morbidities Initial anti-nocardial regimen Length of treatment Outcome Ref.
83/F bowel abscess malignancy TMP-SMX >3 months success [8]
73/M brain abscess diabetes mellitus meropenem 1 year success [9]
66/M endophthalmitis heart transplant, diabetes mellitus meropenem, linezolid planned length of 12 months success [12]
42/F mycetoma SLE amoxicillin >6 years success [11]
72/M nodular lymphangitis immunosuppressive therapy for interstitial pneumonitis TMP-SMX planned length of 3 months stable at time of report [13]
40/M peritoneal infection AIDS, chronic hepatitis B, malignancy died before treatment initiation not applicable died before treatment initiation [14]
24/M pulmonary infection chronic granulomatous disease amikacin, ceftriaxone, trimethoprim >3 months stable at time of report [15]
40/F pulmonary infection HIV TMP-SMX 6 months success [16]
43/F pulmonary infection immunosuppressive therapy for SLE TMP-SMX 6 months success [17]
47/M pulmonary infection liver transplant TMP-SMX 6 months success [17]
52/M pulmonary infection not specified not reported not reported not reported [18]
52/M pulmonary infection HSCT recipient treated for GVHD TMP-SMX 397 days success [19]
52/F pulmonary infection HSCT recipient treated for GVHD TMP-SMX 154 days success [19]
54/M pulmonary infection heart transplant TMP-SMX 15 days success [16]
59/M pulmonary infection liver transplant imipenem >6 months success [16]
63/M pulmonary infection lung transplant, immunosuppressive therapy for bronchiolitis obliterans TMP-SMX 16 weeks died after discontinuing immunosuppression [15]
65/M pulmonary infection HSCT recipient treated for GVHD imipenem/cilastatin, amikacin 722 days died from encephalitis of unknown aetiology [6]
67/F pulmonary infection recurrent pneumonias and bronchiectasis minocycline >7 weeks symptomatic improvement at time of report [17]
78/M pulmonary infection history of tuberculosis not reported not reported not reported [4]
not reported pulmonary infection lung transplant TMP-SMX 30 days success [7]
58/M pulmonary infection with bacteraemia malignancy, recent prednisone course for autoimmune haemolytic anaemia TMP-SMX, azithromycin, piperacillin-tazobactam 3 weeks success [20]
30/M pulmonary infection with bacteraemia HIV, chronic hepatitis B, history of tuberculosis TMP-SMX <1 month died from multi-organ failure [5]
51/M pulmonary and urinary tract infections with bacteraemia malignancy, peritoneal dialysis TMP-SMX <2 months died from underlying malignancy [21]
59/F soft-tissue abscess HSCT recipient treated for GVHD TMP-SMX 1 year success our case
Abbreviations: AIDS, acquired immunodeficiency syndrome; GVHD, graft-versus-host disease; HIV, human immunodeficiency virus; HSCT, haematopoietic stem cell transplantation; SLE, systemic lupus erythematosus; TMP-SMX, trimethoprim-sulfamethoxazole.
Mean age was 55 years, and 29% were women. Pulmonary infections accounted for 17 of 24 infections, with abscesses being the second most common (3 of 24). In total, 25% had previous solid organ transplantations, 17% of patients had undergone haematopoietic stem cell transplantation and were undergoing treatment for GVHD, and 13% were people living with human immunodeficiency virus. The duration of treatment ranged from 3 weeks to >6 years. Trimethoprim-sulfamethoxazole monotherapy was used as initial anti-nocardial therapy for 13 of 24 individuals and led to treatment success in 9 of 13 (69%) of them. Combination therapy or other monotherapy (e.g. amoxicillin) was successful for six of eight (75%) individuals. The number of patients was too small to determine whether the difference in outcome is statistically significant.
Overall, N. veterana has a predilection for causing pulmonary infections in individuals with immunocompromising conditions [[4], [5], [6], [7],[15], [16], [17], [18], [19], [20]], and trimethoprim-sulfamethoxazole is commonly used to treat infections caused by Nocardia spp. [1]. When planning management for an immunocompromised host, a prolonged treatment duration is recommended. For our patient, the concurrent use of immunosuppressive therapy to manage GVHD heightened her susceptibility to N. veterana infection, and disseminated disease was fortunately averted by extended antibiotic therapy. The rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Conflict of interest
The authors declare no conflicts of interest. | Recovered | ReactionOutcome | CC BY-NC-ND | 33456780 | 18,797,291 | 2021-01 |
What was the outcome of reaction 'Acute kidney injury'? | Nocardia veterana infections: case report and systematic review.
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments. In 2001, the species Nocardia veterana was first isolated, and it predominantly causes pulmonary infections in immunocompromised hosts. We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease. After failing to improve with empirical treatment, two incision and drainage procedures were required. She subsequently completed a 1-year course of oral antibiotic therapy consisting of trimethoprim-sulfamethoxazole then azithromycin. No relapse occurred over the next 5 years of follow up. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases. Overall, the rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Introduction
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments [1,2]. They classically lead to infections in immunocompromised hosts [1], but 15% of patients in a large series had no predisposing conditions [3]. In 2001, the species Nocardia veterana was first isolated at a veterans' hospital in Australia, from which its name is derived [4]. It has been demonstrated to predominantly cause pulmonary infections in immunocompromised hosts [[5], [6], [7]], and only two reports have identified N. veterana as the cause of abscesses [8,9].
Materials and methods
We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease (GVHD). Review of medical records was approved by our institution's institutional review board. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases.
Case presentation
A 59-year-old woman with a history of acute lymphoblastic leukaemia—status post-haematopoietic stem cell transplantation—presented to the emergency department for evaluation of a right shoulder cutaneous abscess. Her post-transplant course had been complicated by multiple episodes of gastrointestinal and cutaneous GVHD. At this time, she was receiving phototherapy for chronic cutaneous GVHD and had started taking prednisone (30 mg daily) 6 months before presentation. Her medications included tacrolimus, acyclovir, fluconazole and monthly pentamidine. Two weeks before presentation, she had been evaluated by her oncologist for a 5 × 7 cm erythematous, indurated region on her right shoulder, and empiric treatment with oral minocycline (100 mg twice a day) was initiated. Continued pain prompted an outpatient ultrasound, which demonstrated a fluid collection. Her referring provider then sent her to the emergency department for further evaluation.
Incision and drainage were performed in the emergency department and yielded copious, purulent drainage that was sent for culture. Antibiotic therapy was empirically switched to oral clindamycin (600 mg three times a day). She was afebrile and discharged shortly thereafter. Two days later, she was admitted after a wound check showed increasing erythema around the incision and drainage site. Laboratory studies were notable for leucocytosis (15 200/μL; reference range 4000–10 000/μL), but she remained afebrile. Magnetic resonance imaging of her right upper extremity demonstrated a 2-cm soft-tissue abscess involving superficial fascia of the lateral deltoid and focal myositis (Fig. 1). Antibiotic therapy was broadened to intravenous vancomycin and piperacillin-tazobactam.Fig. 1 Nocardia veterana abscess: T2-weighted magnetic resonance imaging demonstrates 2-cm abscess involving the superficial fascia of the right lateral deltoid muscle.
Fig. 1
On day 2 of hospitalization, the abscess was incised and drained by general surgery. The following day, the culture from her initial presentation to the emergency department grew 4+ Gram-positive rods, prompting Nocardia spp. to be suspected. Antibiotic therapy was switched to oral trimethoprim-sulfamethoxazole (800 mg-160–mg twice a day). Magnetic resonance imaging of the brain and a CT scan of the chest showed no evidence of involvement, and she was discharged on day 4.
Four days after discharge, the isolate from her initial presentation was identified as N. veterana. The MicroSEQ® 500bp 16S rRNA Sequencing Kit (Applied Biosystems, Foster City, CA, USA) was used. Samples were processed and analysed consistent with the manufacturer's instructions. Data were assembled with MicroSEQ software, and amplicons were compared against the MicroSEQ database. Clinical and Laboratory Standards Institute MM18 criteria were used for making an identification. The aligned sequence was 409 bp, with no mixed bases. The isolate was 100% match to N. veterana in the MicroSEQ database; however, the National Center for Biotechnology Information BLAST database has been updated since the time of the isolate's processing, and a Nocardia elegans strain was retrospectively identified as a 100% match during the preparation of this report. Notably, three strains of N. veterana were 100% matches.
Susceptibility testing was sent out to the University of Texas Health Center's Department of Microbiology Research in Tyler, Texas. The isolate's susceptibility profile is summarized in Table 1. Two weeks later, the woman was seen as an outpatient and had been tolerating trimethoprim-sulfamethoxazole therapy. Seventy-three days after discharge, elevated creatinine (3.1 mg/dL, baseline 1.9 mg/dL; reference range 0.6–1.2 mg/dL) was attributed to the use of trimethoprim-sulfamethoxazole in combination with tacrolimus, and antibiotic therapy was switched to oral azithromycin (500 mg daily). This decision was informed by the isolate's susceptibility profile and discussion with the reference laboratory.Table 1 Nocardia veterana isolate susceptibility profilea
Table 1Susceptible Intermediate Resistant No standardized breakpoint for Nocardia spp.
Amikacin (MIC ≤1 μg/mL) Ceftriaxone (MIC 16 μg/mL) Amoxicillin-clavulanate (MIC 32–16 μg/mL) Ertapenem (MIC unavailable; susceptible by bacterial breakpoint)
Clarithromycin (MIC ≤0.06 μg/mL) Kanamycin (MIC unavailable) Ciprofloxacin (MIC >4 μg/mL) Meropenem (MIC unavailable; susceptible by rapidly growing mycobacteria breakpoint)
Imipenem (MIC ≤2 μg/mL) Minocycline (MIC 2 μg/mL) Doxycycline (MIC 16 μg/mL) Tigecycline (MIC 4 μg/mL)
Linezolid (MIC 2 μg/mL) Moxifloxacin (MIC 4 μg/mL)
Trimethoprim-sulfamethoxazole (MIC 1–19 μg/mL) Tobramycin (MIC >16 μg/mL)
a Susceptibility results are reported with reference to their MICs and respective, standardized breakpoints.
Roughly 1.5 months later, her creatinine had returned to baseline (1.7 mg/dL), and she had been tolerating azithromycin without adverse events. In the absence of symptoms attributable to her N. veterana infection, azithromycin therapy was discontinued 289 days after its initiation. She continued to receive phototherapy for GVHD and remained on prednisone (20 mg daily), acyclovir, fluconazole and monthly pentamidine. She was seen 6 months after completing her 1-year course of therapy and displayed no signs of relapse. More than 5 years since completing therapy, no relapse has occurred.
Literature review and discussion
Our case concerned an N. veterana infection in a 59-year-old woman who had been receiving immunosuppressive therapy for chronic cutaneous GVHD. She failed to respond to empiric minocycline, and an abscess was incised and drained twice before resolving. Fortunately, oral antibiotic therapy was capable of treating the infection then serving as prophylaxis against relapse. Acute kidney injury complicated her course, but azithromycin therapy ultimately proved tolerable and successful. The isolate was resistant to several antibiotic choices, and susceptibility testing was integral to her management.
To better characterize N. veterana infections, we searched PubMed with the following operators: (‘Nocardia veterana’ OR ‘N. veterana’) AND (infection OR infections). Articles' citation lists were also reviewed to identify cases. We excluded one abridged report of a mycetoma [10] whose full details were published in a later manuscript [11]. Table 2 summarizes our case and all reported cases of N. veterana infections.Table 2 Nocardia veterana infections
Table 2Age/sex Clinical syndrome Immunocompromising co-morbidities Initial anti-nocardial regimen Length of treatment Outcome Ref.
83/F bowel abscess malignancy TMP-SMX >3 months success [8]
73/M brain abscess diabetes mellitus meropenem 1 year success [9]
66/M endophthalmitis heart transplant, diabetes mellitus meropenem, linezolid planned length of 12 months success [12]
42/F mycetoma SLE amoxicillin >6 years success [11]
72/M nodular lymphangitis immunosuppressive therapy for interstitial pneumonitis TMP-SMX planned length of 3 months stable at time of report [13]
40/M peritoneal infection AIDS, chronic hepatitis B, malignancy died before treatment initiation not applicable died before treatment initiation [14]
24/M pulmonary infection chronic granulomatous disease amikacin, ceftriaxone, trimethoprim >3 months stable at time of report [15]
40/F pulmonary infection HIV TMP-SMX 6 months success [16]
43/F pulmonary infection immunosuppressive therapy for SLE TMP-SMX 6 months success [17]
47/M pulmonary infection liver transplant TMP-SMX 6 months success [17]
52/M pulmonary infection not specified not reported not reported not reported [18]
52/M pulmonary infection HSCT recipient treated for GVHD TMP-SMX 397 days success [19]
52/F pulmonary infection HSCT recipient treated for GVHD TMP-SMX 154 days success [19]
54/M pulmonary infection heart transplant TMP-SMX 15 days success [16]
59/M pulmonary infection liver transplant imipenem >6 months success [16]
63/M pulmonary infection lung transplant, immunosuppressive therapy for bronchiolitis obliterans TMP-SMX 16 weeks died after discontinuing immunosuppression [15]
65/M pulmonary infection HSCT recipient treated for GVHD imipenem/cilastatin, amikacin 722 days died from encephalitis of unknown aetiology [6]
67/F pulmonary infection recurrent pneumonias and bronchiectasis minocycline >7 weeks symptomatic improvement at time of report [17]
78/M pulmonary infection history of tuberculosis not reported not reported not reported [4]
not reported pulmonary infection lung transplant TMP-SMX 30 days success [7]
58/M pulmonary infection with bacteraemia malignancy, recent prednisone course for autoimmune haemolytic anaemia TMP-SMX, azithromycin, piperacillin-tazobactam 3 weeks success [20]
30/M pulmonary infection with bacteraemia HIV, chronic hepatitis B, history of tuberculosis TMP-SMX <1 month died from multi-organ failure [5]
51/M pulmonary and urinary tract infections with bacteraemia malignancy, peritoneal dialysis TMP-SMX <2 months died from underlying malignancy [21]
59/F soft-tissue abscess HSCT recipient treated for GVHD TMP-SMX 1 year success our case
Abbreviations: AIDS, acquired immunodeficiency syndrome; GVHD, graft-versus-host disease; HIV, human immunodeficiency virus; HSCT, haematopoietic stem cell transplantation; SLE, systemic lupus erythematosus; TMP-SMX, trimethoprim-sulfamethoxazole.
Mean age was 55 years, and 29% were women. Pulmonary infections accounted for 17 of 24 infections, with abscesses being the second most common (3 of 24). In total, 25% had previous solid organ transplantations, 17% of patients had undergone haematopoietic stem cell transplantation and were undergoing treatment for GVHD, and 13% were people living with human immunodeficiency virus. The duration of treatment ranged from 3 weeks to >6 years. Trimethoprim-sulfamethoxazole monotherapy was used as initial anti-nocardial therapy for 13 of 24 individuals and led to treatment success in 9 of 13 (69%) of them. Combination therapy or other monotherapy (e.g. amoxicillin) was successful for six of eight (75%) individuals. The number of patients was too small to determine whether the difference in outcome is statistically significant.
Overall, N. veterana has a predilection for causing pulmonary infections in individuals with immunocompromising conditions [[4], [5], [6], [7],[15], [16], [17], [18], [19], [20]], and trimethoprim-sulfamethoxazole is commonly used to treat infections caused by Nocardia spp. [1]. When planning management for an immunocompromised host, a prolonged treatment duration is recommended. For our patient, the concurrent use of immunosuppressive therapy to manage GVHD heightened her susceptibility to N. veterana infection, and disseminated disease was fortunately averted by extended antibiotic therapy. The rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Conflict of interest
The authors declare no conflicts of interest. | Recovered | ReactionOutcome | CC BY-NC-ND | 33456780 | 18,817,070 | 2021-01 |
What was the outcome of reaction 'Focal myositis'? | Nocardia veterana infections: case report and systematic review.
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments. In 2001, the species Nocardia veterana was first isolated, and it predominantly causes pulmonary infections in immunocompromised hosts. We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease. After failing to improve with empirical treatment, two incision and drainage procedures were required. She subsequently completed a 1-year course of oral antibiotic therapy consisting of trimethoprim-sulfamethoxazole then azithromycin. No relapse occurred over the next 5 years of follow up. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases. Overall, the rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Introduction
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments [1,2]. They classically lead to infections in immunocompromised hosts [1], but 15% of patients in a large series had no predisposing conditions [3]. In 2001, the species Nocardia veterana was first isolated at a veterans' hospital in Australia, from which its name is derived [4]. It has been demonstrated to predominantly cause pulmonary infections in immunocompromised hosts [[5], [6], [7]], and only two reports have identified N. veterana as the cause of abscesses [8,9].
Materials and methods
We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease (GVHD). Review of medical records was approved by our institution's institutional review board. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases.
Case presentation
A 59-year-old woman with a history of acute lymphoblastic leukaemia—status post-haematopoietic stem cell transplantation—presented to the emergency department for evaluation of a right shoulder cutaneous abscess. Her post-transplant course had been complicated by multiple episodes of gastrointestinal and cutaneous GVHD. At this time, she was receiving phototherapy for chronic cutaneous GVHD and had started taking prednisone (30 mg daily) 6 months before presentation. Her medications included tacrolimus, acyclovir, fluconazole and monthly pentamidine. Two weeks before presentation, she had been evaluated by her oncologist for a 5 × 7 cm erythematous, indurated region on her right shoulder, and empiric treatment with oral minocycline (100 mg twice a day) was initiated. Continued pain prompted an outpatient ultrasound, which demonstrated a fluid collection. Her referring provider then sent her to the emergency department for further evaluation.
Incision and drainage were performed in the emergency department and yielded copious, purulent drainage that was sent for culture. Antibiotic therapy was empirically switched to oral clindamycin (600 mg three times a day). She was afebrile and discharged shortly thereafter. Two days later, she was admitted after a wound check showed increasing erythema around the incision and drainage site. Laboratory studies were notable for leucocytosis (15 200/μL; reference range 4000–10 000/μL), but she remained afebrile. Magnetic resonance imaging of her right upper extremity demonstrated a 2-cm soft-tissue abscess involving superficial fascia of the lateral deltoid and focal myositis (Fig. 1). Antibiotic therapy was broadened to intravenous vancomycin and piperacillin-tazobactam.Fig. 1 Nocardia veterana abscess: T2-weighted magnetic resonance imaging demonstrates 2-cm abscess involving the superficial fascia of the right lateral deltoid muscle.
Fig. 1
On day 2 of hospitalization, the abscess was incised and drained by general surgery. The following day, the culture from her initial presentation to the emergency department grew 4+ Gram-positive rods, prompting Nocardia spp. to be suspected. Antibiotic therapy was switched to oral trimethoprim-sulfamethoxazole (800 mg-160–mg twice a day). Magnetic resonance imaging of the brain and a CT scan of the chest showed no evidence of involvement, and she was discharged on day 4.
Four days after discharge, the isolate from her initial presentation was identified as N. veterana. The MicroSEQ® 500bp 16S rRNA Sequencing Kit (Applied Biosystems, Foster City, CA, USA) was used. Samples were processed and analysed consistent with the manufacturer's instructions. Data were assembled with MicroSEQ software, and amplicons were compared against the MicroSEQ database. Clinical and Laboratory Standards Institute MM18 criteria were used for making an identification. The aligned sequence was 409 bp, with no mixed bases. The isolate was 100% match to N. veterana in the MicroSEQ database; however, the National Center for Biotechnology Information BLAST database has been updated since the time of the isolate's processing, and a Nocardia elegans strain was retrospectively identified as a 100% match during the preparation of this report. Notably, three strains of N. veterana were 100% matches.
Susceptibility testing was sent out to the University of Texas Health Center's Department of Microbiology Research in Tyler, Texas. The isolate's susceptibility profile is summarized in Table 1. Two weeks later, the woman was seen as an outpatient and had been tolerating trimethoprim-sulfamethoxazole therapy. Seventy-three days after discharge, elevated creatinine (3.1 mg/dL, baseline 1.9 mg/dL; reference range 0.6–1.2 mg/dL) was attributed to the use of trimethoprim-sulfamethoxazole in combination with tacrolimus, and antibiotic therapy was switched to oral azithromycin (500 mg daily). This decision was informed by the isolate's susceptibility profile and discussion with the reference laboratory.Table 1 Nocardia veterana isolate susceptibility profilea
Table 1Susceptible Intermediate Resistant No standardized breakpoint for Nocardia spp.
Amikacin (MIC ≤1 μg/mL) Ceftriaxone (MIC 16 μg/mL) Amoxicillin-clavulanate (MIC 32–16 μg/mL) Ertapenem (MIC unavailable; susceptible by bacterial breakpoint)
Clarithromycin (MIC ≤0.06 μg/mL) Kanamycin (MIC unavailable) Ciprofloxacin (MIC >4 μg/mL) Meropenem (MIC unavailable; susceptible by rapidly growing mycobacteria breakpoint)
Imipenem (MIC ≤2 μg/mL) Minocycline (MIC 2 μg/mL) Doxycycline (MIC 16 μg/mL) Tigecycline (MIC 4 μg/mL)
Linezolid (MIC 2 μg/mL) Moxifloxacin (MIC 4 μg/mL)
Trimethoprim-sulfamethoxazole (MIC 1–19 μg/mL) Tobramycin (MIC >16 μg/mL)
a Susceptibility results are reported with reference to their MICs and respective, standardized breakpoints.
Roughly 1.5 months later, her creatinine had returned to baseline (1.7 mg/dL), and she had been tolerating azithromycin without adverse events. In the absence of symptoms attributable to her N. veterana infection, azithromycin therapy was discontinued 289 days after its initiation. She continued to receive phototherapy for GVHD and remained on prednisone (20 mg daily), acyclovir, fluconazole and monthly pentamidine. She was seen 6 months after completing her 1-year course of therapy and displayed no signs of relapse. More than 5 years since completing therapy, no relapse has occurred.
Literature review and discussion
Our case concerned an N. veterana infection in a 59-year-old woman who had been receiving immunosuppressive therapy for chronic cutaneous GVHD. She failed to respond to empiric minocycline, and an abscess was incised and drained twice before resolving. Fortunately, oral antibiotic therapy was capable of treating the infection then serving as prophylaxis against relapse. Acute kidney injury complicated her course, but azithromycin therapy ultimately proved tolerable and successful. The isolate was resistant to several antibiotic choices, and susceptibility testing was integral to her management.
To better characterize N. veterana infections, we searched PubMed with the following operators: (‘Nocardia veterana’ OR ‘N. veterana’) AND (infection OR infections). Articles' citation lists were also reviewed to identify cases. We excluded one abridged report of a mycetoma [10] whose full details were published in a later manuscript [11]. Table 2 summarizes our case and all reported cases of N. veterana infections.Table 2 Nocardia veterana infections
Table 2Age/sex Clinical syndrome Immunocompromising co-morbidities Initial anti-nocardial regimen Length of treatment Outcome Ref.
83/F bowel abscess malignancy TMP-SMX >3 months success [8]
73/M brain abscess diabetes mellitus meropenem 1 year success [9]
66/M endophthalmitis heart transplant, diabetes mellitus meropenem, linezolid planned length of 12 months success [12]
42/F mycetoma SLE amoxicillin >6 years success [11]
72/M nodular lymphangitis immunosuppressive therapy for interstitial pneumonitis TMP-SMX planned length of 3 months stable at time of report [13]
40/M peritoneal infection AIDS, chronic hepatitis B, malignancy died before treatment initiation not applicable died before treatment initiation [14]
24/M pulmonary infection chronic granulomatous disease amikacin, ceftriaxone, trimethoprim >3 months stable at time of report [15]
40/F pulmonary infection HIV TMP-SMX 6 months success [16]
43/F pulmonary infection immunosuppressive therapy for SLE TMP-SMX 6 months success [17]
47/M pulmonary infection liver transplant TMP-SMX 6 months success [17]
52/M pulmonary infection not specified not reported not reported not reported [18]
52/M pulmonary infection HSCT recipient treated for GVHD TMP-SMX 397 days success [19]
52/F pulmonary infection HSCT recipient treated for GVHD TMP-SMX 154 days success [19]
54/M pulmonary infection heart transplant TMP-SMX 15 days success [16]
59/M pulmonary infection liver transplant imipenem >6 months success [16]
63/M pulmonary infection lung transplant, immunosuppressive therapy for bronchiolitis obliterans TMP-SMX 16 weeks died after discontinuing immunosuppression [15]
65/M pulmonary infection HSCT recipient treated for GVHD imipenem/cilastatin, amikacin 722 days died from encephalitis of unknown aetiology [6]
67/F pulmonary infection recurrent pneumonias and bronchiectasis minocycline >7 weeks symptomatic improvement at time of report [17]
78/M pulmonary infection history of tuberculosis not reported not reported not reported [4]
not reported pulmonary infection lung transplant TMP-SMX 30 days success [7]
58/M pulmonary infection with bacteraemia malignancy, recent prednisone course for autoimmune haemolytic anaemia TMP-SMX, azithromycin, piperacillin-tazobactam 3 weeks success [20]
30/M pulmonary infection with bacteraemia HIV, chronic hepatitis B, history of tuberculosis TMP-SMX <1 month died from multi-organ failure [5]
51/M pulmonary and urinary tract infections with bacteraemia malignancy, peritoneal dialysis TMP-SMX <2 months died from underlying malignancy [21]
59/F soft-tissue abscess HSCT recipient treated for GVHD TMP-SMX 1 year success our case
Abbreviations: AIDS, acquired immunodeficiency syndrome; GVHD, graft-versus-host disease; HIV, human immunodeficiency virus; HSCT, haematopoietic stem cell transplantation; SLE, systemic lupus erythematosus; TMP-SMX, trimethoprim-sulfamethoxazole.
Mean age was 55 years, and 29% were women. Pulmonary infections accounted for 17 of 24 infections, with abscesses being the second most common (3 of 24). In total, 25% had previous solid organ transplantations, 17% of patients had undergone haematopoietic stem cell transplantation and were undergoing treatment for GVHD, and 13% were people living with human immunodeficiency virus. The duration of treatment ranged from 3 weeks to >6 years. Trimethoprim-sulfamethoxazole monotherapy was used as initial anti-nocardial therapy for 13 of 24 individuals and led to treatment success in 9 of 13 (69%) of them. Combination therapy or other monotherapy (e.g. amoxicillin) was successful for six of eight (75%) individuals. The number of patients was too small to determine whether the difference in outcome is statistically significant.
Overall, N. veterana has a predilection for causing pulmonary infections in individuals with immunocompromising conditions [[4], [5], [6], [7],[15], [16], [17], [18], [19], [20]], and trimethoprim-sulfamethoxazole is commonly used to treat infections caused by Nocardia spp. [1]. When planning management for an immunocompromised host, a prolonged treatment duration is recommended. For our patient, the concurrent use of immunosuppressive therapy to manage GVHD heightened her susceptibility to N. veterana infection, and disseminated disease was fortunately averted by extended antibiotic therapy. The rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Conflict of interest
The authors declare no conflicts of interest. | Recovered | ReactionOutcome | CC BY-NC-ND | 33456780 | 18,817,070 | 2021-01 |
What was the outcome of reaction 'Nocardiosis'? | Nocardia veterana infections: case report and systematic review.
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments. In 2001, the species Nocardia veterana was first isolated, and it predominantly causes pulmonary infections in immunocompromised hosts. We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease. After failing to improve with empirical treatment, two incision and drainage procedures were required. She subsequently completed a 1-year course of oral antibiotic therapy consisting of trimethoprim-sulfamethoxazole then azithromycin. No relapse occurred over the next 5 years of follow up. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases. Overall, the rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Introduction
Members of the genus Nocardia are filamentous, Gram-positive, aerobic bacteria and exist ubiquitously in most environments [1,2]. They classically lead to infections in immunocompromised hosts [1], but 15% of patients in a large series had no predisposing conditions [3]. In 2001, the species Nocardia veterana was first isolated at a veterans' hospital in Australia, from which its name is derived [4]. It has been demonstrated to predominantly cause pulmonary infections in immunocompromised hosts [[5], [6], [7]], and only two reports have identified N. veterana as the cause of abscesses [8,9].
Materials and methods
We present the first report of a soft-tissue abscess caused by N. veterana in a 59-year-old woman being treated for chronic cutaneous graft-versus-host disease (GVHD). Review of medical records was approved by our institution's institutional review board. To better characterize N. veterana infections, we performed a systematic literature review and summarized all previously reported cases.
Case presentation
A 59-year-old woman with a history of acute lymphoblastic leukaemia—status post-haematopoietic stem cell transplantation—presented to the emergency department for evaluation of a right shoulder cutaneous abscess. Her post-transplant course had been complicated by multiple episodes of gastrointestinal and cutaneous GVHD. At this time, she was receiving phototherapy for chronic cutaneous GVHD and had started taking prednisone (30 mg daily) 6 months before presentation. Her medications included tacrolimus, acyclovir, fluconazole and monthly pentamidine. Two weeks before presentation, she had been evaluated by her oncologist for a 5 × 7 cm erythematous, indurated region on her right shoulder, and empiric treatment with oral minocycline (100 mg twice a day) was initiated. Continued pain prompted an outpatient ultrasound, which demonstrated a fluid collection. Her referring provider then sent her to the emergency department for further evaluation.
Incision and drainage were performed in the emergency department and yielded copious, purulent drainage that was sent for culture. Antibiotic therapy was empirically switched to oral clindamycin (600 mg three times a day). She was afebrile and discharged shortly thereafter. Two days later, she was admitted after a wound check showed increasing erythema around the incision and drainage site. Laboratory studies were notable for leucocytosis (15 200/μL; reference range 4000–10 000/μL), but she remained afebrile. Magnetic resonance imaging of her right upper extremity demonstrated a 2-cm soft-tissue abscess involving superficial fascia of the lateral deltoid and focal myositis (Fig. 1). Antibiotic therapy was broadened to intravenous vancomycin and piperacillin-tazobactam.Fig. 1 Nocardia veterana abscess: T2-weighted magnetic resonance imaging demonstrates 2-cm abscess involving the superficial fascia of the right lateral deltoid muscle.
Fig. 1
On day 2 of hospitalization, the abscess was incised and drained by general surgery. The following day, the culture from her initial presentation to the emergency department grew 4+ Gram-positive rods, prompting Nocardia spp. to be suspected. Antibiotic therapy was switched to oral trimethoprim-sulfamethoxazole (800 mg-160–mg twice a day). Magnetic resonance imaging of the brain and a CT scan of the chest showed no evidence of involvement, and she was discharged on day 4.
Four days after discharge, the isolate from her initial presentation was identified as N. veterana. The MicroSEQ® 500bp 16S rRNA Sequencing Kit (Applied Biosystems, Foster City, CA, USA) was used. Samples were processed and analysed consistent with the manufacturer's instructions. Data were assembled with MicroSEQ software, and amplicons were compared against the MicroSEQ database. Clinical and Laboratory Standards Institute MM18 criteria were used for making an identification. The aligned sequence was 409 bp, with no mixed bases. The isolate was 100% match to N. veterana in the MicroSEQ database; however, the National Center for Biotechnology Information BLAST database has been updated since the time of the isolate's processing, and a Nocardia elegans strain was retrospectively identified as a 100% match during the preparation of this report. Notably, three strains of N. veterana were 100% matches.
Susceptibility testing was sent out to the University of Texas Health Center's Department of Microbiology Research in Tyler, Texas. The isolate's susceptibility profile is summarized in Table 1. Two weeks later, the woman was seen as an outpatient and had been tolerating trimethoprim-sulfamethoxazole therapy. Seventy-three days after discharge, elevated creatinine (3.1 mg/dL, baseline 1.9 mg/dL; reference range 0.6–1.2 mg/dL) was attributed to the use of trimethoprim-sulfamethoxazole in combination with tacrolimus, and antibiotic therapy was switched to oral azithromycin (500 mg daily). This decision was informed by the isolate's susceptibility profile and discussion with the reference laboratory.Table 1 Nocardia veterana isolate susceptibility profilea
Table 1Susceptible Intermediate Resistant No standardized breakpoint for Nocardia spp.
Amikacin (MIC ≤1 μg/mL) Ceftriaxone (MIC 16 μg/mL) Amoxicillin-clavulanate (MIC 32–16 μg/mL) Ertapenem (MIC unavailable; susceptible by bacterial breakpoint)
Clarithromycin (MIC ≤0.06 μg/mL) Kanamycin (MIC unavailable) Ciprofloxacin (MIC >4 μg/mL) Meropenem (MIC unavailable; susceptible by rapidly growing mycobacteria breakpoint)
Imipenem (MIC ≤2 μg/mL) Minocycline (MIC 2 μg/mL) Doxycycline (MIC 16 μg/mL) Tigecycline (MIC 4 μg/mL)
Linezolid (MIC 2 μg/mL) Moxifloxacin (MIC 4 μg/mL)
Trimethoprim-sulfamethoxazole (MIC 1–19 μg/mL) Tobramycin (MIC >16 μg/mL)
a Susceptibility results are reported with reference to their MICs and respective, standardized breakpoints.
Roughly 1.5 months later, her creatinine had returned to baseline (1.7 mg/dL), and she had been tolerating azithromycin without adverse events. In the absence of symptoms attributable to her N. veterana infection, azithromycin therapy was discontinued 289 days after its initiation. She continued to receive phototherapy for GVHD and remained on prednisone (20 mg daily), acyclovir, fluconazole and monthly pentamidine. She was seen 6 months after completing her 1-year course of therapy and displayed no signs of relapse. More than 5 years since completing therapy, no relapse has occurred.
Literature review and discussion
Our case concerned an N. veterana infection in a 59-year-old woman who had been receiving immunosuppressive therapy for chronic cutaneous GVHD. She failed to respond to empiric minocycline, and an abscess was incised and drained twice before resolving. Fortunately, oral antibiotic therapy was capable of treating the infection then serving as prophylaxis against relapse. Acute kidney injury complicated her course, but azithromycin therapy ultimately proved tolerable and successful. The isolate was resistant to several antibiotic choices, and susceptibility testing was integral to her management.
To better characterize N. veterana infections, we searched PubMed with the following operators: (‘Nocardia veterana’ OR ‘N. veterana’) AND (infection OR infections). Articles' citation lists were also reviewed to identify cases. We excluded one abridged report of a mycetoma [10] whose full details were published in a later manuscript [11]. Table 2 summarizes our case and all reported cases of N. veterana infections.Table 2 Nocardia veterana infections
Table 2Age/sex Clinical syndrome Immunocompromising co-morbidities Initial anti-nocardial regimen Length of treatment Outcome Ref.
83/F bowel abscess malignancy TMP-SMX >3 months success [8]
73/M brain abscess diabetes mellitus meropenem 1 year success [9]
66/M endophthalmitis heart transplant, diabetes mellitus meropenem, linezolid planned length of 12 months success [12]
42/F mycetoma SLE amoxicillin >6 years success [11]
72/M nodular lymphangitis immunosuppressive therapy for interstitial pneumonitis TMP-SMX planned length of 3 months stable at time of report [13]
40/M peritoneal infection AIDS, chronic hepatitis B, malignancy died before treatment initiation not applicable died before treatment initiation [14]
24/M pulmonary infection chronic granulomatous disease amikacin, ceftriaxone, trimethoprim >3 months stable at time of report [15]
40/F pulmonary infection HIV TMP-SMX 6 months success [16]
43/F pulmonary infection immunosuppressive therapy for SLE TMP-SMX 6 months success [17]
47/M pulmonary infection liver transplant TMP-SMX 6 months success [17]
52/M pulmonary infection not specified not reported not reported not reported [18]
52/M pulmonary infection HSCT recipient treated for GVHD TMP-SMX 397 days success [19]
52/F pulmonary infection HSCT recipient treated for GVHD TMP-SMX 154 days success [19]
54/M pulmonary infection heart transplant TMP-SMX 15 days success [16]
59/M pulmonary infection liver transplant imipenem >6 months success [16]
63/M pulmonary infection lung transplant, immunosuppressive therapy for bronchiolitis obliterans TMP-SMX 16 weeks died after discontinuing immunosuppression [15]
65/M pulmonary infection HSCT recipient treated for GVHD imipenem/cilastatin, amikacin 722 days died from encephalitis of unknown aetiology [6]
67/F pulmonary infection recurrent pneumonias and bronchiectasis minocycline >7 weeks symptomatic improvement at time of report [17]
78/M pulmonary infection history of tuberculosis not reported not reported not reported [4]
not reported pulmonary infection lung transplant TMP-SMX 30 days success [7]
58/M pulmonary infection with bacteraemia malignancy, recent prednisone course for autoimmune haemolytic anaemia TMP-SMX, azithromycin, piperacillin-tazobactam 3 weeks success [20]
30/M pulmonary infection with bacteraemia HIV, chronic hepatitis B, history of tuberculosis TMP-SMX <1 month died from multi-organ failure [5]
51/M pulmonary and urinary tract infections with bacteraemia malignancy, peritoneal dialysis TMP-SMX <2 months died from underlying malignancy [21]
59/F soft-tissue abscess HSCT recipient treated for GVHD TMP-SMX 1 year success our case
Abbreviations: AIDS, acquired immunodeficiency syndrome; GVHD, graft-versus-host disease; HIV, human immunodeficiency virus; HSCT, haematopoietic stem cell transplantation; SLE, systemic lupus erythematosus; TMP-SMX, trimethoprim-sulfamethoxazole.
Mean age was 55 years, and 29% were women. Pulmonary infections accounted for 17 of 24 infections, with abscesses being the second most common (3 of 24). In total, 25% had previous solid organ transplantations, 17% of patients had undergone haematopoietic stem cell transplantation and were undergoing treatment for GVHD, and 13% were people living with human immunodeficiency virus. The duration of treatment ranged from 3 weeks to >6 years. Trimethoprim-sulfamethoxazole monotherapy was used as initial anti-nocardial therapy for 13 of 24 individuals and led to treatment success in 9 of 13 (69%) of them. Combination therapy or other monotherapy (e.g. amoxicillin) was successful for six of eight (75%) individuals. The number of patients was too small to determine whether the difference in outcome is statistically significant.
Overall, N. veterana has a predilection for causing pulmonary infections in individuals with immunocompromising conditions [[4], [5], [6], [7],[15], [16], [17], [18], [19], [20]], and trimethoprim-sulfamethoxazole is commonly used to treat infections caused by Nocardia spp. [1]. When planning management for an immunocompromised host, a prolonged treatment duration is recommended. For our patient, the concurrent use of immunosuppressive therapy to manage GVHD heightened her susceptibility to N. veterana infection, and disseminated disease was fortunately averted by extended antibiotic therapy. The rising prevalence of immunocompromising conditions warrants increased vigilance for infections caused by atypical or opportunistic pathogens.
Conflict of interest
The authors declare no conflicts of interest. | Recovered | ReactionOutcome | CC BY-NC-ND | 33456780 | 19,015,718 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abdominal pain'. | Evolution of chest CT scan manifestations in a patient recovered from COVID-19 severe pneumonia with acute respiratory distress syndrome.
A male patient with severe pneumonia due to coronavirus disease 2019 (COVID-19) had acute respiratory distress syndrome (ARDS) which developed in the second week since the first symptoms and improved without mechanical ventilation. The patient had epilepsy as a comorbid disease and his routinely consumed antiepileptic drugs were likely to cause alterations of the immune system. Ground-glass opacity (GGO), consolidation, and reticular pattern are typical radiological features of COVID-19 pneumonia. Less common findings were septal thickening, bronchiectasis, pleural thickening, and subpleural involvement. These radiological abnormalities evolve throughout the course of the disease. In this case report, a GGO lesion was seen in thin-section CT scans on the 30th and 45th day since the onset of symptoms. The consolidation subsided with time and on the 65th day, minimal GGO was seen in CT scan without pulmonary fibrosis and bronchiectasis.
1 Introduction
At the end of December 2019, several cases of pneumonia of unknown etiology were seen in several hospitals in Wuhan city, China. Those acute respiratory infections were eventually known to be caused by coronavirus infection (nCoV2) and were officially entitled as coronavirus disease 2019 (COVID-19) by World Health Organization (WHO) [1,2] (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 Chest CT scan on the 30th day of the onset of symptoms (axial and coronal views): Multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions. A pleural band was seen in the lower posterior part of both lungs, and traction bronchiectasis.
Fig. 1
Fig. 2 Chest CT scan on the 45th day of the onset of symptoms (axial and coronal views): GGO was still visible in the posterior and peripheral part of both lungs (improvement compared to the previous CT), with less bronchiectasis and fibrosis.
Fig. 2
Fig. 3 Chest CT scan on the 65th day of the onset of symptoms: (a). Minimal GGO was seen in the inspiration phase, and (b). On the expiration phase, an “enhancement” of GGO lesion was seen due to an increase of intrathoracic pressure without the sign of “air-trapping”.
Fig. 3
Symptoms that are often found in SARS-CoV2 infection are fever and dry cough. Some patients complain of sore throat, runny nose, anosmia, or diarrhea. Based on the data of hospitalized patients, the majority of COVID 19 cases (around 80%) presented without symptoms (asymptomatic) or with mild symptoms, while the rest of the cases had severe symptoms or critical condition [2]. In severe cases, patients complain of shortness of breath and/or had hypoxemia 1 week after the onset of the disease, and promptly develop into acute respiratory distress syndrome (ARDS), septic shock, and death [3]. Ground-glass opacity (GGO), consolidation, reticular pattern are typical radiological features of COVID-19 pneumonia. In survived patients, these radiological features subsided or disappear [4,5].
2 Case presentation
A 35-year-old man came to the hospital with the chief complaint of fever for 5 days. On the sixth day since the onset of fever, the patient complained of coughing when deep inhaling, coughing up phlegm especially after a shower, shortness of breath, odynophagia, and he went to the emergency room. He also complained of nausea, without vomiting, abdominal pain, and diarrhea. The patient had a history of epilepsy since 12 years-old, routinely taking phenytoin and divalproex sodium.
On physical examination, the patient looks dyspnea with respiration rate 20–21 x/min, temperature 37.3 °C, blood pressure 120/80 mmHg, heart rate 108 x/min, chest X-ray revealed peripheral bilateral patchy consolidation, normal laboratory results, CD4 result 322 cells/mm3 (range 410–1.590 cells/mm3). During hospitalization, the patient was given oxygen 2–4 L/min with a nasal cannula. On the 9th day since the onset of symptoms, the patient complained of worsening shortness of breath and his peripheral oxygen saturation was 88% (8 L/min oxygen therapy with face mask), oxygen therapy was increased to 10–12 L/min with non-rebreathing mask and his peripheral oxygen saturation gradually rose to 95%. The result of blood gas analysis (BGA) was: pH 7.43, PaCO2 38.3, PaO2 88.6, HCO3-25, BE 1.0, SaO2 97.3%, (A-a)DO2 153.3, PaO2/FiO2 2.3 with FiO240%. The result of BGA obtained the following day was: pH 7.49, PaCO2 41.7, PaO2 77.0, HCO3-31.2, BE 7.2, SaO2 96.3%, (A-a)DO2 568.1, PaO2/FiO2 0.78 with FiO2 99%. PCR results for SARS-CoV 2 were positive on days 8 and 14 since the onset of the chief complaint. This report has been granted the patient's approval for publication.
A chest computed tomography (CT) scan was performed on supine position with a 64-slice LightSpeed VCT GE Healthcare with a single breath-hold post of inspiration, except for the last CT scan done in two inspirational and expiratory phases. The image was reconstructed with a thickness of 1.2 mm. On the 30th day of the onset of symptoms, a chest CT scan revealed multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions, scantily in the upper left and central right lung, a pleural band in the lower posterior part of both lungs, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma.
On the 45th day of the onset of symptom; GGO was still visible in the peripheral posterior part of both lung (an improvement was seen compared to the previous CT though), the subpleural band was seen in the peripheral posterior part of both lung, there was no visible vascular thickening. Improvement was also seen as the disappearance of bronchiectasis and its surrounding fibrosis. Day 65th chest CT scan illustrated thinner GGO compared to previous CT, without fibrosis or bronchiectasis.
3 Discussion
We presented a case of severe COVID-19 pneumonia complicated with acute respiratory distress syndrome (ARDS) which was diagnosed with WHO criteria [6] who recovered with minimal GGO lesion outcome. ARDS is one of the COVID pneumonia complications with high mortality [7]. Age, high body temperature, comorbidities, neutrophilia, lymphocytopenia, index of impaired organ function, increased index of inflammation, and disorders of coagulopathy are risk factors for ARDS [7]. This patient experienced clinical and oxygenation improvement with medical therapy without mechanical ventilation. He had epilepsy since 12 years-old (rarely having seizure episode) as a comorbid and routinely consumes phenytoin and divalproex sodium. Antiepileptic drugs are known to have an immunosuppressant effect. Carbamazepine or valproic acid affects the concentration of cytokines in the blood. Increased proinflammatory cytokines can lead to immune system disorders [8].
Chest CT scan plays an important role in the diagnosis and follow-up of COVID-19 cases [9]. Early features of thin-section CT in COVID-19 cases are predominantly GGO with reticular pattern and/or interlobar septal thickening. Changes in chest CT scan images in patients with COVID-19 pneumonia begin with a predominance of ground-glass opacity at 0–4 days of the onset of symptom, crazy-paving (reticular) pattern at 5–8 days, consolidation at 9–13 days, and consolidation with a gradual resolution at ≥14 days, but in this phase, a diffuse GGO can be seen as a manifestation of consolidation absorption [10].
Radiological evolution in COVID-19 pneumonia is generally consistent with the clinical course. Shi et al. [5] reported 4 radiological patterns up to week 3 of the disease. 1) Initial progression until the peak which was followed by radiological improvement (46%) and 92% of patients were discharged from the hospital, 2) Radiologically worsened (32%) followed by 11% deaths, 3) Radiologically improved (14%), 63% of patients discharged from the hospital with a median of 19 days hospitalization, 4). No alteration radiologically (9%).
Thin-section chest CT scan with full inspiration since 30th day since the onset of symptoms in this patient showed GGO in both of the lung, pleural band, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma. These findings were consistent with his clinical conditions (shortness of breath during exertion, peripheral oxygen saturation 93–95% on room air, heart rate 110–112 x/min). Improvement of lung sequelae was seen on the 45th day, CT scan results were still dominated by GGO, however less bronchiectasis and fibrosis. The complaint of shortness of breath had subsided, peripheral oxygen saturation 97–98%, heart rate 84–88 x/min, and RT-PCR result had converted to negative. CT scan result of the 65th day revealed minimal GGO, no fibrosis nor air trapping was seen in the thin-section expiratory phase of the CT scan as commonly found in the severe acute respiratory syndrome (SARS) cases [11].
4 Conclusion
We presented a COVID-19 severe pneumonia case with neurological diseases comorbid (epilepsy controlled with antiepileptic drugs) which was complicated by ARDS. High body temperature, neutrophilia, lymphocytopenia, decreased CD4 T cells are risk factors for ARDS. Three follow-ups thin-section chest CT scan since the onset of symptoms revealed an improvement and the outcome was minimal GGO without pulmonary fibrosis or bronchiectasis.
Declaration of competing interest
There was no conflict of interest in this study. No funding was received for this study. Written informed consent was obtained for publication of this case report.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Acknowledgement
none.
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101342. | DIVALPROEX SODIUM, PHENYTOIN SODIUM | DrugsGivenReaction | CC BY-NC-ND | 33457203 | 19,948,680 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute respiratory distress syndrome'. | Evolution of chest CT scan manifestations in a patient recovered from COVID-19 severe pneumonia with acute respiratory distress syndrome.
A male patient with severe pneumonia due to coronavirus disease 2019 (COVID-19) had acute respiratory distress syndrome (ARDS) which developed in the second week since the first symptoms and improved without mechanical ventilation. The patient had epilepsy as a comorbid disease and his routinely consumed antiepileptic drugs were likely to cause alterations of the immune system. Ground-glass opacity (GGO), consolidation, and reticular pattern are typical radiological features of COVID-19 pneumonia. Less common findings were septal thickening, bronchiectasis, pleural thickening, and subpleural involvement. These radiological abnormalities evolve throughout the course of the disease. In this case report, a GGO lesion was seen in thin-section CT scans on the 30th and 45th day since the onset of symptoms. The consolidation subsided with time and on the 65th day, minimal GGO was seen in CT scan without pulmonary fibrosis and bronchiectasis.
1 Introduction
At the end of December 2019, several cases of pneumonia of unknown etiology were seen in several hospitals in Wuhan city, China. Those acute respiratory infections were eventually known to be caused by coronavirus infection (nCoV2) and were officially entitled as coronavirus disease 2019 (COVID-19) by World Health Organization (WHO) [1,2] (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 Chest CT scan on the 30th day of the onset of symptoms (axial and coronal views): Multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions. A pleural band was seen in the lower posterior part of both lungs, and traction bronchiectasis.
Fig. 1
Fig. 2 Chest CT scan on the 45th day of the onset of symptoms (axial and coronal views): GGO was still visible in the posterior and peripheral part of both lungs (improvement compared to the previous CT), with less bronchiectasis and fibrosis.
Fig. 2
Fig. 3 Chest CT scan on the 65th day of the onset of symptoms: (a). Minimal GGO was seen in the inspiration phase, and (b). On the expiration phase, an “enhancement” of GGO lesion was seen due to an increase of intrathoracic pressure without the sign of “air-trapping”.
Fig. 3
Symptoms that are often found in SARS-CoV2 infection are fever and dry cough. Some patients complain of sore throat, runny nose, anosmia, or diarrhea. Based on the data of hospitalized patients, the majority of COVID 19 cases (around 80%) presented without symptoms (asymptomatic) or with mild symptoms, while the rest of the cases had severe symptoms or critical condition [2]. In severe cases, patients complain of shortness of breath and/or had hypoxemia 1 week after the onset of the disease, and promptly develop into acute respiratory distress syndrome (ARDS), septic shock, and death [3]. Ground-glass opacity (GGO), consolidation, reticular pattern are typical radiological features of COVID-19 pneumonia. In survived patients, these radiological features subsided or disappear [4,5].
2 Case presentation
A 35-year-old man came to the hospital with the chief complaint of fever for 5 days. On the sixth day since the onset of fever, the patient complained of coughing when deep inhaling, coughing up phlegm especially after a shower, shortness of breath, odynophagia, and he went to the emergency room. He also complained of nausea, without vomiting, abdominal pain, and diarrhea. The patient had a history of epilepsy since 12 years-old, routinely taking phenytoin and divalproex sodium.
On physical examination, the patient looks dyspnea with respiration rate 20–21 x/min, temperature 37.3 °C, blood pressure 120/80 mmHg, heart rate 108 x/min, chest X-ray revealed peripheral bilateral patchy consolidation, normal laboratory results, CD4 result 322 cells/mm3 (range 410–1.590 cells/mm3). During hospitalization, the patient was given oxygen 2–4 L/min with a nasal cannula. On the 9th day since the onset of symptoms, the patient complained of worsening shortness of breath and his peripheral oxygen saturation was 88% (8 L/min oxygen therapy with face mask), oxygen therapy was increased to 10–12 L/min with non-rebreathing mask and his peripheral oxygen saturation gradually rose to 95%. The result of blood gas analysis (BGA) was: pH 7.43, PaCO2 38.3, PaO2 88.6, HCO3-25, BE 1.0, SaO2 97.3%, (A-a)DO2 153.3, PaO2/FiO2 2.3 with FiO240%. The result of BGA obtained the following day was: pH 7.49, PaCO2 41.7, PaO2 77.0, HCO3-31.2, BE 7.2, SaO2 96.3%, (A-a)DO2 568.1, PaO2/FiO2 0.78 with FiO2 99%. PCR results for SARS-CoV 2 were positive on days 8 and 14 since the onset of the chief complaint. This report has been granted the patient's approval for publication.
A chest computed tomography (CT) scan was performed on supine position with a 64-slice LightSpeed VCT GE Healthcare with a single breath-hold post of inspiration, except for the last CT scan done in two inspirational and expiratory phases. The image was reconstructed with a thickness of 1.2 mm. On the 30th day of the onset of symptoms, a chest CT scan revealed multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions, scantily in the upper left and central right lung, a pleural band in the lower posterior part of both lungs, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma.
On the 45th day of the onset of symptom; GGO was still visible in the peripheral posterior part of both lung (an improvement was seen compared to the previous CT though), the subpleural band was seen in the peripheral posterior part of both lung, there was no visible vascular thickening. Improvement was also seen as the disappearance of bronchiectasis and its surrounding fibrosis. Day 65th chest CT scan illustrated thinner GGO compared to previous CT, without fibrosis or bronchiectasis.
3 Discussion
We presented a case of severe COVID-19 pneumonia complicated with acute respiratory distress syndrome (ARDS) which was diagnosed with WHO criteria [6] who recovered with minimal GGO lesion outcome. ARDS is one of the COVID pneumonia complications with high mortality [7]. Age, high body temperature, comorbidities, neutrophilia, lymphocytopenia, index of impaired organ function, increased index of inflammation, and disorders of coagulopathy are risk factors for ARDS [7]. This patient experienced clinical and oxygenation improvement with medical therapy without mechanical ventilation. He had epilepsy since 12 years-old (rarely having seizure episode) as a comorbid and routinely consumes phenytoin and divalproex sodium. Antiepileptic drugs are known to have an immunosuppressant effect. Carbamazepine or valproic acid affects the concentration of cytokines in the blood. Increased proinflammatory cytokines can lead to immune system disorders [8].
Chest CT scan plays an important role in the diagnosis and follow-up of COVID-19 cases [9]. Early features of thin-section CT in COVID-19 cases are predominantly GGO with reticular pattern and/or interlobar septal thickening. Changes in chest CT scan images in patients with COVID-19 pneumonia begin with a predominance of ground-glass opacity at 0–4 days of the onset of symptom, crazy-paving (reticular) pattern at 5–8 days, consolidation at 9–13 days, and consolidation with a gradual resolution at ≥14 days, but in this phase, a diffuse GGO can be seen as a manifestation of consolidation absorption [10].
Radiological evolution in COVID-19 pneumonia is generally consistent with the clinical course. Shi et al. [5] reported 4 radiological patterns up to week 3 of the disease. 1) Initial progression until the peak which was followed by radiological improvement (46%) and 92% of patients were discharged from the hospital, 2) Radiologically worsened (32%) followed by 11% deaths, 3) Radiologically improved (14%), 63% of patients discharged from the hospital with a median of 19 days hospitalization, 4). No alteration radiologically (9%).
Thin-section chest CT scan with full inspiration since 30th day since the onset of symptoms in this patient showed GGO in both of the lung, pleural band, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma. These findings were consistent with his clinical conditions (shortness of breath during exertion, peripheral oxygen saturation 93–95% on room air, heart rate 110–112 x/min). Improvement of lung sequelae was seen on the 45th day, CT scan results were still dominated by GGO, however less bronchiectasis and fibrosis. The complaint of shortness of breath had subsided, peripheral oxygen saturation 97–98%, heart rate 84–88 x/min, and RT-PCR result had converted to negative. CT scan result of the 65th day revealed minimal GGO, no fibrosis nor air trapping was seen in the thin-section expiratory phase of the CT scan as commonly found in the severe acute respiratory syndrome (SARS) cases [11].
4 Conclusion
We presented a COVID-19 severe pneumonia case with neurological diseases comorbid (epilepsy controlled with antiepileptic drugs) which was complicated by ARDS. High body temperature, neutrophilia, lymphocytopenia, decreased CD4 T cells are risk factors for ARDS. Three follow-ups thin-section chest CT scan since the onset of symptoms revealed an improvement and the outcome was minimal GGO without pulmonary fibrosis or bronchiectasis.
Declaration of competing interest
There was no conflict of interest in this study. No funding was received for this study. Written informed consent was obtained for publication of this case report.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Acknowledgement
none.
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101342. | DIVALPROEX SODIUM, PHENYTOIN | DrugsGivenReaction | CC BY-NC-ND | 33457203 | 18,940,086 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Bronchiectasis'. | Evolution of chest CT scan manifestations in a patient recovered from COVID-19 severe pneumonia with acute respiratory distress syndrome.
A male patient with severe pneumonia due to coronavirus disease 2019 (COVID-19) had acute respiratory distress syndrome (ARDS) which developed in the second week since the first symptoms and improved without mechanical ventilation. The patient had epilepsy as a comorbid disease and his routinely consumed antiepileptic drugs were likely to cause alterations of the immune system. Ground-glass opacity (GGO), consolidation, and reticular pattern are typical radiological features of COVID-19 pneumonia. Less common findings were septal thickening, bronchiectasis, pleural thickening, and subpleural involvement. These radiological abnormalities evolve throughout the course of the disease. In this case report, a GGO lesion was seen in thin-section CT scans on the 30th and 45th day since the onset of symptoms. The consolidation subsided with time and on the 65th day, minimal GGO was seen in CT scan without pulmonary fibrosis and bronchiectasis.
1 Introduction
At the end of December 2019, several cases of pneumonia of unknown etiology were seen in several hospitals in Wuhan city, China. Those acute respiratory infections were eventually known to be caused by coronavirus infection (nCoV2) and were officially entitled as coronavirus disease 2019 (COVID-19) by World Health Organization (WHO) [1,2] (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 Chest CT scan on the 30th day of the onset of symptoms (axial and coronal views): Multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions. A pleural band was seen in the lower posterior part of both lungs, and traction bronchiectasis.
Fig. 1
Fig. 2 Chest CT scan on the 45th day of the onset of symptoms (axial and coronal views): GGO was still visible in the posterior and peripheral part of both lungs (improvement compared to the previous CT), with less bronchiectasis and fibrosis.
Fig. 2
Fig. 3 Chest CT scan on the 65th day of the onset of symptoms: (a). Minimal GGO was seen in the inspiration phase, and (b). On the expiration phase, an “enhancement” of GGO lesion was seen due to an increase of intrathoracic pressure without the sign of “air-trapping”.
Fig. 3
Symptoms that are often found in SARS-CoV2 infection are fever and dry cough. Some patients complain of sore throat, runny nose, anosmia, or diarrhea. Based on the data of hospitalized patients, the majority of COVID 19 cases (around 80%) presented without symptoms (asymptomatic) or with mild symptoms, while the rest of the cases had severe symptoms or critical condition [2]. In severe cases, patients complain of shortness of breath and/or had hypoxemia 1 week after the onset of the disease, and promptly develop into acute respiratory distress syndrome (ARDS), septic shock, and death [3]. Ground-glass opacity (GGO), consolidation, reticular pattern are typical radiological features of COVID-19 pneumonia. In survived patients, these radiological features subsided or disappear [4,5].
2 Case presentation
A 35-year-old man came to the hospital with the chief complaint of fever for 5 days. On the sixth day since the onset of fever, the patient complained of coughing when deep inhaling, coughing up phlegm especially after a shower, shortness of breath, odynophagia, and he went to the emergency room. He also complained of nausea, without vomiting, abdominal pain, and diarrhea. The patient had a history of epilepsy since 12 years-old, routinely taking phenytoin and divalproex sodium.
On physical examination, the patient looks dyspnea with respiration rate 20–21 x/min, temperature 37.3 °C, blood pressure 120/80 mmHg, heart rate 108 x/min, chest X-ray revealed peripheral bilateral patchy consolidation, normal laboratory results, CD4 result 322 cells/mm3 (range 410–1.590 cells/mm3). During hospitalization, the patient was given oxygen 2–4 L/min with a nasal cannula. On the 9th day since the onset of symptoms, the patient complained of worsening shortness of breath and his peripheral oxygen saturation was 88% (8 L/min oxygen therapy with face mask), oxygen therapy was increased to 10–12 L/min with non-rebreathing mask and his peripheral oxygen saturation gradually rose to 95%. The result of blood gas analysis (BGA) was: pH 7.43, PaCO2 38.3, PaO2 88.6, HCO3-25, BE 1.0, SaO2 97.3%, (A-a)DO2 153.3, PaO2/FiO2 2.3 with FiO240%. The result of BGA obtained the following day was: pH 7.49, PaCO2 41.7, PaO2 77.0, HCO3-31.2, BE 7.2, SaO2 96.3%, (A-a)DO2 568.1, PaO2/FiO2 0.78 with FiO2 99%. PCR results for SARS-CoV 2 were positive on days 8 and 14 since the onset of the chief complaint. This report has been granted the patient's approval for publication.
A chest computed tomography (CT) scan was performed on supine position with a 64-slice LightSpeed VCT GE Healthcare with a single breath-hold post of inspiration, except for the last CT scan done in two inspirational and expiratory phases. The image was reconstructed with a thickness of 1.2 mm. On the 30th day of the onset of symptoms, a chest CT scan revealed multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions, scantily in the upper left and central right lung, a pleural band in the lower posterior part of both lungs, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma.
On the 45th day of the onset of symptom; GGO was still visible in the peripheral posterior part of both lung (an improvement was seen compared to the previous CT though), the subpleural band was seen in the peripheral posterior part of both lung, there was no visible vascular thickening. Improvement was also seen as the disappearance of bronchiectasis and its surrounding fibrosis. Day 65th chest CT scan illustrated thinner GGO compared to previous CT, without fibrosis or bronchiectasis.
3 Discussion
We presented a case of severe COVID-19 pneumonia complicated with acute respiratory distress syndrome (ARDS) which was diagnosed with WHO criteria [6] who recovered with minimal GGO lesion outcome. ARDS is one of the COVID pneumonia complications with high mortality [7]. Age, high body temperature, comorbidities, neutrophilia, lymphocytopenia, index of impaired organ function, increased index of inflammation, and disorders of coagulopathy are risk factors for ARDS [7]. This patient experienced clinical and oxygenation improvement with medical therapy without mechanical ventilation. He had epilepsy since 12 years-old (rarely having seizure episode) as a comorbid and routinely consumes phenytoin and divalproex sodium. Antiepileptic drugs are known to have an immunosuppressant effect. Carbamazepine or valproic acid affects the concentration of cytokines in the blood. Increased proinflammatory cytokines can lead to immune system disorders [8].
Chest CT scan plays an important role in the diagnosis and follow-up of COVID-19 cases [9]. Early features of thin-section CT in COVID-19 cases are predominantly GGO with reticular pattern and/or interlobar septal thickening. Changes in chest CT scan images in patients with COVID-19 pneumonia begin with a predominance of ground-glass opacity at 0–4 days of the onset of symptom, crazy-paving (reticular) pattern at 5–8 days, consolidation at 9–13 days, and consolidation with a gradual resolution at ≥14 days, but in this phase, a diffuse GGO can be seen as a manifestation of consolidation absorption [10].
Radiological evolution in COVID-19 pneumonia is generally consistent with the clinical course. Shi et al. [5] reported 4 radiological patterns up to week 3 of the disease. 1) Initial progression until the peak which was followed by radiological improvement (46%) and 92% of patients were discharged from the hospital, 2) Radiologically worsened (32%) followed by 11% deaths, 3) Radiologically improved (14%), 63% of patients discharged from the hospital with a median of 19 days hospitalization, 4). No alteration radiologically (9%).
Thin-section chest CT scan with full inspiration since 30th day since the onset of symptoms in this patient showed GGO in both of the lung, pleural band, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma. These findings were consistent with his clinical conditions (shortness of breath during exertion, peripheral oxygen saturation 93–95% on room air, heart rate 110–112 x/min). Improvement of lung sequelae was seen on the 45th day, CT scan results were still dominated by GGO, however less bronchiectasis and fibrosis. The complaint of shortness of breath had subsided, peripheral oxygen saturation 97–98%, heart rate 84–88 x/min, and RT-PCR result had converted to negative. CT scan result of the 65th day revealed minimal GGO, no fibrosis nor air trapping was seen in the thin-section expiratory phase of the CT scan as commonly found in the severe acute respiratory syndrome (SARS) cases [11].
4 Conclusion
We presented a COVID-19 severe pneumonia case with neurological diseases comorbid (epilepsy controlled with antiepileptic drugs) which was complicated by ARDS. High body temperature, neutrophilia, lymphocytopenia, decreased CD4 T cells are risk factors for ARDS. Three follow-ups thin-section chest CT scan since the onset of symptoms revealed an improvement and the outcome was minimal GGO without pulmonary fibrosis or bronchiectasis.
Declaration of competing interest
There was no conflict of interest in this study. No funding was received for this study. Written informed consent was obtained for publication of this case report.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Acknowledgement
none.
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101342. | DIVALPROEX SODIUM, PHENYTOIN SODIUM | DrugsGivenReaction | CC BY-NC-ND | 33457203 | 19,948,680 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'COVID-19 pneumonia'. | Evolution of chest CT scan manifestations in a patient recovered from COVID-19 severe pneumonia with acute respiratory distress syndrome.
A male patient with severe pneumonia due to coronavirus disease 2019 (COVID-19) had acute respiratory distress syndrome (ARDS) which developed in the second week since the first symptoms and improved without mechanical ventilation. The patient had epilepsy as a comorbid disease and his routinely consumed antiepileptic drugs were likely to cause alterations of the immune system. Ground-glass opacity (GGO), consolidation, and reticular pattern are typical radiological features of COVID-19 pneumonia. Less common findings were septal thickening, bronchiectasis, pleural thickening, and subpleural involvement. These radiological abnormalities evolve throughout the course of the disease. In this case report, a GGO lesion was seen in thin-section CT scans on the 30th and 45th day since the onset of symptoms. The consolidation subsided with time and on the 65th day, minimal GGO was seen in CT scan without pulmonary fibrosis and bronchiectasis.
1 Introduction
At the end of December 2019, several cases of pneumonia of unknown etiology were seen in several hospitals in Wuhan city, China. Those acute respiratory infections were eventually known to be caused by coronavirus infection (nCoV2) and were officially entitled as coronavirus disease 2019 (COVID-19) by World Health Organization (WHO) [1,2] (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 Chest CT scan on the 30th day of the onset of symptoms (axial and coronal views): Multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions. A pleural band was seen in the lower posterior part of both lungs, and traction bronchiectasis.
Fig. 1
Fig. 2 Chest CT scan on the 45th day of the onset of symptoms (axial and coronal views): GGO was still visible in the posterior and peripheral part of both lungs (improvement compared to the previous CT), with less bronchiectasis and fibrosis.
Fig. 2
Fig. 3 Chest CT scan on the 65th day of the onset of symptoms: (a). Minimal GGO was seen in the inspiration phase, and (b). On the expiration phase, an “enhancement” of GGO lesion was seen due to an increase of intrathoracic pressure without the sign of “air-trapping”.
Fig. 3
Symptoms that are often found in SARS-CoV2 infection are fever and dry cough. Some patients complain of sore throat, runny nose, anosmia, or diarrhea. Based on the data of hospitalized patients, the majority of COVID 19 cases (around 80%) presented without symptoms (asymptomatic) or with mild symptoms, while the rest of the cases had severe symptoms or critical condition [2]. In severe cases, patients complain of shortness of breath and/or had hypoxemia 1 week after the onset of the disease, and promptly develop into acute respiratory distress syndrome (ARDS), septic shock, and death [3]. Ground-glass opacity (GGO), consolidation, reticular pattern are typical radiological features of COVID-19 pneumonia. In survived patients, these radiological features subsided or disappear [4,5].
2 Case presentation
A 35-year-old man came to the hospital with the chief complaint of fever for 5 days. On the sixth day since the onset of fever, the patient complained of coughing when deep inhaling, coughing up phlegm especially after a shower, shortness of breath, odynophagia, and he went to the emergency room. He also complained of nausea, without vomiting, abdominal pain, and diarrhea. The patient had a history of epilepsy since 12 years-old, routinely taking phenytoin and divalproex sodium.
On physical examination, the patient looks dyspnea with respiration rate 20–21 x/min, temperature 37.3 °C, blood pressure 120/80 mmHg, heart rate 108 x/min, chest X-ray revealed peripheral bilateral patchy consolidation, normal laboratory results, CD4 result 322 cells/mm3 (range 410–1.590 cells/mm3). During hospitalization, the patient was given oxygen 2–4 L/min with a nasal cannula. On the 9th day since the onset of symptoms, the patient complained of worsening shortness of breath and his peripheral oxygen saturation was 88% (8 L/min oxygen therapy with face mask), oxygen therapy was increased to 10–12 L/min with non-rebreathing mask and his peripheral oxygen saturation gradually rose to 95%. The result of blood gas analysis (BGA) was: pH 7.43, PaCO2 38.3, PaO2 88.6, HCO3-25, BE 1.0, SaO2 97.3%, (A-a)DO2 153.3, PaO2/FiO2 2.3 with FiO240%. The result of BGA obtained the following day was: pH 7.49, PaCO2 41.7, PaO2 77.0, HCO3-31.2, BE 7.2, SaO2 96.3%, (A-a)DO2 568.1, PaO2/FiO2 0.78 with FiO2 99%. PCR results for SARS-CoV 2 were positive on days 8 and 14 since the onset of the chief complaint. This report has been granted the patient's approval for publication.
A chest computed tomography (CT) scan was performed on supine position with a 64-slice LightSpeed VCT GE Healthcare with a single breath-hold post of inspiration, except for the last CT scan done in two inspirational and expiratory phases. The image was reconstructed with a thickness of 1.2 mm. On the 30th day of the onset of symptoms, a chest CT scan revealed multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions, scantily in the upper left and central right lung, a pleural band in the lower posterior part of both lungs, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma.
On the 45th day of the onset of symptom; GGO was still visible in the peripheral posterior part of both lung (an improvement was seen compared to the previous CT though), the subpleural band was seen in the peripheral posterior part of both lung, there was no visible vascular thickening. Improvement was also seen as the disappearance of bronchiectasis and its surrounding fibrosis. Day 65th chest CT scan illustrated thinner GGO compared to previous CT, without fibrosis or bronchiectasis.
3 Discussion
We presented a case of severe COVID-19 pneumonia complicated with acute respiratory distress syndrome (ARDS) which was diagnosed with WHO criteria [6] who recovered with minimal GGO lesion outcome. ARDS is one of the COVID pneumonia complications with high mortality [7]. Age, high body temperature, comorbidities, neutrophilia, lymphocytopenia, index of impaired organ function, increased index of inflammation, and disorders of coagulopathy are risk factors for ARDS [7]. This patient experienced clinical and oxygenation improvement with medical therapy without mechanical ventilation. He had epilepsy since 12 years-old (rarely having seizure episode) as a comorbid and routinely consumes phenytoin and divalproex sodium. Antiepileptic drugs are known to have an immunosuppressant effect. Carbamazepine or valproic acid affects the concentration of cytokines in the blood. Increased proinflammatory cytokines can lead to immune system disorders [8].
Chest CT scan plays an important role in the diagnosis and follow-up of COVID-19 cases [9]. Early features of thin-section CT in COVID-19 cases are predominantly GGO with reticular pattern and/or interlobar septal thickening. Changes in chest CT scan images in patients with COVID-19 pneumonia begin with a predominance of ground-glass opacity at 0–4 days of the onset of symptom, crazy-paving (reticular) pattern at 5–8 days, consolidation at 9–13 days, and consolidation with a gradual resolution at ≥14 days, but in this phase, a diffuse GGO can be seen as a manifestation of consolidation absorption [10].
Radiological evolution in COVID-19 pneumonia is generally consistent with the clinical course. Shi et al. [5] reported 4 radiological patterns up to week 3 of the disease. 1) Initial progression until the peak which was followed by radiological improvement (46%) and 92% of patients were discharged from the hospital, 2) Radiologically worsened (32%) followed by 11% deaths, 3) Radiologically improved (14%), 63% of patients discharged from the hospital with a median of 19 days hospitalization, 4). No alteration radiologically (9%).
Thin-section chest CT scan with full inspiration since 30th day since the onset of symptoms in this patient showed GGO in both of the lung, pleural band, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma. These findings were consistent with his clinical conditions (shortness of breath during exertion, peripheral oxygen saturation 93–95% on room air, heart rate 110–112 x/min). Improvement of lung sequelae was seen on the 45th day, CT scan results were still dominated by GGO, however less bronchiectasis and fibrosis. The complaint of shortness of breath had subsided, peripheral oxygen saturation 97–98%, heart rate 84–88 x/min, and RT-PCR result had converted to negative. CT scan result of the 65th day revealed minimal GGO, no fibrosis nor air trapping was seen in the thin-section expiratory phase of the CT scan as commonly found in the severe acute respiratory syndrome (SARS) cases [11].
4 Conclusion
We presented a COVID-19 severe pneumonia case with neurological diseases comorbid (epilepsy controlled with antiepileptic drugs) which was complicated by ARDS. High body temperature, neutrophilia, lymphocytopenia, decreased CD4 T cells are risk factors for ARDS. Three follow-ups thin-section chest CT scan since the onset of symptoms revealed an improvement and the outcome was minimal GGO without pulmonary fibrosis or bronchiectasis.
Declaration of competing interest
There was no conflict of interest in this study. No funding was received for this study. Written informed consent was obtained for publication of this case report.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Acknowledgement
none.
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101342. | DIVALPROEX SODIUM, PHENYTOIN | DrugsGivenReaction | CC BY-NC-ND | 33457203 | 18,940,086 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cough'. | Evolution of chest CT scan manifestations in a patient recovered from COVID-19 severe pneumonia with acute respiratory distress syndrome.
A male patient with severe pneumonia due to coronavirus disease 2019 (COVID-19) had acute respiratory distress syndrome (ARDS) which developed in the second week since the first symptoms and improved without mechanical ventilation. The patient had epilepsy as a comorbid disease and his routinely consumed antiepileptic drugs were likely to cause alterations of the immune system. Ground-glass opacity (GGO), consolidation, and reticular pattern are typical radiological features of COVID-19 pneumonia. Less common findings were septal thickening, bronchiectasis, pleural thickening, and subpleural involvement. These radiological abnormalities evolve throughout the course of the disease. In this case report, a GGO lesion was seen in thin-section CT scans on the 30th and 45th day since the onset of symptoms. The consolidation subsided with time and on the 65th day, minimal GGO was seen in CT scan without pulmonary fibrosis and bronchiectasis.
1 Introduction
At the end of December 2019, several cases of pneumonia of unknown etiology were seen in several hospitals in Wuhan city, China. Those acute respiratory infections were eventually known to be caused by coronavirus infection (nCoV2) and were officially entitled as coronavirus disease 2019 (COVID-19) by World Health Organization (WHO) [1,2] (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 Chest CT scan on the 30th day of the onset of symptoms (axial and coronal views): Multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions. A pleural band was seen in the lower posterior part of both lungs, and traction bronchiectasis.
Fig. 1
Fig. 2 Chest CT scan on the 45th day of the onset of symptoms (axial and coronal views): GGO was still visible in the posterior and peripheral part of both lungs (improvement compared to the previous CT), with less bronchiectasis and fibrosis.
Fig. 2
Fig. 3 Chest CT scan on the 65th day of the onset of symptoms: (a). Minimal GGO was seen in the inspiration phase, and (b). On the expiration phase, an “enhancement” of GGO lesion was seen due to an increase of intrathoracic pressure without the sign of “air-trapping”.
Fig. 3
Symptoms that are often found in SARS-CoV2 infection are fever and dry cough. Some patients complain of sore throat, runny nose, anosmia, or diarrhea. Based on the data of hospitalized patients, the majority of COVID 19 cases (around 80%) presented without symptoms (asymptomatic) or with mild symptoms, while the rest of the cases had severe symptoms or critical condition [2]. In severe cases, patients complain of shortness of breath and/or had hypoxemia 1 week after the onset of the disease, and promptly develop into acute respiratory distress syndrome (ARDS), septic shock, and death [3]. Ground-glass opacity (GGO), consolidation, reticular pattern are typical radiological features of COVID-19 pneumonia. In survived patients, these radiological features subsided or disappear [4,5].
2 Case presentation
A 35-year-old man came to the hospital with the chief complaint of fever for 5 days. On the sixth day since the onset of fever, the patient complained of coughing when deep inhaling, coughing up phlegm especially after a shower, shortness of breath, odynophagia, and he went to the emergency room. He also complained of nausea, without vomiting, abdominal pain, and diarrhea. The patient had a history of epilepsy since 12 years-old, routinely taking phenytoin and divalproex sodium.
On physical examination, the patient looks dyspnea with respiration rate 20–21 x/min, temperature 37.3 °C, blood pressure 120/80 mmHg, heart rate 108 x/min, chest X-ray revealed peripheral bilateral patchy consolidation, normal laboratory results, CD4 result 322 cells/mm3 (range 410–1.590 cells/mm3). During hospitalization, the patient was given oxygen 2–4 L/min with a nasal cannula. On the 9th day since the onset of symptoms, the patient complained of worsening shortness of breath and his peripheral oxygen saturation was 88% (8 L/min oxygen therapy with face mask), oxygen therapy was increased to 10–12 L/min with non-rebreathing mask and his peripheral oxygen saturation gradually rose to 95%. The result of blood gas analysis (BGA) was: pH 7.43, PaCO2 38.3, PaO2 88.6, HCO3-25, BE 1.0, SaO2 97.3%, (A-a)DO2 153.3, PaO2/FiO2 2.3 with FiO240%. The result of BGA obtained the following day was: pH 7.49, PaCO2 41.7, PaO2 77.0, HCO3-31.2, BE 7.2, SaO2 96.3%, (A-a)DO2 568.1, PaO2/FiO2 0.78 with FiO2 99%. PCR results for SARS-CoV 2 were positive on days 8 and 14 since the onset of the chief complaint. This report has been granted the patient's approval for publication.
A chest computed tomography (CT) scan was performed on supine position with a 64-slice LightSpeed VCT GE Healthcare with a single breath-hold post of inspiration, except for the last CT scan done in two inspirational and expiratory phases. The image was reconstructed with a thickness of 1.2 mm. On the 30th day of the onset of symptoms, a chest CT scan revealed multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions, scantily in the upper left and central right lung, a pleural band in the lower posterior part of both lungs, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma.
On the 45th day of the onset of symptom; GGO was still visible in the peripheral posterior part of both lung (an improvement was seen compared to the previous CT though), the subpleural band was seen in the peripheral posterior part of both lung, there was no visible vascular thickening. Improvement was also seen as the disappearance of bronchiectasis and its surrounding fibrosis. Day 65th chest CT scan illustrated thinner GGO compared to previous CT, without fibrosis or bronchiectasis.
3 Discussion
We presented a case of severe COVID-19 pneumonia complicated with acute respiratory distress syndrome (ARDS) which was diagnosed with WHO criteria [6] who recovered with minimal GGO lesion outcome. ARDS is one of the COVID pneumonia complications with high mortality [7]. Age, high body temperature, comorbidities, neutrophilia, lymphocytopenia, index of impaired organ function, increased index of inflammation, and disorders of coagulopathy are risk factors for ARDS [7]. This patient experienced clinical and oxygenation improvement with medical therapy without mechanical ventilation. He had epilepsy since 12 years-old (rarely having seizure episode) as a comorbid and routinely consumes phenytoin and divalproex sodium. Antiepileptic drugs are known to have an immunosuppressant effect. Carbamazepine or valproic acid affects the concentration of cytokines in the blood. Increased proinflammatory cytokines can lead to immune system disorders [8].
Chest CT scan plays an important role in the diagnosis and follow-up of COVID-19 cases [9]. Early features of thin-section CT in COVID-19 cases are predominantly GGO with reticular pattern and/or interlobar septal thickening. Changes in chest CT scan images in patients with COVID-19 pneumonia begin with a predominance of ground-glass opacity at 0–4 days of the onset of symptom, crazy-paving (reticular) pattern at 5–8 days, consolidation at 9–13 days, and consolidation with a gradual resolution at ≥14 days, but in this phase, a diffuse GGO can be seen as a manifestation of consolidation absorption [10].
Radiological evolution in COVID-19 pneumonia is generally consistent with the clinical course. Shi et al. [5] reported 4 radiological patterns up to week 3 of the disease. 1) Initial progression until the peak which was followed by radiological improvement (46%) and 92% of patients were discharged from the hospital, 2) Radiologically worsened (32%) followed by 11% deaths, 3) Radiologically improved (14%), 63% of patients discharged from the hospital with a median of 19 days hospitalization, 4). No alteration radiologically (9%).
Thin-section chest CT scan with full inspiration since 30th day since the onset of symptoms in this patient showed GGO in both of the lung, pleural band, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma. These findings were consistent with his clinical conditions (shortness of breath during exertion, peripheral oxygen saturation 93–95% on room air, heart rate 110–112 x/min). Improvement of lung sequelae was seen on the 45th day, CT scan results were still dominated by GGO, however less bronchiectasis and fibrosis. The complaint of shortness of breath had subsided, peripheral oxygen saturation 97–98%, heart rate 84–88 x/min, and RT-PCR result had converted to negative. CT scan result of the 65th day revealed minimal GGO, no fibrosis nor air trapping was seen in the thin-section expiratory phase of the CT scan as commonly found in the severe acute respiratory syndrome (SARS) cases [11].
4 Conclusion
We presented a COVID-19 severe pneumonia case with neurological diseases comorbid (epilepsy controlled with antiepileptic drugs) which was complicated by ARDS. High body temperature, neutrophilia, lymphocytopenia, decreased CD4 T cells are risk factors for ARDS. Three follow-ups thin-section chest CT scan since the onset of symptoms revealed an improvement and the outcome was minimal GGO without pulmonary fibrosis or bronchiectasis.
Declaration of competing interest
There was no conflict of interest in this study. No funding was received for this study. Written informed consent was obtained for publication of this case report.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Acknowledgement
none.
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101342. | DIVALPROEX SODIUM, PHENYTOIN SODIUM | DrugsGivenReaction | CC BY-NC-ND | 33457203 | 19,948,680 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diarrhoea'. | Evolution of chest CT scan manifestations in a patient recovered from COVID-19 severe pneumonia with acute respiratory distress syndrome.
A male patient with severe pneumonia due to coronavirus disease 2019 (COVID-19) had acute respiratory distress syndrome (ARDS) which developed in the second week since the first symptoms and improved without mechanical ventilation. The patient had epilepsy as a comorbid disease and his routinely consumed antiepileptic drugs were likely to cause alterations of the immune system. Ground-glass opacity (GGO), consolidation, and reticular pattern are typical radiological features of COVID-19 pneumonia. Less common findings were septal thickening, bronchiectasis, pleural thickening, and subpleural involvement. These radiological abnormalities evolve throughout the course of the disease. In this case report, a GGO lesion was seen in thin-section CT scans on the 30th and 45th day since the onset of symptoms. The consolidation subsided with time and on the 65th day, minimal GGO was seen in CT scan without pulmonary fibrosis and bronchiectasis.
1 Introduction
At the end of December 2019, several cases of pneumonia of unknown etiology were seen in several hospitals in Wuhan city, China. Those acute respiratory infections were eventually known to be caused by coronavirus infection (nCoV2) and were officially entitled as coronavirus disease 2019 (COVID-19) by World Health Organization (WHO) [1,2] (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 Chest CT scan on the 30th day of the onset of symptoms (axial and coronal views): Multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions. A pleural band was seen in the lower posterior part of both lungs, and traction bronchiectasis.
Fig. 1
Fig. 2 Chest CT scan on the 45th day of the onset of symptoms (axial and coronal views): GGO was still visible in the posterior and peripheral part of both lungs (improvement compared to the previous CT), with less bronchiectasis and fibrosis.
Fig. 2
Fig. 3 Chest CT scan on the 65th day of the onset of symptoms: (a). Minimal GGO was seen in the inspiration phase, and (b). On the expiration phase, an “enhancement” of GGO lesion was seen due to an increase of intrathoracic pressure without the sign of “air-trapping”.
Fig. 3
Symptoms that are often found in SARS-CoV2 infection are fever and dry cough. Some patients complain of sore throat, runny nose, anosmia, or diarrhea. Based on the data of hospitalized patients, the majority of COVID 19 cases (around 80%) presented without symptoms (asymptomatic) or with mild symptoms, while the rest of the cases had severe symptoms or critical condition [2]. In severe cases, patients complain of shortness of breath and/or had hypoxemia 1 week after the onset of the disease, and promptly develop into acute respiratory distress syndrome (ARDS), septic shock, and death [3]. Ground-glass opacity (GGO), consolidation, reticular pattern are typical radiological features of COVID-19 pneumonia. In survived patients, these radiological features subsided or disappear [4,5].
2 Case presentation
A 35-year-old man came to the hospital with the chief complaint of fever for 5 days. On the sixth day since the onset of fever, the patient complained of coughing when deep inhaling, coughing up phlegm especially after a shower, shortness of breath, odynophagia, and he went to the emergency room. He also complained of nausea, without vomiting, abdominal pain, and diarrhea. The patient had a history of epilepsy since 12 years-old, routinely taking phenytoin and divalproex sodium.
On physical examination, the patient looks dyspnea with respiration rate 20–21 x/min, temperature 37.3 °C, blood pressure 120/80 mmHg, heart rate 108 x/min, chest X-ray revealed peripheral bilateral patchy consolidation, normal laboratory results, CD4 result 322 cells/mm3 (range 410–1.590 cells/mm3). During hospitalization, the patient was given oxygen 2–4 L/min with a nasal cannula. On the 9th day since the onset of symptoms, the patient complained of worsening shortness of breath and his peripheral oxygen saturation was 88% (8 L/min oxygen therapy with face mask), oxygen therapy was increased to 10–12 L/min with non-rebreathing mask and his peripheral oxygen saturation gradually rose to 95%. The result of blood gas analysis (BGA) was: pH 7.43, PaCO2 38.3, PaO2 88.6, HCO3-25, BE 1.0, SaO2 97.3%, (A-a)DO2 153.3, PaO2/FiO2 2.3 with FiO240%. The result of BGA obtained the following day was: pH 7.49, PaCO2 41.7, PaO2 77.0, HCO3-31.2, BE 7.2, SaO2 96.3%, (A-a)DO2 568.1, PaO2/FiO2 0.78 with FiO2 99%. PCR results for SARS-CoV 2 were positive on days 8 and 14 since the onset of the chief complaint. This report has been granted the patient's approval for publication.
A chest computed tomography (CT) scan was performed on supine position with a 64-slice LightSpeed VCT GE Healthcare with a single breath-hold post of inspiration, except for the last CT scan done in two inspirational and expiratory phases. The image was reconstructed with a thickness of 1.2 mm. On the 30th day of the onset of symptoms, a chest CT scan revealed multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions, scantily in the upper left and central right lung, a pleural band in the lower posterior part of both lungs, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma.
On the 45th day of the onset of symptom; GGO was still visible in the peripheral posterior part of both lung (an improvement was seen compared to the previous CT though), the subpleural band was seen in the peripheral posterior part of both lung, there was no visible vascular thickening. Improvement was also seen as the disappearance of bronchiectasis and its surrounding fibrosis. Day 65th chest CT scan illustrated thinner GGO compared to previous CT, without fibrosis or bronchiectasis.
3 Discussion
We presented a case of severe COVID-19 pneumonia complicated with acute respiratory distress syndrome (ARDS) which was diagnosed with WHO criteria [6] who recovered with minimal GGO lesion outcome. ARDS is one of the COVID pneumonia complications with high mortality [7]. Age, high body temperature, comorbidities, neutrophilia, lymphocytopenia, index of impaired organ function, increased index of inflammation, and disorders of coagulopathy are risk factors for ARDS [7]. This patient experienced clinical and oxygenation improvement with medical therapy without mechanical ventilation. He had epilepsy since 12 years-old (rarely having seizure episode) as a comorbid and routinely consumes phenytoin and divalproex sodium. Antiepileptic drugs are known to have an immunosuppressant effect. Carbamazepine or valproic acid affects the concentration of cytokines in the blood. Increased proinflammatory cytokines can lead to immune system disorders [8].
Chest CT scan plays an important role in the diagnosis and follow-up of COVID-19 cases [9]. Early features of thin-section CT in COVID-19 cases are predominantly GGO with reticular pattern and/or interlobar septal thickening. Changes in chest CT scan images in patients with COVID-19 pneumonia begin with a predominance of ground-glass opacity at 0–4 days of the onset of symptom, crazy-paving (reticular) pattern at 5–8 days, consolidation at 9–13 days, and consolidation with a gradual resolution at ≥14 days, but in this phase, a diffuse GGO can be seen as a manifestation of consolidation absorption [10].
Radiological evolution in COVID-19 pneumonia is generally consistent with the clinical course. Shi et al. [5] reported 4 radiological patterns up to week 3 of the disease. 1) Initial progression until the peak which was followed by radiological improvement (46%) and 92% of patients were discharged from the hospital, 2) Radiologically worsened (32%) followed by 11% deaths, 3) Radiologically improved (14%), 63% of patients discharged from the hospital with a median of 19 days hospitalization, 4). No alteration radiologically (9%).
Thin-section chest CT scan with full inspiration since 30th day since the onset of symptoms in this patient showed GGO in both of the lung, pleural band, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma. These findings were consistent with his clinical conditions (shortness of breath during exertion, peripheral oxygen saturation 93–95% on room air, heart rate 110–112 x/min). Improvement of lung sequelae was seen on the 45th day, CT scan results were still dominated by GGO, however less bronchiectasis and fibrosis. The complaint of shortness of breath had subsided, peripheral oxygen saturation 97–98%, heart rate 84–88 x/min, and RT-PCR result had converted to negative. CT scan result of the 65th day revealed minimal GGO, no fibrosis nor air trapping was seen in the thin-section expiratory phase of the CT scan as commonly found in the severe acute respiratory syndrome (SARS) cases [11].
4 Conclusion
We presented a COVID-19 severe pneumonia case with neurological diseases comorbid (epilepsy controlled with antiepileptic drugs) which was complicated by ARDS. High body temperature, neutrophilia, lymphocytopenia, decreased CD4 T cells are risk factors for ARDS. Three follow-ups thin-section chest CT scan since the onset of symptoms revealed an improvement and the outcome was minimal GGO without pulmonary fibrosis or bronchiectasis.
Declaration of competing interest
There was no conflict of interest in this study. No funding was received for this study. Written informed consent was obtained for publication of this case report.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Acknowledgement
none.
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101342. | DIVALPROEX SODIUM, PHENYTOIN SODIUM | DrugsGivenReaction | CC BY-NC-ND | 33457203 | 19,948,680 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dyspnoea'. | Evolution of chest CT scan manifestations in a patient recovered from COVID-19 severe pneumonia with acute respiratory distress syndrome.
A male patient with severe pneumonia due to coronavirus disease 2019 (COVID-19) had acute respiratory distress syndrome (ARDS) which developed in the second week since the first symptoms and improved without mechanical ventilation. The patient had epilepsy as a comorbid disease and his routinely consumed antiepileptic drugs were likely to cause alterations of the immune system. Ground-glass opacity (GGO), consolidation, and reticular pattern are typical radiological features of COVID-19 pneumonia. Less common findings were septal thickening, bronchiectasis, pleural thickening, and subpleural involvement. These radiological abnormalities evolve throughout the course of the disease. In this case report, a GGO lesion was seen in thin-section CT scans on the 30th and 45th day since the onset of symptoms. The consolidation subsided with time and on the 65th day, minimal GGO was seen in CT scan without pulmonary fibrosis and bronchiectasis.
1 Introduction
At the end of December 2019, several cases of pneumonia of unknown etiology were seen in several hospitals in Wuhan city, China. Those acute respiratory infections were eventually known to be caused by coronavirus infection (nCoV2) and were officially entitled as coronavirus disease 2019 (COVID-19) by World Health Organization (WHO) [1,2] (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 Chest CT scan on the 30th day of the onset of symptoms (axial and coronal views): Multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions. A pleural band was seen in the lower posterior part of both lungs, and traction bronchiectasis.
Fig. 1
Fig. 2 Chest CT scan on the 45th day of the onset of symptoms (axial and coronal views): GGO was still visible in the posterior and peripheral part of both lungs (improvement compared to the previous CT), with less bronchiectasis and fibrosis.
Fig. 2
Fig. 3 Chest CT scan on the 65th day of the onset of symptoms: (a). Minimal GGO was seen in the inspiration phase, and (b). On the expiration phase, an “enhancement” of GGO lesion was seen due to an increase of intrathoracic pressure without the sign of “air-trapping”.
Fig. 3
Symptoms that are often found in SARS-CoV2 infection are fever and dry cough. Some patients complain of sore throat, runny nose, anosmia, or diarrhea. Based on the data of hospitalized patients, the majority of COVID 19 cases (around 80%) presented without symptoms (asymptomatic) or with mild symptoms, while the rest of the cases had severe symptoms or critical condition [2]. In severe cases, patients complain of shortness of breath and/or had hypoxemia 1 week after the onset of the disease, and promptly develop into acute respiratory distress syndrome (ARDS), septic shock, and death [3]. Ground-glass opacity (GGO), consolidation, reticular pattern are typical radiological features of COVID-19 pneumonia. In survived patients, these radiological features subsided or disappear [4,5].
2 Case presentation
A 35-year-old man came to the hospital with the chief complaint of fever for 5 days. On the sixth day since the onset of fever, the patient complained of coughing when deep inhaling, coughing up phlegm especially after a shower, shortness of breath, odynophagia, and he went to the emergency room. He also complained of nausea, without vomiting, abdominal pain, and diarrhea. The patient had a history of epilepsy since 12 years-old, routinely taking phenytoin and divalproex sodium.
On physical examination, the patient looks dyspnea with respiration rate 20–21 x/min, temperature 37.3 °C, blood pressure 120/80 mmHg, heart rate 108 x/min, chest X-ray revealed peripheral bilateral patchy consolidation, normal laboratory results, CD4 result 322 cells/mm3 (range 410–1.590 cells/mm3). During hospitalization, the patient was given oxygen 2–4 L/min with a nasal cannula. On the 9th day since the onset of symptoms, the patient complained of worsening shortness of breath and his peripheral oxygen saturation was 88% (8 L/min oxygen therapy with face mask), oxygen therapy was increased to 10–12 L/min with non-rebreathing mask and his peripheral oxygen saturation gradually rose to 95%. The result of blood gas analysis (BGA) was: pH 7.43, PaCO2 38.3, PaO2 88.6, HCO3-25, BE 1.0, SaO2 97.3%, (A-a)DO2 153.3, PaO2/FiO2 2.3 with FiO240%. The result of BGA obtained the following day was: pH 7.49, PaCO2 41.7, PaO2 77.0, HCO3-31.2, BE 7.2, SaO2 96.3%, (A-a)DO2 568.1, PaO2/FiO2 0.78 with FiO2 99%. PCR results for SARS-CoV 2 were positive on days 8 and 14 since the onset of the chief complaint. This report has been granted the patient's approval for publication.
A chest computed tomography (CT) scan was performed on supine position with a 64-slice LightSpeed VCT GE Healthcare with a single breath-hold post of inspiration, except for the last CT scan done in two inspirational and expiratory phases. The image was reconstructed with a thickness of 1.2 mm. On the 30th day of the onset of symptoms, a chest CT scan revealed multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions, scantily in the upper left and central right lung, a pleural band in the lower posterior part of both lungs, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma.
On the 45th day of the onset of symptom; GGO was still visible in the peripheral posterior part of both lung (an improvement was seen compared to the previous CT though), the subpleural band was seen in the peripheral posterior part of both lung, there was no visible vascular thickening. Improvement was also seen as the disappearance of bronchiectasis and its surrounding fibrosis. Day 65th chest CT scan illustrated thinner GGO compared to previous CT, without fibrosis or bronchiectasis.
3 Discussion
We presented a case of severe COVID-19 pneumonia complicated with acute respiratory distress syndrome (ARDS) which was diagnosed with WHO criteria [6] who recovered with minimal GGO lesion outcome. ARDS is one of the COVID pneumonia complications with high mortality [7]. Age, high body temperature, comorbidities, neutrophilia, lymphocytopenia, index of impaired organ function, increased index of inflammation, and disorders of coagulopathy are risk factors for ARDS [7]. This patient experienced clinical and oxygenation improvement with medical therapy without mechanical ventilation. He had epilepsy since 12 years-old (rarely having seizure episode) as a comorbid and routinely consumes phenytoin and divalproex sodium. Antiepileptic drugs are known to have an immunosuppressant effect. Carbamazepine or valproic acid affects the concentration of cytokines in the blood. Increased proinflammatory cytokines can lead to immune system disorders [8].
Chest CT scan plays an important role in the diagnosis and follow-up of COVID-19 cases [9]. Early features of thin-section CT in COVID-19 cases are predominantly GGO with reticular pattern and/or interlobar septal thickening. Changes in chest CT scan images in patients with COVID-19 pneumonia begin with a predominance of ground-glass opacity at 0–4 days of the onset of symptom, crazy-paving (reticular) pattern at 5–8 days, consolidation at 9–13 days, and consolidation with a gradual resolution at ≥14 days, but in this phase, a diffuse GGO can be seen as a manifestation of consolidation absorption [10].
Radiological evolution in COVID-19 pneumonia is generally consistent with the clinical course. Shi et al. [5] reported 4 radiological patterns up to week 3 of the disease. 1) Initial progression until the peak which was followed by radiological improvement (46%) and 92% of patients were discharged from the hospital, 2) Radiologically worsened (32%) followed by 11% deaths, 3) Radiologically improved (14%), 63% of patients discharged from the hospital with a median of 19 days hospitalization, 4). No alteration radiologically (9%).
Thin-section chest CT scan with full inspiration since 30th day since the onset of symptoms in this patient showed GGO in both of the lung, pleural band, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma. These findings were consistent with his clinical conditions (shortness of breath during exertion, peripheral oxygen saturation 93–95% on room air, heart rate 110–112 x/min). Improvement of lung sequelae was seen on the 45th day, CT scan results were still dominated by GGO, however less bronchiectasis and fibrosis. The complaint of shortness of breath had subsided, peripheral oxygen saturation 97–98%, heart rate 84–88 x/min, and RT-PCR result had converted to negative. CT scan result of the 65th day revealed minimal GGO, no fibrosis nor air trapping was seen in the thin-section expiratory phase of the CT scan as commonly found in the severe acute respiratory syndrome (SARS) cases [11].
4 Conclusion
We presented a COVID-19 severe pneumonia case with neurological diseases comorbid (epilepsy controlled with antiepileptic drugs) which was complicated by ARDS. High body temperature, neutrophilia, lymphocytopenia, decreased CD4 T cells are risk factors for ARDS. Three follow-ups thin-section chest CT scan since the onset of symptoms revealed an improvement and the outcome was minimal GGO without pulmonary fibrosis or bronchiectasis.
Declaration of competing interest
There was no conflict of interest in this study. No funding was received for this study. Written informed consent was obtained for publication of this case report.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Acknowledgement
none.
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101342. | DIVALPROEX SODIUM, PHENYTOIN SODIUM | DrugsGivenReaction | CC BY-NC-ND | 33457203 | 19,948,680 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lung opacity'. | Evolution of chest CT scan manifestations in a patient recovered from COVID-19 severe pneumonia with acute respiratory distress syndrome.
A male patient with severe pneumonia due to coronavirus disease 2019 (COVID-19) had acute respiratory distress syndrome (ARDS) which developed in the second week since the first symptoms and improved without mechanical ventilation. The patient had epilepsy as a comorbid disease and his routinely consumed antiepileptic drugs were likely to cause alterations of the immune system. Ground-glass opacity (GGO), consolidation, and reticular pattern are typical radiological features of COVID-19 pneumonia. Less common findings were septal thickening, bronchiectasis, pleural thickening, and subpleural involvement. These radiological abnormalities evolve throughout the course of the disease. In this case report, a GGO lesion was seen in thin-section CT scans on the 30th and 45th day since the onset of symptoms. The consolidation subsided with time and on the 65th day, minimal GGO was seen in CT scan without pulmonary fibrosis and bronchiectasis.
1 Introduction
At the end of December 2019, several cases of pneumonia of unknown etiology were seen in several hospitals in Wuhan city, China. Those acute respiratory infections were eventually known to be caused by coronavirus infection (nCoV2) and were officially entitled as coronavirus disease 2019 (COVID-19) by World Health Organization (WHO) [1,2] (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 Chest CT scan on the 30th day of the onset of symptoms (axial and coronal views): Multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions. A pleural band was seen in the lower posterior part of both lungs, and traction bronchiectasis.
Fig. 1
Fig. 2 Chest CT scan on the 45th day of the onset of symptoms (axial and coronal views): GGO was still visible in the posterior and peripheral part of both lungs (improvement compared to the previous CT), with less bronchiectasis and fibrosis.
Fig. 2
Fig. 3 Chest CT scan on the 65th day of the onset of symptoms: (a). Minimal GGO was seen in the inspiration phase, and (b). On the expiration phase, an “enhancement” of GGO lesion was seen due to an increase of intrathoracic pressure without the sign of “air-trapping”.
Fig. 3
Symptoms that are often found in SARS-CoV2 infection are fever and dry cough. Some patients complain of sore throat, runny nose, anosmia, or diarrhea. Based on the data of hospitalized patients, the majority of COVID 19 cases (around 80%) presented without symptoms (asymptomatic) or with mild symptoms, while the rest of the cases had severe symptoms or critical condition [2]. In severe cases, patients complain of shortness of breath and/or had hypoxemia 1 week after the onset of the disease, and promptly develop into acute respiratory distress syndrome (ARDS), septic shock, and death [3]. Ground-glass opacity (GGO), consolidation, reticular pattern are typical radiological features of COVID-19 pneumonia. In survived patients, these radiological features subsided or disappear [4,5].
2 Case presentation
A 35-year-old man came to the hospital with the chief complaint of fever for 5 days. On the sixth day since the onset of fever, the patient complained of coughing when deep inhaling, coughing up phlegm especially after a shower, shortness of breath, odynophagia, and he went to the emergency room. He also complained of nausea, without vomiting, abdominal pain, and diarrhea. The patient had a history of epilepsy since 12 years-old, routinely taking phenytoin and divalproex sodium.
On physical examination, the patient looks dyspnea with respiration rate 20–21 x/min, temperature 37.3 °C, blood pressure 120/80 mmHg, heart rate 108 x/min, chest X-ray revealed peripheral bilateral patchy consolidation, normal laboratory results, CD4 result 322 cells/mm3 (range 410–1.590 cells/mm3). During hospitalization, the patient was given oxygen 2–4 L/min with a nasal cannula. On the 9th day since the onset of symptoms, the patient complained of worsening shortness of breath and his peripheral oxygen saturation was 88% (8 L/min oxygen therapy with face mask), oxygen therapy was increased to 10–12 L/min with non-rebreathing mask and his peripheral oxygen saturation gradually rose to 95%. The result of blood gas analysis (BGA) was: pH 7.43, PaCO2 38.3, PaO2 88.6, HCO3-25, BE 1.0, SaO2 97.3%, (A-a)DO2 153.3, PaO2/FiO2 2.3 with FiO240%. The result of BGA obtained the following day was: pH 7.49, PaCO2 41.7, PaO2 77.0, HCO3-31.2, BE 7.2, SaO2 96.3%, (A-a)DO2 568.1, PaO2/FiO2 0.78 with FiO2 99%. PCR results for SARS-CoV 2 were positive on days 8 and 14 since the onset of the chief complaint. This report has been granted the patient's approval for publication.
A chest computed tomography (CT) scan was performed on supine position with a 64-slice LightSpeed VCT GE Healthcare with a single breath-hold post of inspiration, except for the last CT scan done in two inspirational and expiratory phases. The image was reconstructed with a thickness of 1.2 mm. On the 30th day of the onset of symptoms, a chest CT scan revealed multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions, scantily in the upper left and central right lung, a pleural band in the lower posterior part of both lungs, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma.
On the 45th day of the onset of symptom; GGO was still visible in the peripheral posterior part of both lung (an improvement was seen compared to the previous CT though), the subpleural band was seen in the peripheral posterior part of both lung, there was no visible vascular thickening. Improvement was also seen as the disappearance of bronchiectasis and its surrounding fibrosis. Day 65th chest CT scan illustrated thinner GGO compared to previous CT, without fibrosis or bronchiectasis.
3 Discussion
We presented a case of severe COVID-19 pneumonia complicated with acute respiratory distress syndrome (ARDS) which was diagnosed with WHO criteria [6] who recovered with minimal GGO lesion outcome. ARDS is one of the COVID pneumonia complications with high mortality [7]. Age, high body temperature, comorbidities, neutrophilia, lymphocytopenia, index of impaired organ function, increased index of inflammation, and disorders of coagulopathy are risk factors for ARDS [7]. This patient experienced clinical and oxygenation improvement with medical therapy without mechanical ventilation. He had epilepsy since 12 years-old (rarely having seizure episode) as a comorbid and routinely consumes phenytoin and divalproex sodium. Antiepileptic drugs are known to have an immunosuppressant effect. Carbamazepine or valproic acid affects the concentration of cytokines in the blood. Increased proinflammatory cytokines can lead to immune system disorders [8].
Chest CT scan plays an important role in the diagnosis and follow-up of COVID-19 cases [9]. Early features of thin-section CT in COVID-19 cases are predominantly GGO with reticular pattern and/or interlobar septal thickening. Changes in chest CT scan images in patients with COVID-19 pneumonia begin with a predominance of ground-glass opacity at 0–4 days of the onset of symptom, crazy-paving (reticular) pattern at 5–8 days, consolidation at 9–13 days, and consolidation with a gradual resolution at ≥14 days, but in this phase, a diffuse GGO can be seen as a manifestation of consolidation absorption [10].
Radiological evolution in COVID-19 pneumonia is generally consistent with the clinical course. Shi et al. [5] reported 4 radiological patterns up to week 3 of the disease. 1) Initial progression until the peak which was followed by radiological improvement (46%) and 92% of patients were discharged from the hospital, 2) Radiologically worsened (32%) followed by 11% deaths, 3) Radiologically improved (14%), 63% of patients discharged from the hospital with a median of 19 days hospitalization, 4). No alteration radiologically (9%).
Thin-section chest CT scan with full inspiration since 30th day since the onset of symptoms in this patient showed GGO in both of the lung, pleural band, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma. These findings were consistent with his clinical conditions (shortness of breath during exertion, peripheral oxygen saturation 93–95% on room air, heart rate 110–112 x/min). Improvement of lung sequelae was seen on the 45th day, CT scan results were still dominated by GGO, however less bronchiectasis and fibrosis. The complaint of shortness of breath had subsided, peripheral oxygen saturation 97–98%, heart rate 84–88 x/min, and RT-PCR result had converted to negative. CT scan result of the 65th day revealed minimal GGO, no fibrosis nor air trapping was seen in the thin-section expiratory phase of the CT scan as commonly found in the severe acute respiratory syndrome (SARS) cases [11].
4 Conclusion
We presented a COVID-19 severe pneumonia case with neurological diseases comorbid (epilepsy controlled with antiepileptic drugs) which was complicated by ARDS. High body temperature, neutrophilia, lymphocytopenia, decreased CD4 T cells are risk factors for ARDS. Three follow-ups thin-section chest CT scan since the onset of symptoms revealed an improvement and the outcome was minimal GGO without pulmonary fibrosis or bronchiectasis.
Declaration of competing interest
There was no conflict of interest in this study. No funding was received for this study. Written informed consent was obtained for publication of this case report.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Acknowledgement
none.
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101342. | DIVALPROEX SODIUM, PHENYTOIN SODIUM | DrugsGivenReaction | CC BY-NC-ND | 33457203 | 19,948,680 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nausea'. | Evolution of chest CT scan manifestations in a patient recovered from COVID-19 severe pneumonia with acute respiratory distress syndrome.
A male patient with severe pneumonia due to coronavirus disease 2019 (COVID-19) had acute respiratory distress syndrome (ARDS) which developed in the second week since the first symptoms and improved without mechanical ventilation. The patient had epilepsy as a comorbid disease and his routinely consumed antiepileptic drugs were likely to cause alterations of the immune system. Ground-glass opacity (GGO), consolidation, and reticular pattern are typical radiological features of COVID-19 pneumonia. Less common findings were septal thickening, bronchiectasis, pleural thickening, and subpleural involvement. These radiological abnormalities evolve throughout the course of the disease. In this case report, a GGO lesion was seen in thin-section CT scans on the 30th and 45th day since the onset of symptoms. The consolidation subsided with time and on the 65th day, minimal GGO was seen in CT scan without pulmonary fibrosis and bronchiectasis.
1 Introduction
At the end of December 2019, several cases of pneumonia of unknown etiology were seen in several hospitals in Wuhan city, China. Those acute respiratory infections were eventually known to be caused by coronavirus infection (nCoV2) and were officially entitled as coronavirus disease 2019 (COVID-19) by World Health Organization (WHO) [1,2] (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 Chest CT scan on the 30th day of the onset of symptoms (axial and coronal views): Multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions. A pleural band was seen in the lower posterior part of both lungs, and traction bronchiectasis.
Fig. 1
Fig. 2 Chest CT scan on the 45th day of the onset of symptoms (axial and coronal views): GGO was still visible in the posterior and peripheral part of both lungs (improvement compared to the previous CT), with less bronchiectasis and fibrosis.
Fig. 2
Fig. 3 Chest CT scan on the 65th day of the onset of symptoms: (a). Minimal GGO was seen in the inspiration phase, and (b). On the expiration phase, an “enhancement” of GGO lesion was seen due to an increase of intrathoracic pressure without the sign of “air-trapping”.
Fig. 3
Symptoms that are often found in SARS-CoV2 infection are fever and dry cough. Some patients complain of sore throat, runny nose, anosmia, or diarrhea. Based on the data of hospitalized patients, the majority of COVID 19 cases (around 80%) presented without symptoms (asymptomatic) or with mild symptoms, while the rest of the cases had severe symptoms or critical condition [2]. In severe cases, patients complain of shortness of breath and/or had hypoxemia 1 week after the onset of the disease, and promptly develop into acute respiratory distress syndrome (ARDS), septic shock, and death [3]. Ground-glass opacity (GGO), consolidation, reticular pattern are typical radiological features of COVID-19 pneumonia. In survived patients, these radiological features subsided or disappear [4,5].
2 Case presentation
A 35-year-old man came to the hospital with the chief complaint of fever for 5 days. On the sixth day since the onset of fever, the patient complained of coughing when deep inhaling, coughing up phlegm especially after a shower, shortness of breath, odynophagia, and he went to the emergency room. He also complained of nausea, without vomiting, abdominal pain, and diarrhea. The patient had a history of epilepsy since 12 years-old, routinely taking phenytoin and divalproex sodium.
On physical examination, the patient looks dyspnea with respiration rate 20–21 x/min, temperature 37.3 °C, blood pressure 120/80 mmHg, heart rate 108 x/min, chest X-ray revealed peripheral bilateral patchy consolidation, normal laboratory results, CD4 result 322 cells/mm3 (range 410–1.590 cells/mm3). During hospitalization, the patient was given oxygen 2–4 L/min with a nasal cannula. On the 9th day since the onset of symptoms, the patient complained of worsening shortness of breath and his peripheral oxygen saturation was 88% (8 L/min oxygen therapy with face mask), oxygen therapy was increased to 10–12 L/min with non-rebreathing mask and his peripheral oxygen saturation gradually rose to 95%. The result of blood gas analysis (BGA) was: pH 7.43, PaCO2 38.3, PaO2 88.6, HCO3-25, BE 1.0, SaO2 97.3%, (A-a)DO2 153.3, PaO2/FiO2 2.3 with FiO240%. The result of BGA obtained the following day was: pH 7.49, PaCO2 41.7, PaO2 77.0, HCO3-31.2, BE 7.2, SaO2 96.3%, (A-a)DO2 568.1, PaO2/FiO2 0.78 with FiO2 99%. PCR results for SARS-CoV 2 were positive on days 8 and 14 since the onset of the chief complaint. This report has been granted the patient's approval for publication.
A chest computed tomography (CT) scan was performed on supine position with a 64-slice LightSpeed VCT GE Healthcare with a single breath-hold post of inspiration, except for the last CT scan done in two inspirational and expiratory phases. The image was reconstructed with a thickness of 1.2 mm. On the 30th day of the onset of symptoms, a chest CT scan revealed multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions, scantily in the upper left and central right lung, a pleural band in the lower posterior part of both lungs, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma.
On the 45th day of the onset of symptom; GGO was still visible in the peripheral posterior part of both lung (an improvement was seen compared to the previous CT though), the subpleural band was seen in the peripheral posterior part of both lung, there was no visible vascular thickening. Improvement was also seen as the disappearance of bronchiectasis and its surrounding fibrosis. Day 65th chest CT scan illustrated thinner GGO compared to previous CT, without fibrosis or bronchiectasis.
3 Discussion
We presented a case of severe COVID-19 pneumonia complicated with acute respiratory distress syndrome (ARDS) which was diagnosed with WHO criteria [6] who recovered with minimal GGO lesion outcome. ARDS is one of the COVID pneumonia complications with high mortality [7]. Age, high body temperature, comorbidities, neutrophilia, lymphocytopenia, index of impaired organ function, increased index of inflammation, and disorders of coagulopathy are risk factors for ARDS [7]. This patient experienced clinical and oxygenation improvement with medical therapy without mechanical ventilation. He had epilepsy since 12 years-old (rarely having seizure episode) as a comorbid and routinely consumes phenytoin and divalproex sodium. Antiepileptic drugs are known to have an immunosuppressant effect. Carbamazepine or valproic acid affects the concentration of cytokines in the blood. Increased proinflammatory cytokines can lead to immune system disorders [8].
Chest CT scan plays an important role in the diagnosis and follow-up of COVID-19 cases [9]. Early features of thin-section CT in COVID-19 cases are predominantly GGO with reticular pattern and/or interlobar septal thickening. Changes in chest CT scan images in patients with COVID-19 pneumonia begin with a predominance of ground-glass opacity at 0–4 days of the onset of symptom, crazy-paving (reticular) pattern at 5–8 days, consolidation at 9–13 days, and consolidation with a gradual resolution at ≥14 days, but in this phase, a diffuse GGO can be seen as a manifestation of consolidation absorption [10].
Radiological evolution in COVID-19 pneumonia is generally consistent with the clinical course. Shi et al. [5] reported 4 radiological patterns up to week 3 of the disease. 1) Initial progression until the peak which was followed by radiological improvement (46%) and 92% of patients were discharged from the hospital, 2) Radiologically worsened (32%) followed by 11% deaths, 3) Radiologically improved (14%), 63% of patients discharged from the hospital with a median of 19 days hospitalization, 4). No alteration radiologically (9%).
Thin-section chest CT scan with full inspiration since 30th day since the onset of symptoms in this patient showed GGO in both of the lung, pleural band, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma. These findings were consistent with his clinical conditions (shortness of breath during exertion, peripheral oxygen saturation 93–95% on room air, heart rate 110–112 x/min). Improvement of lung sequelae was seen on the 45th day, CT scan results were still dominated by GGO, however less bronchiectasis and fibrosis. The complaint of shortness of breath had subsided, peripheral oxygen saturation 97–98%, heart rate 84–88 x/min, and RT-PCR result had converted to negative. CT scan result of the 65th day revealed minimal GGO, no fibrosis nor air trapping was seen in the thin-section expiratory phase of the CT scan as commonly found in the severe acute respiratory syndrome (SARS) cases [11].
4 Conclusion
We presented a COVID-19 severe pneumonia case with neurological diseases comorbid (epilepsy controlled with antiepileptic drugs) which was complicated by ARDS. High body temperature, neutrophilia, lymphocytopenia, decreased CD4 T cells are risk factors for ARDS. Three follow-ups thin-section chest CT scan since the onset of symptoms revealed an improvement and the outcome was minimal GGO without pulmonary fibrosis or bronchiectasis.
Declaration of competing interest
There was no conflict of interest in this study. No funding was received for this study. Written informed consent was obtained for publication of this case report.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Acknowledgement
none.
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101342. | DIVALPROEX SODIUM, PHENYTOIN SODIUM | DrugsGivenReaction | CC BY-NC-ND | 33457203 | 19,948,680 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Odynophagia'. | Evolution of chest CT scan manifestations in a patient recovered from COVID-19 severe pneumonia with acute respiratory distress syndrome.
A male patient with severe pneumonia due to coronavirus disease 2019 (COVID-19) had acute respiratory distress syndrome (ARDS) which developed in the second week since the first symptoms and improved without mechanical ventilation. The patient had epilepsy as a comorbid disease and his routinely consumed antiepileptic drugs were likely to cause alterations of the immune system. Ground-glass opacity (GGO), consolidation, and reticular pattern are typical radiological features of COVID-19 pneumonia. Less common findings were septal thickening, bronchiectasis, pleural thickening, and subpleural involvement. These radiological abnormalities evolve throughout the course of the disease. In this case report, a GGO lesion was seen in thin-section CT scans on the 30th and 45th day since the onset of symptoms. The consolidation subsided with time and on the 65th day, minimal GGO was seen in CT scan without pulmonary fibrosis and bronchiectasis.
1 Introduction
At the end of December 2019, several cases of pneumonia of unknown etiology were seen in several hospitals in Wuhan city, China. Those acute respiratory infections were eventually known to be caused by coronavirus infection (nCoV2) and were officially entitled as coronavirus disease 2019 (COVID-19) by World Health Organization (WHO) [1,2] (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 Chest CT scan on the 30th day of the onset of symptoms (axial and coronal views): Multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions. A pleural band was seen in the lower posterior part of both lungs, and traction bronchiectasis.
Fig. 1
Fig. 2 Chest CT scan on the 45th day of the onset of symptoms (axial and coronal views): GGO was still visible in the posterior and peripheral part of both lungs (improvement compared to the previous CT), with less bronchiectasis and fibrosis.
Fig. 2
Fig. 3 Chest CT scan on the 65th day of the onset of symptoms: (a). Minimal GGO was seen in the inspiration phase, and (b). On the expiration phase, an “enhancement” of GGO lesion was seen due to an increase of intrathoracic pressure without the sign of “air-trapping”.
Fig. 3
Symptoms that are often found in SARS-CoV2 infection are fever and dry cough. Some patients complain of sore throat, runny nose, anosmia, or diarrhea. Based on the data of hospitalized patients, the majority of COVID 19 cases (around 80%) presented without symptoms (asymptomatic) or with mild symptoms, while the rest of the cases had severe symptoms or critical condition [2]. In severe cases, patients complain of shortness of breath and/or had hypoxemia 1 week after the onset of the disease, and promptly develop into acute respiratory distress syndrome (ARDS), septic shock, and death [3]. Ground-glass opacity (GGO), consolidation, reticular pattern are typical radiological features of COVID-19 pneumonia. In survived patients, these radiological features subsided or disappear [4,5].
2 Case presentation
A 35-year-old man came to the hospital with the chief complaint of fever for 5 days. On the sixth day since the onset of fever, the patient complained of coughing when deep inhaling, coughing up phlegm especially after a shower, shortness of breath, odynophagia, and he went to the emergency room. He also complained of nausea, without vomiting, abdominal pain, and diarrhea. The patient had a history of epilepsy since 12 years-old, routinely taking phenytoin and divalproex sodium.
On physical examination, the patient looks dyspnea with respiration rate 20–21 x/min, temperature 37.3 °C, blood pressure 120/80 mmHg, heart rate 108 x/min, chest X-ray revealed peripheral bilateral patchy consolidation, normal laboratory results, CD4 result 322 cells/mm3 (range 410–1.590 cells/mm3). During hospitalization, the patient was given oxygen 2–4 L/min with a nasal cannula. On the 9th day since the onset of symptoms, the patient complained of worsening shortness of breath and his peripheral oxygen saturation was 88% (8 L/min oxygen therapy with face mask), oxygen therapy was increased to 10–12 L/min with non-rebreathing mask and his peripheral oxygen saturation gradually rose to 95%. The result of blood gas analysis (BGA) was: pH 7.43, PaCO2 38.3, PaO2 88.6, HCO3-25, BE 1.0, SaO2 97.3%, (A-a)DO2 153.3, PaO2/FiO2 2.3 with FiO240%. The result of BGA obtained the following day was: pH 7.49, PaCO2 41.7, PaO2 77.0, HCO3-31.2, BE 7.2, SaO2 96.3%, (A-a)DO2 568.1, PaO2/FiO2 0.78 with FiO2 99%. PCR results for SARS-CoV 2 were positive on days 8 and 14 since the onset of the chief complaint. This report has been granted the patient's approval for publication.
A chest computed tomography (CT) scan was performed on supine position with a 64-slice LightSpeed VCT GE Healthcare with a single breath-hold post of inspiration, except for the last CT scan done in two inspirational and expiratory phases. The image was reconstructed with a thickness of 1.2 mm. On the 30th day of the onset of symptoms, a chest CT scan revealed multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions, scantily in the upper left and central right lung, a pleural band in the lower posterior part of both lungs, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma.
On the 45th day of the onset of symptom; GGO was still visible in the peripheral posterior part of both lung (an improvement was seen compared to the previous CT though), the subpleural band was seen in the peripheral posterior part of both lung, there was no visible vascular thickening. Improvement was also seen as the disappearance of bronchiectasis and its surrounding fibrosis. Day 65th chest CT scan illustrated thinner GGO compared to previous CT, without fibrosis or bronchiectasis.
3 Discussion
We presented a case of severe COVID-19 pneumonia complicated with acute respiratory distress syndrome (ARDS) which was diagnosed with WHO criteria [6] who recovered with minimal GGO lesion outcome. ARDS is one of the COVID pneumonia complications with high mortality [7]. Age, high body temperature, comorbidities, neutrophilia, lymphocytopenia, index of impaired organ function, increased index of inflammation, and disorders of coagulopathy are risk factors for ARDS [7]. This patient experienced clinical and oxygenation improvement with medical therapy without mechanical ventilation. He had epilepsy since 12 years-old (rarely having seizure episode) as a comorbid and routinely consumes phenytoin and divalproex sodium. Antiepileptic drugs are known to have an immunosuppressant effect. Carbamazepine or valproic acid affects the concentration of cytokines in the blood. Increased proinflammatory cytokines can lead to immune system disorders [8].
Chest CT scan plays an important role in the diagnosis and follow-up of COVID-19 cases [9]. Early features of thin-section CT in COVID-19 cases are predominantly GGO with reticular pattern and/or interlobar septal thickening. Changes in chest CT scan images in patients with COVID-19 pneumonia begin with a predominance of ground-glass opacity at 0–4 days of the onset of symptom, crazy-paving (reticular) pattern at 5–8 days, consolidation at 9–13 days, and consolidation with a gradual resolution at ≥14 days, but in this phase, a diffuse GGO can be seen as a manifestation of consolidation absorption [10].
Radiological evolution in COVID-19 pneumonia is generally consistent with the clinical course. Shi et al. [5] reported 4 radiological patterns up to week 3 of the disease. 1) Initial progression until the peak which was followed by radiological improvement (46%) and 92% of patients were discharged from the hospital, 2) Radiologically worsened (32%) followed by 11% deaths, 3) Radiologically improved (14%), 63% of patients discharged from the hospital with a median of 19 days hospitalization, 4). No alteration radiologically (9%).
Thin-section chest CT scan with full inspiration since 30th day since the onset of symptoms in this patient showed GGO in both of the lung, pleural band, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma. These findings were consistent with his clinical conditions (shortness of breath during exertion, peripheral oxygen saturation 93–95% on room air, heart rate 110–112 x/min). Improvement of lung sequelae was seen on the 45th day, CT scan results were still dominated by GGO, however less bronchiectasis and fibrosis. The complaint of shortness of breath had subsided, peripheral oxygen saturation 97–98%, heart rate 84–88 x/min, and RT-PCR result had converted to negative. CT scan result of the 65th day revealed minimal GGO, no fibrosis nor air trapping was seen in the thin-section expiratory phase of the CT scan as commonly found in the severe acute respiratory syndrome (SARS) cases [11].
4 Conclusion
We presented a COVID-19 severe pneumonia case with neurological diseases comorbid (epilepsy controlled with antiepileptic drugs) which was complicated by ARDS. High body temperature, neutrophilia, lymphocytopenia, decreased CD4 T cells are risk factors for ARDS. Three follow-ups thin-section chest CT scan since the onset of symptoms revealed an improvement and the outcome was minimal GGO without pulmonary fibrosis or bronchiectasis.
Declaration of competing interest
There was no conflict of interest in this study. No funding was received for this study. Written informed consent was obtained for publication of this case report.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Acknowledgement
none.
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101342. | DIVALPROEX SODIUM, PHENYTOIN SODIUM | DrugsGivenReaction | CC BY-NC-ND | 33457203 | 19,948,680 | 2021 |
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