








key: cord-293367-0fe62h2f
authors: Henderson, Lauren A.; Canna, Scott W.; Friedman, Kevin G.; Gorelik, Mark; Lapidus, Sivia K.; Bassiri, Hamid; Behrens, Edward M.; Ferris, Anne; Kernan, Kate F.; Schulert, Grant S.; Seo, Philip; F. Son, Mary Beth; Tremoulet, Adriana H.; Yeung, Rae S.M.; Mudano, Amy S.; Turner, Amy S.; Karp, David R.; Mehta, Jay J.
title: American College of Rheumatology Clinical Guidance for Pediatric Patients with Multisystem Inflammatory Syndrome in Children (MIS‐C) Associated with SARS‐CoV‐2 and Hyperinflammation in COVID‐19. Version 1
date: 2020-07-23
journal: Arthritis Rheumatol
DOI: 10.1002/art.41454
sha: 
doc_id: 293367
cord_uid: 0fe62h2f

OBJECTIVE: To provide guidance on the management of Multisystem Inflammatory Syndrome in Children (MIS‐C), a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests late in the course of SARS‐CoV‐2 infection. The Task Force also provided recommendations for children with hyperinflammation during COVID‐19, the acute, infectious phase of SARS‐CoV‐2 infection. METHODS: The Task Force was composed of 9 pediatric rheumatologists, 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. Preliminary statements addressing clinical questions related to MIS‐C and hyperinflammation in COVID‐19 were developed based on evidence reports. Consensus was built through a modified Delphi process that involved 2 rounds of anonymous voting and 2 webinars. A 9‐point scale was used to determine the appropriateness of each statement (1‐3, inappropriate; 4‐6, uncertain; 7‐9, appropriate), and consensus was rated as low (L), moderate (M), or high (H) based on dispersion of the votes along the numeric scale. Approved guidance statements had to be classified as appropriate with moderate or high levels of consensus, which were pre‐specified prior to voting. RESULTS: A total of 128 statements were approved by the Task Force, which were refined into 40 final guidance statements accompanied by a flow diagram depicting the diagnostic pathway for MIS‐C. CONCLUSION: Our understanding of SARS‐CoV‐2‐related syndromes in the pediatric population continues to evolve. This guidance document reflects currently available evidence coupled with expert opinion but is meant to be modified as additional data become available.

Since its initial description in December 2019 in Wuhan China, coronavirus disease 2019 , caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly evolved into a worldwide pandemic affecting millions of lives.(1) Unlike adults, the vast majority of children with COVID-19 have mild symptoms. However, there are children who have significant respiratory disease, and some children may develop a hyperinflammatory response similar to what has been observed in adults with COVID-19. Furthermore, in late April 2020, reports emerged of children with a different clinical syndrome resembling Kawasaki Disease (KD) and toxic shock syndrome; these patients frequently had evidence of prior exposure to SARS-CoV-2. (2, 3) Subsequent to these initial reports from Italy and the United Kingdom, multiple case series from Europe and the United States have surfaced describing a similar phenomenon.(4-10) While this constellation of symptoms has been given many names, for the purposes of this discussion we will use "Multisystem Inflammatory Syndrome in Children" (MIS-C).

For a number of reasons, there is an urgent need to provide guidance to healthcare providers evaluating patients in whom MIS-C is a diagnostic consideration. These reasons include: 1) Variable case definitions for MIS-C; 2) The clinical description of MIS-C is limited to case series; 3) MIS-C clinical features may also be seen in infectious, malignant, and other rheumatologic entities; 4) Suggested treatment strategies have relied on extrapolation from other inflammatory or rheumatologic conditions presenting similarly; 5) Myocardial dysfunction may present insidiously but is a major source of morbidity and mortality in MIS-C. In addition, pediatric rheumatologists are often asked to recommend immunomodulatory therapy for patients with a hyperinflammatory state due to acute SARS-CoV-2 infection. Therefore, the American College of Rheumatology (ACR) convened the MIS-C and COVID-19-Related Hyperinflammation Task Force on May 22, 2020, charged by ACR leadership to provide guidance to clinicians in the evaluation and management of MIS-C and COVID-19-related hyperinflammatory syndromes. Clinical guidance generated from this effort is intended to aid in the care of individual patients, but it is not meant to supplant clinical decision-making.

Modifications to treatment plans, particularly in patients with complex conditions, are highly disease-, patient-, geography-, and time-specific and, therefore, must be individualized as part of a shared decision-making process.

This article is protected by copyright. All rights reserved 2020, participants agreed with the importance of addressing these 4 overarching topics as well as the structure of the workgroups. The first webinar was used to confirm the target audience for the guidance, which focuses on clinicians in North America managing pediatric patients with inflammatory syndromes related to recent or concurrent infections with SARS-CoV-2. Notably, the Task Force deliberately did not attempt to create a new case definition for MIS-C as several already exist (Table 1) (4) (5) (6) . Instead, the Task Force elected to leverage consensus building to identify the most appropriate diagnostic and therapeutic steps that providers should consider at the present time.

All panelists agreed to develop consensus through a modified Delphi process that involved 2 rounds of asynchronous, anonymous voting and 2 webinars to discuss voting results.

Evidence Review. From May 22-May 29, 2020, the workgroups developed preliminary recommendation statements within their assigned topic based on expert opinion and evidence reviewed from publications listed in PubMed, scientific briefings from the World Health Organization (WHO), health alerts from the Centers of Disease Control and Prevention (CDC), and guidance provided by the Royal College of Paediatrics and Child Health (RCPCH). Each workgroup generated an evidence report supporting the recommendations that was shared with the entire Task Force. This article is protected by copyright. All rights reserved

The Task Force evaluated a total of 125 statements in the first round of voting that addressed the management of MIS-C and hyperinflammation in pediatric patients with COVID-19. Of these, 112 statements met the criteria for approval with a median score of 7-9 and moderate or high consensus while 13 statements were rated as uncertain (median score [4] [5] [6] . After refining the statements based on the input from the initial phase, 128 guidance statements were approved in round 2 voting (Supplemental Table 1 -4) . These statements were organized into 40 final guidance statements accompanied by 1 figure, which were approved by the entire Task Force and the ACR Board of Directors. (12) Topics covered in the guidance include: 1) Diagnostic evaluation of MIS-C (Table 2, (Table 7) .

Our understanding of SARS-CoV-2-related syndromes in the pediatric population continues to evolve. The recommendations provided by the Task Force reflect expert opinion and currently available evidence, which is of low quality and based on a limited number of case series and retrospective cohort studies. Thus, this guidance is meant to be a "living document" and will be modified as additional data become available. The recommendations provided in the guidance document do not replace the importance of clinical judgment tailored to the unique circumstances of an individual patient.

Maintaining a Broad Differential Diagnosis. Multiple case definitions for MIS-C have been proposed, some of which are broader than others (Table 1) . (4) (5) (6) Common clinical features of MIS-C include fever, mucocutaneous findings (rash, conjunctivitis, edema of the hands/feet, red/cracked lips, and strawberry tongue), myocardial dysfunction, cardiac conduction abnormalities, shock, gastrointestinal symptoms, and lymphadenopathy. (2, (7) (8) (9) (10) (13) (14) (15) (16) (17) (18) There are also increasing reports of neurologic involvement, manifesting as severe headache, altered mental status, cranial nerve palsies, or meningismus, in select patients. (8-10, 13, 14) These findings are non-specific and can occur in other infections as well as non-infectious etiologies such as oncologic or inflammatory conditions. Therefore, it is imperative that a diagnostic evaluation for MIS-C include investigation for other possible causes as deemed appropriate by the treating provider. MIS-C is temporally

This article is protected by copyright. All rights reserved associated with SARS-CoV-2 infections, and clusters of cases have been reported in geographic areas with dense COVID-19 disease burden, typically 2-6 weeks after the peak incidence of acute, infectious COVID-19 cases. (7, 13, 14, 17) Thus, the prevalence and chronology of SARS-CoV-2 infection in a given location, which may change over time, should also inform the diagnostic evaluation. The incidence of MIS-C is unknown; however, it appears to be a rare complication of SARS-CoV-2 infections with some estimating that MIS-C occurs in 2 out of 200,000 individuals under the age of 21 years. (19) The relative rarity of MIS-C should also be considered in the diagnostic approach.

Tier 1 Screening Evaluation for MIS-C. Based on our review of the literature and diagnostic algorithms that are publicly available, the Task Force chose to cast a broad net with respect to the evaluation of patients with possible MIS-C while simultaneously balancing the need to reduce indiscriminate over-testing and unnecessary use of resources on pediatric patients who have unrelated causes for fever. (2, 7, 8, 10, 13-16, 20, 21) To date, there are no clear data indicating the pre-test positive or negative predictive probabilities for each clinical symptom or laboratory value in diagnosing MIS-C. It should be noted that due to the paucity of data, our recommendations reflect a multidisciplinary consensus that is likely to be revised as these data become available. Children with fever, an epidemiologic link to SARS-CoV-2, and suggestive clinical symptoms should be considered "under investigation" for MIS-C while alternative diagnoses that could explain the patient's clinical presentation are also explored ( Figure 1) . A tiered diagnostic approach is recommended in patients without life-threatening manifestations; this includes performing an initial screening evaluation (Tier 1), and proceeding to a complete diagnostic work-up (Tier 2) only in patients with laboratory results from the Tier 1 screening that are concerning. Tier 1 consists of laboratory studies that are easily obtained at most clinical facilities (complete blood cell count with manual differential, complete metabolic panel, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and testing for SARS-CoV-2 by PCR or serology). The overwhelming majority of MIS-C cases reported in the literature have elevated inflammatory markers, particularly CRP, as values higher than 10 mg/dL or even 20 mg/dL are common. (2, 7-9, 13, 14, 17) Thus, to enter the second stage of testing, children should have elevated ESR and/or CRP and at least 1 other suggestive laboratory feature: lymphopenia, neutrophilia, thrombocytopenia, hyponatremia, or hypoalbuminemia. (2, 7-9, 13, 14, 17) 

This article is protected by copyright. All rights reserved Tier 2 Evaluation for MIS-C. Tier 2 encompasses more complex testing that typically requires additional time to complete. Reports in the literature and unpublished observations by members of the panel both note that some patients with MIS-C can decompensate rapidly; however, the risk factors that predispose patients to such severe and progressive illness have not been identified.(10, 13) Accordingly, children with abnormal vital signs, concerning physical examination findings, significantly elevated inflammatory markers, or signs of cardiac involvement will need to be admitted to the hospital for supportive care while Tier 2 testing is completed. The panel also noted that MIS-C appears to be a continuum of disease that encompasses milder phenotypes that have not been fully represented in the published literature. Some patients present with fever, rash, and systemic inflammation and no other organ damage. While these children require close monitoring, they do not always need to be hospitalized. Thus, in some cases, well-appearing children with reassuring vital signs and physical examinations may be suitable for outpatient diagnostic evaluations as long as close clinical follow-up can be assured.

Prominent cardiac involvement has been reported in a proportion of MIS-C patients in every retrospective cohort study published to date. (2, 7-9, 13, 14, 17) These include left ventricular (LV) dysfunction, coronary artery dilation or coronary artery aneurysms (CAA), and electrical conduction abnormalities. Valvular dysfunction and pericardial effusion are less frequently described. Among the initial descriptions of MIS-C, LV dysfunction was present in 20-55% of cases and coronary artery dilation or CAA in ~20%. (2, 7, 13) Although the early reports may overestimate the incidence of cardiac features as they likely represent the most severe component of the MIS-C spectrum, these numbers nonetheless highlight the significant risk of cardiac involvement in MIS-C. For these reasons, EKG and echocardiogram are key components of the full diagnostic evaluation. The echocardiogram should include quantification of LV size and systolic function using end-diastolic volume (and z-score) and ejection fraction (EF). (22, 23) Detailed evaluation of all coronary artery segments and normalization of coronary artery measurements to body surface area using z-scores is necessary. (23, 24) Cardiac laboratory values at the time of diagnosis, specifically troponin T and Btype natriuretic peptide (BNP)/N-terminal-proBNP, may help identify patients with cardiac sequelae from MIS-C. (7-9, 13, 14, 17) In particular, highly elevated BNP/NT-proBNP may be helpful in distinguishing between MIS-C patient with and without LV dysfunction; however, mild and transient elevations in these laboratory parameters are likely non-specific and do not necessarily indicate Accepted Article cardiac involvement. (14, 25, 26) BNP, in particular, is an acute phase reactant and, therefore, may be elevated in inflammatory conditions without cardiac involvement. (25) Tier 2 testing should also include further assessment for systemic inflammation. In addition to ESR and CRP, MIS-C patients typically demonstrate other markers of inflammation including high Ddimer levels, moderately elevated ferritin (often ranging from 500-2,000 ng/dL), profoundly increased procalcitonin levels in the absence of bacterial infection, and increased lactate dehydrogenase (LDH). (8-10, 13, 14, 17) Cytokine panels, when available, can assist in the diagnostic evaluation as IL-6, tumor necrosis factor (TNF), or IL-10 are often increased; however, cytokine levels measured in this manner should not dictate treatment choices and are not required to determine treatment plans. (8, 9, 13) Finally, SARS-CoV-2 serologies have been reported positive in a greater proportion (80-90%) of MIS-C patients than PCR testing (20-40%) and both should be sent to evaluate the epidemiologic link to the infection.(7-9, 13, 17)

In an early sentinel report from Bergamo, the Italian epicenter of the COVID-19 pandemic, KD and KD-like illnesses were observed at a rate 30 times higher than the pre-pandemic era. 

This article is protected by copyright. All rights reserved 20% of MIS-C patients and at least 3 patients have developed giant CAAs. (2, 7, 13, 14, 17) It is unknown if the incidence or progression of CAAs differ in MIS-C as compared to KD. Importantly, it is clear that MIS-C patients without KD symptoms can develop CAAs, highlighting the need for cardiac evaluation in all patients with MIS-C regardless of phenotypic features, and providing support for the treatment rationale discussed below. (14) Fourth, although gastrointestinal and neurologic symptoms are reported in KD, the panel felt that these findings were more frequently encountered in the MIS-C population. Finally, laboratory parameters that differ in retrospective MIS-C cohorts compared to historical KD cohorts include lower platelet counts and absolute lymphocyte counts and higher CRP levels. (7, 14) 

Children with MIS-C will need close clinical follow-up with cardiology. Extrapolating data from KD, another condition that can be complicated by CAA, the panel recommended that all children with MIS-C undergo repeat echocardiograms at a minimum of 7-14 days and then 4-6 weeks after the initial presentation. (22) For those patients with cardiac involvement noted during the acute phase of illness, another echocardiogram at 1 year after MIS-C diagnosis could be considered. Children with LV dysfunction and CAAs will require more frequent echocardiograms. Although LV function improves rapidly in most MIS-C patients, the long-term complications of myocardial inflammation in this syndrome are not known and may include myocardial fibrosis and scarring that has been seen in other forms of pediatric myocarditis.(9, 13, 33) Cardiac magnetic resonance imaging at 2-6 months post-acute illness in those patients who had moderate to severe LV dysfunction will allow for evaluation of fibrosis and scarring. Electrical conduction abnormalities are increasingly noted in MIS-C patients and may develop after the initial presentation; therefore, EKGs should be performed at a minimum of every 48 hours in patients who are hospitalized and at each follow-up visit. (8, 9, 13, 14) If conduction abnormalities are present, the patient should be placed on telemetry while in the hospital and may need Holter monitoring at clinical follow-up.

Immunomodulatory Treatment in MIS-C. Goals of treatment in the MIS-C population are to stabilize patients with life-threatening manifestations such as shock and prevent long term sequelae Accepted Article that may include CAAs, myocardial fibrosis/scarring, and fixed cardiac conduction abnormalities.

There is no available literature that directly compares therapeutic approaches in MIS-C.

Recommendations approved by the Task Force are derived from experience in managing MIS-C patients and higher quality data in other pediatric conditions with similar features. Initiation of treatment will often depend on the severity of the patient's presentation. There was consensus among the panelists that patients under investigation for MIS-C without life-threatening manifestations should undergo a diagnostic evaluation for MIS-C as well as other possible infectious and non-infectious etiologies before immunomodulatory treatment is initiated. This is to prevent the use of therapies that could be potentially harmful in patients who do not have MIS-C. Further, a subgroup of patients with MIS-C will develop progressive cardiac involvement rapidly; therefore, hospital admission and sequential monitoring of inflammatory markers, BNP/ NT-proBNP, and troponin T without instituting treatment can sometimes inform the diagnostic evaluation.(10, 13) Children with a life-threatening presentation such as shock will clearly require supportive care and may benefit from early initiation of immunomodulatory treatment, sometimes before a full diagnostic evaluation can be completed. In such cases, ongoing diagnostic evaluation should be pursued with a multidisciplinary team in parallel with treatment. Finally, the current recommendations address the treatment of MIS-C that is uncomplicated by macrophage activation syndrome (MAS). Importantly, there is a subgroup of patients with MIS-C who may also develop overt MAS and the treatment of those patients may need to deviate from the recommendations presented in this document. (7) A stepwise approach to immunomodulatory treatment in MIS-C is recommended, with intravenous immunoglobulin (IVIG) and/or glucocorticoids considered first tier agents. Both IVIG and glucocorticoids, either alone or in combination, are the most commonly used immunomodulatory medications in MIS-C patients reported to date.(2, 7-10, [13] [14] [15] 17) There is insufficient data available to compare the efficacy of IVIG vs. glucocorticoids in MIS-C or to determine if these treatments should be provided individually or as dual therapy. Accordingly, the Task Force recommended that IVIG and glucocorticoids could be used alone or in combination to treat MIS-C.

Evidence for IVIG and glucocorticoids in MIS-C is also based on their use in KD and fulminant myocarditis, two conditions that resemble MIS-C in some aspects. IVIG at a dose of 2 gm/kg prevents CAAs in KD while the benefit of IVIG in myocarditis remains unclear; however, case reports of successful use of IVIG in coronavirus associated myocarditis have been published. (22, 32, (34) (35) (36) (37) (38) (39) (40) Before IVIG is given, cardiac function and fluid status should be assessed. If abnormal, the rate of Accepted Article IVIG infusion may be slowed or treatment delayed until cardiac function is restored. Glucocorticoids reduce rates of CAA development when used in KD patients at high risk for IVIG resistance. (41, 42) Compared to a historic KD cohort, Verdoni and colleagues reported a high rate of IVIG resistance in KD patients who presented during the COVID-19 pandemic, which may suggest a role for glucocorticoids in MIS-C. (7) Panelists reported that low to moderate doses (1-2 mg/kg/day) of glucocorticoids were sufficient to treat many MIS-C patients. Some children with shock, requiring multiple inotropes and/or vasopressors, have responded best to high doses of intravenous 

Severe COVID-19 in Children. The Task Force also addressed immunomodulatory treatment in severe COVID-19, which panelists felt (given current information) was readily distinguishable from 

This article is protected by copyright. All rights reserved RECOVERY trial) report that low to moderate dose dexamethasone significantly reduced mortality in COVID-19 patients requiring mechanical ventilation; but was reported after voting had occurred.(90, 91) Based on these studies that suggest that patients with severe COVID-19 pneumonia may benefit from immunomodulation with glucocorticoids, the Task Force achieved moderate consensus that glucocorticoid treatment could be considered in pediatric patients with severe COVID-19 and signs of hyperinflammation.

Targeted neutralization of inflammatory cytokines is another approach that can be employed to reduce pathologic inflammation in COVID-19. In contrast to glucocorticoids, the panel was able to achieve high consensus on considering anakinra (recombinant human IL-1 receptor antagonist) for pediatric patients with COVID-19 and hyperinflammation. Anakinra appears to be safe in severe infections based on results of a randomized controlled trial in sepsis that showed no difference in adverse events in the anakinra arm compared to the placebo group.(49) Further, a re-analysis of data from this trial in sepsis showed increased survival in patients treated with anakinra who also had excessive inflammation manifested as hepatobiliary dysfunction and coagulopathy, which is commonly seen in COVID-19. Our group agreed that the features of severe COVID-19 were sufficiently similar between the described adult and pediatric cases to cautiously extrapolate from adult studies. Overall, the consensus among panelists was that immunomodulatory treatment should be considered in pediatric patients with hyperinflammation and severe symptoms in the acute phase of illness. While the data are still too sparse to make definitive recommendations based on high quality evidence, the panel favored the use of anakinra in this setting.

There has been an evolution in our understanding of SARS-CoV-2 infections in children.

Initially, it was believed that COVID-19 was almost entirely benign and of little consequence in the pediatric population. There has been a sudden reversal from this stance in the context of the emergence of MIS-C cases. The goals of this ACR Task Force were to synthesize available data and expert opinion to provide a resource for clinicians on the frontlines caring for children with inflammatory syndromes due to recent or concurrent infections with SARS-CoV-2.

Recognizing the need to address the unique challenges facing children with inflammatory conditions triggered by SARS-CoV-2 infections, the ACR convened the Task Force to provide guidance in a short period of time. To accomplish this charge, a multidisciplinary panel was assembled that included clinicians from North America with expertise encompassing pediatric rheumatology, cardiology, infectious disease, and critical care. Well established methodology in the form of the RAND/UCLA appropriateness methods was used to achieve consensus. There are limitations inherent in our approach. Given the need for expedited decision making, we were unable to provide guidance on all topics of interest. In particular, the Task Force focused its efforts on providing diagnostic and treatment recommendations for MIS-C instead of developing a new case definition for this condition. This choice was made because several case definitions for MIS-C exist and the data needed to develop a sensitive and specific set of criteria are not yet available. The guidance provided in this document is targeted to clinicians with access to complex diagnostic tools and biologic treatments. Thus, some of the recommendations are not practical in less resource rich settings. The Task Force recognizes the need to provide support to our international colleagues and

This article is protected by copyright. All rights reserved plans to provide additional recommendations for developing countries in subsequent versions of this guidance. In addition, the work product of the Task Force is considered guidance instead of formal treatment guidelines that must adhere to the strict methodology endorsed by the ACR.

The guidance provided in this document is supported by reports from the scientific literature and recommendations from public health institutions. Yet, available data remains restricted to low quality evidence that often must be extrapolated from the experience in adults. This approach is particularly problematic when confronting clinical questions regarding MIS-C, which to date has been reported primarily in children. This unique manifestation of COVID-19 in children and adolescents highlights the need to prioritize and fund rigorous research in the pediatric population. For now, our understanding of pediatric SARS-CoV-2 infections is rudimentary and will continue to change as higher quality evidence becomes available. Thus, the recommendations contained in this document should be interpreted in the setting of this shifting landscape and will be modified prospectively as our understanding of COVID-19 improves. For these reasons, this guidance does not replace the critical role of clinical judgment that is essential to address the unique needs of individual patients.

As the SARS-CoV-2 pandemic continues to unfold, the ACR will support clinicians caring for children with COVID-19 by enabling this Task Force to continue the work of reviewing evidence and providing expert opinion through revised versions of this guidance document. It is the ultimate goal of both the ACR and panelists to disseminate knowledge quickly in an effort to improve outcomes for children with SARS-CoV-2 infections.

Hu H, Ma F, Wei X, Fang Y. Coronavirus fulminant myocarditis saved with glucocorticoid and human immunoglobulin. European heart journal. 2020. 

This article is protected by copyright. All rights reserved 

The 

This article is protected by copyright. All rights reserved Table 3 . Comparing and Contrasting Features of MIS-C and KD.

Patients with KD that is unrelated to SARS-CoV-2 will continue to require evaluation, diagnosis, and treatment during the SARS-CoV-2 pandemic. 1) There is an increased incidence of MIS-C in patients of African, Afro-Caribbean, and possibly Hispanic descent, but a lower incidence in those of East Asian descent.

2) Patients with MIS-C encompass a broader age range, have more prominent GI and neurologic symptoms, present more frequently in shock, and are more likely to display cardiac dysfunction (arrhythmias and ventricular dysfunction) than children with KD.

3) At presentation, patients with MIS-C tend to have lower platelet counts, lower absolute lymphocyte counts, and higher CRP levels than patients with KD.

It is unknown if the incidence of CAA is different in MIS-C compared to 

Serial laboratory testing and cardiac assessment should guide immunomodulatory treatment response and tapering. Patients will often require a 2-3-week taper of immunomodulatory medications.

High MIS-C, multisystem inflammatory syndrome in children; IVIG, intravenous immunoglobulin;

CAA, coronary artery aneurysms

This article is protected by copyright. All rights reserved Table 6 . Antiplatelet and Anticoagulation Therapy in MIS-C.

Low dose aspirin (3-5 mg/kg/day; max 81 mg/day) should be used in patients with MIS-C and KD-like features and/or thrombocytosis (platelet count ≥450,000/ L) and continued until normalization of platelet count and confirmed normal coronary arteries at ≥4 weeks after diagnosis. Treatment with aspirin should be avoided in patients with a platelet count ≤80,000/ L. 

Patients with MIS-C and documented thrombosis or an EF <35% should receive therapeutic anticoagulation with enoxaparin until at least 2 weeks after discharge from the hospital.

Indications for longer outpatient therapeutic enoxaparin dosing include:

CAA with z-score >10.0 (indefinite treatment), documented thrombosis (treatment for ≥3 months pending thrombus resolution), or ongoing moderate to severe LV dysfunction.

For MIS-C patients who do not meet the above criteria, the approach to antiplatelet and anticoagulation management should be tailored to the patient's risk for thrombosis.

High MIS-C, multisystem inflammatory syndrome in children; KD, Kawasaki disease; CAA, coronary artery aneurysms; EF, ejection fraction; LV, left ventricular

This article is protected by copyright. All rights reserved Table 7 . Hyperinflammation in COVID-19.

Medically complex children and those on immunosuppressive medications, including moderate to high dose glucocorticoids, may be at higher risk for severe outcomes in COVID-19.

Children and adults admitted to the hospital with COVID-19 present with similar symptoms, including fever, upper respiratory tract symptoms, abdominal pain, and diarrhea.

Children with severe respiratory symptoms due to COVID-19 with any of the following should be considered for immunomodulatory therapy: ARDS, shock/cardiac dysfunction, substantially elevated LDH, D-dimer, IL-6, IL-2R, CRP, and/or ferritin, and depressed lymphocyte count, albumin, and/or platelet count.

Glucocorticoids may be considered for use as immunomodulatory therapy in patients with COVID-19 and hyperinflammation (as outlined in point above 

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Accepted Article This article is protected by copyright. All rights reserved 73

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Low-dose corticosteroid therapy does not delay viral clearance in patients with COVID-19

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Blockade Is Associated With Reduced Mortality in Sepsis Patients With Features of Macrophage Activation Syndrome: Reanalysis of a Prior Phase III Trial

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Targeting the inflammatory cascade with anakinra in moderate to severe COVID-19 pneumonia: case series. Annals of the rheumatic diseases

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Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia

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This article is protected by copyright. All rights reserved Accepted Article

