key: cord-0967686-1vn9lwvo
authors: Elias, Matthew D.; McCrindle, Brian W.; Larios, Guillermo; Choueiter, Nadine F.; Dahdah, Nagib; Harahsheh, Ashraf S.; Jain, Supriya; Manlhiot, Cedric; Portman, Michael A.; Raghuveer, Geetha; Giglia, Therese M.; Dionne, Audrey
title: Management of Multisystem Inflammatory Syndrome in Children Associated with COVID-19: A Survey from the International Kawasaki Disease Registry
date: 2020-09-11
journal: CJC Open
DOI: 10.1016/j.cjco.2020.09.004
sha: 992d2db8a2d1099d55e59cd6abd79dfdeb2addac
doc_id: 967686
cord_uid: 1vn9lwvo

BACKGROUND: Since April 2020, there have been numerous reports of children presenting with systemic inflammation, often in critical condition, and with evidence of recent infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This condition, since defined as the multisystem inflammatory syndrome in children (MIS-C), is assumed to be a delayed immune response to COVID-19, and there are frequently cardiac manifestations of ventricular dysfunction and/or coronary artery dilation. METHODS: We surveyed the inpatient MIS-C management approaches of the members of the International Kawasaki Disease Registry across 38 institutions and 11 countries. RESULTS: Among the respondents, 56% reported using immunomodulatory treatment for all MIS-C patients, regardless of presentation. Every respondent reported use of intravenous immunoglobulin (IVIG), including 53% administering IVIG in all patients. Steroids were most often used for patients with severe clinical presentation or lack of response to IVIG, and only a minority used steroids in all patients (14%). ASA was frequently used among respondents (91%), including anti-inflammatory and/or anti-platelet dosing. Respondents reported use of prophylactic anticoagulation, especially in patients at higher risk for venous thromboembolism, and therapeutic anticoagulation, particularly for patients with giant coronary artery aneurysms. CONCLUSIONS: There is variation in management of MIS-C patients with suboptimal evidence to assess superiority of the various treatments; evidence-based gaps in knowledge should be addressed through worldwide collaboration to optimize treatment strategies.

In April 2020, the National Health Service in the United Kingdom alerted the medical community of children presenting critically ill with findings similar to Kawasaki disease (KD) or toxic shock syndrome in the setting of recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. 1 This syndrome was later referred to as Pediatric Multisystem Inflammatory Syndrome (PIMS) and Multisystem Inflammatory Syndrome in Children (MIS-C), with several proposed case definitions (Table 1) . [2] [3] [4] Since that time, there have been numerous reports of MIS-C patients across Europe and the United States. Patients with MIS-C are most commonly 8-11 years old with slight male predominance and normally previously healthy. 7, 24, 25, 28, 29 There is typically a delay in MIS-C presentation after the peak in coronavirus disease 2019 cases in the local population by 2-6 weeks with the current hypothesis that MIS-C is a delayed immune response to a recent SARS-CoV-2 infection rather than direct viral injury. 16, 21, 24, 25 Patients most commonly present with fever, gastrointestinal symptoms, and KD-like symptoms, such as rash and conjunctival injection, along with laboratory evidence of significant inflammation. Presentation varies by age, with younger patients presenting more often with KD-like features and older patients presenting with more myocarditis-like findings, including 73% with myocarditis in the 13-20 year old cohort compared to 39% in the 0-5 year old cohort in a recent large case series. 24 Cardiac involvement is common, particularly in those with severe presentations, with markedly elevated brain natriuretic peptide (BNP) (or pro-BNP) levels and mild-moderate troponin elevation.

There have been numerous descriptive case series over the past few months describing clinical presentations of MIS-C. However, there are very little data regarding specific indications for treatment in MIS-C patients, with variation among series. Thus, we surveyed the members of the J o u r n a l P r e -p r o o f International Kawasaki Disease Registry (IKDR) to improve our understanding of treatment practices amongst a large group of pediatric cardiologists.

The IKDR was established in 2013 with the primary objective at inception to study the prevalence, clinical, and management factors associated with outcomes of coronary artery aneurysms after KD. 30 Current members of the IKDR include mainly pediatric cardiologists from 65 participating hospitals representing Canada and the United States primarily, with additional sites in Taiwan, Chile, Brazil, Argentina, Mexico, Italy, Australia, Israel, and the United Kingdom. Since the onset of the current pandemic and emergence of MIS-C, the focus of the IKDR has been directed to characterizing MIS-C given the important cardiac manifestations noted in children and the similarities to KD.

We performed an online survey to assess management decisions during hospitalizations for MIS-C. The physicians were asked to identify criteria used for administration of different immunomodulatory and antithrombotic therapies. The 12-question survey was approved by the institutional review board of The Children's Hospital of Philadelphia with exempt determination.

The survey was reviewed independently by three cardiologists (ME, AD, BM) and underwent a pilot test trial prior to distribution to the IKDR. Responses were anonymous and voluntary, and IKDR members were approached via email and routine virtual meetings with request for completion (Supplemental Table S1 ). Only one IKDR member per institution was asked to complete the survey, and answers were collected via the web-based application Research Electronic Data Capture (REDCap) hosted at The Children's Hospital of Philadelphia.

Among the IKDR membership, members from 36 of 65 institutions completed the survey with two additional members commenting that they have not encountered MIS-C yet, for an overall response rate of 58%.

The most frequently reported specialties treating inpatient and outpatient MIS-C included cardiology (94% inpatient and outpatient), infectious disease (86% inpatient, 47% outpatient), and rheumatology (83% inpatient, 69% outpatient) (Supplemental Figure S1 ). Additional inpatient providers included general pediatrics (78%), followed by hematology (42%) and immunology (17%).

Among the respondents, 56% reported using immunomodulatory treatment for all MIS-C patients, regardless of presentation. All respondents reported that intravenous immunoglobulin (IVIG) was indicated for MIS-C patients, but the circumstances varied and included the presence of clinical features of KD (44%), coronary artery involvement (44%), myocardial involvement (39%), and severe clinical presentation, such as intensive care admission or presentation with shock (39%). Most often, the IVIG dose of 2 g/kg was reported (86%). For 53% of respondents, IVIG was indicated for all MIS-C patients regardless of the presence of additional features ( Figure 1 ).

Respondents reported steroid use most frequently in patients with severe clinical presentation (64%), followed by those who do not respond to IVIG (ongoing fevers and/or inflammation; 56%) ( Figure 1 ). Only a minority of respondents indicated that they would use steroids for all patients (14%). Other individual responses regarding indications for steroids included the presence of valve dysfunction noted on echocardiogram even without ventricular dysfunction, patients deemed to be at a higher risk of developing coronary artery aneurysms (ex: very young age), and patients with macrophage activation syndrome.

Respondents indicated that they would use adjunct immunomodulatory medications, particularly in severe or refractory cases of MIS-C, including anakinra (58%), infliximab (28%), and tocilizumab (8%). Two additional respondents commented that while they have not encountered a patient with refractory disease yet, they would consider using anakinra or infliximab in that setting.

Acetylsalicylic acid (ASA) was felt to be indicated by 91% of respondents. Respondents reported anti-inflammatory dosing at 30-50 mg/kg/day (56%) rather than 80-100 mg/kg/day (25%) more frequently, with 17% reporting that they did not use anti-inflammatory dosing. Respondents indicated that anti-inflammatory dosing would be used most commonly for those patients with KD features (53%) and/or coronary artery ectasia or aneurysms (50%) (Figure 2 ). Anti-platelet dosing (3-5 mg/kg/day) would be used most commonly in those with KD features (47%) and coronary artery involvement (39%), but sometimes for all MIS-C patients (33%).

Respondents indicated that they would use prophylactic anticoagulation most commonly for patients felt to have a higher baseline risk for venous thromboembolism, such as the presence of altered mobility and obesity (31% of respondents), in addition to giant coronary artery aneurysms (25%) and elevated D-dimer levels (19%). Therapeutic anticoagulation dosing would be used for patients with giant coronary artery aneurysms (61%) and those with a severe clinical presentation (33%) (Figure 3 ).

In this survey, we found important variation regarding the management approaches for patients with MIS-C. Approximately half of respondents would treat all MIS-C patients with immunomodulatory therapies, regardless of presentation, while others recommended treatment J o u r n a l P r e -p r o o f only in severe cases. IVIG was most often indicated, and steroids were typically reserved for more critical cases. Biologic therapies, such as an anakinra, were also commonly reported.

Respondents frequently used anti-platelet therapy and prophylactic anticoagulation, reserving therapeutic anticoagulation for patients with giant coronary artery aneurysms or severe clinical presentations.

There have been several phenotypes reported in the literature for MIS-C, including 1) severe presentation with shock with or without ventricular dysfunction, 2) KD-like presentation with evidence of systemic inflammation, and 3) fever with evidence of inflammation not requiring intensive care support ( Figure 4 ). The degree of shock and hypotension are often out of proportion to the degree of ventricular dysfunction. Some patients have presented with severe ventricular dysfunction with a myocarditis-like presentation, yet others have had milder ventricular dysfunction without evidence of shock. Ventricular systolic dysfunction is common among MIS-C patients, reported in 33%-55% of patients. 14, 24, 25, 29 Left ventricular systolic dysfunction has been most commonly in the mild-moderately diminished range, although several studies have reported patients with severely diminished ventricular function. 7, 25 The presence of coronary artery involvement is less common than ventricular dysfunction, typically 8-19% but as high as 36% of cases. 7, 14, 24, 25, 28, 29 While the majority of studies have described mild coronary artery ectasia/aneurysms, the presence of giant coronary artery aneurysms has been reported. 5,14,27 Arrhythmias are not common in MIS-C patients but can occur, 5, 7, 11, 13, 14, 19, 23, 25 reported in 12 of 186 patients in one large series. 25 These arrhythmias have included atrial arrhythmias (premature atrial contractions and atrial fibrillation), ventricular arrhythmias (premature ventricular contractions, nonsustained ventricular tachycardia, and one patient with a wide complex tachycardia requiring extracorporeal membrane oxygenation (ECMO)), and J o u r n a l P r e -p r o o f atrioventricular block (first and second degree without further details on second degree). 14, 25 The cardiac presentation of patients with MIS-C is summarized in Table 2 .

Naturally, given the clinical presentation similar to KD and KD shock syndrome, authors have questioned whether MIS-C is SARS-CoV-2-triggered KD or a distinct entity. [31] [32] [33] [34] [35] In Bergamo, Italy, authors compared 19 KD patients prior to the pandemic from 2015 to 10 patients with KDlike presentations in the current era. 6 In addition to the higher incidence, recent patients have been older with more frequent cardiac involvement, higher serum ferritin levels, higher neutrophils, lower lymphocytes, lower platelets, and lower sodium levels. Similarly, when comparing 16 MIS-C patients across 7 hospitals in France to patients with KD, MIS-C patients were again older with the similar laboratory differences, increased prevalence of myocarditis, and increased prevalence of IVIG resistance. 17 Whittaker et. al compared the laboratory features for 58 MIS-C children to those with KD and KD shock syndrome, based on prior database records from California. In comparison, MIS-C patients had consistently different laboratory values in addition to older age: higher white blood cell count, higher neutrophils, lower lymphocytes, lower hemoglobin, lower platelets, higher C-reactive protein, lower albumin, higher ferritin, higher troponin, and higher D-dimer levels. 14 Additionally, there have been different racial and ethnic backgrounds between MIS-C and KD. Several studies have commented on the relatively high proportion of MIS-C patients of African-American or Afro-Caribbean descent. 5,11,14,18 There is typically a higher incidence of KD in Asian populations, but authors from South Korea have reported no cases of MIS-C. 36 Lastly, while about 5% of patients with KD present with shock, MIS-C patients present with shock at least 35-50% of the time. 25, 29 Further research, particularly immunologic profiling, will be necessary before any conclusions 38 and has sometimes been used in the treatment of myocarditis. Among the largest case series, 70-81% of patients have received IVIG, with variation in the dose of IVIG used (1 g/kg vs. 2 g/kg). 7, 24, 25, 28, 29 The use of IVIG varies by presentation, with one series reporting 100% use in those with KD-like presentations, 72% for those with shock, and 61% for those with fever and inflammation alone, although the effect on outcome cannot be determined from these data. 14 Steroid use, most often methylprednisolone, has been frequently reported in the literature for MIS-C, with a range of 49-73% of patients receiving steroids across large case series. 24, 25, 28, 29 The rationale for using steroids are its anti-inflammatory properties and frequent use in KD, particularly in high risk KD patients, 39 has been no improvement after initial treatment with IVIG, but others have used them for primary treatment, particularly tocilizumab in the presence of cytokine storm. 8 Patients frequently present with shock, often requiring inotropic support, including epinephrine, norepinephrine, dopamine, dobutamine, and milrinone. 5-28 One particular study commented on their goal of avoiding milrinone due to concern of peripheral vasodilation. 18 The use of ECMO varied considerably as well, with the most prevalent use in France where 10 of 35 patients with ventricular dysfunction received ECMO support. 7 Children with MIS-C have laboratory features suggestive of a pro-coagulable state, and the use of anti-platelet and/or anticoagulation therapies have been frequently reported. While many studies did not report any ASA use, others have reported using anti-inflammatory dosing or more commonly anti-platelet dosing. 5, 6, 9, 11, 13, 15, 17, 18, 20, 21, 23, 28, 29 There have only been scattered reports of thrombosis with MIS-C, including two patients in the 78 patient United Kingdom study. 28 Several series have discussed anticoagulation, 5, 7, 12, 13, 20, 21, 23, 25, 28, 29 most commonly prophylactic dosing rather than therapeutic dosing. Indications for prophylactic anticoagulation were typically not provided, although one study commented that anticoagulation was indicated for patients with elevated D-dimer or fibrinogen levels, left ventricular dysfunction, electrocardiographic changes, or any coronary artery abnormality. 21 The management of MIS-C has been individualized at institutions with various clinical pathways and management algorithms. Recent studies have summarized and sometimes proposed specific therapeutic approaches, 41-46 but there has not been any study comparing these treatment J o u r n a l P r e -p r o o f strategies to assess outcomes. Based on the IKDR survey and review of the literature, we propose best practices for management of MIS-C, which warrants a multidisciplinary approach ( Figure 5) .

The IKDR survey regarding management of MIS-C has limitations. We may not have detailed all of the many possible nuances in MIS-C management, but our goal was to assess generally accepted management strategies. The survey may not be reflective of actual practice. The questions asked members about current institutional practices, but members may have responded with the approach that they would possibly use in patient scenarios rather than the actual use.

Bias is also possible given that the IKDR members are nearly all pediatric cardiologists, and while practice variation may certainly exist among institutions, there may be variation relative to other providers and IKDR members within the individual institutions as well.

Treatment of patients with MIS-C often includes management of shock, the use of immunomodulatory therapies, and the use of thromboprophylaxis agents. Using these approaches, the vast majority of reported patients have fortunately recovered quickly. However, there is wide variation in management and suboptimal evidence to assess efficacy and superiority of the different treatment algorithms. Gaps in knowledge should be addressed through prospective trials and registries. Due to the rarity of the condition, multi-center collaboration will be critical to understand this disease with the potential for generating increased knowledge regarding KD in the process. 

•It is reasonable to anticipate that patients with MIS-C may be presenting with ventricular dysfunction. Therefore, consider 10 cc/kg fluid boluses, along with careful reassessments between each administration.

•If there is persistent hypotension or evidence of poor perfusion despite fluid resuscitation, consider inotropic support.

•Patients with mild symptoms, no significant ventricular dysfunction, and no coronary artery involvement may not require any immunomodulatory therapy but would warrant close monitoring.

•IVIG should be considered in patients with KD features and/or coronary artery involvement, but it could be considered in all MIS-C patients. Monitor patients closely when administering IVIG due to associated volume load in setting of potential ventricular dysfunction.

•Consider addition of steroids in patients with more severe presentations, including those requiring intensive care and/or presenting in shock, and in those who do not respond to IVIG.

•Biologic agents, such as anakinra, could be considered as second-line agents.

•Refer to the 2017 American Heart Association guidelines for KD when considering antiplatelet and/or anticoagulation therapies in patients with KD features or coronary artery involvement. 38 •Low dose aspirin (3-5 mg/kg, maximum 81 mg daily) is reasonable to consider in patients with KD-like presentations and/or coronary artery involvement, with consideration of use in all MIS-C patients.

•Consider prophylactic dosing of anticoagulation, such as enoxaparin, in patients at higher baseline risk of venous thromboembolism (ex: patients ≥ 12 years old with altered mobility, obesity, known thrombophilia or history of thrombus, critical presentation, etc.), along with pneumatic sequential compression devices.

•Consider therapeutic dosing of anticoagulation in patients with the following:

•Giant coronary aneurysms •At least moderately diminished ventricular systolic function •Thrombosis concerns

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We would like to thank and acknowledge the members of the International Kawasaki Disease Registry for their voluntary participation in the survey. We thank all healthcare providers and essential workers providing care for MIS-C patients during this pandemic and certainly to the patients and their families.