Multisystem Inflammatory Syndrome in Children in Association With COVID-19.

Abstract

HomeCirculationVol. 142, No. 5Multisystem Inflammatory Syndrome in Children in Association With COVID-19 Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBMultisystem Inflammatory Syndrome in Children in Association With COVID-19 John M. Simpson, MD and Jane W. Newburger, MD, MPH John M. SimpsonJohn M. Simpson John Simpson, MD, Department of Congenital Heart Disease, Evelina London Children’s Hospital, London SE1 7EH, UK. Email E-mail Address: [email protected] https://orcid.org/0000-0002-9773-7441 Department of Congenital Heart Disease, Evelina London Children’s Hospital, UK (J.M.S.). Search for more papers by this author and Jane W. NewburgerJane W. Newburger Department of Cardiology, Boston Children’s Hospital, MA (J.W.N.). Department of Pediatrics, Harvard Medical School, Boston, MA (J.W.N.). Search for more papers by this author Originally published11 Jun 2020https://doi.org/10.1161/CIRCULATIONAHA.120.048726Circulation. 2020;142:437–440This article is a commentary on the followingAcute Heart Failure in Multisystem Inflammatory Syndrome in Children in the Context of Global SARS-CoV-2 PandemicOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: June 11, 2020: Ahead of Print Article, see p 429Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused >5 million infections worldwide with over 350 000 deaths at the time of this writing. In adults, severe hypoxemia in the acute phase and a profound inflammatory response with cytokine storm have been implicated in high mortality rates in vulnerable groups. The risks from the acute disease in young people, however, have been consistently lower; <2% of laboratory-confirmed cases of COVID-19 in the United States have occurred in children.1 Among children with COVID-19 admitted to pediatric intensive care units in the United States, only 4% died, even though >80% had preexisting medical conditions.2 This initially led to the belief that children were largely spared from the disease.Recent reports have emerged of multisystem inflammation in children, mimicking Kawasaki disease in some aspects of clinical presentation and clinical course,3,4 and variously termed Kawasaki-like disease,4 pediatric multisystem inflammatory syndrome temporally associated with COVID-19,5 or multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19.6 Case definitions for MIS-C have been produced by the US Centers for Disease Control and Prevention6 and the UK Royal College of Paediatrics and Child Health5 (Table), as well as by the World Health Organization.7 These case definitions include association with COVID-19, as defined by a positive test for SARS-CoV-2 by reverse transcriptase polymerase chain reaction for viral RNA, antigen, or antibody, or exposure to others with COVID-19 within the 4 weeks before the onset of symptoms.Table. Case Definitions for Multisystem Inflammatory Syndrome in Children (MIS-C)Royal College of Paediatrics and Child Health5Centers for Disease Control and Prevention6 • A child presenting with persistent fever, inflammation (neutrophilia, elevated C-reactive protein, and lymphopenia), and evidence of single organ or multiorgan dysfunction (shock, cardiac, respiratory, renal, gastrointestinal, or neurologic disorder) with additional clinical, laboratory, or imaging and ECG features; children fulfilling full or partial criteria for Kawasaki disease may be included• An individual age <21 years presenting with fever,* laboratory evidence of inflammation,† and evidence of clinically severe illness requiring hospitalization, with multisystem (≥2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, or neurologic); AND • Exclusion of any other microbial cause, including bacterial sepsis, staphylococcal or streptococcal shock syndromes, and infections associated with myocarditis such as enterovirus• No alternative plausible diagnoses; AND • SARS-CoV-2 PCR testing positive or negative• Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or COVID-19 exposure within the 4 weeks before the onset of symptomsSome individuals may fulfill full or partial criteria for Kawasaki disease but should be reported if they meet the case definition for MIS-C. MIS-C should be considered in any pediatric death with evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. COVID-19 indicates coronavirus disease 2019; PCR, polymerase chain reaction; and RT-PCR, reverse transcriptase polymerase chain reaction.*Fever ≥38.0°C for ≥24 hours or report of subjective fever lasting ≥24 hours.†Including, but not limited to, one or more of the following: elevated C-reactive protein, erythrocyte sedimentation rate, fibrinogen, procalcitonin, D-dimer, ferritin, lactic acid dehydrogenase, or interleukin-6; elevated neutrophils; or reduced lymphocytes and low albumin.Ascertainment of COVID-19 infection and exposure is hampered by the sensitivity and specificity of tests for SARS-CoV-28 and unavailability of testing of family contacts. The epidemiologic association of MIS-C with COVID-19 is well established: in Europe, regions heavily affected by SARS-CoV-2 are reporting many cases of MIS-C; clinical findings are relatively consistent across geographically distinct regions; and the timing of MIS-C is consistent with a mechanism related to host response and hyperinflammation.9 Prospective reporting of this condition has now been initiated by agencies worldwide to capture prevalence, early clinical course, and outcome.10In this issue of Circulation, Belhadjer et al11 report a French and Swiss cohort of 35 children, mean age 10 years, with acute left ventricular dysfunction, fever, and a multisystem inflammatory state, who were admitted for intensive care across 13 hospitals. All had evidence of SARS-CoV-2 infection by reverse transcriptase polymerase chain reaction, serologic evidence of infection, or typical lung computed tomography features of SARS-CoV-2 pneumonia. A striking number of children presented with abdominal symptoms, prompting 2 surgeries for suspected appendicitis. Although skin rash and cheilitis suggestive of incomplete Kawasaki disease were frequent, no child met full criteria for Kawasaki disease.12 Importantly, <20% of patients reported chest pain, and the ECG was uninformative in all but 1 patient. These findings are consistent with reports from other centers.3 Markers of inflammation and cardiac involvement—including troponin I, brain natriuretic peptide, D-dimer, C-reactive protein, and interleukin 6—were all elevated.11Cardiovascular dysfunction necessitated the use of intravenous inotropes in most children, and almost 30% required venoarterial extracorporeal membrane oxygen support. Treatments included intravenous immunoglobulin (71%), steroids (35%), heparin (65%), and anakinra (8%). Ventricular function assessed by echocardiogram was moderately to severely depressed in all patients on admission to intensive care, consistent with entry criteria for this case series. In most cases, ventricular dysfunction was global. Coronary artery dilation, defined as Z score >2, was noted in 17% of patients but none was reported to have coronary artery aneurysms. At the time of publication, some patients remained hospitalized, but 80% no longer required intensive care support, and recovery of ventricular function had been observed in almost three-quarters of patients, with no mortality.11Previous reports of clinical presentation have described “warm, vasoplegic shock”3 requiring inotropic and vasoconstrictor support of blood pressure and tissue perfusion. Belhadjer et al11 found that a majority of patients had “respiratory distress” requiring ventilatory support, which is less prominent in other reports.3,4 Perhaps owing to the timing of presentation in relation to initial infection with SARS-CoV-2, respiratory distress is less evident in series where patients are seropositive but antigen negative.3 From the experience of >60 cases managed at Evelina London Children’s Hospital, clinical deterioration with evidence of decreased cardiac function can occur rapidly, suggesting that cases should be managed where there is ready access to cardiac investigation and intensive care including ventricular assist devices.3 Development of myocardial edema has been reported,11 and myocardial infarction has been confirmed in some cases at Evelina London Children’s Hospital by cardiac magnetic resonance imaging (Dr James Wong, personal communication, 2020).Findings of coronary artery dilation and aneurysms among children with MIS-C have alarmed cardiologists and raised the specter of long-term coronary artery sequelae akin to those seen in classic Kawasaki disease. In children, coronary dimensions are normalized for body surface area as Z scores based on normative data for coronary artery dimensions in afebrile children.12 The 2017 American Heart Association statement on Kawasaki disease defines coronary artery dilation as Z score of ≥2.0 and <2.5, and coronary artery aneurysm as Z score ≥2.5.12 However, coronary artery dilation is not specific to Kawasaki disease. Children with common febrile illnesses have larger mean coronary artery dimensions than afebrile controls, although their mean Z scores are below those in patients with Kawasaki disease.13,14 Febrile patients without Kawasaki disease in these studies did not have as much inflammation as those with MIS-C, and the severity of systemic inflammation could affect the degree of coronary enlargement. Coronary dilation and aneurysms have also been noted in rheumatologic and infectious diseases.15–17 If coronary dilation in MIS-C is related to fever and circulating inflammatory mediators rather than disruption of the arterial wall, we would expect dimensions to return quickly to normal.Although Belhadjer et al11 do not describe coronary artery aneurysm development, others have reported patients with MIS-C with aneurysms, including giant aneurysms.3,4 The progression of COVID-19–associated coronary aneurysms has been rapid in some patients managed at Evelina London Children’s Hospital (Dr Paraskevi Theocharis, personal communication, 2020). Variation in the incidence of aneurysms across series could reflect differences in definition, frequency of coronary imaging, or quality of echocardiographic imaging. Moreover, few data are available on the longer-term impact of MIS-C on myocardial function and coronary arteries. Standardized protocols for acquisition of coronary images and interpretation across centers, together with systematic longer-term surveillance, are needed to provide greater clarity on the cardiac sequelae of MIS-C.Investigators across the globe are considering how MIS-C with complete or incomplete features of Kawasaki disease is similar to and different from Kawasaki disease as we knew it before the COVID-19 pandemic. Despite more than 4 decades of ongoing research, the search for a single cause for Kawasaki disease has been elusive. Most investigators believe that Kawasaki disease is a syndrome caused by an immunologic reaction to different infectious triggers in the genetically susceptible host. Data from Italy quantified the time course and incidence of Kawasaki-like disease in children before and after the COVID-19 pandemic, documenting a 30-fold increase in incidence of Kawasaki-like disease, uncorrected for seasonal variation.4 Although MIS-C has been compared with Kawasaki disease, there are important differences. MIS-C presents at an older age compared with Kawasaki disease (mean age 7 years versus 3 years), with a higher incidence of shock and myocardial dysfunction.4 Some laboratory findings differ, with patients with MIS-C manifesting higher inflammatory markers, elevated BNP (brain natriuretic peptide) or NT-proBNP (N-terminal proBNP), and lymphopenia. The approach of early recognition, prompt therapy with treatments often used for Kawasaki disease, and supportive intensive care is associated with a high rate of recovery.The optimal treatment regimen for MIS-C is uncertain. The majority of patients in published series have received immunomodulatory therapy with intravenous immunoglobulin and steroids.3,11,18–20 Fewer have been treated with anakinra,11,20 infliximab,3,20 or tocilizumab.18 Patients with features of Kawasaki disease or coronary artery dilation should receive antiplatelet dose aspirin, and anticoagulation may be added for those with coagulopathy (eg, elevated D-dimer) or large or giant aneurysms. Choice of treatments should be optimized through improved understanding of disease mechanisms, as well as multicenter randomized, controlled trials and registries with propensity matching.The study of Belhadjer et al11 adds to an emerging literature about this rare new pediatric multisystem inflammatory syndrome associated with COVID-19. Because this study includes only those patients with shock or left ventricular dysfunction requiring intensive care, its findings may not be generalizable to the likely much larger number of children who are affected less severely. Research is needed on the immunobiology of the disease, its manifestations across the spectrum of severity, the best therapies, and its long-term sequelae, particularly those involving the heart. Prospective registries are now being set up, and related research will provide further insights into the pathophysiology and natural history of MIS-C.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circJohn Simpson, MD, Department of Congenital Heart Disease, Evelina London Children’s Hospital, London SE1 7EH, UK. Email john.[email protected]nhs.uk