key: cord-0729526-cs3un6hd
authors: Kiss, Andreea; Ryan, Paul MacDaragh; Mondal, Tapas
title: Management of COVID-19-associated multisystem inflammatory syndrome in children: A comprehensive literature review
date: 2021-04-09
journal: Prog Pediatr Cardiol
DOI: 10.1016/j.ppedcard.2021.101381
sha: 0e568169dbe197561ae344166c7b1fb2fb242560
doc_id: 729526
cord_uid: cs3un6hd

INTRODUCTION: The prevalence and severity of COVID-19 is greatly reduced in children, yet some pediatric patients develop a syndrome resembling Kawasaki Disease (KD), termed Multisystem Inflammatory Syndrome in Children (MIS-C). With an estimated incidence of 2/100,000 children, MIS-C is relatively rare, but can be fatal. Clinical features can include fever, hyperinflammatory state, gastrointestinal symptoms, myocardial dysfunction, and shock. The pathogenesis of MIS-C, although yet to be completely elucidated, appears to be distinct from KD in terms of epidemiology, severity, and biochemical signature. METHODS: This comprehensive review searched AMED, EBM Reviews, Embase, Healthstar, MEDLINE, ERIC, and Cochrane for studies that reported treatments and outcomes of MIS-C. RESULTS: The search strategy yielded 42 papers, from which 15 underwent full-text review (n = 386). A majority of children received intravenous immunoglobulin (77%) and some form of anticoagulation (63%). Steroid use was also common (44%), with immunotherapy used only in severe cases (n = 72). Outcomes reported included PICU admission (77%), need for extracorporeal membrane oxygenation (5%), and mortality (1.3%). Although efficacy of treatments for MIS-C have largely not yet been investigated, we propose close monitoring by a multidisciplinary team, symptomatic treatment (e.g., intravenous immunoglobulin for KD-like symptoms, steroids/immunotherapy for multisystem inflammation), and long-term follow-up. CONCLUSION: Although outcomes are largely favorable, management is based on a different disease entity (KD), which may not be appropriate given the likely pathophysiologic divergences. Further research is required to evaluate the effectiveness of current MIS-C treatments and to determine more refined therapies.

A novel coronavirus was identified in early January 2020 (1) (4) and declared it a pandemic on March 11, 2020 (2) . As of October 11, 2020, there have been over 37 million confirmed cases and just over 1 million deaths worldwide (5) .

SARS-CoV-2 is an enveloped, single stranded, zoonotic RNA virus that is part of the coronaviridae family, order nidovirales (6, 7) . These groups of viruses have a characteristic crown-like resemblance when viewed using electron microscopy (8) , with the spike (S) protein, which is responsible for host cell receptor binding and membrane fusion, forming the spikes of the "crown" (9) . Seven viruses in this family are known to infect humans, four of which cause mild, self-limiting respiratory symptoms (229E, NL63, HKU1, and OC43) (10) . However, three coronaviruses are known to cause severe respiratory illness in individuals: severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and the novel SARS-CoV-2 (3, 10) . SARS-CoV-2 enters the host cell similar to SARS-CoV, through binding to the angiotensin-converting enzyme 2 (ACE2) receptor (11) via its S protein (12, 13) . The ACE2 receptor is a membrane bound protein expressed by vascular and the incidence is higher in different ethnic groups than in KD (41, [54] [55] [56] 66, 67) . Also, gastrointestinal symptoms are much more prominent (41, 46, 51, 66, 67) , and inflammatory markers tend to be more elevated (67) while lymphocyte and platelet counts are lower on average (68) . The coronary artery effects of MIS-C appear to be different as well, presenting in a distinct pattern of uniformly ectactic vessel dilation and left main coronary artery orifice implication (47). KD, in comparison, spares the left main coronary artery orifice and has aneurysms that are separated by normal segments of vessel (69, 70) . This may suggest that the coronary artery involvement in MIS-C is caused by the fever response and cytokine storm, as opposed the KD-induced arterial wall changes (47, 71, 72) . Furthermore, what is most worrisome is that the clinical course for MIS-C appears to be more severe, with myocardial dysfunction, shock, and resistance to single intravenous immunoglobulin (IVIG) treatment occurring more often than in KD (50, 68) .

The pathophysiology of MIS-C is being actively explored. Theories for the mechanism underlying the myocardial involvement include direct invasion of the myocytes by the virus, systemic inflammatory response causing myocyte injury, and myocardial ischemia from hypotension (73) . Indeed, a recent in vitro report of human induced pluripotent stem cell-derived cardiomyocytes revealed the susceptibility of such cells to SARS-CoV-2 infection, ultimately indicating that viral myocarditis is possible and perhaps partially explanatory of this syndrome (74) . However, given the elevated inflammatory markers observed, the involvement of multiple organ systems (41,47, [54] [55] [56] [57] , and the late onset of the syndrome in the disease course (46, 50, 67, 75) , the most likely mechanism is that of a delayed inflammatory response.

To discover the exact pathophysiology, a recent preprint created structural based computation models of SARS-CoV-2 and found that the S protein has a sequence motif that is not present on any other similar coronaviruses (76) . Interestingly, this sequence motif closely J o u r n a l P r e -p r o o f resembles, in both sequence and structure, bacterial superantigens that cause toxic shock syndrome (73) (74) (75) (Figure 1 ). The motif is most similar to that of staphylococcal enterotoxin B and as such, would cause large-scale T-cell activation and proliferation, causing an immense release of pro-inflammatory cytokines from T cells (interferon gamma, tumor necrosis factor alpha, interleukin-2) and antigen presenting cells (interleukin-1 and tumor necrosis factor alpha) (76, 79) . This cytokine storm results in multi-organ tissue damage as is seen in MIS-C and thus, may be at least in part culpable. The superantigen activity of the SARS-CoV-2 S protein may also be the cause of the cytokine storm seen in adults (76) . Adding further evidence, the signs and symptoms of TSS and MIS-C are very similar -including desquamation, altered mental status, gastrointestinal upset, myalgia, low platelets, as well as elevated PT/PTT, d-dimer and CRP -and they both occur in an older age group of children (80) . What is not explained by this recent finding is the timeline of presentation, as well as the presence of cardiac manifestations, which are rare in TSS (80, 81) . That being said, data is still very limited, and further research is needed.

Various institutions, such as The Hospital for Sick Children (82) , have put together a management algorithm for MIS-C. However, as this is a novel syndrome with limited data, we aim to conduct a comprehensive review to highlight treatments used around the world, their rationale, and outcomes to better inform guidelines in the future. Using our findings, along with expert opinion, we will also outline an approach to MIS-C management.

The following databases were included in the search strategy: Ovid databases (including AMED, EBM Reviews, Embase, Healthstar, MEDLINE, University of Ottawa Full Text Journals), ERIC, and Cochrane. The search strategy combined the terms for the name of the syndrome J o u r n a l P r e -p r o o f The initial search yielded 57 results. The titles and abstracts were manually reviewed with the following inclusion criteria:

1) The paper is a primary study with at least one study participant

2) The paper's target population was children with a multisystem inflammatory disorder associated with SARS-CoV-2

3) The paper detailed the treatment and management given to the pediatric patients 4) The paper mentions the outcome of the treatment, such as symptom resolution, successful hospital discharge, or mortality.

Based on these criteria, 42 were excluded and 15 papers were examined and analyzed in full.

J o u r n a l P r e -p r o o f

MIS-C is relatively uncommon, with an estimated incidence of 2 per 100,000 individuals less than 21 years old (75) . According to our literature review, there were a total of 386 cases of MIS-C or cases resembling MIS-C ( Table 2) . Roughly 77% were admitted to the PICU, the median length of PICU admission was 5 days, and about 53% needed inotropic support of some sort. Few children required ECMO (n=19, 5%), and there were 5 fatalities (1.3%) in total.

However, these percentages do not accurately reflect the risk in all MIS-C cases as some study criteria included only MIS-C patients that presented to hospital or were admitted to the PICU, thus representing a more acute population. Likely, the risk of PICU admission, fatality, and need for inotropic support or ECMO is more modest.

Currently, treatment algorithms at renowned tertiary pediatric hospitals recommend management based on severity, congruence with complete KD criteria, presence of macrophage activation syndrome, and inflammatory marker levels (82) . A number of expert societies have created management protocols as well, including the American College of Rheumatology (91) , and PICU guidelines have been put forward by an international group of experienced internists (92) . Nevertheless, there is no definitive data on the most appropriate management as of yet (92) .

In the studies analyzed, four out of 15 explicitly explained the management guidelines that were followed: three used the American Heart Association 2017 KD guidelines and one used a case-by-case multidisciplinary team approach. All but two studies modelled the KD treatment approach initially, even if not explicitly mentioned. However, as MIS-C is a distinct entity from KD, it is likely to require a different management approach. Additionally, there is the aforementioned possibility that the pathophysiology might be related to that of TSS. However, J o u r n a l P r e -p r o o f there is notable overlap between KD and TSS treatment, as the gold-standard for severe KD cases, IVIG, has high affinity for the staphylococcal enterotoxin B (93) and therefore, potentially the SARS-CoV-2 superantigen. If further research does reveal such superantigens to underly this condition, other approved medications for staphylococcal enterotoxin B may be considered for MIS-C treatment, such as the CD28 co-stimulation inhibitor CLTA1-Ig (94) or the mTOR inhibitor rapamycin (95) .

Two studies managed cases without using IVIG as the first line therapy, including a case series of five pediatric patients with potentially acute abdomen due to COVID-19 (87) and a case report of a patient with MIS-C and concomitant newly diagnosed Crohn's disease (86) . In the case series, the children received heterogenous treatments for acute COVID-19 infection, such as hydroxychloroquine and lopinavir/ritonavir. Although this group of patients had signs of MIS-C, it is more probable that they were experiencing a severe case of initial COVID-19 infection, making the treatment approach appropriate (87) . As for the case report, the authors opted for infliximab as a treatment that might address both the cytokine storm of MIS-C and the dysregulated immune reaction of Crohn's disease (86) .

As mentioned previously, guidelines for PICU management of COVID-19 pediatric patients have been proposed (92) . Eight recommendations from the document were related to MIS-C treatment, with the best practice suggestions being supportive management and close monitoring, use of a multidisciplinary team, laboratory tests (SARS-CoV-2 antigens, inflammatory markers, organ system dysfunction), and empirical antibiotics until bacterial causes are excluded (92) . These were based largely on management of other severe inflammatory diseases (92) .

It is important to note that not all MIS-C patients need some form of immunomodulatory therapy (91) ; supportive care and close monitoring may be enough. The expert panel of J o u r n a l P r e -p r o o f internists was even inconclusive whether IVIG should be given empirically in MIS-C patients (92) . For instance, in one case report of 58 children, 22% of MIS-C patients made a full recovery with supportive care alone (67) . In our literature search, there were few patients that received supportive care alone, but this again may be due to the acuity of patients included. Further research will hopefully elucidate what/if specific therapies are superior to supportive care and whether clinical inaction may bring with it serious long-term sequelae, as is the case in KD.

It is well known that IVIG (2g/kg) prevents coronary artery aneurysm in KD (64, 96, 97) and there have been reports of benefit from the therapy in COVID-19-associated myocarditis also (98) . In addition, glucocorticoids have been shown to reduce coronary artery aneurysm in KD patients with a high risk of IVIG failure (99, 100) . However, since MIS-C is a separate disease entity from KD, using KD management strategies may not be as efficacious, potentially explaining the higher IVIG failure rate in MIS-C patients (46). As most centers were following KD treatment guidelines, a majority of patients in our literature review did receive IVIG (n=298, 77%). The treatment appeared reasonably robust, but a substantial percentage required a second dose of IVIG (18%). Moreover, 171 patients (43%) were given methylprednisolone at some point during admission. According to the COVID-19 PICU recommendations, for patients that meet classical or atypical KD criteria, administering IVIG (2g/kg) and aspirin (50m/kg) is strongly encouraged (92) . However, in the context of MIS-C, the use of methylprednisolone and IVIG should be considered with multidisciplinary input as both have insufficient evidence (92) .

Similarly, the American Rheumatology College task force recommends IVIG and steroids alone or together, but there is not enough data to compare the effectiveness of one versus the other, or when used in combination (91) .

It is theorized that IL-6 plays a central role in KD pathophysiology via megakaryocyte maturation, thereby leading to thrombocytosis. The cytokine also potentially causes vasculitis through triggering a cascade that stimulates polyclonal B cell autoantibody production, resulting in acute inflammation and antibody mediated endothelial damage (101, 102) . Recent evidence suggested that the cytokine IL-6 may be culpable for myocardial injury in COVID-19 (103) and studies have found IL-6 levels to be significantly elevated in MIS-C patients (49,51,65,68,86).

Therefore, IL-6 inhibitors may prove to be a valuable treatment option in MIS-C. Tocilizumab, a monoclonal antibody that serves an IL-6 inhibitor, is used to treat systemic onset juvenile idiopathic arthritis (104) , which shares many features with MIS-C, such as skin rash, major inflammatory syndrome, macrophage activation syndrome, and fever. Several institutions are already using tocilizumab or another IL-6 receptor monoclonal antibody, with 6 of 15 studies administering the immunotherapy to at least one patient, and 33 children (8.55%) receiving it in total, all with promising results (50, 65, 68, 84, 87, 88) . Also, tocilizumab is already undergoing clinical trial (ClinicalTrials.gov Identifier: NCT04331808) to be used in severely ill COVID-19 adult patients (105, 106) . However, formal investigation of tocilizumab use in pediatric MIS-C patients is awaited.

Anakinra is an IL-1 receptor antagonist that is commonly used to treat systemic juvenile arthritis induced cytokine release syndrome (107) The antiviral remdesiver was given for compassionate use in several instances, with two studies both treating seven patients with the medication (65, 89) . Yet, as the most supported theory for MIS-C pathogenesis is that of post-infection, the potential for benefit of remdesiver in this syndrome may be limited. If the patient is SARS-CoV-2 RT-PCR positive, then remdesiver may theoretically be of use if administered early enough in the infection course (80, 112, 113) ; however, this was the case for only one of the two studies (65) .

Some sort of antiplatelet or anticoagulation therapy (usually aspirin or enoxaparin) was given to over 60% of patients throughout the studies analyzed. Since MIS-C fulfills the high risk of venous thromboembolism criteria, this course of action is entirely appropriate. If there is thrombocytopenia associated with multi-organ failure, which has been seen in MIS-C (68), then the PICU guidelines recommend therapeutic plasma exchange, although the supporting evidence is limited (92) . Additionally, the American College of Rheumatology outline an algorithm for anticoagulation/antiplatelet medications and dosing based on risk, recommending low-dose aspirin in all patients with KD features, coronary artery aneurysm, and thrombocytosis (64, 91) . If a patient has a coronary artery aneurysm with a z-score of 10 or more, then enoxaparin or warfarin is recommended. Additionally, anticoagulation should be considered for patients with moderate to severe left ventricular dysfunction (91) .

Ventricular dysfunction is a common occurrence in MIS-C patients (47,85). Therefore, echocardiography and ECG should be performed early upon admission and subsequently at regular intervals. This is supported by the PICU guidelines for MIS-C and pediatric COVID-19 treatment (92) . However, coronary artery enlargement may be missed in echocardiography alone, so CT may be of additional value in indeterminate cases (47). In terms of MRI use, three J o u r n a l P r e -p r o o f case series have investigated its utility and have shown diffuse myocardial edema and hyperemia acutely in the disease course (47, 85, 114) . In one case series, evidence of myocardial necrosis/fibrosis was also observed (114) . Furthermore, recent evidence shows that subtle cardiac dysfunction may persist past two weeks post PIMS-TS onset (47). Thus, we recommend structured long-term follow-up with echography supplemented with cardiac MRI or CT as needed.

The results of this comprehensive literature review are limited by the heterogeneity of the studies included. Papers included patients of various levels of acuity, used different case definitions, reported different outcomes, and had assorted study designs of varying quality.

Additionally, most of the articles included a small sample size due to the novelty of the condition. Given the few studies published to date and the recent emergence of MIS-C, this could not be avoided in our comprehensive review, and must be taken into consideration when interpreting the data. Additionally, the included studies may have been confounded by patients with true KD that presented during this period of pandemic. Finally, it must be emphasized that the data supporting these treatment stems entirely from case series and reports which lack efficacy-establishing controls. One patient required no treatment and went into remission spontaneously on day 8. The other 15 patients (94%) received IVIG at a dose of 2g/kg, three (19%) of which received a second round of IVIG, and one (6%) of which received a second round of IVIG with steroids and was still undergoing steroid treatment upon study completion due to autoimmune hemolytic anemia that developed after the second IVIG infusion. Two (13%) patients received a steroid adjacent post-IVIG infusion. All patients receiving treatment (n=15, 94%) were given aspirin, with 7 (44%) taking 30-50mg/kg/day and 8 (50%) taking an anti-aggregant dose. One (6%) received IL-1 receptor antagonist anakinra (4mg/kg) due to respiratory distress, and another (6%) received IL-6 antagonist tocilizumab (8mg/kg) for persistent systemic inflammation. Additionally, one patient (6%) was administered hydroxychloroquine, but only due to clinicians initially suspecting systemic lupus erythematosus as the diagnosis. Seven (44%) of all patients were admitted to the pediatric intensive care unit (PICU) and required fluid resuscitation. Six (38%) required inotropic supports as well. All patients that received treatment (n=15) went into remission within a median of 2 days (IQR 1 to 8) of treatment initiation, with remission defined as absence of fever, disappearance of clinical signs, and complete regression of inflammatory biomarkers. All patients were treated in accordance with the American Heart Association indications for KD, with IVIG risk stratification done using the Kobayaski score. All 10 patients (100%) were given IVIG at 2g/kg. In addition, two patients (30%) also received aspirin (50-80mg/kg/day) for 5 days, and eight (80%) received aspirin (30mg/kg) with methylprednisolone (2mg/kg/day) for 5 days, followed by methylprednisolone dose tapering over two weeks. They received steroids as adjuvant due to having features of cytokine storm. Two patients (20%) needed inotropic support. Response to treatment, defined as resolution of signs and symptoms, normal vital signs, normal c-reactive protein levels, and normal blood tests, was observed in all ten patients (100%). 

No evidence of SARS-CoV-2 in any patients (RT-PCR, serology, or contact history).

The patient was admitted to the PICU, where she received fluid boluses for hypotension, later followed by inotropic supports (low dose norepinephrine). She also received broad spectrum antibiotics. On day three in hospital, the patient developed a new heart murmur, their ejection fraction fell to 47%, and chest radiography showed an enlarged cardiac silhouette, pulmonary edema, and bilateral pleural effusion, so milrinone and diuretics were given along with low dose norepinephrine. The patient showed signs of clinical improvement shortly afterwards. She received IVIG (2mg/kg) on day four in the hospital along with a single dose of methylprednisolone (1mg/kg). Within 12 hours of receiving the IVIG, the patient's fever went down and she quickly improved. On day five, her cardiac function normalized, and she was prescribed aspirin (30mg/kg/day). For the next three days, she remained afebrile and was discharged on low dose aspirin.

A multi-centre retrospective observational study.

(n=33) presented to three New York tertiary care children hospitals between April 23 to May 23, 2020. Their median age was 10 years old, and 16 patients (48%) had comorbid conditions including asthma (n=5, 15%), obesity (n=2, 6%), allergic rhinitis/eczema (n=3, 9%), cardiac (n=2, 6%), hematologic (n=2, 6%), and other (n=3, 9%).

SARS-CoV-2 infection.

All patients (n=33) required PICU admission. A majority of patients (n=18, 54%) received IVIG, 17 (51%) were given methylprednisolone due to elevated inflammatory markers, and 2 patients (6%) received both. All patients were given anticoagulation (n=33), 27 (82%) of which had therapeutic dose enoxaparin, 5 (15%) had prophylactic dose enoxaparin, and 1 (3%) had unfractionated heparin at a therapeutic dose. Vasopressors (norepinephrine n=10, dopamine n=9) had to be used in 17 patients (51%), with a mean duration of administration of 72 hours. Antibiotics (empiric coverage) were given for less than 48 hours in 14 (42%) patients and for more than 48 hours in 15 (45%) of patients. In terms of more targeted therapies, 12 (36%) received tocilizumab for high IL-6 levels and 4 (12%) received anakinra. Remdesivir, a nucleoside analog that blocks virus replication during active infection, was compassionately used in 7 patients (21%), all which had a positive RT-PCR. One child (3%) that had severely depressed left ventricle function and was treated with methylprednisolone, also received convalescent plasma along with an intra-aortic balloon pump for 24 hours. Another child (3%) required extracorporeal membrane oxygenation (ECMO) due to severely depressed left ventricle function and cardiogenic shock within 24 hours of presenting to hospital. All but one patient (n=32, 97%) improved clinically based on inflammatory markers and myocardial function and were discharged home after a 7.8 day median stay in the hospital and a 4.7 day median stay in the PICU. The patient with the intra-aortic balloon pump was supported by the pump for 24 hours and was well enough to be weaned off of invasive mechanical ventilation after 2 days and was discharged home after 12 days. Sadly, the child on ECMO developed an ischemic brain infarction accompanied by a subarachnoid hemorrhage on day 6 of the mechanical circulatory support, resulting in J o u r n a l P r e -p r o o f brain death and the appropriate withdrawal of life-sustaining therapies. 

Heart Association criteria for complete and incomplete KD. Two patients did not have evidence of recent SARS-CoV-2 infection.

All 21 patients (100%) received IVIG for a median of 5 days, along with aspirin at a low dose (3-5mg/kg/day). Seven (33%) also received a steroid adjuvant with (2-10mg/kg). Resistance to IVIG, defined as persistent fever 36 hours after the end of initial IVIG infusion and requiring a second round of IVIG, occurred in 5 patients (24%), 4 (19%) of which received a second infusion of corticosteroids (2mg/kg/day). Broad spectrum antibiotics were given to 18 children (86%). PICU admission due to hemodynamic instability was required in 17 patients (81%) who had higher levels of inflammatory markers, where 11 (52%) received intravenous fluid resuscitation. Eight patients (38%) had hypotension that was unresponsive to fluids, and thus, were given vasoactive agents. Inotropic agents were given to 14 children (67%) because of myocarditis with cardiac dysfunction. All patients were discharged home after a median of 8 days in hospital (IQR 5-17), and 5 days (IQR 3-15) days in the PICU.

A multicenter retrospective case series.

Patients (n=20) were from four tertiary care hospitals in Paris, France, and presented to the healthcare centre between April 15th and April 27th, 2020. Their median age was 10 years old, and no comorbidities were reported.

No published case definition used. Inclusion criteria was less than 18 years old, admission to the PICU with fever and cardiogenic shock secondary to myocarditis and having a suspected SARS-CoV-2 infection.

All patients (n=20, 100%) received IVIG (2g/kg) within 2 days at the PICU, 18 (90%) of which had complete fever resolution post-infusion. A small minority of children (n=2, 10%) were given corticosteroids. One patient (5%) received an interleukin-1 receptor antagonist and another (5%) a monoclonal antibody against the interleukin 6 receptor. A majority (n=19, 95%) required inotropic support for a median of 3 days. The average PICU stay was 4 days. All children were successfully discharged with cardiac function recovery and a significant decrease in inflammatory markers.

A single centre retrospective observational study.

All patients (n=15) were from a tertiary paediatric hospital in the United Kingdom and presented between April 10th and May 9th, 2020. The median age was 8.8 PIMS-TS (RCPCH) with referral to cardiology.

Treatment was determined case-by-case by a multidisciplinary team, and supportive treatment was given following the hospital standards. 10 children (67%) received IVIG (2g/kg) and aspirin (12.5mg/kg) four times a day. Patients that continued to have persistent fever and increasing inflammatory markers 36 hours post initial treatment were given a second dose of IVIG (n=2, 13%) and/or a 3 day course of methylprednisolone followed by a weaning course of prednisolone (n=5, 33%). All (n=15) were given broad spectrum antibiotics for a minimum of 5 days. Ten children (67%) had to be admitted to the PICU and stayed a median of 4 days. In the intensive care unit, all ten (67%) required fluid resuscitation and inotropes/vasopressors for a median of 3 days. In eight patients (53%), hydrocortisone was needed for persistent hypotension. All patients were discharged clinically well with normal or improving laboratory results and cardiac function, on low dose aspirin, with a median hospital stay of 12 days. All four children received IVIG. Three (75%) were given vasoactive agents along with volume expanders. Also, three children (75%) required prednisolone and aspirin. All patients recovered to normal ventricular function between 48 hours to 5 days and were discharged from hospital at 13 to 23 days post symptoms onset.

A case report.

A 14-year-old male recently diagnosed with pediatric Crohn's disease was admitted to a hospital in New York with five days of fever and abdominal pain.

The patient was SARS-CoV-2 PCR positive and suspected to have MIS-C (CDC).

The patient initially received intravenous antibiotics for their perianal abscess, along with hydroxychloroquine (5 day course) and azithromycin (3 days course) for the SARS-CoV-2 infection, prophylactic enoxaparin, and intravenous fluids. Despite initial treatment, the patient remained febrile. On day 8, after consultation with multiple specialties, the anti-tumor necrosis factor alpha treatment infliximab (10mg/kg) was given as it could address the Crohns' disease and potentially the cytokine storm seen in MIS-C. Just a few hours after infliximab administration, the fever and hypotension resolved, along with inflammatory markers beginning to decrease. He received a second dose of infliximab 5 days later because of active perianal disease and remaining inflammation and was discharged that day. Two weeks after discharge, the patient had complete resolution of all previous clinical findings and normalization of all laboratory values, including inflammatory markers. was azithromycin and lopinavir/ritonavir. Tocilizumab was administered to 4 children (80%). One child (20%) received therapeutic dose low molecular weight heparin, and 4 (80%) were given the prophylactic dosage. All children were given various antibiotics due to suspected acute abdomen, and all were successfully discharged after a median of 5 days (2-13 range) in the PICU.

A retrospective multi-centre observational study.

All patients (n=35) were admitted to one of 13 hospitals in France and Switzerland between March 22 and April 30, 2020. The median age was 10 years. Ten patients (28%) had comorbidities, including asthma (n=3, 9%), lupus (n=1, 3%), and being overweight (n=6, 17%).

All patients met MIS-C (CDC) criteria, but the inclusion criteria for the study was even more specific. The criteria were the presence of fever, cardiogenic shock or acute left ventricular dysfunction, with an inflammatory state. SARS-CoV-2 confirmation was not needed, and laboratory evidence of the virus was found in 31 (89%) patients.

A majority of patients (n=25, 71%) received IVIG. One patient (3%) had persistent fever two days after initial infusion, so was given a second dose of IVIG. Steroids were given to 12 children (34%) because they were deemed to be high risk. Three patients (9%) received anakinra due to persistent severe inflammatory state. Also, 23 patients (66%) were given heparin at a therapeutic dose. Most patients (n=29, 83%) had to be admitted to the ICU for a median of 7 days, and required inotropic support (n=28, 80%). Ten (29%) of those in intensive care required mechanical circulatory assistance with venoarterial ECMO but were successfully weaned and removed successfully after 4.5 days on average. Clinical resolution of signs and symptoms occurred in 28 patients (80%) so far. The median hospital stay of patients that were discharged at the time of study publication was 10 days. Seven (20%) children were either still in hospital or had residual impaired cardiac function. J o u r n a l P r e -p r o o f

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Coronary artery dimensions in febrile children without Kawasaki disease

Coronary artery dilation in acute Kawasaki disease and acute illnesses associated with fever

The cardiovascular burden of coronavirus disease 2019 (COVID-19) with a focus on congenital heart disease

Human iPSC-Derived Cardiomyocytes are Susceptible to SARS-CoV-2

Multisystem inflammatory syndrome in children in New York State

An insertion unique to SARS-CoV-2 exhibits superantigenic character strengthened by recent mutations

Toxic shock syndrome: major advances in pathogenesis, but not treatment

Manifestations of Toxic Shock Syndrome in Children

Staphylococcal superantigens: pyrogenic toxins induce toxic shock

Multi-system inflammatory syndrome in children (MIS-C) following SARS-CoV-2 infection: review of clinical presentation, hypothetical pathogenesis, and proposed management

Early differentiation of Kawasaki disease shock syndrome and toxic shock syndrome in a pediatric intensive care unit

Practice alert: Rise in cases of paediatric multisystem inflammatory syndrome in the setting of the COVID-19 outbreak

A case of pediatric multisystem inflammatory syndrome temporally associated with COVID-19 in South Dakota

Acute myocarditis and multisystem inflammatory emerging disease following SARS-CoV-2 infection in critically ill children

Cardiac MRI of Children with Multisystem Inflammatory Syndrome (MIS-C) Associated with COVID-19: Case Series

Pediatric Crohn's Disease and Multisystem Inflammatory Syndrome in Children (MIS-C) and COVID-19 Treated with Infliximab

Severe SARS-CoV-2 infection in children with suspected acute abdomen: a case series from a tertiary hospital in Spain

Emergence of Kawasaki disease related to SARS-CoV-2 infection in an epicentre of the French COVID-19 epidemic: a timeseries analysis

Distinct clinical and immunological features of SARS-COV-2-induced multisystem inflammatory syndrome in children

COVID-19 and Kawasaki disease: novel virus and novel case

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

COVID-19 PICU guidelines: for high-and limited-resource settings

B cell epitope mapping of the bacterial superantigen staphylococcal enterotoxin B: the dominant epitope region recognized by intravenous IgG

Interference of the T cell and antigen-presenting cell costimulatory pathway using CTLA4-Ig (abatacept) prevents Staphylococcal enterotoxin B pathology

Rapamycin protects mice from staphylococcal enterotoxin B-induced toxic shock and blocks cytokine release in vitro and in vivo

High-dose intravenous gammaglobulin for Kawasaki disease. The Lancet

The treatment of Kawasaki syndrome with intravenous gamma globulin

Recognition and initial management of fulminant myocarditis: a scientific statement from the

Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomised, open-label, blinded-endpoints trial

Corticosteroids for the treatment of Kawasaki disease in children

The acute phase nature of interleukin 6: studies in Kawasaki disease and other febrile illnesses

Cytokines predict coronary aneurysm formation in Kawasaki disease patients

A comparison of serum IL6 and CRP levels with respect to coronary changes and treatment response in Kawasaki disease patients: a prospective study

American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features

Tocilizumab treatment in COVID-19: A single center experience

Cohort Multiple Randomized Controlled Trials Open-label of Immune Modulatory Drugs and Other Treatments in COVID-19 Patients -Tocilizumab Trial -CORIMUNO-19 -TOCI (CORIMUNO-TOCI)

Anakinra (Kineret) Prescribing Information

Report No.: NCT02390596. Available from

The use of interleukin 1 receptor antagonist (anakinra) in Kawasaki disease: a retrospective cases series

High-dose anakinra as treatment for macrophage activation syndrome caused by refractory Kawasaki disease in an infant

Usefulness and safety of anakinra in refractory Kawasaki disease complicated by coronary artery aneurysm

Retracted: Clinical and epidemiological characteristics of 34 children with 2019 novel coronavirus infection in Shenzhen

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. The Lancet

Cardiovascular Magnetic Resonance in Myocarditis Related to Multisystem Inflammatory Syndrome in Children

United States. median age was 8.3 years. Comorbidities were noted in 51 patients (27%), including respiratory (n=33, 18%), cardiac (n=5, 3%), immunocompromised or autoimmune (n=10, 5%), and other (n=20, 11%). Out of the patients who had BMI reported, 29% were obese (n=45, out of the 153 patient who had data available). patients (70%) were successfully discharged, and 52 (28%) were still in hospital. The patients that were discharged spent, on average, 7 days in the hospital. Sadly, 4 patients (2%) passed away. All were above 10 years old, two had underlying comorbidities, and 3 had ECMO support.J o u r n a l P r e -p r o o f Patients were treated based on KD management guidelines. Most children (n=9, 90%) were given IVIG as first line, from which 6 (60%) was considered unsuccessful and required a second line treatment. The second line treatment included a second dose of IVIG plus methylprednisolone (n=5, 50%) or tocilizumab (n=1, 10%). Six patients (60%) required PICU admission, from which 5 (50%) needed inotropic support. All patients were discharged successfully after a median of 13.5 days in hospital (range 4 to 27 days).

A retrospective single centre observational study that compared data with historic cohorts of KD and macrophage activation syndrome.The study included 28 patients with a median age of 9 years. Children all presented to hospital in Boston, United States between March to June 2020. Half of the patients (n=14) had comorbidities including asthma (n=3, 11%), congenital heart disease (n=1, 4%), KD previously diagnosed (n=2, 7%), sickle cell anemia (n=1, 4%), autism (n=1, 4%), mitochondrial disorder (n=1, 4%),

Most patients (n=20, 71%) were given IVIG (n=13, 46%, 2 g/kg; n=6, 21%, 1 g/kg; n=1, 4%, 0.5 g/kg), and 17 (61%) received methylprednisolone (1-4 mg/kg/day). Two patients (7%) required a second dose of IVIG. Anakinra (5-13 mg/kg/day) was administered in 5 children (18%) that were refractory to IVIG and steroids and in one child (4%) that had sickle cell to prevent the use of methylprednisolone. Antibiotics were given to 15 children (54%), remdesivir to 7 (25%), and hydroxychloroquine in one (4%). In terms of anticoagulation therapy, 14 patients (50%) received low dose aspirin (3-6 mg/kg/day), 5 (18%) received high dose aspirin (20-50 mg/kg/day), 13 (46%) were administered enoxaparin at the prophylactic dosing, and 5 (18%) were administered treatment dose enoxaparin. PICU admission was required in 17 patients (61%), where 7 (25%) received inotropes. All cases showed clinical improvement, defined as fever resolution, inflammatory marker improvement, and cessation of intorope need. The median hospital stay was 8 days. In patients that were treated with immunomodulatory therapies, fever resolution was seen after a median of 4 days from admission. Also, 3 of the 6 cases that had coronary artery abnormalities and were treated with IVIG (n=6, 21%) and methylprednisolone (n=4, 14%) showed normalization of coronary vessels post-treatment (50%), one J o u r n a l P r e -p r o o f Journal Pre-proof chromosomal abnormalities (n=1, 4%), and obesity (n=4, 14%).showed improvement (17%), and the other two showed stabilization (33%).

A case report.A 6-month-old female infant that presented to a pediatric hospital in California in early April 2020. She had no comorbidities.Classic KD with confirmed SARS-CoV-2 infection (RT-PCR positive).Treated according to KD management guidelines. She was given IVIG (2g/kg) and high dose acetylsalicylic acid (20mg/kg four times a day). The patient's fever resolved quite quickly after treatment. There were no cardiac findings, and the patient was discharged 2 days post-IVIG treatment on low