MIS-C: Clinical profile, outcomes and predictors of severe disease

MIS-C: Clinical profile, outcomes and predictors of severe disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article MIS-C: Clinical profile, outcomes and predictors of severe disease Swathy Subhash, Prameela Joji, Greeshma Baby, Nisha Nair, Shiju Kumar, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1685192/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective MIS-C is a novel disease entity. We aimed to outline the clinical features and laboratory parameters of children with moderate to severe MIS-C and to study predictors of more severe disease. Methods In this prospective longitudinal study, all children less than 15 years of age requiring admission to the Paediatric Intensive Care Unit (PICU) or High Dependency Unit (HDU) with three or more days of fever were screened for MIS-C according to the WHO case definition. Children with alternative diagnoses were excluded. Those included were tested for active or past infection with SARS-COV2 using RTPCR or antibody testing. Severe MIS-C was defined as presence of ventricular dysfunction, coronary dilatation, need for respiratory support, inotropes or invasive ventilation. Clinical features, laboratory parameters and risk factors for severe disease was studied. Results 60 children were included in the study. Median age group was 5yrs(IQR 2.175,9)The median duration of PICU/HDU stay was 4 days(IQR 2,5.75). Two children died of the illness. Gastrointestinal symptoms were most common(73%) followed by muco-cutaneous(56%), respiratory(46%) and cardiovascular system(41%) involvement. Majority showed neutrophilia(73%), leucopenia(53%) and raised inflammatory markers including ESR,CRP, D-dimer, ferritin and NT-proBNP which showed significant association with need for respiratory support, inotropes, cardiac dysfunction and prolonged ICU stay. Gastrointestinal symptoms, respiratory distress, reduced urine output at admission, platelet counts less than 1.5 lakhs, D-dimer >2000ng/mL, CRP >70mg/L, NT-proBNP>500pg/mL, ferritin >250mcg/L were markers of severe MIS-C. Conclusion Clinical features and laboratory parameters aid in early recognition of severe MIS-C resulting in greater probability of survival. Article Summary The challenges of recognizing and treating MIS-C in developing countries and identifying risk factors for morbidity. What’s Known on This Subject MIS-C is a post covid hyper-inflammatory syndrome with diverse disease manifestations. Early recognition and rapid implementation of treatment is vital. What This Study Adds MIS-C is a relatively new disease entity with a wide spectrum of disease severity. Our study describes the clinical spectrum of children with more severe disease and attempts to identify predictors of severe MIS-C. Introduction Covid 19 has put the world through previously unforeseen circumstances since its arrival in January 2020. Among the many surprises seeded along its course is the post covid Multisystem Inflammatory Syndrome in Children (MIS-C) with its mixed presentations and potentially fatal outcome if not recognised and treated early.( 1 , 2 ) The possibility of a post covid hyper-inflammatory state was first reported from clusters of children in the UK and North America who developed multi-organ failure similar to Toxic Shock Syndrome and also bore resemblance to Kawasaki disease.( 3 ) The World Health Organisation (WHO) then issued a case definition based on clinical and laboratory parameters for the early recognition and treatment of Multisystem Inflammatory Syndrome in Children.( 4 ) Children with MIS-C show a wide spectrum of illness ranging from mild to severe. The involvement of cardiovascular system causing cardiogenic shock and coronary artery dilatation have been of particular concern prompting the use of steroids and immunomodulators like Intravenous Immunoglobulin (IVIG) and TNF-alpha inhibitors to limit the hyperimmune response.( 5 ) Studies from western literature have shown no difference in outcomes irrespective of the immunomodulators used.( 6 ) But literature is sparse from third world countries where tropical fevers add to the diagnostic dilemma and patient loads are higher. We aimed to find the various presentations, the laboratory parameters of prognostic significance, echocardiographic findings and short term outcomes of MIS-C. Materials And Methods We conducted a single centre prospective observational study between September 2020 to September 2021 in a tertiary care referral centre in South India. All children less than 15 years of age requiring admission to the Paediatric Intensive Care (PICU) or High Dependency Unit (HDU) with three or more days of fever were screened for MIS-C according to the WHO case definition.( 4 ) Children who fulfilled the criteria and had no alternative diagnosis were enrolled in the study after written informed consent from their parents. Evidence of active or recent covid infection was confirmed using Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) test or the presence of covid IgG/ IgM antibodies. Children with co-morbidities were not included in our study. The study was approved by the Institution Ethics Committee. Baseline demographic data, clinical features, laboratory parameters including complete blood counts, liver and renal function tests, inflammatory markers before initiation of treatment- Erythrocyte Sedimentation Rate (ESR), C-Reactive Protein (CRP), ferritin, cardiac markers including Troponin T and N-terminal B- type Natriuretic Peptide( NTproBNP) and echocardiographic findings were recorded. Left ventricular (LV) dysfunction was defined as an ejection fraction less than 50%. Coronary artery dilatation was defined as a zscore ≥ 2 of the left anterior descending artery or right coronary artery.( 7 ) The presence of shock ( blood pressure < 5th centile), clinical symptoms, length of PICU stay, requirement for respiratory support (low flow oxygen, non-invasive ventilation or invasive ventilation), inotropes, Extra Corporeal Membrane Oxygenation (ECMO), Continuous Renal Replacement Therapy (CRRT), treatment administered (pulse steroids-30mg/kg methylprednisolone, IVIG, both or IVIG with low dose steroids) and outcomes were also documented. Oliguria was defined as < 0.5ml/kg/hr urine output for more than 6 hours. Acute Kidney Injury (AKI) was defined as creatinine elevated more than age appropriate levels. Severe MIS-C was defined as presence of ventricular dysfunction, coronary dilatation, need for respiratory support, inotropes or invasive ventilation. They were treated according to national guidelines for treatment of MIS-C which is based on the ACR guidelines.( 8 , 9 , 10 ) We aimed to study the clinical characteristics of children with MIS-C getting admitted to the PICU, to study the association between laboratory markers and disease severity and analyse the predictors of severe MIS-C. Results We enrolled 60 patients in our study between September 2020 and September 2021. More than half the study population (58%) were girls and 5% were infants. The median age was 5years (IQR 2.175,9). Our study population had no children with co-morbidities. The median duration of PICU/HDU stay was 4 days (IQR 2, 5.75) with 25% patients staying for more than 5days. Of the 60 patients included in our study, 58 were discharged home while two children died of the illness. The basic demographic details, clinical features and laboratory parameters are depicted in Table 1 . Table 1 Basic demographic details, clinical features and laboratory parameters Demography, Clinical features n = 60 Males n(%) 25(41.6%) Age median (IQR) 5(2,9) Duration of PICU stay median (IQR) 4(2,5.7) Gastrointestinal symptoms n(%) 44 (73.3) Rash n(%) 34 (56.6) Mucus membrane, conjunctival congestion n (%) 39 (65) Respiratory distress n(%) 28 (46.6) Hypotensive shock n(%) 45 (75%) Oliguria n(%) 13 (21.6) Encephalitis n(%) 4 (6.6) Laboratory parameters Median (IQR) Total leucocyte count(cells/mm 3 ) 11300(7725,16575) Neutrophils (%) 75(59.25,82.5) Lymphocytes (%) 16.5(10,26.75) Platelet count (* 10 5 /mm 3 ) 2(1.3,4.475) ESR(mm/h) 57(25.25,88) CRP(mg/L) 106.5(62.75,149.25) Aspartate aminotransferase (U/L) 31.5 (24,50.75) Alanine aminotransferase (U/L) 32 (21,52.25) Blood Urea Nitrogen 10(7.5,13) Creatinine (mg/dL) 0.5 (0.4,0.6) Ferritin (ng/mL) 346 (207.5,812.5) D-dimer (ng/mL) 3065 (1548.25,5989.75) NT-proBNP (pg/mL) 1310.5 (369.5,4078) Clinical features and organ dysfunction All children enrolled in our study had fever. Gastrointestinal symptoms were the next most common (73%) with children having loose stools, vomiting and/or abdominal pain. We also had two patients with acute liver failure and coagulopathy. Dermatological manifestations were also common. More than half the children had rashes (56%) during the course of their illness whereas almost 2/3rd had mucus membrane involvement and non-purulent conjunctival congestion. One child presented with an extensive vasculitis rash and had persistently elevated inflammatory markers requiring prolonged treatment. Almost half (46%) our cohort had respiratory symptoms requiring support during the course of their illness. Low flow oxygen was administered to 12 children, while 9 received non-invasive ventilatory support and five needed invasive mechanical ventilation. Two children received ECMO, of which one survived. 25 children required inotropic support during the course of their illness. 11 children had LV dysfunction on echocardiogram, 12 had pericardial effusion and 3 had dilated coronaries. Age had a significant association with cardiovascular involvement with children in the age group between 1 to 10years being commonly affected. The need for invasive ventilation showed a significant association with LV dysfunction and pericardial effusion. 20% children had oliguria at admission. We had 7 children with AKI of which three were non-oliguric and recovered spontaneously. Both children who required ECMO needed CRRT. One child required peritoneal dialysis. There were four children who presented with symptoms suggestive of acute encephalitis of which one succumbed to the illness. Laboratory markers Complete blood counts showed neutrophilia (73%), leucopenia (53%) and thrombocytopenia( 36%). Almost all patients had elevated ESR, CRP, d-dimer levels, troponin and NT-proBNP. CRP more than 70mg/L, ESR > 40mm/h, Ferritin > 250mcg/L, NT-proBNP > 500pg/mL showed a significant association with the need for respiratory support and inotropes. D-dimer > 2000ng/mL had significant association with cardiac dysfunction need for inotropic support. Ferritin > 250mcg/L also had significant association with cardiac dysfunction (p 40mm/h and platelet count < 1.5lakhs/mm 3 showed significant association with longer PICU stay. Treatment 80% of our study population received IVIG. Almost half the children (49%) were treated with both IV immunoglobulin (2g/kg) and pulse dose steroids ( 30mg/kg), 20% with IVIG and low dose steroids (2mg/kg), 20% with pulse steroids alone and 11% with IVIG alone. Low dose steroids were tapered and stopped over 2 weeks except in one child who continued to have persistently elevated inflammatory markers and was treated with tocilizumab and 8 weeks of low dose steroids. Children with cardiac involvement and those with D-dimer elevated more than 2500ng/mL were also treated with low dose anti-platelet (acetylsalicylic acid) for 6 weeks where-in repeat echocardiogram was done. No child had persistent coronary artery dilatation at follow up and thus did not require long term antiplatelet therapy. Prognostic markers Gastrointestinal symptoms, respiratory distress, reduced urine output at admission, platelet counts less than 1.5 lakhs, D-dimer > 2000ng/mL, CRP > 70mg/L( p 500(p 250mcg/L(p < 0.1) were markers of severe MIS-C. Statistical analysis Descriptive statistics was obtained for all study variables. Continuous data were expressed as mean (SD) or median and inter-quartile range [IQR] values. Univariate association was established between categorical variables using χ 2 test and p value ≤ 0.05 was taken as significant. In certain cases, we have accepted a p value of ≤ 0.1 as we consider this a pilot study exploring new areas. For independent association between significant univariates and outcomes, one way Analysis Of Variance was done. For continuous variables, means were compared between two groups. Discussion MIS-C presents as a spectrum of illness ranging from the very mild to a very severe and life-threatening disease condition. We report the clinical features, laboratory parameters and their association with short term outcomes in sixty children admitted to our PICU/HDU with MIS-C following covid 19 infection. We have attempted to identify subtle markers of more severe disease so that clinicians can identify patients at risk of rapid deterioration at the outset and commence early treatment. Of the 60 children included in our study, 28 were SARS COV2 RTPCR positive in the 8–12 weeks prior to the onset of their symptoms while the rest 32 were antibody positive. The median age of our study population was 5 years which is lesser than that reported in literature.( 5 , 11 ) 20% were more than 10 years of age and there were 3 infants as well. In the initial cohorts of MIS-C abdominal pain acted as a red herring creating suspicions of an acute abdominal emergency possibly requiring surgical intervention, thus distracting clinicians from the diagnosis of a post covid hyperinflammatory syndrome and possibly delaying treatment. But now with case reports and studies from various parts of the world, we have realised that gastrointestinal symptoms including severe abdominal pain, loose stools and vomiting are the commonest presenting symptoms of MIS-C.( 5 , 11 , 12 ) The same findings have been reflected in our study as well and is an indicator of morbidity. Patients have presented with such severe abdominal pain that around 5% have even had to undergo computerised tomography of the abdomen to ensure the absence of any other pathology. Interestingly, we also had two patients with acute liver failure who recovered with immunomodulation and supportive care. The Kawasaki disease phenotype either in its classical or incomplete form has gained prominence in its association with MIS-C.( 5 , 10 , 13 )This was the next most common presentation in our study as well and maybe because of the younger age of the study population. More than half the children had rash or mucus membrane involvement in the form of cracked lips, red tongue or non-purulent conjunctival congestion. Several dermatological manifestations of MIS-C have been reported.( 14 , 15 ) The association of coronaviridae family with vasculitis and vasculopathy is evident from its KD like presentation which maybe either the result of direct invasion of the cells by the virus or as a result of cytokine storm. Echocardiogram is vital in the treatment of children with MIS-C. An echocardiogram should be done not only in children with KD like presentation but in any child with suspected MIS-C. While Kawasaki disease is known for its predilection to affect the coronaries, the commonest finding noted in our patients were pericardial effusion and ventricular dysfunction with valvular regurgitation (20%); coronary artery dilatation was rare (5%). Similar echo findings have been recorded in other clusters of children with MIS-C. 7,13,16 The three children who coronary artery dilatation in our study had had complete resolution at 6 weeks review but is on long term follow up. Similar encouraging results of complete resolution of cardiac abnormalities have been reported world-wide.( 7 , 17 ) One child with severe left ventricular dysfunction who required ECMO has mild LV dysfunction at 6 months and is on follow up. Several studies have reported MIS-C to be a disease of children more than 5 years of age and adolescents while we found that younger children are equally affected and those in the age group between 1 to 10 years were more likely to develop cardiac complications.( 5 , 16 , 17 ) Our results may be skewed because 75% of our study population belonged to this age group. Predictably, abnormalities on echocardiogram signalled a more severe course of disease progression and had a significant association with the need for mechanical ventilation. This has not been reported from previous studies.( 7 ) One-third of the children enrolled in our study required respiratory support in the form of low flow oxygen, non-invasive ventilation or invasive mechanical ventilation. Respiratory distress was identified as an indicator of severe MIS-C. Patients in our study had respiratory symptoms like tachypnoea and laboured breathing mostly due to underlying cardiac dysfunction and shock; it was not due to pulmonary involvement. Overall, majority of studies on MIS-C report lower incidence of respiratory symptoms compared to gastro-intestinal and cardiac involvement. The need for invasive ventilation varies widely between different studies.( 5 , 7 , 17 ) AKI has also been reported in significant numbers among children with MIS-C.( 1 , 5 , 11 , 18 ) This is likely due to microvascular injury triggered by macrophage activation and subsequent cytokine storm. As most of these patients have elevated cardiac markers causing a false alarm of underlying cardiac dysfunction, judicious hydration maybe withheld thus contributing to pre-renal failure as well. As was noted in our study, children with non- oliguric AKI tend to recover rapidly with good hydration and supportive care. Children with oliguria signalled severe MIS-C. For those on the sicker end of the spectrum with multifactorial aetiology contributing to kidney injury like shock and renal toxic drugs, dialysis maybe warranted. We also had a few unusual presentations of MIS-C in our study population. We had a 10 year old with severe retropharyngeal phlegmon, features of KD and cardiac dysfunction who improved rapidly with IVIG. Similar cases have been reported.( 19 ) There was a 5 year old child with extensive rashes similar to vasculitis; skin biopsy taken after initiation of steroids was consistent with small vessel vasculopathy. She had persistently raised inflammatory markers and was treated with tocilizumab and long term low dose steroids. She was asymptomatic at review but may need long term follow up to watch for an evolving rheumatic illness. Various cutaneous manifestations and leukoclastic vasculitis have been during and after covid 19 infection.( 20 ) We had four children with encephalitis like presentation. Cerebro Spinal Fluid (CSF) study was suggestive of an acute bacterial meningitis along with elevated inflammatory markers; all aetiological workup including CSF PCR assay were negative and they failed to respond to conventional antibiotics and antiviral treatment. As they were positive for covid antibody, treatment for MIS-C was instituted to which they promptly responded expect one child who rapidly deteriorated and succumbed to the illness. In alignment with previous studies, we recorded neutrophilia, lymphopenia and thrombocytopenia in our patients, liver enzymes remained normal in majority of patients with few exceptions but more than 10% patients showed a tendency to develop AKI. Of note, inflammatory and cardiac markers were invariably raised in almost all patients.( 5 , 16 , 18 , 21 ) This reiterates the fact that cardiac markers may not directly indicate myocardial involvement and cannot be used to predict the same but they are useful in identifying patients with more severe disease. Raised inflammatory markers have been associated with adverse outcomes in a large multicentric study from United States.( 22 ) We found a cut off of ESR more than 40mm/h, CRP > 70mg/L, NT-proBNP > 500 were individual predictors of the need for inotropes, need for respiratory support and overall more severe disease. Higher NT-proBNP values has shown association with severe MISC in earlier studies as well.( 23 ) We did not have any patients with thrombotic events but D-dimer was found to be elevated in almost all our patients with 75% having more than threefold rise in values. Elevated d-dimer in MIS-C maybe due to ongoing endothelial damage which places patients at risk of thrombosis. We believe that we did not experience any thrombotic events due to early initiation of antiplatelet therapy once a fivefold rise in values were noted. A fivefold rise in D-dimer also appeared to predict the possibility of ventricular dysfunction and need for inotropes. Various studies have shown ferritin to be a maker of more severe MIS-C.( 2 , 11 , 22 ) We were also able to identify ferritin as a marker of cardiac dysfunction, need for respiratory support and inotropes. Ferritin is well known as a proinflammatory mediator but it is important to highlight its immunomodulatory effects as well, the loss of which can lead to autoimmune disease states. It was interesting to note that even though a higher than normal value of ferritin is considered poor prognostic marker of MIS-C, exceptionally high values like those seen in Macrophage Activating Syndrome or severe dengue is hardly ever reported in MIS-C. The reason behind this needs to be explored because MIS-C shares the same cytokine storm as seen in other hyperferritinemic syndromes and can trigger other autoimmune conditions. We have treated our patients with either IVIG, pulse steroids, both or IVIG and low doses steroids. We are unable to comment on the efficacy of the various treatment modalities as our study was not designed for the same. Irrespective of the treatment modality used, our mortality rate (3%) is in line with western literature and much lesser than that reported from other studies in India.( 2 , 5 ) Wide-spread health education, early referral and prompt initiation of treatment has contributed to the low mortality rate. Kerala is a proactive state with well-established primary health centers and gained worldwide fame for our initial success in the fight against covid 19. We have strong health care facilities, health indices and literacy rates akin to the West and hence better prepared to face the pandemic than other states in India. Limitations Considering the large number of variables analysed and the smaller number of adverse events among our study population, significant associations between the same may have been under recognised. We have included children only up to the age of 14 years (hospital admission policy) and have not been able to study the disease in older children. Our study was conducted at the same time as the disease was first recognised and various treatment options were being studied. We have used different combinations of treatment modalities based on clinical experience and expert advice. Hence we are unable to propose treatment options which were most effective. Conclusion MISC presents itself in the guise of various disease conditions familiar to us like fever with rash, acute gastroenteritis or meningitis. Difficulties arise when conventional treatment fails and patients rapidly deteriorate. Most patients may be diagnosed straight away but at times can be a diagnostic conundrum even for experts. A thorough history followed by tiered investigative approach backed by comprehensive echocardiography helps clinch the diagnosis in time. Early recognition and rapid initiation of treatment makes a substantial impact on the prognosis of the clinical course of the patient. Abbreviations MIS-C : Multi-system Inflammatory Syndrome in Children WHO: World Health Organisation IVIG: Intravenous Immunoglobulin (IVIG) PICU: Paediatric Intensive Care HDU: High Dependency Unit RT-PCR: Reverse Transcriptase Polymerase Chain Reaction ESR: Erythrocyte Sedimentation Rate CRP: C-Reactive Protein NT-pro BNP: N-terminal B- type Natriuretic Peptide LV: Left ventricular ECMO: Extra Corporeal Membrane Oxygenation CRRT: Continuous Renal Replacement Therapy AKI: Acute Kidney Injury Declarations Conflict of Interest Disclosures (includes financial disclosures): All authors have no conflicts of interest to disclose. Funding/Support: No funding was secured for this study. Role of Funder/Sponsor (if any): None Availability of data and material: The data that supports the findings of this study are available on request from the corresponding author Code availability: N/A Authors’ Contributions Drs Subhash and Joji conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript. Drs Baby, Nair, and Kumar the designed the study proforma, collected data, carried out the initial analyses, and reviewed and revised the manuscript. Dr Gupta conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. Acknowledgments Thank you to Dr. Zulfikar Ahamed M, Pediatric Cardiologist and Dr Prijo Philip, Pediatric Nephrologist for all their efforts in the completion of this study. References Pereira MFB, Litvinov N, Farhat SCL, et al. Severe clinical spectrum with high mortality in pediatric patients with COVID-19 and multisystem inflammatory syndrome. Clinics (Sao Paulo) . 2020;75:e2209. doi: 10.6061/clinics/2020/e2209 Bagri, N.K., Deepak, R.K., Meena, S. et al. Outcomes of multisystem inflammatory syndrome in children temporally related to COVID-19: a longitudinal study. Rheumatol Int 42 , 477–484 (2022). https://doi.org/10.1007/s00296-021-05030-y Belhadjer Z, Méot M, Bajolle F, et al. Acute Heart Failure in Multisystem Inflammatory Syndrome in Children in the Context of Global SARS-CoV-2 Pandemic. Circulation . 2020;142(5):429–436. doi: 10.1161/CIRCULATIONAHA.120.048360 World Health Organization. Multisystem inflammatory syndrome in children and adolescents with COVID-19. Scientific brief (2020). ( https://www.who.int/publications/i/item/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19 ) Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem Inflammatory Syndrome in U.S. Children and Adolescents. N Engl J Med . 2020;383(4):334–346. doi: 10.1056/NEJMoa2021680 McArdle AJ, Vito O, Patel H, et al. Treatment of Multisystem Inflammatory Syndrome in Children. N Engl J Med . 2021;385(1):11–22. doi: 10.1056/NEJMoa2102968 Farooqi KM, Chan A, Weller RJ, et al. Longitudinal Outcomes for Multisystem Inflammatory Syndrome in Children [published correction appears in Pediatrics. 2021 Nov;148(5):]. Pediatrics . 2021;148(2):e2021051155. doi: 10.1542/peds.2021-051155 Henderson LA, Canna SW, Friedman KG, et al. American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 1. Arthritis Rheumatol . 2020;72(11):1791–1805. doi: 10.1002/art.41454 Henderson LA, Canna SW, Friedman KG, et al. American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 2. Arthritis Rheumatol . 2021;73(4):e13-e29. doi: 10.1002/art.41616 Sugunan S, Bindusha S, Geetha S, Niyas HR, Kumar AS. Clinical Profile and Short-Term Outcome of Children With SARS-CoV-2 Related Multisystem Inflammatory Syndrome (MIS-C) Treated With Pulse Methylprednisolone. Indian Pediatr . 2021;58(8):718–722. doi: 10.1007/s13312-021-2277-4 Acevedo L, Piñeres-Olave BE, Niño-Serna LF, et al. Mortality and clinical characteristics of multisystem inflammatory syndrome in children (MIS-C) associated with covid-19 in critically ill patients: an observational multicenter study (MISCO study). BMC Pediatr . 2021;21(1):516. Published 2021 Nov 18. doi: 10.1186/s12887-021-02974-9 Santos MO, Gonçalves LC, Silva PAN, et al. Multisystem inflammatory syndrome (MIS-C): a systematic review and meta-analysis of clinical characteristics, treatment, and outcomes [published online ahead of print, 2021 Dec 3]. J Pediatr (Rio J) . 2021;S0021-7557(21)00148–0. doi: 10.1016/j.jped.2021.08.006 Toubiana J, Poirault C, Corsia A, et al. Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study. BMJ . 2020;369:m2094. Published 2020 Jun 3. doi: 10.1136/bmj.m2094 Bouaziz JD, Duong TA, Jachiet M, et al. Vascular skin symptoms in COVID-19: a French observational study. J Eur Acad Dermatol Venereol . 2020;34(9):e451-e452. doi: 10.1111/jdv.16544 Genovese G, Moltrasio C, Berti E, Marzano AV. Skin Manifestations Associated with COVID-19: Current Knowledge and Future Perspectives. Dermatology . 2021;237(1):1–12. doi: 10.1159/000512932 Valverde I, Singh Y, Sanchez-de-Toledo J, et al. Acute Cardiovascular Manifestations in 286 Children With Multisystem Inflammatory Syndrome Associated With COVID-19 Infection in Europe. Circulation . 2021;143(1):21–32. doi: 10.1161/CIRCULATIONAHA.120.050065 Feldstein LR, Tenforde MW, Friedman KG, et al. Characteristics and Outcomes of US Children and Adolescents With Multisystem Inflammatory Syndrome in Children (MIS-C) Compared With Severe Acute COVID-19. JAMA. 2021;325(11):1074–1087. doi: 10.1001/jama.2021.2091 Whittaker E, Bamford A, Kenny J, et al. Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2. JAMA . 2020;324(3):259–269. doi: 10.1001/jama.2020.10369 Daube A, Rickert S, Madan RP, Kahn P, Rispoli J, Dapul H. Multisystem inflammatory syndrome in children (MIS-C) and retropharyngeal edema: A case series. Int J Pediatr Otorhinolaryngol . 2021;144:110667. doi: 10.1016/j.ijporl.2021.110667 Caputo V, Schroeder J, Rongioletti F. A generalized purpuric eruption with histopathologic features of leucocytoclastic vasculitis in a patient severely ill with COVID-19. J Eur Acad Dermatol Venereol . 2020;34(10):e579-e581. doi: 10.1111/jdv.16737 Torres JP, Izquierdo G, Acuña M, et al. Multisystem inflammatory syndrome in children (MIS-C): Report of the clinical and epidemiological characteristics of cases in Santiago de Chile during the SARS-CoV-2 pandemic. Int J Infect Dis . 2020;100:75–81. doi: 10.1016/j.ijid.2020.08.062 Abrams JY, Oster ME, Godfred-Cato SE, et al. Factors linked to severe outcomes in multisystem inflammatory syndrome in children (MIS-C) in the USA: a retrospective surveillance study. Lancet Child Adolesc Health . 2021;5(5):323–331. doi: 10.1016/S2352-4642(21)00050-X Zhao Y, Patel J, Huang Y, Yin L, Tang L. Cardiac markers of multisystem inflammatory syndrome in children (MIS-C) in COVID-19 patients: A meta-analysis. Am J Emerg Med . 2021;49:62–70. doi: 10.1016/j.ajem.2021.05.044 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1685192","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":108863566,"identity":"251b0680-2ef8-4dbc-bd85-5ad6c1be970e","order_by":0,"name":"Swathy Subhash","email":"","orcid":"","institution":"Kerala Institute of Medical Sciences, KIMSHEALTH","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Swathy","middleName":"","lastName":"Subhash","suffix":""},{"id":108863567,"identity":"0dfe3f52-7647-4790-a25d-70292f233193","order_by":1,"name":"Prameela Joji","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABD0lEQVRIie3RsUrEMBjA8a8Uckubrjn07l4hUhCHcuKbJAQyFfEBDiwI3cT1RNBX0CVzjkKneq6Fc4g4C10PFL3goQ6tp5tg/kvCx/cbQgBcrr+YXp8YgAGhCQBZT9Amgt6J/B2xFZ+kK7y4LZtlmgxRTz+YvaM7fnZxMjMwSQBvZa2kPz8U56dKxihgghK64NP7UlAoJaBt3UpoFcQQqoLnwCSxJKvTXeJlBSDCOon3ol6P88hYMudXPyF+qDRbLVii+fUm0q+w8AdK7OTE2LeI+KaWgrJSBl0EV2HhPanxKIpS/kiex4PLWsxMM0mGo2k7AQg+LsxffclBZu/sy/wb0tNeA7DfvelyuVz/tTe4J1mwfSzYiQAAAABJRU5ErkJggg==","orcid":"","institution":"Kerala Institute of Medical Sciences, KIMSHEALTH","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Prameela","middleName":"","lastName":"Joji","suffix":""},{"id":108863568,"identity":"65ca415a-ddcc-4faf-8592-45382f4cfafc","order_by":2,"name":"Greeshma Baby","email":"","orcid":"","institution":"Kerala Institute of Medical Sciences, KIMSHEALTH","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Greeshma","middleName":"","lastName":"Baby","suffix":""},{"id":108863569,"identity":"513ba867-fa8f-4705-a34a-f5f223163c99","order_by":3,"name":"Nisha Nair","email":"","orcid":"","institution":"Kerala Institute of Medical Sciences, KIMSHEALTH","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nisha","middleName":"","lastName":"Nair","suffix":""},{"id":108863570,"identity":"1486e364-d0a0-4e35-bc74-e0adb2223a92","order_by":4,"name":"Shiju Kumar","email":"","orcid":"","institution":"Kerala Institute of Medical Sciences, KIMSHEALTH","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shiju","middleName":"","lastName":"Kumar","suffix":""},{"id":108863571,"identity":"0bf0a726-b3f9-4c7f-8795-757b80a469f6","order_by":5,"name":"Neetu Gupta","email":"","orcid":"","institution":"Kerala Institute of Medical Sciences, KIMSHEALTH","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Neetu","middleName":"","lastName":"Gupta","suffix":""}],"badges":[],"createdAt":"2022-05-23 14:14:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1685192/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1685192/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":21988234,"identity":"edaf7652-f79b-4fe9-adef-234a99efba02","added_by":"auto","created_at":"2022-05-28 07:29:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":280179,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1685192/v1/5383e8ef-22fd-47c0-91b0-1477b11489b6.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eMIS-C: Clinical profile, outcomes and predictors of severe disease\u003c/p\u003e","fulltext":[{"header":"Article Summary ","content":"\u003cp\u003eThe challenges of recognizing and treating MIS-C in developing countries and identifying risk factors for morbidity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWhat\u0026rsquo;s Known on This Subject\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMIS-C is a post covid hyper-inflammatory syndrome with diverse disease manifestations. Early recognition and rapid implementation of treatment is vital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWhat This Study Adds\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMIS-C is a relatively new disease entity with a wide spectrum of disease severity. Our study describes the clinical spectrum of children with more severe disease and attempts to identify predictors of severe MIS-C.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eCovid 19 has put the world through previously unforeseen circumstances since its arrival in January 2020. Among the many surprises seeded along its course is the post covid Multisystem Inflammatory Syndrome in Children (MIS-C) with its mixed presentations and potentially fatal outcome if not recognised and treated early.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) The possibility of a post covid hyper-inflammatory state was first reported from clusters of children in the UK and North America who developed multi-organ failure similar to Toxic Shock Syndrome and also bore resemblance to Kawasaki disease.(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) The World Health Organisation (WHO) then issued a case definition based on clinical and laboratory parameters for the early recognition and treatment of Multisystem Inflammatory Syndrome in Children.(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eChildren with MIS-C show a wide spectrum of illness ranging from mild to severe. The involvement of cardiovascular system causing cardiogenic shock and coronary artery dilatation have been of particular concern prompting the use of steroids and immunomodulators like Intravenous Immunoglobulin (IVIG) and TNF-alpha inhibitors to limit the hyperimmune response.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) Studies from western literature have shown no difference in outcomes irrespective of the immunomodulators used.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) But literature is sparse from third world countries where tropical fevers add to the diagnostic dilemma and patient loads are higher. We aimed to find the various presentations, the laboratory parameters of prognostic significance, echocardiographic findings and short term outcomes of MIS-C.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cp\u003eWe conducted a single centre prospective observational study between September 2020 to September 2021 in a tertiary care referral centre in South India. All children less than 15 years of age requiring admission to the Paediatric Intensive Care (PICU) or High Dependency Unit (HDU) with three or more days of fever were screened for MIS-C according to the WHO case definition.(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) Children who fulfilled the criteria and had no alternative diagnosis were enrolled in the study after written informed consent from their parents. Evidence of active or recent covid infection was confirmed using Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) test or the presence of covid IgG/ IgM antibodies. Children with co-morbidities were not included in our study. The study was approved by the Institution Ethics Committee.\u003c/p\u003e \u003cp\u003eBaseline demographic data, clinical features, laboratory parameters including complete blood counts, liver and renal function tests, inflammatory markers before initiation of treatment- Erythrocyte Sedimentation Rate (ESR), C-Reactive Protein (CRP), ferritin, cardiac markers including Troponin T and N-terminal B- type Natriuretic Peptide( NTproBNP) and echocardiographic findings were recorded. Left ventricular (LV) dysfunction was defined as an ejection fraction less than 50%. Coronary artery dilatation was defined as a zscore\u0026thinsp;\u0026ge;\u0026thinsp;2 of the left anterior descending artery or right coronary artery.(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) The presence of shock ( blood pressure\u0026thinsp;\u0026lt;\u0026thinsp;5th centile), clinical symptoms, length of PICU stay, requirement for respiratory support (low flow oxygen, non-invasive ventilation or invasive ventilation), inotropes, Extra Corporeal Membrane Oxygenation (ECMO), Continuous Renal Replacement Therapy (CRRT), treatment administered (pulse steroids-30mg/kg methylprednisolone, IVIG, both or IVIG with low dose steroids) and outcomes were also documented. Oliguria was defined as \u0026lt;\u0026thinsp;0.5ml/kg/hr urine output for more than 6 hours. Acute Kidney Injury (AKI) was defined as creatinine elevated more than age appropriate levels. Severe MIS-C was defined as presence of ventricular dysfunction, coronary dilatation, need for respiratory support, inotropes or invasive ventilation. They were treated according to national guidelines for treatment of MIS-C which is based on the ACR guidelines.(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eWe aimed to study the clinical characteristics of children with MIS-C getting admitted to the PICU, to study the association between laboratory markers and disease severity and analyse the predictors of severe MIS-C.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eWe enrolled 60 patients in our study between September 2020 and September 2021. More than half the study population (58%) were girls and 5% were infants. The median age was 5years (IQR 2.175,9). Our study population had no children with co-morbidities. The median duration of PICU/HDU stay was 4 days (IQR 2, 5.75) with 25% patients staying for more than 5days. Of the 60 patients included in our study, 58 were discharged home while two children died of the illness. The basic demographic details, clinical features and laboratory parameters are depicted in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBasic demographic details, clinical features and laboratory parameters\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDemography, Clinical features\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;60\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMales n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25(41.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5(2,9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of PICU stay median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4(2,5.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGastrointestinal symptoms n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44 (73.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRash n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (56.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMucus membrane, conjunctival congestion n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39 (65)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRespiratory distress n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (46.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypotensive shock n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45 (75%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOliguria n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (21.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEncephalitis n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (6.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLaboratory parameters\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eMedian (IQR)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal leucocyte count(cells/mm\u003csup\u003e3\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11300(7725,16575)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutrophils (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75(59.25,82.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphocytes (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16.5(10,26.75)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelet count (* 10\u003csup\u003e5\u003c/sup\u003e/mm\u003csup\u003e3\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2(1.3,4.475)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eESR(mm/h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e57(25.25,88)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP(mg/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e106.5(62.75,149.25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAspartate aminotransferase (U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31.5 (24,50.75)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlanine aminotransferase (U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (21,52.25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood Urea Nitrogen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10(7.5,13)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCreatinine (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.5 (0.4,0.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFerritin (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e346 (207.5,812.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD-dimer (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3065 (1548.25,5989.75)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNT-proBNP (pg/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1310.5 (369.5,4078)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eClinical features and organ dysfunction\u003c/p\u003e \u003cp\u003eAll children enrolled in our study had fever. Gastrointestinal symptoms were the next most common (73%) with children having loose stools, vomiting and/or abdominal pain. We also had two patients with acute liver failure and coagulopathy. Dermatological manifestations were also common. More than half the children had rashes (56%) during the course of their illness whereas almost 2/3rd had mucus membrane involvement and non-purulent conjunctival congestion. One child presented with an extensive vasculitis rash and had persistently elevated inflammatory markers requiring prolonged treatment.\u003c/p\u003e \u003cp\u003eAlmost half (46%) our cohort had respiratory symptoms requiring support during the course of their illness. Low flow oxygen was administered to 12 children, while 9 received non-invasive ventilatory support and five needed invasive mechanical ventilation. Two children received ECMO, of which one survived.\u003c/p\u003e \u003cp\u003e25 children required inotropic support during the course of their illness. 11 children had LV dysfunction on echocardiogram, 12 had pericardial effusion and 3 had dilated coronaries. Age had a significant association with cardiovascular involvement with children in the age group between 1 to 10years being commonly affected. The need for invasive ventilation showed a significant association with LV dysfunction and pericardial effusion.\u003c/p\u003e \u003cp\u003e20% children had oliguria at admission. We had 7 children with AKI of which three were non-oliguric and recovered spontaneously. Both children who required ECMO needed CRRT. One child required peritoneal dialysis. There were four children who presented with symptoms suggestive of acute encephalitis of which one succumbed to the illness.\u003c/p\u003e \u003cp\u003eLaboratory markers\u003c/p\u003e \u003cp\u003eComplete blood counts showed neutrophilia (73%), leucopenia (53%) and thrombocytopenia( 36%). Almost all patients had elevated ESR, CRP, d-dimer levels, troponin and NT-proBNP. CRP more than 70mg/L, ESR\u0026thinsp;\u0026gt;\u0026thinsp;40mm/h, Ferritin\u0026thinsp;\u0026gt;\u0026thinsp;250mcg/L, NT-proBNP\u0026thinsp;\u0026gt;\u0026thinsp;500pg/mL showed a significant association with the need for respiratory support and inotropes. D-dimer\u0026thinsp;\u0026gt;\u0026thinsp;2000ng/mL had significant association with cardiac dysfunction need for inotropic support. Ferritin\u0026thinsp;\u0026gt;\u0026thinsp;250mcg/L also had significant association with cardiac dysfunction (p\u0026thinsp;\u0026lt;\u0026thinsp;0.1). ESR\u0026thinsp;\u0026gt;\u0026thinsp;40mm/h and platelet count\u0026thinsp;\u0026lt;\u0026thinsp;1.5lakhs/mm\u003csup\u003e3\u003c/sup\u003e showed significant association with longer PICU stay.\u003c/p\u003e \u003cp\u003eTreatment\u003c/p\u003e \u003cp\u003e80% of our study population received IVIG. Almost half the children (49%) were treated with both IV immunoglobulin (2g/kg) and pulse dose steroids ( 30mg/kg), 20% with IVIG and low dose steroids (2mg/kg), 20% with pulse steroids alone and 11% with IVIG alone. Low dose steroids were tapered and stopped over 2 weeks except in one child who continued to have persistently elevated inflammatory markers and was treated with tocilizumab and 8 weeks of low dose steroids. Children with cardiac involvement and those with D-dimer elevated more than 2500ng/mL were also treated with low dose anti-platelet (acetylsalicylic acid) for 6 weeks where-in repeat echocardiogram was done. No child had persistent coronary artery dilatation at follow up and thus did not require long term antiplatelet therapy.\u003c/p\u003e \u003cp\u003ePrognostic markers\u003c/p\u003e \u003cp\u003eGastrointestinal symptoms, respiratory distress, reduced urine output at admission, platelet counts less than 1.5 lakhs, D-dimer\u0026thinsp;\u0026gt;\u0026thinsp;2000ng/mL, CRP\u0026thinsp;\u0026gt;\u0026thinsp;70mg/L( p\u0026thinsp;\u0026lt;\u0026thinsp;0.1), NT-proBNP\u0026thinsp;\u0026gt;\u0026thinsp;500(p\u0026thinsp;\u0026lt;\u0026thinsp;0.1), ferritin\u0026thinsp;\u0026gt;\u0026thinsp;250mcg/L(p\u0026thinsp;\u0026lt;\u0026thinsp;0.1) were markers of severe MIS-C.\u003c/p\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eDescriptive statistics was obtained for all study variables. Continuous data were expressed as mean (SD) or median and inter-quartile range [IQR] values. Univariate association was established between categorical variables using χ\u003csup\u003e2\u003c/sup\u003e test and p value\u0026thinsp;\u0026le;\u0026thinsp;0.05 was taken as significant. In certain cases, we have accepted a p value of \u0026le;\u0026thinsp;0.1 as we consider this a pilot study exploring new areas. For independent association between significant univariates and outcomes, one way Analysis Of Variance was done. For continuous variables, means were compared between two groups.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eMIS-C presents as a spectrum of illness ranging from the very mild to a very severe and life-threatening disease condition. We report the clinical features, laboratory parameters and their association with short term outcomes in sixty children admitted to our PICU/HDU with MIS-C following covid 19 infection. We have attempted to identify subtle markers of more severe disease so that clinicians can identify patients at risk of rapid deterioration at the outset and commence early treatment. Of the 60 children included in our study, 28 were SARS COV2 RTPCR positive in the 8\u0026ndash;12 weeks prior to the onset of their symptoms while the rest 32 were antibody positive. The median age of our study population was 5 years which is lesser than that reported in literature.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) 20% were more than 10 years of age and there were 3 infants as well.\u003c/p\u003e \u003cp\u003eIn the initial cohorts of MIS-C abdominal pain acted as a red herring creating suspicions of an acute abdominal emergency possibly requiring surgical intervention, thus distracting clinicians from the diagnosis of a post covid hyperinflammatory syndrome and possibly delaying treatment. But now with case reports and studies from various parts of the world, we have realised that gastrointestinal symptoms including severe abdominal pain, loose stools and vomiting are the commonest presenting symptoms of MIS-C.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) The same findings have been reflected in our study as well and is an indicator of morbidity. Patients have presented with such severe abdominal pain that around 5% have even had to undergo computerised tomography of the abdomen to ensure the absence of any other pathology. Interestingly, we also had two patients with acute liver failure who recovered with immunomodulation and supportive care.\u003c/p\u003e \u003cp\u003eThe Kawasaki disease phenotype either in its classical or incomplete form has gained prominence in its association with MIS-C.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)This was the next most common presentation in our study as well and maybe because of the younger age of the study population. More than half the children had rash or mucus membrane involvement in the form of cracked lips, red tongue or non-purulent conjunctival congestion. Several dermatological manifestations of MIS-C have been reported.(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) The association of coronaviridae family with vasculitis and vasculopathy is evident from its KD like presentation which maybe either the result of direct invasion of the cells by the virus or as a result of cytokine storm.\u003c/p\u003e \u003cp\u003eEchocardiogram is vital in the treatment of children with MIS-C. An echocardiogram should be done not only in children with KD like presentation but in any child with suspected MIS-C. While Kawasaki disease is known for its predilection to affect the coronaries, the commonest finding noted in our patients were pericardial effusion and ventricular dysfunction with valvular regurgitation (20%); coronary artery dilatation was rare (5%). Similar echo findings have been recorded in other clusters of children with MIS-C.\u003csup\u003e7,13,16\u003c/sup\u003e The three children who coronary artery dilatation in our study had had complete resolution at 6 weeks review but is on long term follow up. Similar encouraging results of complete resolution of cardiac abnormalities have been reported world-wide.(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) One child with severe left ventricular dysfunction who required ECMO has mild LV dysfunction at 6 months and is on follow up.\u003c/p\u003e \u003cp\u003eSeveral studies have reported MIS-C to be a disease of children more than 5 years of age and adolescents while we found that younger children are equally affected and those in the age group between 1 to 10 years were more likely to develop cardiac complications.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) Our results may be skewed because 75% of our study population belonged to this age group. Predictably, abnormalities on echocardiogram signalled a more severe course of disease progression and had a significant association with the need for mechanical ventilation. This has not been reported from previous studies.(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eOne-third of the children enrolled in our study required respiratory support in the form of low flow oxygen, non-invasive ventilation or invasive mechanical ventilation. Respiratory distress was identified as an indicator of severe MIS-C. Patients in our study had respiratory symptoms like tachypnoea and laboured breathing mostly due to underlying cardiac dysfunction and shock; it was not due to pulmonary involvement. Overall, majority of studies on MIS-C report lower incidence of respiratory symptoms compared to gastro-intestinal and cardiac involvement. The need for invasive ventilation varies widely between different studies.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eAKI has also been reported in significant numbers among children with MIS-C.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) This is likely due to microvascular injury triggered by macrophage activation and subsequent cytokine storm. As most of these patients have elevated cardiac markers causing a false alarm of underlying cardiac dysfunction, judicious hydration maybe withheld thus contributing to pre-renal failure as well. As was noted in our study, children with non- oliguric AKI tend to recover rapidly with good hydration and supportive care. Children with oliguria signalled severe MIS-C. For those on the sicker end of the spectrum with multifactorial aetiology contributing to kidney injury like shock and renal toxic drugs, dialysis maybe warranted.\u003c/p\u003e \u003cp\u003eWe also had a few unusual presentations of MIS-C in our study population. We had a 10 year old with severe retropharyngeal phlegmon, features of KD and cardiac dysfunction who improved rapidly with IVIG. Similar cases have been reported.(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) There was a 5\u0026nbsp;year old child with extensive rashes similar to vasculitis; skin biopsy taken after initiation of steroids was consistent with small vessel vasculopathy. She had persistently raised inflammatory markers and was treated with tocilizumab and long term low dose steroids. She was asymptomatic at review but may need long term follow up to watch for an evolving rheumatic illness. Various cutaneous manifestations and leukoclastic vasculitis have been during and after covid 19 infection.(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) We had four children with encephalitis like presentation. Cerebro Spinal Fluid (CSF) study was suggestive of an acute bacterial meningitis along with elevated inflammatory markers; all aetiological workup including CSF PCR assay were negative and they failed to respond to conventional antibiotics and antiviral treatment. As they were positive for covid antibody, treatment for MIS-C was instituted to which they promptly responded expect one child who rapidly deteriorated and succumbed to the illness.\u003c/p\u003e \u003cp\u003eIn alignment with previous studies, we recorded neutrophilia, lymphopenia and thrombocytopenia in our patients, liver enzymes remained normal in majority of patients with few exceptions but more than 10% patients showed a tendency to develop AKI. Of note, inflammatory and cardiac markers were invariably raised in almost all patients.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) This reiterates the fact that cardiac markers may not directly indicate myocardial involvement and cannot be used to predict the same but they are useful in identifying patients with more severe disease. Raised inflammatory markers have been associated with adverse outcomes in a large multicentric study from United States.(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) We found a cut off of ESR more than 40mm/h, CRP\u0026thinsp;\u0026gt;\u0026thinsp;70mg/L, NT-proBNP\u0026thinsp;\u0026gt;\u0026thinsp;500 were individual predictors of the need for inotropes, need for respiratory support and overall more severe disease. Higher NT-proBNP values has shown association with severe MISC in earlier studies as well.(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eWe did not have any patients with thrombotic events but D-dimer was found to be elevated in almost all our patients with 75% having more than threefold rise in values. Elevated d-dimer in MIS-C maybe due to ongoing endothelial damage which places patients at risk of thrombosis. We believe that we did not experience any thrombotic events due to early initiation of antiplatelet therapy once a fivefold rise in values were noted. A fivefold rise in D-dimer also appeared to predict the possibility of ventricular dysfunction and need for inotropes.\u003c/p\u003e \u003cp\u003eVarious studies have shown ferritin to be a maker of more severe MIS-C.(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) We were also able to identify ferritin as a marker of cardiac dysfunction, need for respiratory support and inotropes. Ferritin is well known as a proinflammatory mediator but it is important to highlight its immunomodulatory effects as well, the loss of which can lead to autoimmune disease states. It was interesting to note that even though a higher than normal value of ferritin is considered poor prognostic marker of MIS-C, exceptionally high values like those seen in Macrophage Activating Syndrome or severe dengue is hardly ever reported in MIS-C. The reason behind this needs to be explored because MIS-C shares the same cytokine storm as seen in other hyperferritinemic syndromes and can trigger other autoimmune conditions.\u003c/p\u003e \u003cp\u003eWe have treated our patients with either IVIG, pulse steroids, both or IVIG and low doses steroids. We are unable to comment on the efficacy of the various treatment modalities as our study was not designed for the same. Irrespective of the treatment modality used, our mortality rate (3%) is in line with western literature and much lesser than that reported from other studies in India.(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) Wide-spread health education, early referral and prompt initiation of treatment has contributed to the low mortality rate. Kerala is a proactive state with well-established primary health centers and gained worldwide fame for our initial success in the fight against covid 19. We have strong health care facilities, health indices and literacy rates akin to the West and hence better prepared to face the pandemic than other states in India.\u003c/p\u003e \u003cp\u003eLimitations\u003c/p\u003e \u003cp\u003eConsidering the large number of variables analysed and the smaller number of adverse events among our study population, significant associations between the same may have been under recognised. We have included children only up to the age of 14 years (hospital admission policy) and have not been able to study the disease in older children. Our study was conducted at the same time as the disease was first recognised and various treatment options were being studied. We have used different combinations of treatment modalities based on clinical experience and expert advice. Hence we are unable to propose treatment options which were most effective.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eMISC presents itself in the guise of various disease conditions familiar to us like fever with rash, acute gastroenteritis or meningitis. Difficulties arise when conventional treatment fails and patients rapidly deteriorate. Most patients may be diagnosed straight away but at times can be a diagnostic conundrum even for experts. A thorough history followed by tiered investigative approach backed by comprehensive echocardiography helps clinch the diagnosis in time. Early recognition and rapid initiation of treatment makes a substantial impact on the prognosis of the clinical course of the patient.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eMIS-C : Multi-system Inflammatory Syndrome in Children\u003c/p\u003e\n\u003cp\u003eWHO: World Health Organisation\u003c/p\u003e\n\u003cp\u003eIVIG: Intravenous Immunoglobulin (IVIG)\u003c/p\u003e\n\u003cp\u003ePICU:\u0026nbsp;Paediatric Intensive Care\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHDU:\u0026nbsp;High Dependency Unit\u003c/p\u003e\n\u003cp\u003eRT-PCR:\u0026nbsp;Reverse Transcriptase Polymerase Chain Reaction\u003c/p\u003e\n\u003cp\u003eESR:\u0026nbsp;Erythrocyte Sedimentation Rate\u003c/p\u003e\n\u003cp\u003eCRP:\u0026nbsp;C-Reactive Protein\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNT-pro BNP:\u0026nbsp;N-terminal B- type Natriuretic Peptide\u003c/p\u003e\n\u003cp\u003eLV:\u0026nbsp;Left ventricular\u003c/p\u003e\n\u003cp\u003eECMO:\u0026nbsp;Extra Corporeal Membrane Oxygenation\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCRRT:\u0026nbsp;Continuous Renal Replacement Therapy\u003cbr\u003e\u0026nbsp;AKI: Acute Kidney Injury\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of Interest Disclosures (includes financial disclosures):\u003c/strong\u003e All authors \u0026nbsp;have no conflicts of interest to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding/Support:\u003c/strong\u003e No funding was secured for this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRole of Funder/Sponsor (if any):\u0026nbsp;\u003c/strong\u003eNone\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material:\u003c/strong\u003e The data that supports the findings of this study are available on request from the corresponding author\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability:\u003c/strong\u003e N/A\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDrs Subhash and Joji conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript.\u003c/p\u003e\n\u003cp\u003eDrs Baby, Nair, and Kumar the designed the study proforma, collected data, carried out the initial analyses, and reviewed and revised the manuscript.\u003c/p\u003e\n\u003cp\u003eDr Gupta conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content.\u003c/p\u003e\n\u003cp\u003eAll authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\n\u003cp\u003eThank you to Dr. Zulfikar Ahamed M, Pediatric Cardiologist and Dr Prijo Philip, Pediatric Nephrologist for all their efforts in the completion of this study.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003e\u003cspan\u003ePereira MFB, Litvinov N, Farhat SCL, et al. Severe clinical spectrum with high mortality in pediatric patients with COVID-19 and multisystem inflammatory syndrome. \u003cem\u003eClinics (Sao Paulo)\u003c/em\u003e. 2020;75:e2209. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.6061/clinics/2020/e2209\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eBagri, N.K., Deepak, R.K., Meena, S. \u003cem\u003eet al.\u003c/em\u003e Outcomes of multisystem inflammatory syndrome in children temporally related to COVID-19: a longitudinal study. \u003cem\u003eRheumatol Int\u003c/em\u003e \u003cstrong\u003e42\u003c/strong\u003e\u0026lt;bvertical-align:super;\u0026gt;,\u0026lt;/bvertical-align:super;\u0026gt;\u0026lt;bvertical-align:super;\u0026gt; \u0026lt;/bvertical-align:super;\u0026gt;477\u0026ndash;484 (2022). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00296-021-05030-y\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eBelhadjer Z, M\u0026eacute;ot M, Bajolle F, et al. Acute Heart Failure in Multisystem Inflammatory Syndrome in Children in the Context of Global SARS-CoV-2 Pandemic. \u003cem\u003eCirculation\u003c/em\u003e. 2020;142(5):429\u0026ndash;436. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/CIRCULATIONAHA.120.048360\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eWorld Health Organization. Multisystem inflammatory syndrome in children and adolescents with COVID-19. Scientific brief (2020). (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.who.int/publications/i/item/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19\u003c/span\u003e\u003c/span\u003e)\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eFeldstein LR, Rose EB, Horwitz SM, et al. Multisystem Inflammatory Syndrome in U.S. Children and Adolescents. \u003cem\u003eN Engl J Med\u003c/em\u003e. 2020;383(4):334\u0026ndash;346. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa2021680\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eMcArdle AJ, Vito O, Patel H, et al. Treatment of Multisystem Inflammatory Syndrome in Children. \u003cem\u003eN Engl J Med\u003c/em\u003e. 2021;385(1):11\u0026ndash;22. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa2102968\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eFarooqi KM, Chan A, Weller RJ, et al. Longitudinal Outcomes for Multisystem Inflammatory Syndrome in Children [published correction appears in Pediatrics. 2021 Nov;148(5):]. \u003cem\u003ePediatrics\u003c/em\u003e. 2021;148(2):e2021051155. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1542/peds.2021-051155\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eHenderson LA, Canna SW, Friedman KG, et al. American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 1. \u003cem\u003eArthritis Rheumatol\u003c/em\u003e. 2020;72(11):1791\u0026ndash;1805. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/art.41454\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eHenderson LA, Canna SW, Friedman KG, et al. American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 2. \u003cem\u003eArthritis Rheumatol\u003c/em\u003e. 2021;73(4):e13-e29. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/art.41616\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eSugunan S, Bindusha S, Geetha S, Niyas HR, Kumar AS. Clinical Profile and Short-Term Outcome of Children With SARS-CoV-2 Related Multisystem Inflammatory Syndrome (MIS-C) Treated With Pulse Methylprednisolone. \u003cem\u003eIndian Pediatr\u003c/em\u003e. 2021;58(8):718\u0026ndash;722. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s13312-021-2277-4\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eAcevedo L, Pi\u0026ntilde;eres-Olave BE, Ni\u0026ntilde;o-Serna LF, et al. Mortality and clinical characteristics of multisystem inflammatory syndrome in children (MIS-C) associated with covid-19 in critically ill patients: an observational multicenter study (MISCO study). \u003cem\u003eBMC Pediatr\u003c/em\u003e. 2021;21(1):516. Published 2021 Nov 18. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12887-021-02974-9\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eSantos MO, Gon\u0026ccedil;alves LC, Silva PAN, et al. Multisystem inflammatory syndrome (MIS-C): a systematic review and meta-analysis of clinical characteristics, treatment, and outcomes [published online ahead of print, 2021 Dec 3]. \u003cem\u003eJ Pediatr (Rio J)\u003c/em\u003e. 2021;S0021-7557(21)00148\u0026ndash;0. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jped.2021.08.006\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eToubiana J, Poirault C, Corsia A, et al. Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study. \u003cem\u003eBMJ\u003c/em\u003e. 2020;369:m2094. Published 2020 Jun 3. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/bmj.m2094\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eBouaziz JD, Duong TA, Jachiet M, et al. Vascular skin symptoms in COVID-19: a French observational study. \u003cem\u003eJ Eur Acad Dermatol Venereol\u003c/em\u003e. 2020;34(9):e451-e452. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/jdv.16544\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eGenovese G, Moltrasio C, Berti E, Marzano AV. Skin Manifestations Associated with COVID-19: Current Knowledge and Future Perspectives. \u003cem\u003eDermatology\u003c/em\u003e. 2021;237(1):1\u0026ndash;12. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1159/000512932\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eValverde I, Singh Y, Sanchez-de-Toledo J, et al. Acute Cardiovascular Manifestations in 286 Children With Multisystem Inflammatory Syndrome Associated With COVID-19 Infection in Europe. \u003cem\u003eCirculation\u003c/em\u003e. 2021;143(1):21\u0026ndash;32. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/CIRCULATIONAHA.120.050065\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eFeldstein LR, Tenforde MW, Friedman KG, et al. Characteristics and Outcomes of US Children and Adolescents With Multisystem Inflammatory Syndrome in Children (MIS-C) Compared With Severe Acute COVID-19. \u003cem\u003eJAMA.\u003c/em\u003e 2021;325(11):1074\u0026ndash;1087. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jama.2021.2091\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eWhittaker E, Bamford A, Kenny J, et al. Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2. \u003cem\u003eJAMA\u003c/em\u003e. 2020;324(3):259\u0026ndash;269. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jama.2020.10369\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eDaube A, Rickert S, Madan RP, Kahn P, Rispoli J, Dapul H. Multisystem inflammatory syndrome in children (MIS-C) and retropharyngeal edema: A case series. \u003cem\u003eInt J Pediatr Otorhinolaryngol\u003c/em\u003e. 2021;144:110667. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ijporl.2021.110667\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eCaputo V, Schroeder J, Rongioletti F. A generalized purpuric eruption with histopathologic features of leucocytoclastic vasculitis in a patient severely ill with COVID-19. \u003cem\u003eJ Eur Acad Dermatol Venereol\u003c/em\u003e. 2020;34(10):e579-e581. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/jdv.16737\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eTorres JP, Izquierdo G, Acu\u0026ntilde;a M, et al. Multisystem inflammatory syndrome in children (MIS-C): Report of the clinical and epidemiological characteristics of cases in Santiago de Chile during the SARS-CoV-2 pandemic. \u003cem\u003eInt J Infect Dis\u003c/em\u003e. 2020;100:75\u0026ndash;81. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ijid.2020.08.062\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eAbrams JY, Oster ME, Godfred-Cato SE, et al. Factors linked to severe outcomes in multisystem inflammatory syndrome in children (MIS-C) in the USA: a retrospective surveillance study. \u003cem\u003eLancet Child Adolesc Health\u003c/em\u003e. 2021;5(5):323\u0026ndash;331. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S2352-4642(21)00050-X\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eZhao Y, Patel J, Huang Y, Yin L, Tang L. Cardiac markers of multisystem inflammatory syndrome in children (MIS-C) in COVID-19 patients: A meta-analysis. \u003cem\u003eAm J Emerg Med\u003c/em\u003e. 2021;49:62\u0026ndash;70. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ajem.2021.05.044\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-1685192/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1685192/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eMIS-C is a novel disease entity. We aimed to outline the clinical features and laboratory parameters of children with moderate to severe MIS-C and to study predictors of more severe disease. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eIn this prospective longitudinal study, all children less than 15 years of age requiring admission to the Paediatric Intensive Care Unit (PICU) or High Dependency Unit (HDU) with three or more days of fever were screened for MIS-C according to the WHO case definition. Children with alternative diagnoses were excluded. Those included were tested for active or past infection with SARS-COV2 using RTPCR or antibody testing. Severe MIS-C was defined as presence of ventricular dysfunction, coronary dilatation, need for respiratory support, inotropes or invasive ventilation. Clinical features, laboratory parameters and risk factors for severe disease was studied.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\u003cp\u003e60 children were included in the study. Median age group was 5yrs(IQR 2.175,9)The median duration of PICU/HDU stay was 4 days(IQR 2,5.75). Two children died of the illness. Gastrointestinal symptoms were most common(73%) followed by muco-cutaneous(56%), respiratory(46%) and cardiovascular system(41%) involvement. Majority showed neutrophilia(73%), leucopenia(53%) and raised inflammatory markers including ESR,CRP, D-dimer, ferritin and NT-proBNP which showed significant association with need for respiratory support, inotropes, cardiac dysfunction and prolonged ICU stay. Gastrointestinal symptoms, respiratory distress, reduced urine output at admission, platelet counts less than 1.5 lakhs, D-dimer \u0026gt;2000ng/mL, CRP \u0026gt;70mg/L, NT-proBNP\u0026gt;500pg/mL, ferritin \u0026gt;250mcg/L were markers of severe MIS-C.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eClinical features and laboratory parameters aid in early recognition of severe MIS-C resulting in greater probability of survival.\u003c/p\u003e","manuscriptTitle":"MIS-C: Clinical profile, outcomes and predictors of severe disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-05-27 15:12:40","doi":"10.21203/rs.3.rs-1685192/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"03e12213-72f3-40af-86f4-e616746c6480","owner":[],"postedDate":"May 27th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-05-28T07:29:13+00:00","versionOfRecord":[],"versionCreatedAt":"2022-05-27 15:12:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1685192","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1685192","identity":"rs-1685192","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}