These authors contributed equally to this study as co-first authors.
Multisystem inflammatory syndrome in children (MIS-C) is a new hyperinflammatory variant that evolved during the coronavirus disease 2019 pandemic. Although the precise pathophysiology of MIS-C is uncertain, it is thought to be due to immune dysregulation occurring after recovery from acute infection.
Our study aimed to analyze the clinical spectrum, laboratory parameters, imaging characteristics, treatment strategies, and short-term outcomes of children with a diagnosis of MIS-C.
This retrospective and prospective observational study included children less than 16 years of age who were admitted to the pediatric unit of a tertiary care teaching hospital in south India between August 2020 to January 2021 with a diagnosis of MIS-C according to World Health Organization criteria.
Twenty-one children were included in the analysis; all had fever with variable combinations of other symptoms. The mean age was 6.9 years; 71.4% were male. Gastrointestinal (80.9%) and cardiovascular (80.9%) systems were the most commonly affected. The majority of children had elevated inflammatory markers, and 16 (76.2%) had echocardiographic abnormalities mimicking Kawasaki disease. Eleven children (52.4%) required intensive care admission, 3 (14.3%) required supplemental oxygen, and 4 (19%) required inotropes. Nine (42.9%) were treated with intravenous immunoglobulin alone, 6 (28.6%) with steroids alone, and 3 (14.3%) with steroids and immunoglobulin. The median hospital stay was 6 days; there were no fatalities. Overweight/obesity, elevated ferritin, and mucocutaneous involvement were significantly associated with a prolonged hospital stay (≥7 days). Sixteen children (76.2%) were followed up till now and all of them had no clinical concerns.
MIS-C is an emerging disease with variable presentation. A high index of suspicion is necessary for its early identification and appropriate management. Further research is essential for developing optimal treatment strategies.
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The coronavirus disease 2019 (COVID-19) pandemic in India is a part of the global pandemic caused by severe acute respiratory syndrome corona virus-2 (SARS-CoV-2). India is one of the countries with the highest burden of confirmed COVID-19 cases in the world and ranks second in the list of countries with a maximum number of cases [
Our study aimed at analyzing the clinical spectrum, laboratory parameters, and imaging characteristics of children less than 16 years admitted with a diagnosis of MIS-C. In addition, this study aimed to analyze the treatment strategies and short-term outcomes.
This study was a partly retrospective and partly prospective observational study done in children admitted with a diagnosis of MIS-C in a tertiary care teaching hospital in south India from August 2020 to January 2021. The hospital is one of the largest COVID-19 care centers in south India and receives referrals from a radius of 200 kilometers. The study was approved by the Institutional Human Ethics Committee of PSGIMS&R (project No. 20/262 dated 27th November, 2020). Informed written consent was obtained from parents prior to the inclusion of children in the prospective part of the study. Waiver of consent was obtained for the retrospective collection of data.
Children less than 16 years of age diagnosed with MIS-C as per WHO criteria were included in the study. The following parameters were considered for diagnosis: (1) fever ≥3 days, (2) 2 of the following: a) rash or bilateral nonpurulent conjunctivitis or mucocutaneous inflammation signs (oral mucosa, hands, or feet), b) hypotension or shock, c) features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities (including echocardiography findings or elevated troponin/N-terminal pro-B-type natriuretic peptide [NT-proBNP]), d) evidence of coagulopathy (by prothrombin time, partial thromboplastin time, elevated D-dimers), e) Acute gastrointestinal problems [diarrhea, vomiting, or abdominal pain], (3) elevated markers of inflammation such as erythrocyte sedimentation rate, C-reactive protein, or procalcitonin, (4) no other obvious microbial cause of inflammation, including bacterial sepsis, staphylococcal or streptococcal toxic shock syndromes, (5) evidence of COVID-19 (real-time reverse transcription polymerase chain reaction [RT-PCR], antigen test or serology positive), or likely contact with patients with COVID-19.
Data on demographics, clinical features, laboratory results, imaging studies, treatment details, outcomes, and follow-up were collected. All the investigations and treatment were carried out as per institutional protocol and treating physician’s discretion.
COVID-19 infection was confirmed by testing for SARS-CoV-2 antibody by chemiluminescence immunoassay (VITROS 3600 immunodiagnostic system, Ortho Clinical Diagnostics, Raritan, NJ, USA) and/or RT-PCR as recommended by Indian Council of Medical Research. The laboratory values were interpreted as either increased or decreased based on the age-specific normal reference ranges. Organ system involvement was described based on clinical features, laboratory reports, and imaging studies. Echocardiography was performed in all children by the pediatric cardiologist to identify the following abnormalities; (a) left ventricular dysfunction (ejection fraction less than 55%), (b) pericarditis or pericardial effusion, (c) coronary artery abnormalities (dilatation, aneurysm, or irregular nontapering coronary arteries), or (d) valvular regurgitation. The dimension of the coronary artery was measured as per standard criteria and a coronary z score above 2 was reported as dilated. Other imaging studies were done as clinically indicated.
Data analysis was done using Microsoft Excel 2019 (Microsoft Corp., Redmond, WA, USA). Descriptive statistics were used to summarize population characteristics. Categorical variables were expressed as frequency or percentage and continuous variables were expressed as mean with standard deviation or median with interquartile range. IBM SPSS Statistics ver. 26.0 (IBM Co., Armonk, NY, USA) was used to perform univariate analysis and a
From August 2020 to January 2021, 21 children met the WHO MIS-C criteria and were included in the analysis. Among them, only 2 children were admitted with active coronavirus-2 infection and were subsequently diagnosed as MIS-C. The demographic and clinical characteristics of the study population are mentioned in
All patients had fever with a variable combination of other symptoms. Gastrointestinal symptoms like abdominal pain, diarrhea, and vomiting were the most common presenting symptoms. The mean duration of symptoms prior to admission was 4.8 days and the mean total duration of fever was 7.9 days. The majority of children in this series had multiorgan involvement. Gastrointestinal (80.9%) and cardiovascular (80.9 %) systems were the most commonly affected organ systems. This was followed by hematological (76.2%), mucocutaneous (71.4%), and central nervous system (14.2%) involvement. None of the children had acute kidney injury in this series. Two children in this series had been treated for COVID-19 3 weeks prior to the diagnosis of MIS-C, and 5 children had history of confirmed exposure to COVID-19 patients in the preceding 3 to 4 weeks. In other children, no history associated with COVID-19 was revealed.
In the study population, 19 children (90.4%) had positive COVID-19 antibody tests, 1 (4.8%) had positive COVID-19 RT-PCR test, and another (4.8%) had both positive COVID-19 RT-PCR and antibody tests. The results of laboratory tests and imaging studies are summarized in
Echocardiography was performed in all the children, and abnormality was noted in 16 children (76.2%). A greater number of children had a combination of abnormalities rather than a single abnormal finding. Coronary artery abnormality (57.1%) was the most common finding, followed by pericardial effusion (52.4%), left ventricular dysfunction (23.8%), and mitral regurgitation (23.8%). Gastrointestinal imaging studies like x-ray, ultrasound, and computed tomography were done as indicated, and ascites (50%) was the most common abnormality, followed by dilated bowel loops (35.7%), and mesenteric lymphadenitis (35.7%). Of the 17 patients who underwent chest imaging (x-ray or computed tomography), pleural effusion and lung infiltrates were observed in 3 (17.6%) and 1 patient (5.9%), respectively. Of the 3 children with central nervous system involvement, 1 had encephalopathy with features of cerebellar involvement, 1 had seizures, and another had headache with bilateral papilledema. All 3 children with central nervous system involvement showed normal neuroimaging. Two children underwent cerebrospinal fluid analysis, and findings of aseptic meningitis were seen in the patient who presented with encephalopathy.
Treatment details and outcomes are summarized in
An 8-year-old girl presented with features of acute appendicitis, and an emergency surgery was done, which revealed a perforated appendix with abscess collection. She was subsequently diagnosed as MIS-C and was treated with IVIG.
The median length of hospitalization was 6 days in this series.
MIS-C is an evolving concept of disease and its exact incidences in different geographic areas are uncertain. The focus of this study was to analyze the clinical spectrum and short-term outcomes of children with MIS-C managed in a tertiary care teaching hospital in south India. We described 21 children under the age of 16 years with MIS-C associated with SARS-CoV-2 infection. All these children had evidences of previous or active COVID-19 infection. The spectrum of clinical presentations in our study was broadly consistent with available literatures. The mean age of children in this study was 6.9 years, and 61.9% of affected children were above 5 years, which was similar to studies by Kaushik et al. [
The incidence of hematological abnormalities like lymphopenia (47.6%) and thrombocytopenia (38.1%) in our study was in agreement with previous reports [
Since MIS-C is an emerging disease, guidelines regarding the management are still evolving and there is a lack of consistency in management. The majority of patients in our study were treated with either IVIG, steroids, or a combination of both and, none required other immunomodulators. The treatment decision for the patients in our study was made based on severity of the illness and the treating physician’s discretion. Significant differences in treatment strategies were noted among studies from different parts of the world, which could be due to lack of standard treatment protocols in the initial phase of disease evolution [
A major limitation of this study is that it was conducted in a single center over a limited period of time, and has a small sample size. Another limitation is that this study only included children under the age of 16 years, because our institutional policy defined children under 16 years to be admitted to the pediatric department. It might have missed MIS-C patients older than 16 years of age.
In conclusion, MIS-C is a novel disease that can present in a myriad of ways with variable severity, and a high index of suspicion is necessary in this era of COVID-19 pandemic for early identification, appropriate management, and favorable outcomes of patients. Further research is essential to develop optimal treatment strategies.
Conflicts of interest: No potential conflict of interest relevant to this article was reported.
Dr. Karthikeyan Shanmugam (Associate professor, Department of Community medicine) for his help in statistical analysis.
Patients’ demographic and clinical characteristics
Population characteristics | Value |
---|---|
Age (yr) | 6.9±4 |
Male sex | 15 (71.4) |
Weight (kg), median (IQR) | 20 (12.8–35.5) |
Overweight/obesity | 2 (9.5) |
Duration of symptoms at admission (day) | 4.8±2.1 |
Contact with COVID-19 patient | 5 (23.8) |
Past COVID-19 infection | 2 (9.5) |
Clinical features General | |
Fever | 21 (100) |
Total duration of fever (day) | 7.9±3.1 |
Highest temperature recorded in hospital admission (℉) | 102.4±1.8 |
Giddiness | 1 (4.8) |
Fatigue±lethargy | 13 (61.9) |
Headache | 5 (23.8) |
Respiratory | |
Cough | 2 (9.5) |
Sore throat/throat pain | 3 (14.3) |
Runny nose±sneezing | 1 (4.8) |
Fast breathing | 4 (19) |
Gastrointestinal | |
Nausea | 3 (14.3) |
Vomiting | 12 (57.1) |
Diarrhea | 11 (52.4) |
Abdominal pain | 11 (52.4) |
Abdominal distension | 5 (23.8) |
Musculoskeletal | |
Joint pain | 1 (4.8) |
Myalgia | 7 (33.3) |
Mucocutaneous | |
Rash | 8 (38.1) |
Bilateral nonexudative conjunctivitis | 12 (57.1) |
Lymphadenopathy | 3 (14.3) |
Strawberry tongue±cracked lips | 7 (33.3) |
Oedema/erythema of hands and feet | 6 (28.6) |
Cardiovascular | |
Shock requiring inotropes | 4 (19) |
Neurological | |
Seizures | 1 (4.8) |
Altered level of consciousness | 3 (14.3) |
Cerebellar signs | 1 (4.8) |
Focal neurological deficit | 1 (4.8) |
Organ system involvement |
|
One | 1 (4.8) |
Two | 3 (14.3) |
Three | 4 (19) |
Four or more | 13 (61.9) |
Values are presented as mean±standard deviation or number (%) unless otherwise indicated.
IQR, interquartile range; COVID-19, coronavirus disease 2019.
Organ system involvement was classified as cardiovascular, gastrointestinal, respiratory, nervous, musculoskeletal, hematological, or renal based on clinical features and investigations.
Laboratory test results
Parameter | Number (%) | Definition |
---|---|---|
Blood counts | ||
Anemia | 4/21 (19) | Hb <10 g/dL in <1 yr |
Hb <9 g/dL in ≥1 yr | ||
Neutrophilia | 16/21 (76.2) | ANC >7.7×103 cells/μL |
Lymphopenia | 10/21 (47.6) | ALC <1.5×103 cells/μL in child > 8 mo |
ALC <4.5×103 cells/μL in child <8 mo | ||
Thrombocytopenia | 8/21 (38.1) | Platelet <150×103 cells/mm3 |
Thrombocytosis | 6/21 (28.6) | Platelet >500×103 cells/mm3 |
Inflammatory markers | ||
Elevated ESR | 17/20 (85) | ≥40 mm/hr |
Elevated CRP | 20/20 (100) | ≥0.6 mg/dL |
Elevated procalcitonin | 5/5 (100) | ≥0.5 ng/mL |
Elevated ferritin | 9/21 (42.9) | >500 ng/mL |
Elevated IL-6 | 19/21 (90.5) | ≥7 pg/mL |
Elevated LDH | 11/16 (68.8) | LDH >300 U/L |
Electrolytes | ||
Hyponatremia | 12/17 (70.6) | Sodium <135 mEq/L |
Hypokalemia | 8/17 (47.1) | Potassium <3.5 mEq/L |
Liver function test | ||
Elevated AST | 6/17 (35.3) | AST >40 U/L |
Elevated ALT | 5/17 (29.4) | ALT >40 U/L |
Hypoalbuminemia | 9/17 (52.9) | Albumin <3 g/dL |
Cardiac biomarkers | ||
Elevated troponin-T | 4/13 (30.8) | ≥14 pg/mL |
Elevated NT-proBNP | 12/15 (80) | >450 pg/mL |
Coagulation profile | ||
Elevated D-dimer | 20/21 (95.2) | ≥0.5 mg/L FEU |
Deranged coagulation | 2/8 (25) | INR ≥1.2 |
Hb, hemoglobin; ANC, absolute neutrophil counts; ALC, absolute lymphocyte counts; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; IL, interleukin; LDH, lactate dehydrogenase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; FEU, fibrinogen equivalent units; INR, international normalized ratio.
Results of COVID-19 tests and imaging studies
Variable | Number (%) |
---|---|
COVID-19 test results | |
Positive serology alone | 19 (90.4) |
Positive RT-PCR alone | 1 (4.8) |
Both serology and RT-PCR positive | 1 (4.8) |
Chest imaging (n=17) | |
Pleural effusion | 3 (17.6) |
Lung infiltrates | 1 (5.9) |
Gastrointestinal imaging (n=14) | |
Ascites | 7 (50) |
Mesenteric lymphadenitis | 5 (35.7) |
Dilated bowel loops | 5 (35.7) |
Appendicular inflammation | 3 (21.4) |
Appendicular abscess | 1 (7.1) |
Hepatomegaly | 3 (21.4) |
Gallbladder wall thickening | 1 (7.1) |
Echocardiography findings (n=21) | |
Abnormal ECHO | 16 (76.2) |
Coronary artery abnormality | 12 (57.1) |
Pericardial effusion | 11 (52.4) |
Left ventricular dysfunction | 5 (23.8) |
Mitral regurgitation | 5 (23.8) |
COVID-19, coronavirus disease 2019; RT-PCR, reverse transcription polymerase chain reaction; ECHO, echocardiogram.
Treatment details and outcomes
Variable | Value |
---|---|
Highest level of care | |
PICU admission | 11 (52.4) |
Duration of PICU stay (hr) | 74.8±41.6 |
Respiratory support | |
Supplemental oxygen requirement | 3 (14.3) |
Duration of oxygen requirement (hr) | 39.6±28.6 |
High flow nasal cannula | 1 (4.8) |
Circulatory support | |
Inotropic support | 4 (19) |
Duration of inotrope requirement (hr) | 37±24.5 |
Pharmacotherapy | |
Antibiotics | 18 (85.7) |
Intravenous immunoglobulin alone | 9 (42.9) |
Steroids (intravenous or oral) alone | 6 (28.6) |
Both intravenous immunoglobulin and steroids | 3 (14.3) |
Aspirin | 14 (66.7) |
Anticoagulant | 3 (14.3) |
Antiepileptics | 1 (4.8) |
Outcomes | |
Length of hospital stay (day), median (IQR) | 6 (5–8) |
Mortality | 0 (0) |
Follow-up | 16 (76.2) |
Values are presented as number (%) or mean±standard unless otherwise indicated.
PICU, pediatric intensive care unit; IQR, interquartile range.
Results of univariate analysis of factors associated with prolonged hospital stay (n=21)
Variable | Hospital stay<7 days (n=14), n (%) | Hospital stay≥7 days (n=7), n (%) | OR (95% CI) | ||
---|---|---|---|---|---|
Age groups | 0.376 | - | |||
Less than 5 yr (n=7) | 6 (85.7) | 1 (14.3) | |||
5 to 9 yr (n=6) | 3 (50.0) | 3 (50.0) | |||
10 to 15 yr (n=8) | 5 (62.5) | 3 (37.5) | |||
Sex | 1.000 | 1.000 (0.134–7.451) | |||
Male (n=15) | 10 (66.7) | 5 (33.3) | |||
Female (n=6) | 4 (66.7) | 2 (33.3) | |||
Overweight/obesity (n=2) | 0 (0) | 2 (100) | 0.035 | 0.263 (0.124–0.558) | |
Temperature > 38.9℃ (n=11) | 5 (45.5) | 6 (54.5) | 0.089 | 10.80 (0.997–116.998) | |
Anemia (n=4) | 2 (50.0) | 2 (50.0) | 0.432 | 2.400 (0.261–22.105) | |
Lymphopenia (n=10) | 5 (50.0) | 5 (50.0) | 0.122 | 4.500 (0.627–32.295) | |
Thrombocytopenia (n=8) | 6 (75.0) | 2 (25.0) | 0.525 | 0.533 (0.076–3.755) | |
Elevated ESR (n=17) | 12 (70.6) | 5 (29.4) | 0.212 | 0.208 (0.015–2.854) | |
Elevated ferritin (n=9) | 3 (33.3) | 6 (66.7) | 0.019 | 22.0 (1.857–260.648) | |
Elevated IL-6 (n=19) | 12 (63.2) | 7 (33.3) | 0.293 | - | |
Elevated D-dimer (n=20) | 13 (65.0) | 7 (35.0) | 0.469 | - | |
Hyponatremia (n=12) | 6 (50.0) | 6 (50.0) | 0.252 | 4.000 (0.340–47.112) | |
Hypokalemia (n=8) | 4 (50.0) | 4 (50.0) | 0.486 | 2.000 (0.282–14.198) | |
Hypoalbuminemia (n=9) | 5 (55.6) | 4 (44.4) | 0.772 | 1.333 (1.191–9.311) | |
Abnormal ECHO (n=16) | 10 (62.5) | 6 (37.5) | 0.469 | 2.400 (0.215–26.822) | |
PICU admission (n= 12) | 7 (58.3) | 5 (41.7) | 0.350 | 2.500 (0.357–17.500) | |
Supplemental oxygen requirement (n=3) | 1 (33.3) | 2(66.7) | 0.186 | 5.200 (0.381–70.903) | |
Inotropic support (n=4) | 2 (50.0) | 2 (50.0) | 0.432 | 2.400 (0.261–22.105) | |
Organ system involvement | |||||
Cardiovascular system (n=17) | 10 (58.8) | 7 (41.2) | 0.116 | - | |
Respiratory system (n=5) | 2 (40.0) | 3 (60.0) | 0.147 | 4.500 (0.542–37.378) | |
Gastrointestinal system (n=17) | 11 (64.7) | 6 (35.3) | 0.694 | 1.636 (0.138–19.387) | |
Central nervous system (n=3) | 2 (66.7) | 1 (33.3) | 1.000 | 1.000 (0.075–13.367) | |
Hematological system (n=16) | 9 (56.3) | 7 (43.8) | 0.070 | 1.778 (1.154–2.379) | |
Mucocutaneous involvement (n=15) | 12 (80.0) | 3 (20.0) | 0.040 | 0.125 (0.15–1.038) | |
Musculoskeletal system (n=5) | 3 (60.0) | 2 (40.0) | 0.717 | 1.467 (0.184–11.718) | |
Multiorgan involvement (≥4 organs) (n=13) | 8 (61.5) | 5 (38.5) | 0.525 | 1.875 (0.266–13.202) |
OR, odds ratio; CI, confidence interval; ESR, erythrocyte sedimentation rate; IL, interleukin; ECHO, echocardiogram; PICU, pediatric intensive care unit.
Boldface indicates a statistically significant difference with
Common clinical characteristics in our study versus those of other studies
Clinical feature | Our study (n=21) | Whittaker et al. [ |
Dhanalakshmi et al. [ |
---|---|---|---|
Fever | 21 (100) | 58 (100) | 19 (100) |
Vomiting | 12 (57.1) | 26 (45) | 6 (31.5) |
Abdominal pain | 11 (52.4) | 31 (53) | 8 (42) |
Diarrhea | 11 (52.4) | 30 (52) | 3 (15.8) |
Rash | 8 (38.1) | 30 (52) | 12 (63.2) |
Bilateral conjunctival congestion | 12 (57.1) | 26 (45) | 9 (47.4) |
Cervical lymphadenopathy | 3 (14.3) | 9 (16) | 6 (31.5) |
Strawberry tongue±cracked lips | 7 (33.3) | 17 (29) | 9 (47.4) |
Oedema/erythema of hands and feet | 6 (28.6) | 9 (16) | 10 (52.6) |
Values are presented as number (%).