This study was conducted at a tertiary care children’s hospital in Chennai, India. We analyzed children presenting to our hospital from May 4, 2020 to July 8, 2020 (8 week period), who satisfied the case definition of PIMS-TS as defined by Royal College of Paediatrics and Child Health (RCPCH) [12]. Retrospectively, four children admitted during the month of April, 2020 were also included, as they met the criteria specified by RCPCH PIMS-TS definition. Data on the following parameters were collected: demographics, clinical findings, radiological findings, underlying comorbidities, echocardiographic findings, laboratory investigations, treatment received including intensive care interventions and outcome. This data is a part of a larger COVID-19 study in children presently undergoing at our institution, and was approved by the ethics committee. All children were included in the study after written informed consent of the caretaker.

Confirmed COVID-19 was defined as either positive SARS-CoV-2 real-time reverse-transcriptase polymerase chain reaction (RT-PCR) performed by Indian Council of Medical Research (ICMR) approved laboratories or positive antibody test performed with ICMR-approved YHLO SARS-CoV-2 IgG and IgM antibody titer assay kits (Shenzhen YHLO Biotech Co. Ltd.) as per manufacturer’s instructions.

Designated doctors and the study nurse collected all details in standardized and approved case report forms, which were then entered into to the Microsoft Excel spreadsheet. Vital signs (tachycardia, tachypnea and hypotension) were classified according to normal values for the age [13]. Data on various laboratory markers were collected and elevated levels were defined in relation to the normal levels for the age [14,15]. Cardiovascular involvement was described as children needing any of the following: fluid bolus (>20 mL/kg) with or without vasoactive medications, an echocardiogram showing decreased left ventricular function (EF <55%), coronary artery abnormality, pericarditis or pericardial effusion, electrocardiogram (ECG) evidence of arrhythmias with or without elevated levels of troponin or pro BNP.

Statistical analyses: Data are presented as median (IQR), numbers and proportions. Statistical analyses were performed using SPSS version 24.0.

A total of 19 children with a median (IQR) age of 6 years (13 months-16 years) who met the criteria of PIMS-TS were included in this series. Between May 1 and July 8, 2020, 15 children were identified and four children were identified in April, 2020.

The male to female ratio was 1:1.4 and 9 children (47%) were younger than 6 year. Of the 19 children, 15 (79%) were tested for COVID 19 by RT-PCR and serological assays and 11 (58%) were identified as confirmed cases of COVID-19. SARS-CoV-2 was confirmed by RT-PCR alone in three children (16%), one child (6%) had evidence from both RT-PCR and serological assay, 7 children (47%) had positive serological assay alone whereas RT-PCR and serological assay was negative in 4 (27%) children (Table I).

Table I  Demographic and Clinical Characteristics of Children With PIMS-TS (N=19)

RT-PCR and/or serological assay negative or COVID-19 status unknown children were included as they met the criteria as specified by RCPCH PIMS-TS definition. All children (100%) presented with fever of more than 3 days and six (31%) presented with lymphadenopathy. Multi-organ involvement was seen in majority of the children (15/19, 79%). Cardiovascular symptoms were reported in 12 (63%) children, of which three had coronary artery abnormality at presentation (Table I).

Elevated CRP (median (IQR): 118 (73-298) mg/L) was noted in all 19 children (100%). Coagulation parameters (PT, APTT and INR) were abnormal in 11/15 children (73%) and D-dimer (median (IQR): 4,250 (339 -7328) ng/mL FEU) was elevated in 13/14 (92.8%) children (Table II).

Chest radiography was performed in 15 children, of which 5 showed evidence of lobar consolidation (uni-lateral). Ultrasound scan of abdomen was performed in 5 children of whom one was suggestive of as possible appendicitis. CT chest and abdomen was performed in the same child, which showed evidence of right lower lobe consolidation. Coronary artery abnormality (dilatation without aneurysm, Z score <2.5) was seen in three children with one of them having evidence of minimal pericardial effusion.

Of the 19 children, 5 (26%) received intravenous immunoglobulins (IVIG) alone, whereas three children (16%) were treated with steroids alone; 8 children (42%) received both IVIG and steroids, and one child received IVIG and tocilizumab. Aspirin was given in 16 (84.2%) children and two children were not given any immuno-modulatory agents. All 19 children received broad-spectrum antibiotics at presentation, which were disconti-nued after negative culture results. No organisms were isolated from blood cultures.

Only one child had underlying co-morbidity (global developmental delay) and one child presented with features mimicking appendicitis along with positive SARS-CoV-2 antibodies. Median length of hospitalization was 6 days (IQR 3-13 days) and 12 (63%) children required PICU support. There was no mortality in our series.

This study is the first series from India describing children presenting with PIMS-TS. Consistent with published data from Europe and US, children in this study also presented with signs and symptoms mimicking complete or incomplete Kawasaki disease (KD), toxic shock syndrome (TSS), hemophagocytic lymphohistiocytosis (HLH) and/or macrophage activation syndrome (MAS) [4,5,10]. Although, cardiac dysfunction is the most commonly reported organ dysfunction [5,7,12], a notable finding in our series was that a fewer number of children were identified to have echocardiographic evidence of coronary artery changes (3/19, 16%), though a significant number of children (57%) developed hypotension requiring admission to the PICU for vasoactive medications. Likewise, when compared to the available data, fewer children (42%) in our series presented with gastrointestinal symptoms as against up to 80% in literature [4-6,16], and more than two-third (74%) presented with mucocutaneous manifestations.

Clinical presentation, epidemiology and pathogenesis of PIMS-TS are still unclear and evolving, but cases of PIMS-TS seem to appear few weeks after the COVID-19 peak in the population [5,17,18]. The COVID-19 peak in the community is possibly yet to occur in several cities in India, and we postulate that we may also see a significant increase of PIMS-TS among children in the coming days.

A positive serologic assay for SARS-CoV-2 or RT-PCR has been a consistent finding in the literature [7,8]; although, there have also been published reports with negative results for SARS-CoV-2 [10]. Most of the children in this study (58%) had laboratory confirmed SARS-CoV2 infection. Serology testing or RT-PCR could not be performed in four children as they presented to us at the beginning of COVID-19 pandemic in Chennai. These four children had no microbiological evidence for other infections. They had multi-organ dysfunction with elevated inflammatory makers (CRP, D-dimer and ESR) in addition to neutrophilia and lympho-penia. However, we plan to perform serological assay in these children during their follow up to establish a link between their symptoms and SARS-CoV-2. PIMS-TS generally tend to occur in older children (reported median age 8 years) [5,6,10], which is slightly more than that seen in our patients. Laboratory testing in our group generally showed significant elevation of inflammatory markers, as reported earlier [6,19].

Currently there is no consensus regarding management of children with PIMS-TS; although there has been a recently published review suggesting a treatment flowchart [20]. IVIG (2 g/kg) has been most commonly used as first line therapy with many children receiving additional high-dose steroids [5-7,16]. Nearly half of the children (42%) in this series received both IVIG and steroids, with a few children requiring a second dose of IVIG and one child needing additional immuno-modulatory medication. The role of aspirin in children with hyperinflammation without KD is not yet described, though it has been used by many in PIMS-TS [10,11]. Lack of uniform guideline for management reinforces the fact that further studies are required to establish optimal treatment in PIMS-TS.

The main limitations of the study are relatively smaller number of patients and a shorter duration of study; hence, we are unable to provide data on long-term sequelae of PIMS-TS. Another limitation is absence of serological confirmation of SARS-CoV-2 infection in nearly one-fifth of the children.

Our study is one of the first series from Asia describing PIMS-TS in children. We report fewer coronary artery abnormalities, as compared to the existing data on PIMS-TS. Finally, we also report low incidence of RT-PCR positivity with increased presence SARS-CoV-2 antibodies. This study underscores the occurrence of PIMS-TS in children in India and will increase awareness of the disease among the clinicians, so as to enable early recognition and prompt management.

Ethics approval: CTMRF-KKCTH Ethics committee; No. ECR/676/Inst/TN/2014/RR-17, dated June 2, 2020.

Acknowledgements: Dr Anand Manoharan, Director Clinical research, CTMRF and the following Senior Pediatric Consultants at Kanchi Kamakoti CHILDS Trust Hospital (KKCTH): Dr Janani Sankar, Dr T Vasanthi, Dr T Ravikumar, Dr S Shivabalan, Dr Asokan and Dr Rajkumar for their support and contribution.

Contributors: SBS, AVR: concept and design; KD, MM, AV: acquisition, analysis and interpretation of data; AV, SBS, SA, KS: drafting of the manuscript; MM,AV: statistical analysis; AV, SP: analysis of laboratory assays; KD, AV, SBS, SA, SP, KS, BR, AVR, SA: critical revision of the manuscript for important intellectual content; KD, AV, SBS, SA, MM, SP, KS, BR, AVR: final approval of the version to be published.

Funding; Child Trust Medical Research Foundation (CTMRF); Competing interests: None stated.