System spectrum analysis and six-month outcome of patients with paediatric inflammatory multisystem syndrome temporarily associated with severe acute respiratory syndrome coronavirus-2 at a tertiary hospital in eastern India

Background: Whilst there are plenty of studies on patients with paediatric inflammatory multisystem syndrome temporarily associated with severe acute respiratory syndrome coronavirus-2 (PIMS-TS), there is a scarcity of studies worldwide regarding follow up of these patients. Objectives: To assess the clinical, laboratory and imaging data and outcome of patients with PIMS-TS in the 6-month follow-up. Method: A retrospective cohort study was conducted in the Department of Paediatrics, Vivekananda Institute of Medical Sciences, Ramakrishna Mission, Seva Pratisthan, Kolkata, India on all children under 12 years of age admitted from 1st March to 31st August 2021 with World Health Organisation criteria of PIMS-TS. Main outcome measures: Clinical features of different systems, routine laboratory investigations, liver and renal function tests, acute phase reactants, cardiac markers like NT-proBNP, urine analysis, echocardiogram, ultrasonography of abdomen and magnetic resonance imaging of brain. Results: Twenty-one patients (13 male, 8 female) were included in this study. Median age of presentation was 3 years; 3 patients had pre-existing comorbidities; all patients had elevated inflammatory markers at baseline; 14 patients had significant findings on echocardiography on admission; all patients were discharged in stable condition. At the 6-month follow-up, 2 patients had ________________________________________


Introduction
Following the spread of the coronavirus disease-2019 (Covid-19) pandemic a new disease entity emerged, termed paediatric inflammatory multisystem syndrome temporarily associated with Covid-19 (PIMS-TS) or multisystem inflammatory syndrome in children (MIS-C) 1 . UK National Health Service first alerted the world regarding the multisystem involvement of children following Covid-19 infection in April 2020 2 . Since then, the World Health Organisation (WHO), Royal College of Paediatrics and Child Health, US Centres for Disease Prevention and Control have all produced several definitions for this multisystem inflammatory disorder following Covid-19 pandemic 3,4,5 .
Children with PIMS-TS typically have a history of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in the weeks before presentation 6,7 . Clinical manifestations include fever, cardiac manifestations, gastrointestinal symptoms, polymorphous rashes, conjunctivitis and respiratory failure 6,7,8 . Children with PIMS-TS often look like children with Kawasaki disease or toxic shock syndrome 9 . Many look very unwell and need admission to the paediatric intensive care unit 6,7 . Initial investigations revealed evidence of hyperinflammation with C-reactive protein (CRP) levels greater than 100mg/L as well as elevated erythrocyte sedimentation rate (ESR), hypertriglyceridaemia, hyponatraemia, and elevated serum ferritin and D-dimer 6,7,8 . . Although the acute phase of PIMS-TS has been characterised, the shortterm, medium-term and long-term effects remain unclear 7, 10 . Exclusion Criteria: Patients who did not attend clinic for follow up 6 months after discharge.

Data collection and analysis:
The PIMS-TS patients who were admitted were prospectively examined by multiple specialities in a PIMS-TS multidisciplinary outpatient clinic that had been set up in November, 2020. Patients were examined by the multidisciplinary team at 6 months after discharge from hospital. Clinical records were evaluated retrospectively by 2 investigators who had collected hospital admission and 6 months followup data. Recent SARS-CoV-2 infection was established by reverse transcription polymerase chain reaction (RT-PCR) of nasopharyngeal sample, serology positivity, a clear epidemiologically established link to an infected contact or a combination of the above. Serology testing checked IgG antibodies to the SARS-CoV-2 spike protein. Follow up serological assay was done on IgG antibodies against the SARS-CoV-2 spike protein. Treatment was done according to the WHO protocol.
All echocardiogram reports were evaluated by qualified paediatric cardiologists (as per qualification criteria of National Medical Council, India). Coronary artery diameters were measured as per standard guideline 11 and indexed with Z scores 12 . Coronary Z scores more than 2.5 were considered as dilated 11 . Abdominal ultrasound examination was done to rule out various abnormal features found in PIMS-TS that were reported earlier like ascites, bowel wall thickening, mesenteric inflammation.
Outcomes: Various outcomes were assessed at the 6-month follow-up after discharge from hospital. PedsQL 4.0 Generic Core Scales were used to measure physical functioning, social functioning, emotional functioning, and school functioning. Higher scores indicated better HRQOL. Number of items in physical, social, emotional, and school functioning was 8, 5, 5 and 3 respectively. Each item was scaled from 0 (never) to 4 (almost always). Scores were converted on a scale from 0 to 100.

Results
This study included 30 patients. At presentation, mean age was 4.3 years, median age 3 years (IQR 6 -2 = 4 years); 18 patients were male and 12 were female. Patients' demographic characteristics, clinical features and treatment are shown in Table 1.
Systemic symptoms in individual patients are shown in Table 2. Nil (Source -Case record sheets of patients admitted with MIS-C) Before initial treatment, mean duration of symptoms was 5.9 days, median 6 days (IQR 7 -5 = 2 days). Rash was commoner as presenting feature in patients 5 years and younger, while pain in abdomen was more common in patients older than 5 years. 4 patients had comorbidities -2 had asthma, 1 had autism and 1 had both tuberous sclerosis and beta thalassaemia trait.  Among 27 of 30 patients who had positive serology at presentation, seropositivity was seen in 1 patient at the 6-month follow-up.
One patient with RT-PCR positive report an admission (among 2) seroconverted at the 6-month follow-up.
 Six of 30 patients presented with hypotension or shock. Nineteen of 30 patients had significant abnormalities on the initial echocardiogram. Six children required inotropic support; 21 of 30 patients had raised troponin and 20 had raised N terminal pro brain natriuretic peptide (NT-pro BNP); by 6 months, systolic function and concentration of troponin and NT-Pro BNP were normal in all patients.
 By 6 months, echocardiograms of 17 of the initially abnormal 19 patients became normal; 2 patients had significant coronary artery dilatation. One patient's coronary artery diameter normalized at the 6-month follow-up and another at 9 months followup.
 Out of 10 patients who had significant coronary artery dilatation, left coronary artery was significantly dilated in 6 patients and left anterior descending artery in 4 patients.
 Pericardial effusion was present in 17 patients.
 Sixteen of 30 patients had neurological symptoms at presentation. Symptoms seen were irritability (n=11), drowsiness (n=4), convulsions (n= 3) and headache (n=1). All patients with abnormal neurological symptoms had no symptoms at the 6-month follow-up. Neurological examination was normal in all.
 Renal involvement (raised creatinine, proteinuria, hypoalbuminaemia or a combination of the above) was present in 5 of 30 during hospital course but none required renal replacement therapy. On follow-up at 6 months, none of the patients had any features of renal involvement.
 Gastrointestinal (GI) involvement (diarrhoea, abdominal pain or vomiting) was present in 24 of 30 patients before or during hospital admission; 6 of 10 patients who had abdominal pain imaging during admission had clinically significant abnormalities (oedematous gut loop in 3, hepatomegaly in 3 and splenomegaly in 3). Persistent GI symptoms were present in one patient (abdominal pain) at the 6month evaluation. All patients with abnormal abdominal imaging on presentation became normal at the 6-month follow-up. Scale assessment and out of 9 patients aged more than 5 years, 8 patients participated in PedsQL 4.0 Generic Core Scale assessment. PedsQL responses at the 6-month follow-up revealed mild impairment by parental report mostly in emotional and psychosocial scale. No patient was in the severe impairment group (Table 3). Table 4 compares the PedsQL 4.0 Generic Core Scale assessment of our study with that of a UK study 16 .   In our study, RT-PCR was positive in 2 (6.6%) children and IgG against Covid-19 was positive in 27 (90%) children. In a study from South India 13 RT-PCR was positive in 16.6% children and IgG against Covid-19 was positive in 47%. One child (6%) was positive to both. In study from Pune 14 , IgG was positive in 56%. In the Study from GOSH 7 RT-PCR was positive in 26% and IgG was positive in 87%.
All patients presented with fever; this was according to the WHO case definition where fever should be present for at least 3 days. In our study, mean duration of fever was 5.9 days. In a study from Mumbai 15 the mean duration of fever was 5.2 days. In our study, rash was present in 24 (80%) patients, compared to 63% in the South Indian study 13 , 68% in the Pune study 14 and 65% in the Mumbai study 15 .
In the study from GOSH, London 7 , the percentage was 52%.
In our study 6 (20%) patients presented with shock. In our study 10% patients required mechanical ventilation which is less than the 28% in the study from Pune 14 . No patient in the study from South India 13 needed mechanical ventilation. In the study from GOSH, London 7 , the percentage was 39.6%. In our study 6 (20%) patients received inotropic support, while 31.5% patients from study in South India 13 and 39% from the study in Mumbai 15 received inotropic support. In the study from GOSH, London 7 , the percentage was 50%. These are much less than the 80% from Pune study 14 . In our study 53.3% patients received intravenous (IV) immunoglobulin, compared to 72% in the Pune study 14 , 79% in the South Indian study 13 and 65% in the Mumbai study 15 . In our study one patient out of 30 received Tocilzumab compared to one out of 25 in the Pune study 14 , one out of 19 in the South India study 13 and 3 out 23 in the Mumbai study 15 .
Our study involved more patients than other contemporary studies from India. We found lower median age of patients, more children presenting with skin rash, less incidence of shock, less requirement of inotropic support and IV immunoglobulin. In our study all laboratory parameters normalized at the 6-month follow up. Our study involved PedsQL 4.0 Generic Core Scales at the 6-month follow-up. None of the other Indian studies considered this scale on follow up. We compared our findings with another study in UK 16 . This is shown in Table 4. This table reveals that at 6 months follow up, there was comparatively less incidence of severe impairment.

Conclusions
When PIMS-TS presented in children aged less than 5 years, skin rash was more common, there was less incidence of shock, less use of IV immunoglobulin on the 6-month follow-up and clinical and laboratory parameters became normal in most. PedsQL Score was also better at the 6-month followup.