A single-center experience from Eastern India depicting the epidemiology and phenotypic variations of Multisystem inflammatory syndrome in children (MISC) associated with SARS-CoV2 seen after first wave and second wave of COVID 19

Mimi Ganguly; Prabhas Prasun Giri; Surupa Basu

doi:10.4103/jpcc.jpcc_99_22

ORIGINAL ARTICLE

Year : 2023 | Volume : 10 | Issue : 2 | Page : 49-55

A single-center experience from Eastern India depicting the epidemiology and phenotypic variations of Multisystem inflammatory syndrome in children (MISC) associated with SARS-CoV2 seen after first wave and second wave of COVID 19

Mimi Ganguly¹, Prabhas Prasun Giri¹, Surupa Basu²
¹ Departments of Paediatrics, Institute of Child Health, Kolkata, West Bengal, India
² Department of Biochemistry, Institute of Child Health, Kolkata, West Bengal, India

Date of Submission	15-Dec-2022
Date of Decision	04-Feb-2023
Date of Acceptance	15-Feb-2023
Date of Web Publication	23-Mar-2023

Correspondence Address:
Dr. Prabhas Prasun Giri
Paediatric Intensive Care Unit, Institute of Child Health, 11 Dr. Biresh Guha Street, Kolkata
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpcc.jpcc_99_22

Abstract

Introduction: Multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2 caused significant health concerns worldwide. In our center, we had encountered the first wave of MIS-C from June 2020 to January 2021, whereas the second wave surged up from April 2021 to August 2021. In this study, we have done a comparative analysis of different phenotypes of MIS-C seen during these two waves.
Subjects and Methods: This was a single-center observational study where the children fulfilled the WHO criteria for MIS-C were included in the study. Clinical and laboratory findings, course of the illness, treatment, and outcome were noted down, and the patients were followed up. Depending on the presentations, cases were classified in four different phenotypes (Type 1: MIS-C overlapping with acute COVID-19, Type 2: MIS-C with shock/MIS-C with multiple organ dysfunction syndrome (MODS), Type 3: MIS-C Kawasaki disease phenotype, Type 4: Mild MIS-C/Febrile inflammatory state), and a comparative analysis of these phenotypes in the two waves was done.
Results: There were 86 cases in 7 months during the first wave, whereas 102 cases in 5-month duration during the second wave. The clinical manifestations and laboratory findings were compared, type 2 phenotypes increased in proportion requiring more pediatric intensive care unit admissions. Mortality was seen during the 2^nd wave which was absent in our cohort during the first wave.
Conclusions: MIS-C typically showed a spectrum of disease manifestations starting from a mild febrile inflammatory state to full-blown MODS. Early phenotypic differentiation and targeted immunomodulatory therapy depending on the phenotype had shown to be useful.

Keywords: Kawasaki disease, multisystem inflammatory syndrome in children, multisystem inflammatory syndrome in children phenotypes, post-COVID inflammatory syndrome

How to cite this article:
Ganguly M, Giri PP, Basu S. A single-center experience from Eastern India depicting the epidemiology and phenotypic variations of Multisystem inflammatory syndrome in children (MISC) associated with SARS-CoV2 seen after first wave and second wave of COVID 19. J Pediatr Crit Care 2023;10:49-55

How to cite this URL:
Ganguly M, Giri PP, Basu S. A single-center experience from Eastern India depicting the epidemiology and phenotypic variations of Multisystem inflammatory syndrome in children (MISC) associated with SARS-CoV2 seen after first wave and second wave of COVID 19. J Pediatr Crit Care [serial online] 2023 [cited 2023 Jun 8];10:49-55. Available from: http://www.jpcc.org.in/text.asp?2023/10/2/49/372438

Introduction

The COVID-19 pandemic has caused a wide spectrum of diseases starting from asymptomatic infected individual to catastrophic diseases worldwide, and children have been relatively spared from the severe illness.^[1],[2] Severe COVID-19 in adults is thought to be associated with declining viral loads and increasing markers of inflammation.^[3],[4] These observations suggest that host tissue damage is mediated by dysregulated innate and adaptive immune responses.^[5] In April 2020, clinicians in the United Kingdom reported eight previously healthy children presenting with fever, mucositis, cardiogenic shock, and laboratory features of hyperinflammation.^[6] After that, similar reports started coming from other parts of the world as well.^[7],[8],[9] On May 14, 2020, the Centre for Disease Control and Prevention (CDC) issued a national health advisory to report cases meeting the criteria for multisystem inflammatory syndrome in children (MIS-C), where many pediatric patients with this hyperinflammatory syndrome have had fever and mucocutaneous manifestations somehow similar to those of Kawasaki disease (KD).^{[10],[11],[12]} The first wave of MIS-C was from June 2020 to January 2021, while the second wave surged up from April 2021 to August 2021. Here, we have tried to compare the epidemiology, clinical presentations, laboratory findings, and outcome of different phenotypes of MIS-C seen during these two waves.

Materials and Methods

This cross-sectional observational study was performed in a 200-bedded tertiary care pediatric teaching hospital in eastern India from June 2020 to January 2021 (first wave) and from April 2021 to August 2021 (second wave). Children (age <18 years) fulfilling the WHO diagnostic criteria of MIS-C^[13] had been included in the study. Ethics committee approval was taken (No.ICH/IEC/47/2020). Written informed consent was obtained from parents of all patients who were included in this study.

All the patients with the history of fever with or without evidences of respiratory tract infection were admitted in the isolation ward. The basic diagnostic workup including a SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR), complete hemogram, and C-reactive protein (CRP) along with liver function tests and renal function tests was done in all patients. Patients who had either a neutrophilic leukocytosis and/or raised CRP with any single organ system affection had been termed as “MIS-C suspect.” Depending on the preliminary COVID RT-PCR report, second-line investigations including a SARS-CoV-2 IgG, interleukin-6 (IL-6), and N-terminal pro brain natriuretic peptide (NT-proBNP) had been done in these patients along with the search for any infectious agent.

As shown by various case series and reports,^[14],[15] similarly, we also found a varying spectrum of the disease ranging from mild to severe and hence, depending on the clinical presentations, course of the disease, and laboratory investigations four different phenotypic variations were made by us:

Type 1: MIS-C overlapping with acute COVID-19 fulfills the diagnostic criteria for MIS-C with COVID RT-PCR positivity with a negative COVID IgG
Type 2: Classic MIS-C/severe MIS-C/MIS-C with shock/MIS-C with multiple organ dysfunction syndrome (MODS) fulfills the diagnostic criteria of MIS-C with features of shock and myocarditis with or without multiple organ dysfunction
Type 3: MIS-C KD phenotype fulfills the diagnostic criteria for KD as well as MIS-C without features of organ dysfunction or shock with SARS-CoV-2 IgG positivity
Type 4: Mild MIS-C/Febrile inflammatory state fulfills the diagnostic criteria for MIS-C but not fitting in any above category with a milder form of disease. Presenting symptoms, clinical features, course in the hospital, investigation findings, treatment modalities, outcome, and follow-up status of all these patients had been noted down in details, and a comparative study between the two waves was done.

Results

A total of 188 patients who fulfilled the WHO diagnostic criteria of MIS-C in these two waves were included in this study. In the first wave, we could see 86 patients spanning over 7 months with a peak in December 2020 (June 2020 to January 2021), where in 2^nd wave, we got 102 parents just over 5 months (April 2021 to August 2021). There were no MIS-C cases in February 2021 and March 2021. We have seen a typical epidemiological pattern of MIS-C cases. During the first wave, in our part of the country, there was the peak of COVID-19 cases in the month of October 2020, and we have seen peak of MIS-C cases in the month of December. The same is applicable for second wave as well where COVID-19 case spikes seen in April 2021 and May 2021, and MIS-C spiked up in late May 2021 and June 2021. It strongly suggests some short of postinfectious immune-mediated etiology in MIS-C [Figure 1] and [Figure 2]. Among the four distinct phenotypic patterns, type 2 phenotypes were more during the second wave (67%) than that during the first wave (59%) [Figure 3].

Figure 1: The two waves of SARS-CoV-2 in India^[16]

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Figure 2: The two MIS-C peaks as per patients admitted in our institute. MIS-C: Multisystem inflammatory syndrome in children

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Figure 3: The proportions of different MIS-C phenotypes during the two waves. MIS-C: Multisystem inflammatory syndrome in children

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Clinical features

All patients of the four phenotypes in both the waves shared similar clinical pictures with some variations. All had fever of various duration ranging from around 3 days to 8 days at presentation. Type 2 phenotypes having higher temperature spikes than Type 4 phenotypes. Mucocutaneous involvement in the form of conjunctival congestion, oral mucositis and/or rash was almost universal in type 2 and 3 phenotypes. As the numbers of type 2 phenotype was higher in second wave, the clinical features of organ dysfunction in the form of acute respiratory distress syndrome, myocarditis and shock, and acute kidney injury were also higher in MIS-C cases of second wave [Table 1].

Table 1: Clinical manifestations seen among the four phenotypes during the two waves

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Laboratory investigations

The laboratory findings were similar during the two waves with some variations. Neutrophilic leukocytosis was present along with raised CRP. NT-proBNP levels were raised, but the levels were higher in Type 2 phenotype than others [Table 2].

Table 2: Lab investigations seen among the four phenotypes during the two waves

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Treatment

The number of patients requiring pediatric intensive care unit (PICU) care was more, and the percentage of Type 2 phenotypes requiring ventilatory support increased during the 2^nd wave. Nearly 92.65% of type 2 phenotype also required inotropic support as compared to 84.31% during the first wave [Table 3].

Table 3: Treatment support required by the four phenotypes during the two waves

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Treatment received

The use of intravenous immune globulin (IVIG) increased during the second wave with 97.06% of Type 2 phenotype and 46.2% of type 4 requiring full-dose IVIG as compared to 86.27% and 29.41%, respectively, during the first wave probably due to increased severity of disease with changing viral strains. Furthermore, the use of steroids increased during this time [Table 4].

Table 4: Treatment received by the different phenotypes during the two waves

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Outcome

We did not face any mortality in the first wave, but there were five deaths in our cohort during the second wave.

Discussion

After the first reporting of MIS-C was done in late April 2020, and we started seeing more and more MIS-C patients, we realized that MIS-C is not a single disease entity rather a spectrum of disorder that mostly occurs after the resolution of the acute infection as a late immunogenic response but can be seen overlapping with severe acute COVID-19 as well.

Here, we tried to describe the whole spectrum and tried to compare the four distinct phenotypes in both the waves.

Although the distribution of phenotypes varied, clinical and laboratory features were almost similar in both the waves [Table 1] and [Table 2].

In a study by Davies et al.,^[17] 78 patients of MIS-C; 87% presented with shock, of which 46% were invasively ventilated and 83% needed vasoactive infusions. Nearly 22% of patients were refractory to steroid and immunoglobulin and received biologics. Nearly 36% had evidence of coronary artery (CA) abnormalities. The whole cohort was mainly representative of the severe disease (type 2 phenotype). In contrast, our patients of severe phenotype in both the waves did reasonably well and less intensive care support, and immunosuppression was needed. Severe phenotype constitutes around 61.3% of total cohort and all except three had evidence of myocarditis in the echocardiography (ECG), or by elevated cardiac biomarkers such as NT-proBNP. We have taken NT-proBNP of more than 1500 pg/ml as a definitive evidence of myocardial injury without any evidence of acute kidney injury.^[18] Similarly, in the report by Feldstein et al.^[19] of 186 patients with MIS-C who were admitted to participating health centers from March 15, 2020 to May 20, 2020 in the USA, 80% received intensive care, 20% received mechanical ventilation, 48% received vasoactive support, and 4 kids (2%) died. Coronary artery aneurysms (Z scores ≥2.5) were documented in 15 patients (8%), and KD-like features were documented in 74 (40%). Most patients (92%) had elevations in at least four biomarkers indicating inflammation. IVIG was used in 144 (77%), glucocorticoids in 91 (49%), and IL-6 or 1RA inhibitors in 38 (20%). Whereas in our study, we had a total of 188 patients admitted during the two waves, of whom 71.3% required PICU care, 17.55% needed mechanical ventilation, 61.7% needed inotropes, and there was no mortality in the first wave but five deaths during the second wave. Our study similarly showed that most patients had raised inflammatory markers, but we used IVIG in 91.5% and steroids in 86.2% of patients combining the two waves, the second wave seeing more the use of such agents.

Dhanalakshmi et al.^[20] reported the first case series of MIS-C of 19 children from India. All of them had high CRP and more than 90% patients had evidence of coagulopathy. Of the 19 children, 5 (26%) received 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. This report also revealed a spectrum of disease of varying severity, but no clear distinction about these phenotypes was made.

In another study by Jain et al.^[21] from Mumbai, the authors have highlighted the phenotypic differences but no clear descriptions were given. About 65% of patients of their study presented with shock and these children had a higher age and significantly higher incidence of myocarditis with elevated troponin, NT pro BNP, and left ventricular dysfunction, along with significant neutrophilia and lymphopenia, as compared to those without shock. In our study also, patients with severe disease (type 2) had higher levels of CRP than others.

In their study, Mehra et al.^[22] have shown and compared the demography, clinical, and laboratory parameters of the four phenotypes as observed in eight hospitals in Delhi, India, during the first wave where they showed the importance of rising CRP and absolute neutrophil counts as the marker of severity in these patients.

In their study with 21 children during the first wave, Shobhavat et al.^[23] had encountered a more severe spectrum with 20 out of 21 children presenting with shock and there were three deaths. In our study, in both the waves, we clearly saw four different phenotypes of MIS-C although the percentage of each variant varied. Severe type of MIS-C presenting with shock was more in the second wave than the first.

In a study of 570 children with MIS-C reported to the CDC through July 2020,^[24] investigators used a statistical modeling technique called latent class analysis to identify different subtypes of the syndrome and they were the first to describe a clear description and definition of three different MIS-C phenotypes which were MIS-C without overlap with acute COVID-19 or KD (similar to type 2 phenotype of our study), MIS-C overlapping with severe acute COVID-19 (similar to type 1 phenotype of our study), and MIS-C overlapping with KD (similar to type 3 phenotype of our study). Going through the pandemic for almost the past 2 years, our observation was similar as we have clearly seen different phenotypic variations of MIS-C in both the waves, and the clinical spectrum is definitely evolving. In addition to this, we describe another phenotype of febrile inflammatory state (type 4) that is mild in severity, fulfilling criteria of MIS-C but not fitting in with any of the above phenotypes. In our study, 17 children out of 86 in the first wave and 13 out of 102 in the second wave falling in this group were typically febrile children without any organ failure where no infectious etiology was identified, and all of them were SARS-CoV-2 IgG positive. They were managed either with immunosuppression or supportive therapy. In this study by CDC, they have found the incidence of CA abnormalities was similar in all three subgroups (21%, 16%, and 18%, respectively), highlighting the importance of routine ECG in all children with MIS-C, regardless of apparent subphenotypes. In our study, we found type 1 phenotypes mostly had isolated myocarditis (80% and 85.75%, respectively) where type 3 (KD Phenotype) had isolated coronary dilatation (Z ≥2.5). Type 2 phenotypes had either isolated myocarditis (80.39% and 83.8%, respectively, in the two waves) or both myocarditis and coronary dilatation (15.69% in the first wave and 14.7% in the second wave, respectively). We have also seen many novel or atypical presentations of MIS-C such as MIS-C presenting with acute necrotizing pancreatitis, MIS-C presenting with refractory status epilepticus, or MIS-C mimicking acute appendicitis.

Limitations

MIS-C being a new menace, there was not adequate literature available during the first wave. Being a tertiary institute, we may have missed many more cases during this period which were milder and were treated at regional centers.

Conclusions

MIS-C typically showed a spectrum of disease manifestations starting from a mild febrile inflammatory state to full-blown MODS. Early phenotypic differentiation and targeted immunomodulatory therapy depending on the phenotype had shown to be useful. Clinicians should be aware of these wide spectrums of clinical manifestations of MIS-C as even after the cessation of these pandemic sporadic cases of MIS-C may be seen in the future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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