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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 8  |  Issue : 6  |  Page : 270-277

A multicenter study of clinical and biochemical profiles, treatments, and short-term outcomes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection from Western India


1 Kokilaben Dhirubhai Ambani Hospital, Mumbai, Maharashtra, India
2 SRCC Children's Hospital, Mumbai, Maharashtra, India
3 Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, India
4 KEM Hospital, Pune, Maharashtra, India
5 Sai Child Care Hospital, Navi Mumbai, Maharashtra, India
6 Department of Pediatrics, Bharati Vidyapeeth Medical College and Hospital, Mumbai, Maharashtra, India
7 Jupitor Hospital, Mumbai, Maharashtra, India
8 Apollo Hospital, Navi Mumbai, Maharashtra, India
9 Fortis Hospital, Mumbai, Maharashtra, India
10 Jehangir Apollo Hospital, Pune, Maharashtra, India
11 Sahyadri Superspeciality Hospital, Pune, Maharashtra, India
12 Shaishav Children's Hospital and Research Center, Pune, Maharashtra, India

Date of Submission23-Jul-2021
Date of Decision11-Oct-2021
Date of Acceptance22-Oct-2021
Date of Web Publication19-Nov-2021

Correspondence Address:
Dr. Rachit Mehta
Department of Pediatric Intensive Care, Kokilaben Dhirubhai Ambani Hospital. Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpcc.jpcc_60_21

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  Abstract 


Background: Severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) infection can lead to multisystem inflammatory syndrome in children (MIS-C). This study was conducted to study epidemiology, clinical profile, treatment strategies associated in children MIS-C in two cities in Western India.
Subjects and Methods: This is a retrospective, observational study of children who fulfilled the criteria for MIS-C, admitted to eleven pediatric intensive care units (PICUs) in Western India during the first wave SARS-CoV-2 infection in India, between February 2020 and December 2020. Demographic and clinical data including laboratory parameters, treatment regimens, and outcomes were collected and analyzed.
Results: Of the 234 children presenting with MIS-C, they were categorized into 3 clinical phenotypes: fever and hyperinflammation, Kawasaki disease (KD)-like, and shock with multisystem organ dysfunction syndrome (MODS). C-reactive protein, procalcitonin (PCT), D-dimer, and pro-B-type natriuretic peptide levels were elevated in all patients. Intravenous immunoglobulin (IVIG) was used in 128 (54.7%), corticosteroids in 214 (91.45%), tocilizumab in 1 (0.4%), and remdesivir in 4 (1.7%). 95 (40.5%) children required vasopressors and invasive mechanical ventilation was necessary in 26 (11.1%). Two hundred and twenty-nine patients were discharged home with median duration of PICU stay of 4 days and hospital stay of 7 days, and 5 (2.1%) patients died during treatment. Significant reduction in the duration of hospital stay was observed in those who received both steroid and IVIG (P < 0.05) and also in the shock ± MODS group (P < 0.05).
Conclusions: Combination of steroid and IVIG for the treatment of MISC, especially with Shock and MODS reduce the duration of PICU stay than treated with steroid alone.

Keywords: Multisystem inflammatory syndrome in children, pediatrics, SARS-CoV-2


How to cite this article:
Mehta R, Joshi VH, Joshi P, Bhondve A, Otiv M, Udani S, Mohite M, Sarang BU, Andankar P, Bagade A, Sadawarte S, Lad SS, Suryawanshi P, Dhongade AR. A multicenter study of clinical and biochemical profiles, treatments, and short-term outcomes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection from Western India. J Pediatr Crit Care 2021;8:270-7

How to cite this URL:
Mehta R, Joshi VH, Joshi P, Bhondve A, Otiv M, Udani S, Mohite M, Sarang BU, Andankar P, Bagade A, Sadawarte S, Lad SS, Suryawanshi P, Dhongade AR. A multicenter study of clinical and biochemical profiles, treatments, and short-term outcomes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection from Western India. J Pediatr Crit Care [serial online] 2021 [cited 2021 Nov 27];8:270-7. Available from: http://www.jpcc.org.in/text.asp?2021/8/6/270/330727




  Introduction Top


In the midst of the global pandemic of COVID-19, with the origin of its first cases identified in December 2019 in Wuhan City in China, most children in the early days of the pandemic were either asymptomatic or mildly symptomatic with fever and cough.[1] Click or tap here to enter text. However, this changed rapidly with the emergence of multisystem inflammatory syndrome in children (MIS-C).[2],[3],[4] Click or tap here to enter text. Since late February 2020, children began presenting with a unique set of symptoms; fever, gastrointestinal symptoms, and features of myocarditis, including some with coronary artery aneurysms (CAAs), as clustered cases in the different parts of world.[5] Initially, there was uncertainty whether these children were manifesting with Kawasaki disease (KD) or toxic shock syndrome, or instead represented a new emerging phenomenon temporally related to the ongoing COVID-19 pandemic. Soon it was recognized that this was a new pediatric inflammatory syndrome caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Interestingly, cases of MIS-C were emerging around 4–5 weeks on average following the peak incidence of COVID-19 in each region.[6],[7],[8],[9],[10]

Furthermore, various studies suggested that most children tested negative for COVID-19 by nasopharyngeal reverse-transcriptase polymerase chain reaction (RT-PCR), but had positive serum levels of anti-SARS-CoV2 antibodies.[6],[7],[11] Collectively, these results suggested that MIS-C is a postviral inflammatory disease rather than an unremitting acute infection. The current definition of MIS-C as used in this study was established by the Centers for Disease Control and Prevention in May 2020 and involved the following: an individual <21 years presenting with a fever for >24 h, laboratory evidence of inflammation, and evidence of severe illness requiring hospitalization, with multisystem involvement of >2 organs (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological); and no alternative diagnoses; and positive recent SARS-CoV-2 infection or exposure to a suspected or confirmed COVID-19 case.[12]

The study of MIS-C in terms of its clinical spectrum, management modalities, and outcomes is the first step toward reducing the mortality and morbidity associated with it. There is a dearth of literature about MIS-C in developing countries. We planned a multicentric observational study to describe the clinical characteristics, management strategies, and resultant outcomes in our demographic profile.

Materials and Methods

The hospital ethical committee of all the participating hospitals had approved this study with data sharing and waiver of informed consent.

Inclusion criteria

  • Age (1 month–18 years) with positive SARS-CoV-2 RT PCR in the preceding months or COVID Antibody positive presently or both and follows the Centers for Disease Control and Prevention (CDC) criteria for MIS-C [Box no.1] admitted from February 2020 to December 2020 in 11 centers in two metropolitan cities in India, Mumbai, and Pune were included in the study.



Exclusion criteria

  • Age <1 month or >18 years
  • Not fulfilling the CDC criteria for MIS-C.


All children presenting with confirmed MIS-C in the study period were categorized into[13]

  • Fever and hyperinflammation
  • KD-like
  • Shock with multisystem organ dysfunction syndrome (MODS).


The outcome of the patients in term of mortality, duration of intensive care unit (ICU), and total hospital stay was studied. Elaborative relevant information was collected from medical records from all participant centers. All these parameters were included in an Excel sheet and the master chart was prepared.

Eleven tertiary care centers from 2 metropolitan cities (Mumbai and Pune) from Western India were selected for the study. The centers which were selected were having similar infrastructure and MIS-C patient care protocols to minimize bias.

Statistical analysis

We included all eligible subjects with MIS-C during the study period. Data analysis was done with the help of SPSS Software version 23. Quantitative data such as age, duration of ICU stay, duration of hospital stay and laboratory parameters such as D-dimers, interleukin-6 (IL-6), troponin, ejection fraction were presented with the help of mean, standard deviation, median, and interquartile range (IQR). Qualitative risk factors such as gender, age group, type and requirement of respiratory support, survival, treatment given, radiological findings, symptoms were presented with the help of frequency and percentage table. Association among two or more risk factors and survival or requirement of ventilation was assessed with the help of Chi-square or fishers exact test. The normality of the data was assessed by Shapiro–Wilk test. We adjusted confounders to calculate the duration of stay in the 4 groups of immunoglobulin, steroid alone, combination, and neither drug used. The comparison among duration of ICU stay, hospital stay, and treatment given was assessed by Kruskal–Wallis H test and Mann–Whitney U test. Linear regression was used to design the model to predict the duration of ICU stay and hospital stay. 95% confidence interval level was taken as statistically significant (P < 0.05).


  Results Top


Case definition, demographic and clinical characteristics

We included and analyzed 234 children with MIS-C who met the CDC case definition of SARS CoV-2 infection based on our inclusion criteria. Demographics and baseline clinical characteristics are presented in [Table 1]: median age was 6.8 years (IQR: 3.15–10.0) years, with male–female ratio of 1.4:1. Common presenting symptoms were fever (97.4%), rash (58.5%), conjunctivitis (51.3%), oliguria (18.8%), respiratory distress (27.8%), cough (17.1%), shock (36.8%), seizure (6%), and stroke (0.9%). Month-wise distribution of cases of MIS-C is presented in [Figure 1] which shows the similar temporal pattern of rise and fall as that of acute COVID infection in the community in the preceding month.
Figure 1: Month-wise distribution of cases with multisystem inflammatory syndrome in children

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Table 1: Demographic and clinical characteristics of patients (n=234) with multisystem inflammatory syndrome in children

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Laboratory findings

Laboratory test results on admission are presented in [Table 2]. In the majority of patients, 193 (82.5%) tested positive only for SARS-CoV-2 antibody; 5 (2.1%) tested positive on SARS-CoV-2 RT-PCR, and 5 (2.1%) patients tested positive for both RT-PCR and antibodies. In differential counts, neutrophilia (62.8%), lymphopenia (42.3%), monocytosis (4.7%) with median neutrophil-lymphocyte ratio of 3.4 were observed. Markers of inflammation were elevated with median C-reactive protein (CRP) 85 (IQR: 37.75–160.0) mg/L, erythrocyte sedimentation rate (ESR) 45 (IQR: 30.5–70) mm/h, procalcitonin (PCT) 7.96 (IQR: 1.07–30.0) ng/mL, IL-6 median of 56 (IQR: 21.0–258.7) pg/ml, and ferritin median of 350 (IQR: 164.0–780.0) ng/ml. 11 (4.7%) had hypoalbuminemia and median D-dimer was 1464.5 (IQR: 543.0–3446.75) μg/ml fibrinogen equivalent unit (FEU). Markers of abnormal cardiac status pro-B-type natriuretic peptide (Pro BNP) was showing median of 630 (IQR: 156.75–3873.0). Median lactate value at admission was 2 (1.4–3). Echocardiograms were performed in 191 patients of which 38 (16.2%) had depressed left ventricle ejection fraction, 59 (25.2%) had abnormal coronaries, and 24 (10.3%) had pericardial effusion.
Table 2: Hematological, biochemical, and echocardiographic parameters of patients (n=234) with multisystem inflammatory syndrome in children

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Treatment

Medical therapies used are presented in [Table 3]. One hundred (42.7%) patients presented in shock and received fluid resuscitation. Vasoactive medications were used in 95 (40.5%) patients of which 50 (21.4%) required single inotrope, 39 (16.7%) required 2-3 inotropes and 6 (2.6%) required ≥4 inotropes. 121 patients (51%) required respiratory support of which 95 (40.5%) received noninvasive ventilation: 55 (23.5%) requiring oxygen by nasal prongs, 28 (23.1%) requiring high flow humidified, heated oxygen by nasal cannula and 12 (5.1%) requiring noninvasive positive pressure ventilation and 26 (21.5%) required invasive mechanical ventilatory support. Both steroid and intravenous immunoglobulin (IVIG) were used in the majority of patients (122/234, 52.1%), only steroids 39.3% (92/234) patients and only IVIG in 2.5% (6/234) patients and 14 patients (6%) received neither IVIG or steroids. 128 (54.7%) patients received IVIG and 214 patients received corticosteroids of which 202 (94.4%) received methylprednisolone (MPS), 8 (3.4%) received methylprednisolone along with hydrocortisone, 3 (1.3%) received dexamethasone and 1 patient (0.4%) received hydrocortisone. One child received tocilizumab and 4 patients (1.7%) received remdesivir. Empiric antibiotic coverage was given in 197 (84.2%) patients. Aspirin was used in all patients and initial dose ranging from 25 to 75 mg/kg/day which was changed to 3–5 mg/kg/day after 48 h of afebrile period. Enoxaparin was also used in almost all patients since D-dimers were highly elevated in most of them. We have gathered information regarding aspirin and enoxaparin (low molecular weight heparin) based on scattered data given to us. Hence, statistical analysis could not be performed.
Table 3: Treatment received in patients with multisystem inflammatory syndrome in children (n=234)

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Outcome

Short-term outcomes of length of ICU and hospital stay according to the treatment modality are presented in [Table 4]. One hundred and fifty-two patients required pediatric ICU (PICU) admission and 82 patients were managed in the ward. Among PICU admission, 21 (9%) required stay for 1–2 days, 98 (41.9%) patients required 3–5 days of stay, 27 (11.5%) required stay for 5–10 days, and 6 (2.6%) required stay for >10 days. Two hundred twenty-nine were discharged home with a median duration of PICU stay of 4 days and hospital stay of 7 days, and 5 (2.1%) patients died during the treatment. When we analyzed the outcome of ICU stay against treatment received, 114 patients received steroids, 105 patients received IVIG, 102 patients received both steroid and IVIG and 14 patients received neither. On comparison between duration of ICU stay and the above-mentioned treatment groups, there was no statistically significant difference in the duration of ICU stay among all the groups (P > 0.05). However, they had median duration (3 and 4 days) of ICU stay with different IQR (3-5). When we compared the hospital stay among the treatment groups [Figure 2], significant reduction in the duration was observed in those who received both steroid and IVIG in the whole MIS-C group (P < 0.05). Comparison between treatments given with median PICU and hospital stay for all the patients with MIS-C is presented in [Table 5]. Among all the MIS-C patients who received steroid and IVIG had shorter duration of PICU and hospital stay as compared to steroid group. Among various phenotypes, shock with MODS group who received steroid with IVIG had shorter hospital and PICU stay compared to steroid group. However, no such difference was observed between the two treatment groups in the “fever with hyper inflammation” phenotype.
Figure 2: Comparison of median intensive care unit stay and hospital stay in different treatment groups

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Table 4: Comparison between treatment given and median intensive care units stay for MIC-C patients

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Table 5: Comparison between treatments given with median paediatric intensive care units and hospital stay for all the patients with multisystem inflammatory syndrome in children

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Interquartile range

Clinical parameters (age, sex, shock, number of inotropes used, cardiac involvement, need for ventilation) and laboratory parameters (pH, pO2, pCO2, lactate, S. creatinine, Serum glutamic oxaloacetic transaminase (SGOT), Serum glutamic pyruvic transaminase (SGPT), ESR, PCT and D Dimer) were analyzed to predict the duration of ICU [Table 6] and hospital stay. Duration of ICU stay was 1.7 days (P = 0.037) and 2.08 days (P = 0.017) higher among patients with shock and need for ventilation, respectively. There was a weak yet significant correlation between duration of hospital stay and no of inotropes used and CRP, respectively (no of inotropes rho = 0.350, P < 0.001, CRP rho = 0.036, P = 0.136). There was no significant correlation between any other clinical and laboratory parameters.
Table 6: Linear regression to predict the factors predicting the intensive care units stay among all the patients

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  Discussion Top


This is a multicenter cohort of patients with MIS-C in two cities in India. In this study, incidence of MIS-C was higher in males than females (58.3% vs 41.2%), and this predominance was even higher in the Kawasaki-like phenotype. This is similar to that observed in other multicenter studies of MIS-C in the United Kingdom and the United States [5],[6] and in critically ill children with COVID-19 alone.[18],[19] Biological differences (genetic and epigenetic) between males and females may affect the immune response to SARS-CoV-2 infection, as has already been described in KD.[20],[21] In our study population, most of the patients were positive for COVID antibody (82.5%) and 2.1% were positive for both COVID RT PCR as well COVID antibody. Five patients tested positive for SARS-CoV-2 by RT-PCR, which generally reflects an acute phase of the infection, although the virus or its fragments may be detected for longer periods in some patients and could be responsible for these results, outside the classical period of positivity of the acute phase of COVID-19. The high frequency of gastrointestinal symptoms, the low prevalence of severe respiratory failure, and the lower degree of mucosal involvement seen in this study have already been described, which characterizes MIS-C as a distinct entity, unrelated to classic KD.[22],[23] Consistent with the diagnosis of MIS-C, multiple inflammatory markers were elevated. Examining the trends of some of these values may provide biological insight into the disease or may serve as potential predictors of MIS-C outcomes. In particular, the following analytes were elevated- PCT (Median 7.96, IQR 1.07–30.0), interleukin-6 (median 56, IQR 21–258.7), and troponin (median 0.8, IQR 0.0–32.2). Our children showed a significant elevation in all the inflammatory markers (CRP, PCT, D-dimer, and ferritin), all of which, showed a gradual reduction concurrent with clinical response. The elevation in these markers has been routinely reported in MIS-C cases across the globe.[24]

In our study, a weak yet significant correlation between duration of hospital stay and number of inotropes used and CRP. Lymphopenia, which has been described as distinct hematological feature of MIS-C and is not present in classic KD, was observed in 42.3% of patients in the present cohort. Anemia and hypoalbuminemia were also common in our patients, however, these findings overlap with KD.[25] Markers of cardiac dysfunction were altered in most of our patients. In the present cohort, troponin (median 0.8), and Pro BNP levels (Mean 4242.1, Median 630) were extremely high in patients with shock who were tested. Echocardiographic findings similar to those of KD were also common in this cohort. These findings are compatible with myocardial dysfunction and inflammation consistently described in MIS-C reports.[22],[23],[26],[27] Its mechanism is not fully understood, but it may be related to microvascular damage, stress cardiomyopathy (Takotsubo syndrome) and systemic inflammatory response syndrome.[28] Aspirin was used in all patients and initial dose ranging from 25 to 75 mg/kg/day which was changed to 3-5 mg/kg/day after 48 h of afebrile period. The role of Aspirin in the treatment of KD is well established and has been used in all patients with a phenotype similar to complete KD. Enoxaparin was also used in almost all patients since D-dimers were highly elevated in most of them. Children with MIS-C are at risk for thrombotic complications of multiple causes, due to a hypercoagulable state, possible endothelial injury, immobilization stasis, ventricular dysfunction, and CAA. For these reasons, antiplatelet and/or anticoagulation treatment is recommended, based on coagulation tests and clinical presentation.[28],[29]

Although there is no current evidence for the best management of MIS-C, guidelines from different organizations recommend treatment based on the clinical phenotype.[23],[28] Combination therapy of steroid and IVIG was used in the majority of patients; steroids 48.7% (114/234) patients, IVIG in 44.8% (105/234) patients, and both in 102 patients (43.5%). On comparison between duration of ICU stay and above-mentioned treatment groups, there was no statistically significant difference in the duration of ICU stay among all the groups (P > 0.05). Similar observation was made by McArdle et al.[30] Click or tap here to enter text. and Feldstein et al.[22]

Although children diagnosed with MIS-C often require intensive care treatment, studies have shown good outcomes and a low mortality rate.[13],[22] Our study found similar outcomes, with only 5 deaths (2.1%), but with a similar length of PICU stay (median: 3.2 days) that had been reported in other cohorts.[13],[26],[31],[32],[33] The comparison of demographic and clinical features among the different phenotypes showed that they were relatively equivalent. Median PICU stay of 3.2 days points toward improvement in the majority of patients by day 3–5 and discharge from hospital by day 7.

Limitation

The study is an observational study, therefore, caution is warranted in interpreting our case series data to infer risk factors for MIS-C, particularly with respect to factors such as age, sex, and race or ethnic group.

Although this is a multicenter study, the cohort is small, which makes the comparison among the phenotypes difficult.

Although we used a standardized case report form, clinical management differs among centers, we may not have captured certain variables completely, including detailed echocardiographic data on coronary-artery outcomes and quality of imaging.

It is important to reinforce the need for long-term multidisciplinary follow-up since it is still not known whether these patients will have chronic cardiac impairment or other sequelae. We intend to maintain a follow-up of these kids over 6 months to 1-year postdischarge.


  Conclusions Top


Critically ill children with MIS-C have a wide spectrum of severity and require careful supportive intensive care management. Combination of steroid and IVIG for the treatment of MISC especially with shock and MODS reduces the duration of PICU stay than treated with steroid alone.

Acknowledgments

Authors would like to thank Dr. Tanu Singhal, Dr. Tanuja Karande, Dr. Dhaval Darji, Dr. Satyajeet Gil, Dr. Shilpa Edathara, Dr. Ram Dhongade, Dr. Ayon Sen Gupta, Dr. Behzad, Dr. Kaustubh Sahastrabuddhe, Dr. Jesal Sheth, Dr. Rahul Verma, Dr. Narjohan Meshram, Dr. Vijay Yewale, Dr. Jitendra Oswal, Dr. Guruprasad Hasan Shankar, Dr. Ajay Walimbe, the Cardiologists, resident doctors, fellows and nursing teams who contributed in managing these patients and collecting the data.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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