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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 9  |  Issue : 4  |  Page : 116-123

Clinical profile and immediate outcome of the multisystem inflammatory syndrome in children: Retrospective observational single center study from the United Arab Emirates


Department of Pediatric Intensive Care, Al Qassimi Women's and Children's Hospital, Sharjah, United Arab Emirates

Date of Submission12-Mar-2022
Date of Decision11-Jun-2022
Date of Acceptance16-Jun-2022
Date of Web Publication20-Jul-2022

Correspondence Address:
Dr. Prashant Prakash Rajebhosale
Flat No 2044, Damas Building, Near Central Post Office, Al Zahra St, Al Gharb, Al Ghuwair P O Box 123, Sharjah
United Arab Emirates
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpcc.jpcc_22_22

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  Abstract 


Background: Multisystem inflammatory syndrome in children (MIS-C) is a post-viral complication that has been described among children after 2–6 weeks of exposure to the COVID-19 virus from various parts of the world. However, published literature regarding MIS-C from the United Arab Emirates (UAE) is limited. The aim of this study was to investigate the demographic details, clinical, radiological and laboratory findings, disease management, and clinical outcomes of a larger group of patients from UAE presenting with features of MIS-C.
Subjects and Methods: This hospital-based retrospective observational study was conducted among children between the age of 1 month and 12 years, hospitalized in the pediatric intensive care unit of a tertiary care hospital in Sharjah, from September 2020 to October 2021.
Results: Our study population belonged to various nationalities from the Middle East, South Asia, and Africa. The median interquartile range age of our patient population was 7.5 (4–10) years. All the study participants presented with fever lasting for a mean duration of 5.17 days. About 93.33% and 83.33% of the patients presented with gastrointestinal and cardiovascular symptoms, respectively. MIS-C overlapping with Kawasaki disease was the most common phenotype. All the patients received intravenous immunoglobulin and steroids. There was only one death in our study cohort.
Conclusions: Although our patient population belonged to mixed ethnicity most characteristics of our MIS-C patients were very similar to that of other cohorts in terms of clinical, laboratory features, and response to treatment.

Keywords: COVID-19, intravenous immunoglobulin, multisystem inflammatory syndrome in children


How to cite this article:
Rajebhosale PP, Mohamed MY, Swilem M, Abdelmogheth A, Nabawi MI, Farahat AS, Alsabbagh WM, Lanqawi NJ, Addas H. Clinical profile and immediate outcome of the multisystem inflammatory syndrome in children: Retrospective observational single center study from the United Arab Emirates. J Pediatr Crit Care 2022;9:116-23

How to cite this URL:
Rajebhosale PP, Mohamed MY, Swilem M, Abdelmogheth A, Nabawi MI, Farahat AS, Alsabbagh WM, Lanqawi NJ, Addas H. Clinical profile and immediate outcome of the multisystem inflammatory syndrome in children: Retrospective observational single center study from the United Arab Emirates. J Pediatr Crit Care [serial online] 2022 [cited 2022 Oct 2];9:116-23. Available from: http://www.jpcc.org.in/text.asp?2022/9/4/116/351513




  Introduction Top


As of March 12, 2022, more than 455 million confirmed cases of coronavirus disease (COVID-19) including more than 6.03 million deaths have been reported worldwide.[1]

While COVID-19 presented with severe interstitial pneumonia and hyperactivation of the inflammatory cascade among adult patients, it followed a benign course of respiratory involvement in children.[2] Nevertheless, several studies have demonstrated a host innate immunity-mediated tissue damage characterized by a cytokine storm among children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).[3],[4] Multisystem inflammatory syndrome in children (MIS-C) is an inflammatory postviral complication that has been described among children after 2–6 weeks of exposure to the COVID-19 virus.[5] This syndrome has been labeled by different terminologies such as MIS-C associated with SARS-CoV-2,[6] pediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIM-TS),[7] and hyperinflammatory shock during COVID-19 pandemic.[8]

The first case series of MIS-C patients was evidenced among eight children from the South Thames Retrieval Service in London, UK[8] who presented with features similar to Kawasaki disease (KD) and toxic shock syndrome.[9] Thereafter, similar cases were reported from various parts of the world such as Latin America, Israel, Italy, France, and the United States.[2],[10],[11],[12] The case definition for MIS-C, developed by the Center for Disease Control and Prevention (CDC) and the World Health Organization (WHO) encompassed “development of fever, elevated inflammatory markers, and involvement of at least two systems, with evidence of prior SARS-CoV-2 infection or exposure, as well as the exclusion of other potential etiologies.”[13] MIS-C shares overlapping clinical features with KD such as conjunctival injection, oropharyngeal findings (red and/or cracked lips and strawberry tongue), rash, swollen and/or erythematous hands and feet, and cervical lymphadenopathy. Unlike KD, the MIS-C patients were more likely to exhibit signs of shock, echocardiographic findings of cardiac dysfunction and coronary artery aneurysms,[14] and prominent gastrointestinal and neurological symptoms.[15]

Apart from the clinical and laboratory manifestations of MIS-C, the existing literature has highlighted the benefit of corticosteroids as a first-line therapeutic drug for the treatment of MIS-C.[13] Son et al. reported 44 times lower risk of cardiovascular dysfunction among MIS-C patients treated with a combination of intravenous immune globulin (IVIG) and glucocorticoids as compared to those treated with IVIG alone.[14]

However, the published literature and data regarding MIS-C from the United Arab Emirates (UAE) and the Middle East are limited. The cardiac, neurological, and other rare presentations of the disease along with the clinical outcomes of the treatment modalities needs to be explored for acquiring an insight into the disease process and the effectiveness of management strategies. In this context, our study aims to investigate the demographic details, clinical history, diagnostic data, clinical features, radiological and laboratory findings, disease management, and clinical outcomes of a larger group of patients from UAE presenting with features of MIS-C.


  Materials and Methods Top


Study design and settings

This hospital-based retrospective observational study was conducted among children between the age of 1 month and 12 years, hospitalized in the pediatric intensive care unit (PICU) of a tertiary care hospital in Sharjah, United Arab Emirates (UAE) from September 1, 2020 to October 31, 2021. Approval from the institutional ethical committee was obtained (MOHAP/DXB-REC/A. M. M/No. 48/2022).

Sample size and sampling technique

During the study period, 42 patients required hospitalization due to MIS-C, of which 30 patients meeting the inclusion criteria were admitted to PICU (71.4%). Admission to PICU was considered appropriate for children with hemodynamic instability (shock, arrhythmia), significant respiratory compromise, or other potentially life-threatening complications.

All the patients were included in the study using consecutive sampling techniques. The inclusion and exclusion criteria for the study participants were as follows:

Inclusion criteria:

  1. All patients admitted to the PICU, between 1 month and 12 years of age, satisfying the WHO definition of MIS-C [Figure 1].[16]
Figure 1: WHO definition of MIS-C. MIS-C: Multisystem inflammatory syndrome in children

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Exclusion criteria:

  1. All patients admitted with the diagnosis of MIS-C in pediatric wards and never required PICU stay during the same hospital admission
  2. Neonates
  3. Any patient whose parents took leave against medical advice and transfer the child to another institute and whose treatment details, clinical course, and final outcome cannot be known.


Study procedure

Data were collected retrospectively using standardized case report forms from all eligible patients admitted with the diagnosis of MIS-C. The demographic data, findings from clinical examination, and medical history of the patient were noted at the time of admission for all patients. The radiological and laboratory investigations, treatment received, and clinical outcome of the patient were also noted subsequently. We classified the enrolled participants into mild, moderate, and severe categories based on the classification suggested by Jonat et al.[17] Mild cases had no vasoactive requirement, minimal respiratory support, and/or minimal signs of organ injury. Moderate cases had a vasoactive inotropic score (VIS) less than or equal to 10, significant supplemental oxygen requirement, and/or mild or isolated organ injury. Severe cases had a VIS>10, noninvasive or invasive ventilatory support, and/or moderate or severe organ injury including moderate-to-severe ventricular dysfunction.[17]

We also classified our children into also four phenotypes: Phenotype A (MIS-C without overlap with acute COVID-19 or KD), Phenotype B (MIS-C overlapping with acute COVID-19), Phenotype C (MIS-C overlapping with typical KD), Phenotype D (MIS-C overlapping with atypical KD).[9]

All children underwent evaluation of hemogram, acute-phase reactants, cardiac enzyme markers, coagulation profile, and liver and renal function tests. Blood, urine, and relevant cultures from other body sites were sent as per the clinical condition. Immunoglobulin profile was obtained before commencing IVIG. Children were also tested for Influenza, Mycoplasma, and other respiratory viruses. Reverse transcription-polymerase chain reaction (RT-PCR) (RT-PCR; SARS-CoV-2 R-GENE, Argene; bioMerieux, Marcy l'Étoile, France) to detect SARS-CoV-2 was done on all patient using oro/nasopharyngeal swabs or tracheal aspirates, whereas serological test to detect COVID antibody (Architect SARS-CoV-2 chemiluminescent microparticle immunoassay-CMIA; Abbott Core Laboratory, IL) was done whenever feasible. Tests to rule out other mimicking conditions were carried out simultaneously. Two-dimensional ECHO was done on all patients by a pediatric cardiologist.

Operational definitions

VIS = Dopamine dose (mcg/kg/min) + Dobutamine dose (mcg/kg/min) + 100 × Epinephrine dose (mcg/kg/min) + 100 × Norepinephrine dose (mcg/kg/min) + 10 × Milrinone dose (mcg/kg/min) + 10,000 × Vasopressin dose (U/kg/min).[17]

Resistance to IVIG was defined as persistent or recrudescent fever at least 36 h and >7 days after completion of the first immunoglobulin infusion. We defined a coronary artery dilation to be present if the coronary artery diameter Z score was between 2.0 and <2.5 and an aneurysm to be present if the Z score was 2.5 or greater.

Statistical analysis

Data analysis was performed using STATA version 14 (Statacorp. Texas, USA). The continuous variables following a parametric distribution were expressed as mean standard deviation (SD) while those following a nonparametric distribution were expressed as the median interquartile range (IQR). The categorical variables were expressed as proportion.


  Results Top


Demographic, clinical history, and diagnostic data

Out of the 30 patients who were found to be eligible for study, 16.6% (n = 5) patients had positive PCR for COVID 19 and 83.33% (n = 25) patients had negative PCR.

Among these positive PCR patients (n = 5), two patients each had positive and negative serology and in one case, serology was unknown. Of the negative PCR patients (n = 25), 14 had positive serology for COVID 19 and 11 patients' serology status was unknown but had a definite history of exposure to COVID-19.

Thirty patients with median (IQR) age of 7.5 (4–10) years were included during the study period. The highest proportion of our study participants hailed from India (n = 7, 23.33%), followed by United Arab Emirate (n = 5, 16.67%), Egypt (n = 4), Syria (n = 4), Comoros (n = 2), Pakistan (n = 2), Jordan (n = 1), Yemen (n = 1), Morocco (n = 1), Libya (n = 1), Iraq (n = 1), and Russia (n = 1) were among the other nationalities included in the study. The other demographic data are depicted in [Figure 2] and [Figure 3].
Figure 2: Age distribution of cohorts (n = 30)

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Figure 3: BMI of patients (n = 30). BMI: Body mass index

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Clinical features and radiological findings

All the study participants presented with fever lasting for a mean duration of 5.17 days. About 93.33% (n = 28) and 83.33% (n = 25) of the patients presented with gastrointestinal and cardiovascular symptoms, respectively. Around 90% (n = 27), 60% (n = 18), 53.33% (n = 16), and 13.33% (n = 4) of the patients presented with any mucocutaneous, respiratory, neurological and musculoskeletal symptoms, respectively. None of the patients presented with chest tightness, stroke, mononeuropathy, and arthralgia as respiratory, cardiovascular, neurological, and musculoskeletal symptoms, respectively. A total of 20% (n = 6) patients had clinical features suggestive of meningoencephalitis; however, further investigations ruled it out. Nearly one-third (n = 9) of our patients had exposure to COVID cases within the past 4 weeks, whereas about 26% (n = 8) of our patients had exposure between 4 and 6 weeks. Three patients had a history of prior COVID-19 infection. All the clinical features, distribution of different phenotypes, and the severity of illness along with diagnostic data are enumerated in [Table 1] and [Table 2].
Table 1: Clinical features of the patients with multisystem inflammatory syndrome in children (n=30)

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Table 2: Phenotypes and severity data

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Laboratory findings

All (100%) of the study participants displayed elevated D-Dimer levels (>0.5 mg/L) in hematological findings. About 96.43% of the study participants had elevated fibrinogen levels. None of the patients presented with severe anemia. Other laboratories and radiological findings of the study participants are described in [Table 3] and [Table 4], respectively.
Table 3: Laboratory findings of patients with multisystem inflammatory syndrome in children (n=30)

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Table 4: Radiological finding of patients with multisystem inflammatory syndrome in children (n=30)

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Disease management and clinical outcomes

All of our patients (n = 30) received IVIG. Almost 16.6% (n = 5) of patients received the 2nd dose of IVIG based on clinical judgment. Methylprednisolone was a preferred steroid and was used in 93.3% (n = 28) patients and only two patients (6.6%) received Dexamethasone.

Dexamethasone was a preferred steroid in patients who had simultaneous COVID-19 pneumonia. Tocilizumab and Anakinra were administered in two patients (6.6%) each, based on the clinical judgment after consultation with Infectious disease and Rheumatology.

All our patients were commenced on broad-spectrum antibiotics which were later stopped once cultures were available. None of our patients had secondary bacterial infections. Among our patient cohorts, all recovered well except one patient who succumbed to myocarditis and multiorgan dysfunction. The mean duration of PICU and hospital stay was 5.5 (mean SD 2–9) and 9.5 days (mean SD 8–11), respectively. [Table 5] describes the other details pertaining to disease management and clinical outcomes.
Table 5: Disease management and clinical outcomes of patients with multisystem inflammatory syndrome in children (n=30)

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  Discussion Top


This study investigated the demographic details, clinical history, diagnostic data, clinical features, radiological and laboratory findings, disease management, and clinical outcomes of patients from presenting with features of MIS-C. The current study is one of the initial single-center studies from the UAE in this domain.

Presentation of multisystem inflammatory syndrome in children

The clinical findings and demographic details like the median age of our study population were found to be very similar to those previously described in the existing literature.[2],[6],[18] Characteristically, age distribution varied as per the clinical phenotype of MIS-C and patients presenting with MIS-C with overlapping KD features were younger compared to those of other phenotype – a finding very similar to Godfred-Cato et al.[9] In our study, males and females were equally represented in contrast to other studies where males were predominantly affected.[6],[19] Small size of our study group and the mixed ethnicity of our cohorts might be responsible for this difference. Obesity and overweight as a risk factor for MIS-C have been well documented and our study further supports this finding.[20] Although underweight has not been a very prominent finding among MIS-C patients across the majority of the pediatric studies, our cohort had a fraction of patients who had this feature. In one of the retrospective studies done among adults at a tertiary care center in the USA, underweight individuals had borderline significant association with increased risk of death or intubation.[21]

Although, we could not find literature on incidence rates of various severity groups based on the classification as suggested by Jonat et al.; probably, multiple factors including admission criteria, ethnicity, and time of presentation must be deciding factors for severe MIS-C. In one of the studies, intensive care unit (ICU) admissions were more likely for patients with shortness of breath, abdominal pain, increased inflammatory markers (C-reactive protein [CRP], Ferritin, D-Dimer, and IL-6), or increased cardiac enzymes (Brain natriuretic peptide, N terminal Pro B-type BNP, troponin) or reduced platelet count or lymphocyte counts.[22] Although more than one-third of our patients had Acute Kidney Injury, it was transient and resolved spontaneously a finding very similar to study described by Lipton et al.[23]

History of COVID contact beyond 4 weeks and before 6 weeks contributed to a significant number of patients in our cohort, a finding which favors the WHO MIS-C definition over the CDC definition[20] as it is more precise, while encompassing most cases. Similar finding was noted in a French study where the median (IQR) interval between reported contact and KD was 36 (18–45) days. Disproportionate immune response to SARS-CoV-2, leading to uncontrolled systemic inflammatory response has also been well described in the literature.[24]

Current reports of an MIS-C may partially or completely fulfill classic diagnostic criteria of KD. However, frequent gastrointestinal symptoms, presence of myocardial dysfunction and shock, lower absolute lymphocyte count, and platelet count has been described among patients with MIS-C as compared to KD which makes MIS-C as a distinct entity.[6],[15] Lymphopenia has also been described as an independent predictor of MIS-C and our study supports this finding. Along with lymphopenia, the presence of thrombocytopenia has been described as a feature which helps to differentiate between MIS-C and KD.[13] An association between KD and viral respiratory infections has also been suspected, especially Rhinovirus and Enterovirus, and various viral agents, including Coronavirus.[25],[26]

Treatment and outcomes

We followed the treatment protocol suggested by Jonat et al. in our study.[17] Two recently published trials have given disparate results for treatment for MIS-C. Best available treatment study consortium did not find any statistically significant difference in odds ratios for endpoints of ventilation, inotropic support, or death or for improvement on an ordinal clinical-severity scale for any of three treatments: IVIG alone, a combination of IVIG and glucocorticoids, or glucocorticoids alone.[27] The risk of escalation of immunomodulatory treatment in patients who received IVIG plus glucocorticoids was significantly lower than the risk in patients who received IVIG alone, a finding that was in line with the results of the U. S.[14],[27] In one of the retrospective studies of 72 patients with MIS-C, patients who were treated with IVIG with infliximab had less ICU length of stay, decreased incidence of left ventricular dysfunction, more rapid decline in CRP and less need of additional therapy.[28] In another study where IVIG use was compared with the use of IVIG with steroids, the latter was associated with a lower risk of treatment failure, use of second-line therapy, hemodynamic support, acute left ventricular dysfunction occurring after initial therapy, and duration of stay in the PICU.[29] Often children with MIS-C require ICU care, studies uniformly have shown overall good outcomes in terms of associated low mortality rates. Our study also demonstrated only one death. The role of aspirin and low–molecular-weight heparin (LMWH) in the treatment of MIS-C is yet not evident and this practice is not based on high-quality evidence. We used aspirin and LMWH only in patients without deranged coagulation or thrombocytopenia. In one of the surveys of protocols conducted across major hospitals across the USA, aspirin was commonly included in protocols, even for mild cases, whereas heparin or LMWH were used primarily in severe cases.[30]

Our study has several strengths. First, we were able to extensively study the clinical, laboratory features, severity, and phenotypes of MIS-C. Second, our study provides information about clinical manifestations and outcomes of patients from the UAE which in itself represents a mixed population from the Middle East, South Asia, and Africa. Third, we included only the PICU population which, although reduced our number of cohorts but gave better insight into the severity and its impact on the outcome. In future, similar studies limited to PICU, in a large patient population may help to develop uniform guidelines for the management of acutely sick cases. Fourth, the data collected during the study were strictly monitored and statistical packages like SPSS were used to minimize methodological errors.

Nonetheless, our study was not without limitations. This was a single-centered study with a comparatively smaller sample size which restricted the comparison between different phenotypes and also among patients with varying severity of illness. Further, we excluded children above 12 years of age as per institutional protocol and therefore could not describe their clinical and laboratory features.

Nevertheless, our study provides relevant information on the clinical, laboratory features, and outcomes of the children and adolescents admitted with MIS-C from the UAE which we believe is important in understanding SARS-CoV-2 infection in children and its short-term outcomes. Similar studies with a larger sample size and reinforcing long-term multidisciplinary follow-up are warranted to explore the cardiac complications and other sequelae associated with this illness.


  Conclusions Top


Although our patient population belonged to mixed ethnicity most characteristics of our MIS-C patients were very similar to that of other cohorts in terms of clinical, laboratory features, and response to treatment. Studies with a larger sample size and exploring other aspects of MIS-C such as severity, phenotype, and response to different treatment regimens are needed.

Acknowledgment

We are thankful to Emirates Health services and Dr. Amal Mohamed Sherif (Head of the department of pediatrics) for providing constant support and guidance.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Lima-Setta F, Magalhães-Barbosa MC, Rodrigues-Santos G, Figueiredo EA, Jacques ML, Zeitel RS, et al. Multisystem inflammatory syndrome in children (MIS-C) during SARS-CoV-2 pandemic in Brazil: A multicenter, prospective cohort study. J Pediatr (Rio J) 2021;97:354-61.  Back to cited text no. 12
    
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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