Comparative Analysis of Clinical and Laboratory Data in Children with Multisystem Inflammatory Syndrome Associated with SARS-CoV-2 in the Republic of Kazakhstan

Indira Jaxybayeva1,3, Riza Boranbayeva1,3, Sagira Abdrakhmanova2, Raikhan Maitbassova1, Pakhitkanym Ishuova1, Dinagul Bayesheva2, Nurila Maltabarova2, Adyl Katarbayev3, Ainagul Kuatbayeva4, Kumisgul Umesheva3, Tatyana Marshalkina1, Lyazat Manzhuova1, Gulnara Abdilova1, Gulshat Alimkhanova1, Gulmira Yerzhanova1, Gulnara Bulabaeva1, Nazgul Zhanuzakova1, Svetlana Anokhina1, Gulnara Tashenova3, Aizhan Yesmagembetova4, Elimira Utegenova4 and Gaukhar Nusupbayeva4.

1 Scientific Center of Pediatrics and Pediatric Surgery, Almaty, Kazakhstan, 50044.
2 Astana Medical University, Nur-Sultan, Kazakhstan, 10000.
3 Asfendiyarov Kazakh National Medical University, Almaty, Kazakhstan, 050040.
4 «Scientific and Practical Center for Sanitary and Epidemiological Expertise and Monitoring» branch of the Republican State enterprise on the right of economic use «National Center of Public Health care of the Ministry of Health of the Republic of Kazakhstan», Nur-Sultan, Kazakhstan, 010000.

Correspondence to: Indira Jaxybayeva, Scientific Center for Pediatric and Child Surgery, Almaty, Kazakhstan, Al-Farabi Avenue 146, E-mail: ind.88@mail.ru

Published: September 1, 2022
Received: April 27, 2022
Accepted: August 10, 2022
Mediterr J Hematol Infect Dis 2022, 14(1): e2022064 DOI 10.4084/MJHID.2022.064

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background and Objectives: Data with more severe mutations of the SARS-CoV-2 virus, compared with the original wild-type strain of COVID-19 disease, were reported worldwide. The study aims to describe the clinical and laboratory manifestations of a multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2 in the Republic of Kazakhstan and to compare the severity of the disease depending on the time of the circulating variant of SARS-CoV-2 virus.
Material and Methods: A retrospective, multicentre, nationwide study of 89 children with MIS-C who received inpatient treatment from August 1, 2020, to December 1, 2021. The patients were allocated into two groups: 1(2020) - 45 children and 2 (2021) - 44 children. Study periods were characterized by the circulation of different strains of the SARS-CoV-2 virus.
Results: In children with MIS-C in 2021, acute renal failure, disseminated intravascular coagulation syndrome, and shock were statistically more frequently found, which led to fairly common admittance to the intensive care unit. When comparing laboratory data, the children with MIS-C in 2021 had higher values of inflammation markers: ferritin, procalcitonin, erythrocyte sedimentation rate, leukocytes, and neutrophils. Furthermore, these children had a lower level of lymphocytes than children with MIS-C in 2020.
Conclusions: MIS-C is a severe, life-threatening systemic disease characterized by multiple organ damage and important inflammatory changes in laboratory parameters. A more aggressive clinical course of MIS-C in 2021 may be associated with the emergence of new SARS-CoV-2 strains.

Introduction

Acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which elicits COVID-19, is mild or asymptomatic in children, with a few reported deaths.[1] However, all viruses, including SARS-CoV-2, accumulate mutations over time, affecting their properties, such as the rate of spread and severity of associated symptoms and the effectiveness of vaccines and treatment medication.[2] In late 2020, a new Delta variant of SARS-CoV-2 B.1.617.2 virus emerged, posing an increased risk to public health and rapidly spreading worldwide.[3] In Scotland, a study was conducted on patients with the Delta variant of SARS-CoV-2, showing that patients were younger and had twice the risk of hospitalization than the Alpha variant.[4] The same excessive causality between B.1.617.2 and severe COVID-19 has been found in England[5] and Canadian[6] studies, but the above studies did not analyze data separately among children. According to the latest report from the US Centers for Disease Control and Prevention, the differences in severity and duration of illness between Delta and previous variants in children are unclear; since the number of cases of children in the U.S. has recently increased, the proportion of hospitalized children requiring intensive care has not changed.[7] A study in England examining children infected with the Delta variant of SARS-CoV-2 showed that these children had more clinical symptoms than children infected with the Alpha variant. However, the duration and severity of the disease did not differ when compared.[8]
In the United States, the Centers for Disease Control and Prevention (CDC)[9] and the World Health Organization (WHO)[10] published MIS-C case definition criteria that included childhood age, fever, multiple organ involvement requiring hospitalization, increased inflammatory biomarkers, absence of alternative diagnosis and positive for SARS-CoV-2 infection by PCR and/or serology. However, in the latest and largest U.S. study from the CDC, researchers say there are some shortcomings in diagnosing children with MIS-C. One of which is that the MIS-C case definition is broad, which may lead to the accidental inclusion of patients with a history of COVID-19 suffering from other acute inflammatory diseases such as severe acute COVID-19, Kawasaki disease, toxic shock syndrome, and other serious illnesses.[11] Given the more severe course of COVID-19 in children during the circulation of the Delta variant in 2021, the objective of our study was to compare the clinical and laboratory features of MIS-C in children depending on the circulation of the SARS-CoV-2 strain in the Republic of Kazakhstan.

Materials and Methods

Taking into account the MIS-C case definition criteria published by the CDC and WHO, a clinical protocol was developed for the diagnosis and treatment of COVID-19 and MIS-C in children in Kazakhstan.[12] Using the resources of the Scientific Center of Pediatrics and Pediatric Surgery, a multidisciplinary working group was formed that included experts in various pediatric specialties. In addition, each MIS-C case was entered into a national registry and discussed by an expert group. As a result, each patient in our study met the diagnostic criteria defined by the WHO and CDC for MIS-C.
A retrospective multicentre study was conducted in children with MIS-C associated with SARS-CoV-2 who received inpatient treatment in multidisciplinary children's medical organizations in 17 regions of Kazakhstan. The study enrolled 89 patients (N=89) diagnosed with MIS-C from August 1, 2020, to December 1, 2021. To compare changes in clinical and laboratory data of the children with MIS-C, they were allocated into two groups: Group 1 included the patients who fell ill and received treatment in 2020 (N=45), and Group 2 consisted of patients who fell ill and received treatment in 2021 (N=44). Among the criteria for diagnosing MIS-C, it was considered the epidemiological data (family history, contact with a patient with COVID-19, a history of COVID-19, etc.), test results for SARS-CoV-2 (PCR swab from the throat or nose, the presence of IgM, IgG antibodies for SARS-CoV-2), general clinical laboratory tests (complete blood count, biochemical studies - alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein, albumin, creatinine, urea), inflammation markers (ferritin, procalcitonin, C-reactive protein (CRP), fibrinogen, D-dimer). Peak values (maximum and minimum) of laboratory test parameters from medical records were entered into the database for statistical processing. In all patients was assessed the frequency of severity of MIS-C clinical manifestations (fever and its duration, changes in the skin and mucous membranes of the oral cavity, lesions of the central nervous system and gastrointestinal tract, respiratory and cardiovascular systems, the acute renal failure, localization of edema and pain syndrome, conjunctivitis, lymphadenitis, shock and disseminated intravascular coagulation syndrome (DIC).
Ethical Statement. This study was approved locally by the ethics committee of Asfendiyarov Kazakh National Medical University (No. 1147).
Statistical analysis. Statistical analysis was performed via the programme StatTech v. 2.4.5.
Quantitative indicators were assessed for compliance with the normal distribution using the Shapiro-Wilk test (with the number of subjects less than 50) or the Kolmogorov-Smirnov test (with the number of subjects more than 50). Quantitative indicators with a normal distribution were described using arithmetic means (M) and standard deviations (S.D.), 95% confidence interval limits (95% CI).
If a normal distribution is absent, the quantitative data were described using the median (Me) and the lower and upper quartiles (Q1 – Q3).
Categorical data were described with absolute values and percentages.
Two groups in terms of a quantitative indicator with a normal distribution, provided that the variances were equal, were compared using Student's t-test.
Two groups in terms of a quantitative indicator, the distribution of which differed from the normal one, were compared using the Mann-Whitney U-test.
The percentages in the analysis of four-field contingency tables were compared using Pearson's chi-square test (for expected phenomena values greater than 10) and Fisher's exact test (for values less than 10).

Results

In the Republic of Kazakhstan (R.K.), from the beginning of the pandemic until December 1, 2021, 972 292 confirmed cases of COVID-19 were recorded, including 90 283 (9.3%) children. Starting in August 2020, the first cases of MIS-C associated with SARS-CoV-2 began to appear in children. In 2020, 7291 children came down with coronavirus infection COVID-19, and in 2021 - 82 986 children. On average, 86% of children had a mild and asymptomatic course of infection, a moderate course was observed in 13% of children, and less than 1% had an infection in a severe and extremely severe form. However, a comparative analysis of the course of COVID-19 in children by year showed that the number of severe forms doubled in 2021, and extremely severe forms of infection and deaths have been recorded (Table 1).
Table 1 Table 1. Comparative characteristics of COVID-19 disease in children by years and severity.
According to the branch of the Scientific and Practical Center for Sanitary and Epidemiological Expertise and Monitoring of the "National Center for Public Health" of the Ministry of Health of the Republic of Kazakhstan, a genetic study was conducted across the country by sequencing in 2020 -56, and in 2021, -582 positive for SARS-CoV-2 laboratory samples, respectively. According to the sequencing results in 2020, all 56 samples belonged to low pathogenic variants of SARS-CoV-2 (B.1.1, B.1, B, A.2, and others). On the other hand, sequencing results in 2021 showed 140 (24%) samples were low pathogenic variants, while 264 (45.5%) samples represented the Delta variant and 178 (30.5%) the Alpha variant of SARS-CoV-2 (Figure 2). Thus, in 2021 the circulation of mutated Delta and Alpha variants of the SARS-CoV-2 virus prevailed in the Republic of Kazakhstan, which could be associated with a more severe course of COVID-19 in children.
The first cases of MIS-C started to be reported in children in August 2020 in Kazakhstan (Figure 1). In 89 children with MIS-C, the median age was six years (Min-10 days; Max-17 years; Interquartile range (IQR) 4-10 years). There were more boys (72%) than girls (28%). In the anamnesis, 36% of children having a history of SARS symptoms had ARVI symptoms (acute respiratory viral infection); in 25% of them, a positive PCR test for SARS-CoV-2 was found. All children had COVID-19 in an asymptomatic, mild, and moderate form. MIS-C developed after Min-2 weeks; Max-12 weeks; Me-6 weeks; IQR 4-6 weeks after a positive PCR test for SARS-CoV-2 or ARVI symptoms. The results of PCR tests for SARS-CoV-2 during hospitalization for MIS-C were positive at 6%; the specific IgG antibodies were in 78%, SARS-CoV-2 IgM antibodies in 14%, total antibodies (IgM and IgG) in 22% of children. 27% of children had an underlying pathology: systemic lupus erythematosus (3.4%), congenital heart defects (10.1%), intrauterine infection (2.2%), obesity (4.5%), cerebral palsy (2.2%), epilepsy (2.2%), protein-energy malnutrition (1.1%), bronchiectasic disease (1.1%).
Figure 1 Figure 1. Reported cases of COVID-19 and MIS-C in children in Kazakhstan.

Figure 2 Figure 2. Results of SARS-CoV-2 sequencing by years in the Republic of Kazakhstan.
Children in the first group were more likely to have conjunctivitis (p=0.04, 95% CI: 1.366–20.174) than children in the second group. In the second group, acute renal failure (p=0.037, 95% CI: 1.042–8.828), DIC (p=0.01, 95% CI: 1.366–20.174), shock (p=0.05, 95% CI: 1.02–11.721), seizures (p = 0.04) were more common in terms of statistical significance. Furthermore, the children in the second group more often needed treatment in the intensive care unit (ICU) (p = 0.044, 95%, CI: 1.016–5.6) than children in the first group, but the length of stay in the ICU and the hospital in both groups did not differ significantly (group 1 - Me five days, IQR 3-7 days; group 2 - Me -7 days, IQR 5-12 days) (Table 2).
When analysing laboratory tests, we identified the following statistically significant differences in the complete blood count: the level of leukocytes (p<0.001), neutrophils (p=0.003), and erythrocyte sedimentation rate (ESR) (p=0.04) in children with MIS-C in 2021 were higher than in children in 2020, and lymphocytes were lower (p=0.01) (Table 2).
When comparing changes in quantitative indicators of laboratory data, the children with MIS-C cases in 2021 had, on average higher values of ferritin (p=0.02) and procalcitonin (p=0.005) compared to children who came down in 2020. Furthermore, the children with MIS-C in 2021 had higher levels of creatinine (p=0.035) and urea (p=0.011) (Table 2).   
Table 2.1 Table 2. General characteristics of patients with MIS-C by years.
Table 2.2
The following differences were found when analysing the therapy performed in the two groups. The children in the first group were more often prescribed acetylsalicylic acid preparations (p = 0.006, 95% CI: 0.095–0.705), compared with children from the second group. In 2021 the children with MIS-C were more likely to need oxygen therapy (p=0.009), transfusion of red blood cells (p=0.014; 95% CI: 1.298–30.805), fresh frozen plasma (p=0.05; 95% CI: 1.02–11.721), dobutamine (p=0.05, 95% CI: 1.02–11.721) and diuretics (p=0.024; 95% CI: 1.112–6.152) (Table 3).
At the diagnostic stage, 13 (14.6%) children with MIS-C underwent laparoscopy and appendectomy due to severe pain syndrome; the peritoneal dialysis was determined in 5 (5.6%) children due to the long-term persistence of anuria and an increase in creatinine and urea. In addition, two children (2.5%) underwent a biopsy of the lymph node, and one child (1.2%) underwent resection of a part of the large intestine due to thrombosis of the mesenteric vessels. When comparing these data in the two groups, no statistically significant differences were found (Table 3).
Table 3 Table 3. Comparative analysis of therapy in children with MIS-C by years.

Discussion

In this study, we presented the experience of diagnosing and treating children with MIS-C in the Republic of Kazakhstan from August 2020 to December 2021 and compared the severity of MIS-C depending on the time of circulation of different strains of the SARS-CoV-2 virus.
In contrast to the systematic review outcomes conducted by Jun Yasuhara,[13] in which the average age of children with MIS-C was 9.3 years, the average age of children in our study was less. It amounted to 6 years, but higher than in the U.K. cohort (4.6 years).[14] In addition, although previously, the cases of multisystem inflammatory syndrome associated with SARS-CoV-2 in new-borns were described in some countries,[15] we also observed one case of severe hyperinflammatory syndrome in the new-born (age ten days).
In a US study which enrolled 272 children, specified by Feldstein LR and her team, it was noted that 80% of children needed intensive care. Four patients with MIS-C who died were between 10 and 16 years of age.[16] In contrast to this US study, among our 89 patients two times fewer children were hospitalized in the ICU (which amounted to 47%), and 80% of the children who died were in early childhood (under 2 years old). In another study conducted in Colombia, it was noted that out of 78 patients hospitalized in the ICU, 7 children died, and 71.4% of children who died were under 7 years old.[17] Mortality among infants in our cohort may be related to late diagnosis, as two out of four infants were diagnosed with MIS-C 3–4 weeks after hospital admission. Also, only one child with a fatal outcome received biological immune therapy, but at the time of the appointment of these drugs, he was in an extremely serious condition.
In our study, as in other previously published papers, rash (78.7%), changes in the gastrointestinal tract (68.4%), respiratory lesions (59.6%), and neurological symptoms (46.1%) were common symptoms other than fever.[18,19] In addition, nearly one-fourth of the patients in our cohort (22.5%) had acute renal failure, consistent with a previous systematic review.[20]   
When compared with the literature data, heart damage in our cohort's children in the form of myocarditis was observed in 29%, according to other studies - in the range from 20 to 55%; pericarditis in 33% and 22-43%, respectively, coronary involvement in the form of aneurysm and/or dilatation in children with MIS-C was less common and amounted to 6% vs. 8-28% in other studies.[21-22]
More than 90% of children in our study had elevated inflammatory markers such as CRP (97%), ferritin (96%), D-dimer (93%), procalcitonin (91%), as well as leukocytosis (85%), lymphopenia ( 95%), neutrophilia (91%) and high ESR (91%) in the complete blood count; the similar results were described in other studies.[23-24]
According to the comparative analysis of the MIS-C course in 2020 and 2021 in Kazakhstan, it was found that SARS-CoV-2-associated multisystem inflammatory syndrome became more severe in 2021, confirming a statistically significant difference. So in 2021, life-threatening conditions such as acute renal failure, DIC, shock and seizures, and general hospitalization of children with MIS-C in the ICU were more common. The severity of the MIS-C course in 2021 confirms higher values of inflammation markers: ferritin, procalcitonin, ESR, leukocytes, and neutrophils. One of the important indicators of the complete blood count, which characterizes the severe course of the hyperinflammatory syndrome, is lymphopenia,[25,26] which was also characteristic of children who came down with the disease in 2021. According to the Centres for Disease Control and Prevention, a paper has been published comparing the differences in clinical and laboratory data of children with MIS-C registered after three waves of COVID-19, which specifies that there was an increase in the number of cases of MIS-C with severe hematological and gastrointestinal intestinal lesions (P<0.001) after the appearance of the Delta variant of SARS-CoV-2. However, the incidence of some cardiovascular complications such as cardiac dysfunction, myocarditis, shock, and renal failure decreased (P<0.001). Likely, hospitalizations to the intensive care unit, including mechanical ventilation (P<0.001) and extracorporeal membrane oxygenation (ECMO; P=0.046), decreased, as did the length of stay and mortality (P<0.001).[12] The authors concede that these data could be related to the introduction of COVID-19 vaccination in children. The discrepancies with our results may be because vaccination for children from 12 years old in the territory of the Republic of Kazakhstan became available only from mid-November 2021.

Limitations of the study

Our study has some limitations. Firstly, not all children were probably identified as MIS-C due to diagnostic defects since this pathology is new and doctors are not always wary of this disease. On the other hand, the multisystem inflammatory syndrome can be caused not only by novel coronavirus infection COVID-19 but also by other pathogens, autoimmune diseases, as well as many other identified diseases that may not be detected at the time of hospitalization in children in our cohort, but the presence of antibodies to SARS-CoV-2 expose them to MIS-C. Thirdly, none of the children underwent SARS-CoV-2 genome sequencing, and division into groups was carried out according to the time intervals of the prevalence of circulating virus variants and according to official sources on the identified Alpha and Delta variants in the territory of Kazakhstan.

Conclusions

MIS-C is a severe, life-threatening systemic disease characterized by inflammatory laboratory changes and multiple organ involvement, as evidenced by the high frequency and variety of severe clinical symptoms. During the circulation of Alpha and Delta variants of SARS-CoV-2 in the territory of the Republic of Kazakhstan, a more severe course of MIS-C was noted, in which more pronounced clinical and laboratory changes were recorded, which required twice as frequently as resuscitation and intensive care due to the development of DIC, shock, and severe kidney damage.

References   


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