Meta-analysis on clinical manifestation and laboratory parameters of COVID-19–associated multisystem inflammatory syndrome in children (MIS-C)

ABSTRACT

Objective:

We aimed to systematically identify clinical manifestations and lab parameters of COVID-19-associated multisystem inflammatory syndrome in children (MIS-C).

Methods:

We searched from Google Scholar, PubMed, and Cochrane Library with the Medical Subject Heading (MeSH) key, which includes information about clinical characteristics and severity of patient’s illness. We analyzed the clinical characteristics and lab parameters of MIS-C.

Results:

We identified a total of 44 eligible studies, including 1840 patients with COVID-19-associated MIS-C. Most common features were abdominal pain 74% (0.67,0.81), shock 72% (0.56,0.86), vomiting 69% (0.60,0.78), diarrhea 62% (0.53,0.72), rashes 60% (0.55,0.65), conjunctival infection 52% (0.44,0.60), others include myocarditis 49% (0.27,0.71), complete Kawasaki presentation 44% (0.23,0.66), respiratory distress 43% (0.16,0.73), oral mucosal changes 40% (0.31,0.49).

Conclusion:

The results of this review show that SARS-CoV-2-associated MIS-C can present with multisystem involvement and can show an increase in inflammatory markers. MIS-C can have presentationslike Kawasaki disease, which needs high index of suspicion to diagnose MIS-C. Clinical features and lab parameters help in early diagnosis and prompt treatment.

Introduction

COVID-19 pandemic was caused by severe acute respiratory coronavirus 2 (SARS-CoV-2). The virus rapidly spread globally and developed into a pandemic that, to date, has caused more than 6.5 million deaths.[1] Initially, children were thought to be immune, but later, they developed a syndrome of fever with a hyperinflammatory process. The Royal College of Pediatrics and Child Health (RCPCH)[2] named it as pediatric multisystem inflammatory syndrome (PMIS). WHO and CDC named it as Multisystem Inflammatory Syndrome in Children (MIS-C). Multisystem inflammatory syndrome in children (MIS-C) is a rare and serious complication in children with COVID-19.[3] It usually affects children 2–6 weeks after COVID-19 infection. MIS-C cases were reported after April 2020 from various hospitals in the United Kingdom and the United States. Children with this complication usually present with persistent fever, diarrhea, vomiting, abdominal pain, rashes, headache, lethargy, dyspnea, and the least common presentations included decreased urine output, seizures, and coronary artery abnormalities. MIS-C is known to occur due to a hyperimmune response to COVID-19 infection in the body. Various laboratory parameters, including inflammatory markers, are increased in this syndrome. Few children also developed severe complications as well. This study focuses on the clinical manifestations and inflammatory markers involved in MIS-C. As a family medicine practitioner, this study helps us to identify various presentation of MIS-C after COVID in children and treat at an early stage.

Methodology

We registered our review on the International Prospective Register of Systematic Reviews database (PROSPERO) on 17 April 2022. (CRD325338).

Search strategy

We searched for Articles in the English language and published from January 2019 to April 2022. Articles were searched from Google Scholar, PubMed, and Cochrane Library with Medical Subject Heading (MeSH) and keywords with synonyms that included MIS-C, COVID 19, MIS- C AND CLINICAL FEATURES.

Inclusion criteria

This analysis included the articles having clinical manifestations and laboratory parameters of children with MIS-C.

1. Articles included in this met analysis are ARTICLES cross-sectional study, case-control study, cohort study, and RCT, Case Reports, Clinical Trial, Controlled Clinical Trial, Observational Study, Multicenter Study, Systemic review, Comparative Study published in the English language.

2. Age between 1 month and 18 years.

Exclusion criteria

1. Inadequate data to study were excluded.

2. Conference proceeding, abstract, and editorial were excluded.

Data extraction

The data were extracted by the study’s last author, country of publication, the total number of subjects, the total number of MIS-C symptoms, setting of a hospital, mean age, etc.

Quality assessment

Two authors independently assessed the methodological quality of the study. A validated JBI scale was used for methodological quality.

The study quality scales consisted of following questionnaire:

1. Was the sample representative of the target population?

2. Were study participants recruited in an appropriate way?

3. Was the sample size adequate?

4. Were the subjects and the settings described in detail?

5. Was the data analysis conducted with sufficient coverage of the identified sample?

6. Were objective, standard criteria used for the measurement of the condition?

7. Was the condition measured reliably?

8. Was there appropriate statistical analysis?

9. Are all important confounding factors and subgroups differences identified and accounted for?

10. Were subpopulations identified using objective criteria?

Statistical analysis

The random-effects model was used to determine pooled proportion with a 95% confidence interval using the metaprop command in STATA software. The arcsine transformation was done to normalize the data. The exact confidence interval was used. Publication bias was examined by funnel plot, used Begg’s and egger’s tests. Meta-regression analysis was done by exploring the sources of heterogeneity. All the analysis was conducted using STATA software. P value less than 0.05 was considered statistically significant.

Study selection

The literature search process is displayed as in flow diagram in. The search strategy initially retrieved 322 articles, of these studies 4 articles were duplicates and 267 articles were in line with exclusion criteria. Finally, 44 articles published between January 1, 2019, and April 30, 2022, were included in this study as shown in Figure 1.

Figure 1.

Flow diagram of literature selection

Clinical symptoms and laboratory parameters were analyzed [Tables 1 and 2]. Most common features were abdominal pain 74% (0.67,0.81), shock72% (0.56,0.86), vomiting 69% (0.60,0.78), diarrhea 62% (0.53,0.72), rashes 60% (0.55,0.65), conjunctival infection 52% (0.44,0.60), others include myocarditis 49% (0.27,0.71), complete Kawasaki presentation 44% (0.23,0.66), respiratory distress 43% (0.16,0.73), and oral mucosal changes 40% (0.31,0.49) [Ref. Table 1].

Table 1.

Analysis of clinical symptoms

Clinical symptoms	Effect size (ES)	95% Confidence interval	I 2	P
Abdominal pain	0.74	0.67, 0.81	70.09	0.00
Acute kidney injury	0.27	0.19,0.36	86.47	0.00
Anosmia	0.27	0.07,0.52	94.22	0.00
Chest pain	0.12	0.05,0.20	69.99	0.01
Complete Kawasaki presentation	0.44	0.23,0.66	89.92	0.00
Confusion	0.15	0.05,0.29	83.85	0.00
Conjunctival injection	0.52	0.44,0.60	74.10	0.00
Coronary artery involvement	0.29	0.19,0.39	88.04	0.00
Cough	0.26	0.17,0.35	74.80	0.00
Diarrhea	0.62	0.53,0.72	84.16	0.00
Drowsiness	0.17	0.02,0.38	86.17	0.00
Dyspnea	0.21	0.13,0.31	67.77	0.00
Hand and foot involvement	0.36	0.02,0.79	94.31	0.00
Headache	0.25	0.17,0.35	80.03	0.00
Lymphedema	0.23	0.14,0.34	85.36	0.00
Meningism	0.24	0.16,0.34	47.21	0.06
Myocarditis	0.49	0.27,0.71	93.81	0.00
Oral mucosal changes	0.40	0.31,0.49	75.34	0.00
Rash	0.60	0.55,0.65	39.33	0.01
Respiratory distress	0.43	0.16,0.73	97.81	0.00
Shock	0.72	0.56,0.86	93.96	0.00
Sore throat	0.08	0.00,0.22	66.32	0.01
Vomiting	0.69	0.60,0.78	84.63	0.00

Table 2.

Analysis of lab parameters

Lab parameters	Effect size (ES)	95% confidence interval	I 2	P
Albumin	2.68	2.55,2.81	55.1%	0.003
BNP	2631.25	1999.52,3262.97	92.1%	0.000
CRP	17.11	14.84,19.39
D-Dimer	1773.71	1311.89,2235.53	43.3%	0.011
ESR	51.97	44.93,59.00	0.0%	0.919
Ferritin	640.49	451.59,841.38	0.0%	1.00
Fibrinogen	452.22	435.40,408.98	70.2%	0.00
Platelets	169.84	152.28,187.39	0.0%	1.00
TLC	11.30	9.32,13.28	0.0%	0.997
Troponin	0.05	0.02,0.08	58.4%	0.00

Lab parameters that were significantly elevated in children with MIS-C in this meta-analysis include D-Dimer 1773.71 (1311.89, 2235.53), Fibrinogen 452.22 (435.40, 408.98), Troponin 0.05 (0.02, 0.08), BNP 2631.25 (1999.52,3262.97). Significant Hypoalbuminemia 2.68 (2.55,2.81) was also noted

Figures: Forest Plots of Children with MIS-C. A- Abdominal pain, B- shock, C- vomiting, D- diarrhea E- coronary artery involvement, F- rash, G- D- Dimer, H- Fibrinogen, I-troponin, J- BNP.

Heterogeneity in the meta-analysis

High I² values were seen for respiratory distress (97.81), hand and foot involvement (94.31), anosmia (94.22), shock (93.96), myocarditis (93.81), complete Kawasaki presentation (89.92), coronary artery involvement (88.04), acute kidney injury (86.47), drowsiness (86.17), lymphedema (85.36), vomiting (84.63), diarrhea (84.16), and confusion (83.85), as shown in Table 2.

Among laboratory parameters, more than 50% I² values were seen for BNP, fibrinogen, troponin, albumin, and D-Dimer.

Discussion

This systematic review analyzed 44 articles with MIS-C which included cross-sectional study, case-control study, cohort study, RCT, Case Reports, Clinical Trial, Controlled Clinical Trial, Observational Study, and Multicenter Study. All relevant details like symptoms and laboratory investigations were noted for analysis. The results of this meta-analysis observed that there are few additional biomarkers which associated with multisystem inflammatory syndrome with SARS-CoV-2 infection.

Following April 2020, children started to present with symptoms involving multiple systems. This was noticed in all parts of the world. Later in Europe, this syndrome was named as Pediatric Multisystem inflammatory syndrome temporally associated with COVID-19 (PIMS-TS)[2] and as Multisystem inflammatory syndrome (MIS-C) by CDC and WHO.[2,3] MIS-C had clinical features like that of Kawasaki disease; however, many studies showed varied differences between the two. The median age was 5 years in Kawasaki disease, whereas in MIS-C, it is between 8 and 11 years.[4,5,6,7,8,9,10,11,12,13,14]

Our review included studies from 10 countries. This review showed that children with MIS-C presented commonly with abdominal pain, shock, vomiting, diarrhea, rashes, and conjunctival infection. Other cardiovascular findings included myocarditis and coronary artery involvement. Myocarditis can be due to direct involvement of the heart via angiotensin-converting enzyme-2 receptor. (ACE-2).[5,9,13,15,16,17,18,19,20,21,22] IL-6 cytokine storm can lead to coronary artery pathology which is seen in MIS-C.[23,24,25,26,27] Various inflammatory markers increased were D-dimer, Troponin, Fibrinogen, and BNP.

It can be inferred from the study that AKI is a significant presentation leading to greater morbidity this is possibly due to immune dysregulation. Similarly, shock is another fatal complication that can result in death in absence of timely intervention. Thus, emergency management of shock is essential to prevent further complications.

Myocarditis as presentation can be due to hypoxia leading to hypoxemia which causes apoptosis of cardiomyocytes this can further complicate to heart failure leading to death.

Systemic inflammation and higher titer of cytokines are associated with endothelial injury leading to increased incidence of coronary artery disease which can complicate to myocardial ischemia. Such similar endothelial injury can also make patient susceptible to vascular or systemic infection. This can also explain higher incidence of rashes and conjunctival infection in patients. Respiratory distress is associated with inflammation of alveoli and hypoxia requiring need of ventilation. We did not mention gender in our discussion because some studies did not address it.

Outcome parameters of patient in terms of death and discharge is shown in Table 3.

Table 3.

Outcome parameters

Outcome	Effect size (ES)	95% CI	I 2	P
Discharged	0.98	0.93,1.00	71.51%	0.00
Death	0.02	0.01,0.04	38.21%	0.09

Conclusion

COVID—Patients had wide variety of symptoms pertaining to various symptoms like central nervous system, cardiovascular system, gastrointestinal, respiratory, hematological, and kidney related.

The laboratory parameters were also compared. In addition, we have noted that MIS-C had similar presentation to Kawasaki diseases, and hence, it require an high index of suspicion to diagnosis MIS-C.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.