Introduction

From the first reported infection caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in December 2019 in Wuhan City, Hubei Province, China, the epidemic spread worldwide and caused a global health crisis1. The WHO has reported 773,119,173 confirmed cases of coronavirus disease in 2019 (COVID-19), including 6,990,067 deaths (https://covid19.who.int/ accessed on 24 December 2023).

At the beginning of the pandemic, reported data suggested that the incidence of SARS-CoV-2 infection occurs more frequently in adults than in children2,3. However, the current studies support the remarkable prevalence of asymptomatic infection among children, causing an underestimated burden of COVID-19 in this population4. Along with the spiking number of SARS-CoV-2 cases after the new emerging Omicron variant, children potentially remain at risk of diverse post-COVID-19 sequelae afterward that can devastate multiple organs and impact quality of life beyond years5,6,7. Specifically, the most severe complication is multisystemic inflammatory syndrome in children (MIS-C) associated with COVID-19, also called pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS). The initial report of MIS-C from the United Kingdom in April 2020 described a cluster of eight children with previous SARS-CoV-2 infection presenting a clinical scenario similar to atypical Kawasaki disease (KD) or toxic shock syndrom8. Since then, similar cases have been reported in other parts of the world9,10,11,12. The theory suggested that the disease is driven by 2–6 weeks post-infectious immune dysregulation; the principal treatment is immunomodulatory therapy combining other supportive therapeutics13,14,15.

MIS-C might present with a heterogeneous spectrum in severity, ranging from mild manifestations to severe complications, including shock, respiratory failure, myocardial involvement, multiorgan dysfunction, coagulopathy, and encephalopathy11,16,17,18,19. MIS-C pathogenesis is characterized by overwhelming immune system responses, leading to hyper‐inflammation and cytokine storm8. This over-inflammatory mechanism is crucial for the explanation of multi-organ damage in MIS-C, in which we hypothesized that the inflammatory markers changes might reflect the MIS-C entity's host response severity and provide clues to identify patients at risk of severity for strict follow-up and timely treatment escalation To date, despite the ongoing efforts to investigate any independent factors that could predict the severity and outcomes of the disease, data on this issue still lacks consistency. Additionally, regardless of the evolution of data from North America and European countries, there are few reports on MIS-C from Asia, leading to an underestimated disease burden in this area9,10,11,12,18,20. Vietnam has experienced the fourth COVID-19 wave of epidemics, of which the fourth wave from early 2021 had been by far the worst of the pandemic21,22. Concomitant with the spiking of COVID-19 infection in children, MIS-C cases increased drastically almost four weeks afterward. However, there is a lack of published data on MIS-C in Vietnam; further investigations are needed. Thus, we conducted this study to identify independent predictors of severity in patients with MIS-C at a tertiary hospital in Vietnam. This available data on epidemiological, clinical, and laboratory characteristics and severe outcomes of MIS-C patients might also enhance pathophysiologic insights and directions for future research.

Methods

Study design and participants

This prospective observational study was conducted from January 2022 to June 2023 at Vietnam National Children’s Hospital (VNCH)—the largest referral tertiary children’s hospital of the country. We obtained written informed consent from the parents or legal guardians of all participants, and the study was approved by Vietnam National Children’s Hospital Institutional Review Board #1 (Approval no. VNCH-TRICH-2022-2A). The study was conducted in accordance with the Declaration of Helsinki.

Case definition

During the study period, we included 391 children aged from 1 month to 18 years old who met the MIS-C case definition of the United States Centers for Disease Control and Prevention (US.CDC)23. Accordingly, any illness in a person aged less than 21 years that meets the clinical and the laboratory criteria, which are as follows: (1) fever > 38.0 °C for ≥ 24 h (subjective or documented fever); (2) laboratory evidence of inflammation, including one or more of the followings: high values of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase (LDH), or interleukin 6 (IL-6); elevated neutrophils, reduced lymphocytes, and low albumin; (3) evidence of at least two organs injury (respiratory, cardiovascular, hematologic, renal, gastrointestinal, or neurological involvement); (4) current or recent SARS-CoV-2 infection diagnosed by a positive reverse transcription polymerase chain reaction (RT-PCR) or positive serological tests (IgM, IgG or IgA), or exposure to a suspected or confirmed COVID-19 case within the 60 days prior to the onset of symptoms.; (5) no alternative plausible diagnosis and exclusion of any other microbial infections, including bacterial sepsis, staphylococcal or streptococcal shock syndromes, and viral infections associated with myocarditis, such as enterovirus. Patients suspected of or confirmed with other microbial (bacterial, viral, fungal, and parasite) infections were excluded.

Data acquisition

Data on clinical and laboratory characteristics

Data on clinical and demographic characteristics, laboratory and therapeutic variables, and echocardiographic findings within 24 h of admission and daily were routinely collected using standard case report forms (CRFs) (available on the Supplementary 1 for further details). The treatment was supported by strategy guidance from the American College of Rheumatology Clinical Guidance and the Rheumatology Study Group of the Italian Society of Pediatrics15.

Severe outcomes

There are previous reports in the literature of sudden fatality in MIS-C due to cardiovascular compromise during the hyperinflammatory phase of the illness, mostly related to cardiovascular failure, with hypotension and decreased left ventricle contractility24. Additionally, severe involvement of the respiratory, cardiac, neurologic, or renal systems in MIS-C cases was significantly associated with PICU admission24,25,26. Therefore, our variables for severe outcomes in MIS-C were the development of shock within the first 72 h of hospitalization and the requirement of pediatric intensive care unit (PICU) admission. Given the low overall mortality from MIS-C and not all patients admitted to the PICU, death and PICU length of stay were not included as severe outcomes. The shock definition include impaired perfusion signs with or without hypotension, which are a weak and fast pulse, cool peripheries, and a capillary refill time of > 3 s27. As there are still no universal criteria for PICU admission, criteria for PICU admission vary by the center worldwide. We defined PICU admission as including one of the following: use of vasopressors, respiratory failure requiring noninvasive or invasive ventilation, abnormal neurological symptoms, evidence of liver or kidney damage, arrhythmia, and presence of myocarditis.

Statistical analysis

We used a convenient method for determining the sample size of our study. All statistical analyses were performed using STATA software version 17.0 (StataCorp LP, College Station, TX, USA). Categorical variables were described as frequencies and percentages, while continuous variables were described as the median and interquartile range. Results were described as odds ratio (OR) and 95% confidence intervals (CIs). The area under the receiver operating characteristic curve was calculated to compare the predictive performance of the difference biomarkers for MIS-C severity. For each variable, the area under the curve (AUC), 95% CI, and the optimal cutoff point were determined. Variables significantly associated with the outcomes in univariate analyses were selected for multivariate logistic progression to identify independent predictors. A two-sided p-value of less than 0.05 was considered statistically significant.

Results

Baseline characteristics of the study population

We analyzed data from 159,410 patients admitted to hospital between January 2022 and June 2023. Of these, 525 patients were reported with MIS-C diagnosis. Among them, 88 patients who unmeet the case definition for MIS-C were excluded. We further excluded 37 patients with insufficient data, 9 patients with microbiologically confirmed infections (5 cases with Staphylococcus aureus infections, 2 cases with Burkholderia pseudomallei infections, and 2 cases with Adenovirus infections). A total of 391 patients (255 boys and 136 girls) were ultimately recruited in this study (See the flow diagram for study participants in the Supplement 2). The median age was 85 (range 2–188) months and only 14 (3.6%) patients had comorbidities. The frequency of children with a COVID-19 infection history was 310 (79.3%) patients, and the median time since the previous infection prior to symptom onset was 36 (29–47) days. We summarized the epidemographic and clinical parameters of the total study population in Table 1. See Supplement 3 for additional details.

Table 1 Characteristics of patients hospitalized with multisystemic inflammatory syndrome in children.
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Among the study population, 161 (41.2%) patients needed PICU admission, and the median PICU LOS was 4 (2–7) days. Shock developed in 140 (35.8%) patients. In our study, we found that 161 patients were admitted to the PICU, with 140 patients experiencing shock that coincided with one or more of the above indications. The remaining 21 patients, without shock, were admitted for respiratory distress (7 cases), seizure (3 cases), evidence of liver or kidney damage (5 cases), arrhythmia (4 cases), and both arrhythmia and respiratory distress (2 cases) (Data not shown). Overall, two deaths (0.5%) occured in our study population.

Lab findings

Median (IQR) of HGB (g/L), absolute LYM count (× 109/L), PLT count (× 109/L), albumin (g/L), and natremia (mmol/L) were presented in Table 2 (114, IQR 105–122; 1.4, IQR 0.9–2.2; 176, IQR 120–245; 134, IQR 131.1–136, respectively).

Table 2 Laboratory characteristics within 24 h of admission.
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Figure 1 showed inflammatory markers were often elevated in the study population, including WBC ≥ 15 (× 109/L) (83.5%), CRP ≥ 50 (mg/L) (79.3%), ferritin ≥ 300 (ng/mL) (62.1%), and d-dimer ≥ 2500 (ng/mL) (43.9%). LYM ≤ 2 (× 109/L) and PLT ≤ 100 (× 109/L) were found in 31.9% and 19.9% of patients at admission, respectively. 27.6% and 12.3% of patients presented with elevated cardiac markers and hyponatremia, respectively.

Figure 1
figure 1

Percentage of patients according to the variable change. WBC white blood cell, CRP C-reactive protein, LYM lymphocyte, proBNP pro B-type natriuretic peptide, PLT platelet, Na natremia.

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Prognostic factors of disease severity

Shock

Shock developed in 140 (35.8%) patients within the first 72 h after admission. The predictors of shock were identified based on indicators with significant differences, followed by an analysis of the univariate and multivariate logistic regression as presented in Table 3.

Table 3 Univariate and multivariate logistic regression for predictors of shock (Linktest p < 0.001 for multivariate logistic regression).
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Absolute LYM count ≤ 2 (× 109/L) (OR 2.48, 95% CI 1.1–5.61, p = 0.029), albumin ≤ 30 (g/L) (OR 2.53, 95% CI 1.22–5.24, p = 0.013), and LVEF < 60 (%) (OR 2.24, 95% CI 1.12–4.51, p = 0.022) were identified to be independently associated with shock on multivariate logistic regression.

PICU admission

One hundreds and sixty-one (41.2%) patients required PICU admission, and the median PICU LOS was 4 (2–7) days. Similarly, the predictors of PICU admission were identified based on indicators with significant differences, followed by an analysis of the univariate and multivariate logistic regression as presented in Table 4.

Table 4 Univariate and multivariate logistic regression for predictors of pediatric intensive care unit admission (Linktest p < 0.001 for multivariate logistic regression).
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Out of these risk factors included in the multivariate model, CRP \(\ge \) 50 (mg/L) (OR 2.52, 95%CI 1.39–4.56, p = 0.002), albumin \(\le \) 30 (g/L) (OR 3.18, 95% CI 1.63–6.02, p = 0.001), LYM \(\le \) 2 (× 109/L) (OR 2.18, 95% CI 1.29–3.71, p = 0.004), ferritin ≥ 300 (ng/mL) (OR 2.35, 95% CI 1.38–4.01), p = 0.002), and LVEF < 60 (%) (OR 2.48, 95% CI 1.28–4.78, p = 0.007) were significantly associated with severe MIS-C requiring PICU admission (Table 4).

Cut-offs of these variables were chosen based on reference values in previous cohort28,29,30.

Discussion

The present study reported independent predictors of severity in 391 pediatric patients with MIS-C in the tertiary hospital from Vietnam. The results found that lymphocytopenia, hypoalbuminemia, high CRP, and decreased LVEF were independently associated with the risk of severity among children with MIS-C.

According to previous systemic reviews, MIS-C might manifest a broad spectrum of scenarios, ranging from mild features to severe complications, including shock, multiorgan failures, and mortality5,6,7. Regarding clinical presentations, the most frequent symptoms were fever (100%), followed by mucocutaneous symptoms (91.8%), GI involvement (62.9%), lymphadenopathy (41.4%), and cardiovascular findings (23.8%) (Table 1). Ahmed et al. found out that the most common symptoms of MIS-C are fever, GI symptoms (abdominal pain, vomiting, and diarrhea), rash, and conjunctivitis31. Similarly, GI symptoms (especially abdominal pain, vomiting, and diarrhea) were also previously considered prevalent symptoms of this novel entity28,32,33. The predominance of GI manifestations in children with MIS-C was striking33. A plausible pathogenesis might be the overwhelming systemic immune response after COVID-19 infection, including the effect on the digestive system34. Besides, by detecting auto-antibodies targeting gastrointestinal antigens in the plasma of MIS-C patients, it was hypothesized that the GI tract may serve as a viral reservoir for continuous exposure to the SARS-CoV-2 SAg-like motif35. In the cohort study, 35.8% developed shock, 11.7% had respiratory distress, 41.2% required PICU admission, and 0.5% were death (Table 1). However, the ICU admission rate was less than in cohorts from Hungary (52.6%)36 and Turkey (54.5%)37. Shock and mortality were documented with a higher proportion in most cohorts from other parts of the world38,39. We hypothesized that the variation in shock definition and PICU admission criteria depending on centers, SARS-CoV-2 variants circulating, study sample sizes, and healthcare settings may account for this difference.

Despite being considered as a “new entity” of KD, MIS-C is common in children 9–10 years, whereas classic KD occurs predominantly in children under five years of age9,18,40. In line with previous studies, our study identified that the median age group was 7 (3–12) years (Table 1)41,42,43. This point can be explained by the findings that younger children are less likely to contract COVID-19 than older children and adolescents due to several hypotheses related to specific properties of young children, including the lower expression in receptors of angiotensin-converting enzyme 2 (ACE2), cross-protection against SARS-CoV-2 infection, and their immature immune system4,44. We found that age ≥ three years was associated with an increased risk of shock (OR 3.62, 95% CI 1.91–7.25, p < 0.001) and PICU admission (OR 1.78, 95% CI 1.07–2.98, p = 0.013) among children with MIS-C, though insignificance of the predictor after adjusting in the multivariate analysis (Tables 3 and 4). Other studies also identified older age as a risk factor for severity in children with MIS-C, despite differences in cut-off point of age. In a previous study on infants with MIS-C, the most severe complications were less common in infants than in the MIS-C cohort in all ages, including cardiovascular involvements, shock, and the ICU admission rate45. Similarly, according to Belay et al., compared with patients in the older age categories, patients aged 0 to 4 years had fewer cardiovascular complications and fewer admissions for intensive care46. Compared with children aged 0–5 years, the adjusted absolute risk of ICU admission was higher among children aged 6–12 years (43.6% vs 18.4%, adjusted risk difference 25.2%, 95% CI 13.6% to 36.9%) and children aged 13–17 (46.2% v. 18.4%, adjusted risk difference 27.7%, 95% CI 8.3% to 47.2%)47. Likewise, the lesser susceptibility to develop severe MIS-C at an early age might not be distinctive in the pediatric population. Recent reviews also highlighted that patients with multisystem inflammatory syndrome in adults (MIS-A) have a higher mortality than MIS-C cases48. The overall mortality of MIS-A is between 5 and 7%, whereas that of MIS-C is approximately 1.7%49. However, the currently available data is limited, and there is a need for additional studies to enlighten this imparity.

MIS-C pathogenesis is characterized by overwhelming immune system responses, leading to hyper‐inflammation and cytokine storm8,48,50. This over-inflammatory mechanism is crucial for explanation of with multi-organ damage in MIS-C, in which biochemical changes could be partly demonstrated by the laboratory inflammatory markers, such as lymphocyte count, CRP, PCT, LDH, ferritin, d-dimer, TNF-α, and IL-6…20,41,50. Common lab findings indicative of MIS-C were elevated levels of CRP, ESR, d-dimer, ferritin, PCT, LDH, and a decrease in serum albumin and lymphocyte count as a panel of biomarkers in the existing guidelines14,15. The inflammatory markers changes might reflect the MIS-C entity's host response patterns and provide clues to identify patients at risk of severity for strict follow-up and timely treatment escalation. In the present study, absolute LYM count ≤ 2 (× 109/L) were recognized to be independently associated with shock (OR 2.48, 95% CI 1.10–5.61) and PICU admission (OR 2.18, 95% CI 1.29–3.71) on the multivariate model, respectively (Tables 3 and 4). Similarly, an observational study showed lymphopenia was common in classic MIS-C with multiple organ involvement and shock51. Bar-Meir et al. reported lymphopenia (lymphocyte count < 1500 µL) was an independent predictor of MIS-C, with an adjusted odds ratio of 24 (95% CI 1.3–326, p = 0.02)52. This raised a question about the mechanisms and the role of lymphopenia observed in MIS-C patients. One proposed explanation is the profound lymphopenia caused by marked T cell exhaustion after SARS-CoV-2 infection, which persists for weeks, leading to uncontrolled inflammation and immune dysregulation53. We emphasized that further studies are needed to validate whether lymphopenia can predict MIS-C development and severity and whether lymphocyte-targeted therapeutics could improve the disease outcome. We also found that other biomarkers, including d-dimer ≥ 2500 (ng/mL), ferritin ≥ 300 (ng/mL), CRP \(\ge \) 50 (mg/L), and albumin ≤ 30 (g/L), significantly related to the severity scenario in the univariate model. However, only albumin ≤ 30 (g/L) was a significant predictor of both shock (OR 2.53, 95% CI 1.22–5.24, p = 0.013) and PICU admission (OR 3.18, 95% CI 1.63–6.02, p = 0.001) (Tables 3 and 4) after adjusted in the multivariate model. The pivotal role of albumin in severity prediction can be explained by an increased capillary permeability and escape of albumin to the interstitial space parallel with the context of the overwhelming inflammation in MIS-C54. In a study in 76 MIS-C patients, an albumin level < 33.6 (g/L) was independently related to the risk of PICU admission26. Sharon et al. concluded that compared to CRP values with a wide range and high variability throughout the illness, albuminemia is a more reliable and accurate inflammatory marker that needs to be monitored regularly, particularly in critically ill children55. Similarly, Abrams J.Y. et al. noted that high ferritin, C-reactive protein, and D-dimer were associated with life-threatening manifestations, including shock and heart depression56. A d-dimer > 2568 ng/mL is an early predictor of severe MIS-C requiring ICU admission57. The surge of these biomarkers may reflect the presence of the known hyper-inflammatory condition and cytokine storm theory seen in MIS-C; therefore, immunoregulatory agents, such as IVIG, corticosteroids, interleukin blockers, are the mainstays in the treatment of MIS-C13,14,15. To date, IVIG (2 g/kg) plus high dose methylprednisolone (10–30 mg/kg/day) for three consecutive days is the first choice in MIS-C patients with shock, cardiac injury, or neurological damage15. The initial guidelines for the MIS-C were extrapolated from KD treatment. However, a more violent inflammatory activation was found in MIS-C, and it raised controversies around whether only IVIG or corticosteroid therapy is sufficient in patients with MIS-C. According to a study comparing efficacy among corticosteroids alone, IVIG alone, and IVIG plus corticosteroids group, there was an insignificant difference in initial responses between patients receiving corticosteroids alone and IVIG plus corticosteroids58. However, this outcome might be due to heterogeneous characteristics in disease severity between the groups; further studies on this issue are needed. In addition, the unavailability and high cost of IVIG and biological agents might strain the approach to this therapy, particularly in resource-limited settings. This point partly explains why our study reported that 19.2% received intravenous corticosteroids plus IVIG and only 1.5% received biological therapy (Table 1).

Cardiovascular complications are common manifestations in MIS-C, with an incidence of 40% to 80%17,46. Cardiovascular complications in MIS-C might present from mild manifestations to severe ones, such as arrhythmias, pericardial effusion, coronary artery aneurysms, myocarditis, shock, and life-threatening10,16,17. Therefore, cardiac markers, including proBNP, NT-proBNP, and troponin, are potential parameters to predict the progression of MIS-C deterioration. Several studies reported elevated BNP or NTpro-BNP, troponin levels, and LVEF related to required ventilation, PICU admission, or mortality17,59,60. Similarly, our study showed that proBNP ≥ 200 (pg/mL) and LVEF < 60 (%) were related to an increased risk of shock and PICU admission. However, we noted that LVEF might be more valuable for the severity prediction, with higher odds risk, than the proBNP level (see Tables 3 and 4). We supposed that this could be explained because proBNP peptides are primarily synthesized and upregulated by myocardial stress; therefore, it only reflects indirect cardiac suppression. Additionally, another report noted that there is a delayed improvement of NT-proBNP levels after myocardial function normalization60. In the present study, we then assessed the LVEF < 60% as an independent predictor for shock (OR 2.24, 95% CI 1.12–4.51, p = 0.022) and PICU admission (OR 2.48, 95% CI 1.28–4.78, p = 0.007) in the multivariate model (Tables 3 and 4).

Our study had some limitations. First, the data were collected from a single center in a tertiary hospital. Nevertheless, to the best of our knowledge, this paper highlighted the largest-sample study of this novel syndrome published in Vietnam. Second, this study performed the laboratory parameters at a single time and did not evaluate their variations during the subsequent days. However, this may be beneficial as we can eliminate the effects of therapy during treatment. Finally, we only evaluate the risk for short-term outcomes; further, well-designed research is required to define the prognostic factors identifying the long-term effects of MIS-C.

Conclusions

In conclusion, our study emphasized that absolute lymphocyte count, serum albumin, CRP, and LVEF were independent predictors for MIS-C severity. Further well-designed investigations are required to validate their efficacy in predicting MIS-C severe cases, especially compared to other parameters. As MIS-C is a new entity and severe courses may progress aggressively, identifying high-risk patients optimizes clinicians' follow-up and management to improve disease outcomes.