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. 2024 Nov 26;13(23):7177.
doi: 10.3390/jcm13237177.

Prognostic Value of Baseline Serum Pro-Inflammatory Cytokines in Severe Multisystem Inflammatory Syndrome in Children

Anita Bartha-Tatár  1   2 , György Sinkovits  3 , János Schnur  4 , Veronika Maráczi  4 , Máté Dávid  4 , Borbála Zsigmond  4 , Éva Rimanóczy  4 , Balázs Szalay  5 , Edina Biró  5 , Gabriella Bekő  5 , Petra Varga  6 , Tamás Szabó  6 , Miklós Fagyas  7 , Zsolt Fejes  1 , János Kappelmayer  1 , Béla Nagy Jr  1
Affiliations

Prognostic Value of Baseline Serum Pro-Inflammatory Cytokines in Severe Multisystem Inflammatory Syndrome in Children

Anita Bartha-Tatár et al. J Clin Med. .

Abstract

Background: Severe clinical manifestations of multisystem inflammatory syndrome in children (MIS-C) are associated with the dysregulation of immune response following SARS-CoV-2 infection. Therefore, we analyzed the levels of 10 selected cytokines at admission to estimate disease severity and to predict the length of hospitalization. In remission samples, these mediators were followed after intravenous immunoglobulin (IVIG) treatment before discharge. Methods: Thirty-five MIS-C patients at the age of 8.4 ± 4.1 years and 11 clinical controls were included. Acute MIS-C patients were divided into two severity subgroups based on their clinical score determined by the WHO criteria. Serum concentrations of IFN-γ, IL-1α, IL-1RA, IL-8, IL-10, IL-17A, IL-18, IP-10, MCP-1, and TNF-α were measured by MILLIPLEX® Human Cytokine/Chemokine panel, while ACE2 activity was determined by a fluorescent kinetic assay. These results were correlated with routinely determined laboratory parameters and clinical characteristics. Results: MIS-C patients demonstrated significantly elevated baseline levels of most of these cytokines compared to controls. Even higher concentrations of IL-18, TNF-α and ferritin with reduced lymphocyte count were found in severe subjects with elevated clinical scores of 4-5 compared to moderate cases with a clinical score of 1-3. Furthermore, the development of cardiovascular dysfunction and prolonged hospitalization (≥8 days) were related to augmented ACE2 and IL-6 levels. IL-18, IL-1RA, IL-10 and TNF-α were diminished in response to IVIG treatment in remission samples. Finally, pre-treatment IL-18 (≥516.8 pg/mL) and TNF-α (≥74.2 pg/mL) effectively differentiated disease severity in MIS-C with AUC values of 0.770 and 0.750, respectively. Conclusions: IL-18 and TNF-α have a prognostic value in disease severity at admission and are capable of monitoring the efficacy of IVIG treatment in MIS-C.

Keywords: IL-18; MIS-C; SARS-CoV-2; TNF-α; biomarker; cytokine; disease severity; inflammation.

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Conflict of interest statement

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Comparison of baseline serum ACE2 activity and IL-6 concentration in MIS-C patients based on disease severity. Dots represent single results, while bars indicate median value. To compare the data of the two groups, the Mann–Whitney U test was applied. Abbreviations: CV sympt: cardiovascular symptoms, Hosp. stay: hospital stay, IL-6: interleukin-6, ACE2: angiotensin converting enzyme 2.
Figure 2
Figure 2
Correlation between baseline routine laboratory parameters and cytokine levels. IL-6, ferritin, and PLT count were significantly correlated with IL-1RA (A), MCP-1 (B), TNF-α (C), and IL-8 (D), respectively. Dots represent single results. Correlations between cytokine levels and other laboratory parameters were determined using Spearman’s test.
Figure 3
Figure 3
Changes in different cytokine levels in all MIS-C patients in response to IVIG treatment. Dots represent single results, while lines connect cytokine values measured in baseline and remission samples. The degree of alterations in pro-inflammatory cytokine values were analyzed using the Wilcoxon matched-pairs signed rank test.
Figure 4
Figure 4
ROC-curve analysis for the comparison of selected baseline cytokine levels and renowned prognostic markers for the assessment of disease severity (A), cardiovascular involvement (B), and in the prediction of length of hospital stay (C) in MIS-C disease. AUC values with p-values as well as sensitivity and specificity values were determined using ROC curve analysis for each parameter.
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