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. 2022 Dec 5:9:1050804.
doi: 10.3389/fmed.2022.1050804. eCollection 2022.

Role of matrix metalloproteinases in multi-system inflammatory syndrome and acute COVID-19 in children

Nathella Pavan Kumar  1 , Aishwarya Venkataraman  1 , Poovazhagi Varadarjan  2 , Arul Nancy  3 , Anuradha Rajamanickam  3 , Elilarasi Selladurai  2 , Thangavelu Sankaralingam  4 , Kannan Thiruvengadam  1 , Ramya Selvam  4 , Akshith Thimmaiah  4 , Suresh Natarajan  5 , Ganesh Ramaswamy  5 , Sulochana Putlibai  6 , Kalaimaran Sadasivam  6 , Balasubramanian Sundaram  6 , Syed Hissar  1 , Uma Devi Ranganathan  1 , Thomas B Nutman  7 , Subash Babu  3   7
Affiliations

Role of matrix metalloproteinases in multi-system inflammatory syndrome and acute COVID-19 in children

Nathella Pavan Kumar et al. Front Med (Lausanne). .

Abstract

Introduction: Multisystem Inflammatory Syndrome in children (MIS-C) is a serious inflammatory sequela of SARS-CoV2 infection. The pathogenesis of MIS-C is vague and matrix metalloproteinases (MMPs) may have an important role. Matrix metalloproteinases (MMPs) are known drivers of lung pathology in many diseases.

Methods: To elucidate the role of MMPs in pathogenesis of pediatric COVID-19, we examined their plasma levels in MIS-C and acute COVID-19 children and compared them to convalescent COVID-19 and children with other common tropical diseases (with overlapping clinical manifestations).

Results: Children with MIS-C had elevated levels of MMPs (P < 0.005 statistically significant) in comparison to acute COVID-19, other tropical diseases (Dengue fever, typhoid fever, and scrub typhus fever) and convalescent COVID-19 children. PCA and ROC analysis (sensitivity 84-100% and specificity 80-100%) showed that MMP-8, 12, 13 could help distinguish MIS-C from acute COVID-19 and other tropical diseases with high sensitivity and specificity. Among MIS-C children, elevated levels of MMPs were seen in children requiring intensive care unit admission as compared to children not needing intensive care. Similar findings were noted when children with severe/moderate COVID-19 were compared to children with mild COVID-19. Finally, MMP levels exhibited significant correlation with laboratory parameters, including lymphocyte counts, CRP, D-dimer, Ferritin and Sodium levels.

Discussion: Our findings suggest that MMPs play a pivotal role in the pathogenesis of MIS-C and COVID-19 in children and may help distinguish MIS-C from other conditions with overlapping clinical presentation.

Keywords: COVID-19; MIS-C; MMPs; biomarker; seropositive.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Heightened plasma levels of matrix metalloproteinases (MMPs) in multisystem inflammatory syndrome in children (MIS-C) and acute COVID-19 children. The plasma levels of MMP-1, 2, 3, 7, 8, 9, 12 and 13 were measured in MIS-C (n = 65), acute COVID-19 (n = 56), children with other diseases (n = 40), convalescent COVID-19 (n = 47) and control children (n = 21). The data are represented as scatter plots with each circle representing a single individual. p values were calculated using the Kruskal-Wallis test with Dunn’s post hoc for multiple comparisons.
FIGURE 2
FIGURE 2
PCA and ROC reveals the trend of matrix metalloproteinases (MMPs) among multisystem inflammatory syndrome in children (MIS-C), COVID-19 and other groups. (A) Principal component analysis (PCA) was performed to show the distribution of data from the combination of five groups: MIS-C (brown), acute COVID-19 (blue), children with other diseases (yellow color), convalescent COVID-19 (green) and control (red) children depicted using normalized data from plasma levels of MMP-8, 12 and 13. (B) CombiROC analysis was performed to determine the role of MMP 8, 12 and 13 in distinguishing between MIS-C vs. acute COVID-19, MIS-C vs. other diseases, MIS-C vs. convalescent and MIS-C vs. Controls.
FIGURE 3
FIGURE 3
Heightened plasma matrix metalloproteinases (MMP) levels are associated with disease severity in multisystem inflammatory syndrome in children (MIS-C) and COVID-19. (A) The plasma levels of MMPs-1, 2, 3, 7, 8, 9, 12 and 13 were measured in MIS-C children with PICU care (n = 39) and MIS-C children no PICU care (n = 26). (B) The plasma levels of MMPs-1, 2, 3, 7, 8, 9, 12 and 13 were measured in COVID-19 children with moderate to severe (n = 5) and children with mild (n = 22) disease. The data are represented as scatter violin plots with each circle representing a single individual. P values were calculated using the Mann–Whitney test with Holm’s correction for multiple comparisons.
FIGURE 4
FIGURE 4
Correlation between matrix metalloproteinases (MMP) levels and other laboratory parameters. Multiparametric matrix correlation plot of MMPs-1, 2, 3, 7, 8, 9, 12 and 13 and laboratory parameters (Lymphocyte, CRP, D-Dimer, Ferritin, LDH, Sodium) with MIS-C and COVID-19. Spearman’s correlation coefficients are visualized by color intensity. P values and spearman r values are ordered by hierarchical clustering in the study cohort.
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References

    1. Dufort EM, Koumans EH, Chow EJ, Rosenthal EM, Muse A, Rowlands J, et al. Multisystem inflammatory syndrome in children in New York state. N Engl J Med. (2020) 383:347–58. 10.1056/NEJMoa2021756 - DOI - PMC - PubMed
    1. Feldstein LR, Rose EB, Randolph AG. Multisystem inflammatory syndrome in children in the United States. Reply. N Engl J Med. (2020) 383:1794–5. - PubMed
    1. Rowley AH. Understanding SARS-CoV-2-related multisystem inflammatory syndrome in children. Nat Rev Immunol. (2020) 20:453–4. 10.1038/s41577-020-0367-5 - DOI - PMC - PubMed
    1. Carter MJ, Shankar-Hari M, Tibby SM. Paediatric inflammatory multisystem syndrome temporally-associated with SARS-CoV-2 infection: an overview. Intensive Care Med. (2021) 47:90–3. 10.1007/s00134-020-06273-2 - DOI - PMC - PubMed
    1. Miller J, Cantor A, Zachariah P, Ahn D, Martinez M, Margolis KG. Gastrointestinal symptoms as a major presentation component of a novel multisystem inflammatory syndrome in children that is related to coronavirus disease 2019: a single center experience of 44 cases. Gastroenterology. (2020) 159:1571–74.e2. 10.1053/j.gastro.2020.05.079 - DOI - PMC - PubMed