Differential Inflammatory Responses in Adult and Pediatric COVID-19 Patients: Implications for Long-Term Consequences and Anti-Inflammatory Treatment

Abstract

BACKGROUND COVID-19 manifests with varying degrees of severity across different age groups; adults typically experience more severe symptoms than children. Matrix metalloproteinases (MMPs), known for their role in tissue remodeling and immune responses, may contribute to the pathophysiological disparities observed between these groups. We sought to delineate differences in serum MMP profiles between adult and pediatric COVID-19 patients, assess the influence of anti-inflammatory treatment on MMP levels, and examine potential implications for long-term consequences. MATERIAL AND METHODS Serum samples from adult and pediatric COVID-19 patients, alongside controls, were analyzed for MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-12, MMP-13, EMMPRIN, TNF-alpha, TIMP-1, TIMP-2, TIMP-3, and TIMP-4. A subset of adult patients received treatment with glucocorticoids, tocilizumab, and convalescent plasma, and MMP levels were compared with those of untreated patients. RESULTS Elevated levels of MMP-1, MMP-7, TIMP-1, and TIMP-2 were observed in adult and pediatric patients. Adult patients displayed higher concentrations of MMP-3, MMP-8, MMP-9, TNF-alpha, and TIMP-4 than children. Post-treatment reduction in MMP-1, MMP-8, MMP-9 levels was observed, with median decreases from 21% to 70%. MMP-3 and MMP-7 remained largely unchanged, and MMP-2 concentrations increased after treatment. Notably, anti-inflammatory treatment correlated with reduced post-treatment MMP levels, suggesting potential therapeutic benefit. CONCLUSIONS Distinctive inflammatory responses in COVID-19 were evident between adults and children. While certain MMPs exhibited post-treatment reduction, the persistence of elevated levels raises concerns about potential long-term consequences, including lung fibrosis. Our findings emphasize the need for personalized treatment strategies and further investigation into the dynamics of MMP regulation in COVID-19.

Figure 1

Violin plots illustrating the concentration of serum levels of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), extracellular matrix metalloproteinase inducer (EMMPRIN), and tumor necrosis factor-alpha (TNF-α) in 3 study groups: (1) adults with COVID-19, (2) children with COVID-19, and (3) healthy control participants. Each panel represents 1 protein, and the violin plots depict the distribution of data within each group. Brackets and corresponding P values indicate significant differences between study groups. Thick horizontal lines drawn inside the plots represent median values.

Figure 2

Before-after plots of serum matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), extracellular matrix metalloproteinase inducer (EMMPRIN), and tumor necrosis factor-alpha (TNF-α) concentrations in adult COVID-19 patients. Within each subplot, lines connect paired data points from the same patient, comparing protein concentrations at 2 time points: T1 (upon admission) and T2 (after symptom resolution and before discharge). Statistical significance assessed using the Wilcoxon matched-pairs signed-rank test is denoted by brackets above the graphs, with corresponding P values.

Figure 3

Heatmap of log₁₀ Fold-Change (Log₁₀FC) in serum protein concentrations comparing T2 to T1 in adult COVID-19 patients, divided by the treatment used. The Log₁₀FC shows the change in serum protein concentrations between the 2 time points, T2 (after symptom resolution and before discharge) and T1 (upon admission), for all 22 recruited adult COVID-19 patients. The proteins analyzed include matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), tumor necrosis factor-alpha (TNFα), and extracellular matrix metalloproteinase inducer (EMMPRIN). Each row represents an individual patient, while each column corresponds to a specific protein. The color-coding scheme is designed such that an increase in protein concentration is represented in red, while a decrease is depicted in blue. The legend below the heatmap provides a reference for the Log₁₀FC scale. CP – convalescent plasma; GCS – glucocorticoids; TOC – tocilizumab

Figure 4

Correlation matrix of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), extracellular matrix metalloproteinase inducer (EMMPRIN), tumor necrosis factor-alpha (TNFα), and other laboratory results, including C-reactive protein (CRP), white blood cell count (WBC), lymphocytes (Lymph), neutrophils (Neutr), D-dimers, and alanine aminotransferase (ALT) in adult and pediatric COVID-19 patients. Statistical analysis conducted using Spearman’s correlation coefficient. Color-coded representation with positive correlations in blue and negative correlations in red. R values are displayed within cells, and missing values indicate correlations lower than 0.01.