Diagnostic and prognostic significance of IL-18 and its -607C/A polymorphism in COVID-19: Implications for CURB-65...

Interleukin-18 (IL-18) is a key inflammasome-related cytokine implicated in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

This study investigated the diagnostic, prognostic, and immunogenetic relevance of IL-18 and its promoter polymorphism (-607C/A, rs1946518) in COVID-19 susceptibility, severity, and mortality among Kurdish coronavirus disease-2019 (COVID-19) patients.

A total of 100 unvaccinated COVID-19 patients and 80 healthy controls (HCs) were enrolled. COVID-19 patients were further classified into non-severe (n=60) and severe cases (n=40), and additionally into survived (n=75) and non-survived groups (n=25). Biochemical markers, CURB-65 scores, and clinical outcomes (severity and survival) were assessed. Genotyping of the IL-18 -607C/A polymorphism was performed using polymerase chain reaction - sequence-specific primer (PCR-SSP).

COVID-19 patients exhibited markedly elevated IL-18 levels compared with HCs (509.1 vs. 228.8pg/mL, p<0.001). IL-18 showed a strong positive correlation with disease severity (r=0.77, p<0.001) and significantly distinguished non-severe from severe cases and survivors from non-survivors (both p<0.001). Severe and non-survived patients demonstrated higher D-dimer, ferritin, C-reactive protein (CRP), fibrinogen, neutrophils, and CURB-65 scores, alongside lower lymphocyte counts. Genotype analysis revealed that the CC genotype was significantly associated with higher IL-18 expression and more severe clinical phenotypes, including elevated CURB-65 scores and inflammatory biomarkers. In contrast, the A allele (CA and AA genotypes) conferred strong protection against severe disease (AA: OR=0.053; CA: OR=0.149) but showed no significant association with mortality. Statistical tests confirmed pronounced genotype-dependent differences in IL-18, D-dimer, ferritin, CRP, leukocyte profiles, and fibrinogen (p<0.05). Diagnostic evaluation showed that IL-18 accurately discriminated COVID-19 cases from HCs (area under curve (AUC)=0.991; sensitivity 95.0%; specificity 95.06%). As a prognostic marker for severe disease, IL-18 demonstrated moderate performance (AUC=0.671).

The IL-18 -607C/A polymorphism influences COVID-19 susceptibility and severity, CC increases risk, while the A allele is protective, but it is not associated with mortality. IL-18 shows excellent diagnostic and moderate prognostic value and may enhance COVID-19 risk-stratification when combined with CURB-65 and genotypic data.