Genome-wide association studies (GWAS) found locus 3p21.31 associated with severe COVID-19. CCR5 resides at the same locus and, given its known biological role in other infection diseases, we investigated if common noncoding and rare coding variants, affecting CCR5, can predispose to severe COVID-19. We combined single nucleotide polymorphisms (SNPs) that met the suggestive significance level (P ≤ 1 × 10⁻⁵) at the 3p21.31 locus in public GWAS datasets (6406 COVID-19 hospitalized patients and 902,088 controls) with gene expression data from 208 lung tissues, Hi-C, and Chip-seq data. Through whole exome sequencing (WES), we explored rare coding variants in 147 severe COVID-19 patients. We identified three SNPs (rs9845542, rs12639314, and rs35951367) associated with severe COVID-19 whose risk alleles correlated with low CCR5 expression in lung tissues. The rs35951367 resided in a CTFC binding site that interacts with CCR5 gene in lung tissues and was confirmed to be associated with severe COVID-19 in two independent datasets. We also identified a rare coding variant (rs34418657) associated with the risk of developing severe COVID-19. Our results suggest a biological role of CCR5 in the progression of COVID-19 as common and rare genetic variants can increase the risk of developing severe COVID-19 by affecting the functions of CCR5.

To identify host genetic determinants involved in humoral immunity and associated with the risk of developing severe COVID-19, we analyzed 500 SARS-CoV-2 positive subjects from Southern Italy. We examined the coding sequences of 10 common variable immunodeficiency-associated genes obtained by the whole-exome sequencing of 121 hospitalized patients. These 10 genes showed significant enrichment in predicted pathogenic point mutations in severe patients compared with the non-severe ones. Moreover, in the TNFRSF13C gene, the minor allele of the p.His159Tyr variant, which is known to increase NF-kB activation and B-cell production, was significantly more frequent in the 38 severe cases compared to both the 83 non-severe patients and the 375 asymptomatic subjects further genotyped. This finding identified a potential genetic risk factor of severe COVID-19 that not only may serve to unravel the mechanisms underlying the disease severity but, also, may contribute to build the rationale for individualized management based on B-cell therapy.

Cardiovascular magnetic resonance (CMR) imaging is a key component of current diagnostic pathways in subjects with acute myocarditis. The 2020 ESC Guidelines on Sports Cardiology recommend athletes with acute myocarditis to abstain from sports during the recovery phase from inflammation and to undergo comprehensive evaluation—including CMR—before safely returning to play. This retrospective study analyzed 95 non-competitive athletes presenting with acute myocarditis and evaluated by initial and repeated CMRs. CMR exams assessed myocardial inflammation, edema, and scarring as defined based on the updated Lake Louise criteria. As per 2020 ESC Guidelines, eligibility was granted by excluding extensive myocardial damage. Initial CMR showed 84% positive STIR (edema) and 79% with LGE ≥ 3 segments. After 3–6 months, STIR positivity dropped to 12%, LGE extent remained globally stable, but with some reduction in 42%. Few experienced recurrent myocarditis or LVEF decline; 24% met return-to-play criteria by repeated CMR. Our study shows that few non-competitive athletes recovering from acute myocarditis meet ESC CMR criteria to resume competitive sports at prescribed follow-up evaluation. The long-term prognostic value of CMR markers like LGE and edema remains unclear, highlighting the need for further research to refine return-to-play guidelines and ensure athlete safety.