ABSTRACT
Introduction. Coronavirus disease 2019 (COVID-19) survivors can develop residual lung abnormalities consistent with lung fibrosis. A shared genetic component between COVID-19 and idiopathic pulmonary fibrosis (IPF) has been shown. However, genetic overlap studies of IPF and COVID-19 have primarily concentrated on the IPF genome-wide significant risk variants that have been previously identified, rather than combined into a genome-wide polygenic risk. Here we used IPF genome-wide association study (GWAS) results to calculate polygenic risk scores (PRSs) and study their association with COVID-19 severity. Methods. We used results from the largest meta-GWAS of clinically defined IPF risk (base dataset; n=24,589) and individual-level imputed data from the SCOURGE study of patients with COVID-19 (target dataset; n=15,024). We calculated IPF PRSs using PRSice-2 and assessed their association with COVID-19 hospitalisation, severe illness, and critical illness. We also evaluated the effect of age and sex stratification. Results were validated using an independent PRS method. Enrichment analyses and pathway-specific PRSs were performed to study biological pathways associated with COVID-19 severity. Results. IPF PRSs were significantly associated with COVID-19 hospitalisation and severe illness. The strongest association was found in patients aged <60 years, especially among younger males (OR=1.16; 95%CI=1.08-1.25; p=6.39x10-5). A pathway enrichment analysis of the variants included in the best model fit and subsequent pathway-specific PRSs analyses supported the link of Cadherin and Integrin signalling pathways to COVID-19 severity when stratified by age and sex. Conclusion. Our results suggest that there is genome-wide genetic overlap between IPF and severe COVID-19 that is dependent on age and sex and adds further support that the pathogenesis of both IPF and severe COVID-19 share underlying biological mechanisms. This could imply that individuals with a high IPF genetic risk are at an overall increased risk of developing lung sequelae resulting from severe COVID-19.
Subject(s)
Fibrosis , Lung Diseases , Critical Illness , Idiopathic Pulmonary Fibrosis , COVID-19ABSTRACT
BackgroundWe aimed to determine whether a 6-day course of intravenous methylprednisolone (MP) improves outcome in patients with SARS CoV-2 infection at risk of developing Acute Respiratory Distress Syndrome (ARDS). MethodsMulticentric, partially randomized, preference, open-label trial, including adults with COVID-19 pneumonia, impaired gas exchange and biochemical evidence of hyper-inflammation. Patients were assigned to standard of care (SOC), or SOC plus intravenous MP [40mg/12h 3 days, then 20mg/12h 3 days]. The primary endpoint was a composite of death, admission to the intensive care unit (ICU) or requirement of non-invasive ventilation (NIV). ResultsWe analyzed 85 patients (34, randomized to MP; 22, assigned to MP by clinicians preference; 29, control group). Patients age (mean 68{+/-}12 yr) was related to outcome. The use of MP was associated with a reduced risk of the composite endpoint in the intention-to-treat, age-stratified analysis (combined risk ratio -RR-0.55 [95% CI 0.33-0.91]; p=0.024). In the per-protocol analysis, RR was 0.11 (0.01-0.83) in patients aged 72 yr or less, 0.61 (0.32-1.17) in those over 72 yr, and 0.37 (0.19-0.74, p=0.0037) in the whole group after age-adjustment by stratification. The decrease in C-reactive protein levels was more pronounced in the MP group (p=0.0003). Hyperglycemia was more frequent in the MP group. ConclusionsA short course of MP had a beneficial effect on the clinical outcome of severe COVID-19 pneumonia, decreasing the risk of the composite end point of admission to ICU, NIV or death. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/20133579v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@1adf5f9org.highwire.dtl.DTLVardef@1efecd8org.highwire.dtl.DTLVardef@a65f07org.highwire.dtl.DTLVardef@a8df92_HPS_FORMAT_FIGEXP M_FIG C_FIG