Background Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (COVID-19), exhibit a wide spectrum of disease behaviour. Since DNA methylation has been implicated in the regulation of viral infections and the immune system, we performed an epigenome-wide association study (EWAS) to identify candidate loci regulated by this epigenetic mark that could be involved in the onset of COVID-19 in patients without comorbidities. Methods Peripheral blood samples were obtained from 407 confirmed COVID-19 patients ≤ 61 years of age and without comorbidities, 194 (47.7%) of whom had mild symptomatology that did not involve hospitalization and 213 (52.3%) had a severe clinical course that required respiratory support. The set of cases was divided into discovery ( n = 207) and validation ( n = 200) cohorts, balanced for age and sex of individuals. We analysed the DNA methylation status of 850,000 CpG sites in these patients. Findings The DNA methylation status of 44 CpG sites was associated with the clinical severity of COVID-19. Of these loci, 23 (52.3%) were located in 20 annotated coding genes. These genes, such as the inflammasome component Absent in Melanoma 2 (AIM2) and the Major Histocompatibility Complex, class I C (HLA-C) candidates, were mainly involved in the response of interferon to viral infection. We used the EWAS-identified sites to establish a DNA methylation signature (EPICOVID) that is associated with the severity of the disease. Interpretation We identified DNA methylation sites as epigenetic susceptibility loci for respiratory failure in COVID-19 patients. These candidate biomarkers, combined with other clinical, cellular and genetic factors, could be useful in the clinical stratification and management of patients infected with the SARS-CoV-2. Funding The Unstoppable campaign of the Josep Carreras Leukaemia Foundation, the Cellex Foundation and the CERCA Programme/Generalitat de Catalunya.

Dear Editor,The mechanistic pathways leading to immune dysregulation and complications driven by uncontrolled severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection remain major challenges. 1,2 Hence, a detailed analysis of the proteome, metabolome and lipidome profile of coronavirus disease 2019 (COVID-19) patients showing different severity grades might shed light on the diseaseF I G U R E 1 Study design and clinical characterization of the study cohort. (A) Flowchart of the clinical strategy followed to categorize patients of the coronavirus disease-2019 (COVID-19) study cohort. (B) Incidence of comorbidities (a), COVID-19 symptoms (b), medication (c), and oxygen & intensive care (d), grouped by disease severity as mild, severe and critical patients. The size of bars (a, c) and circular (b , d) portions is proportional to the percentage of the corresponding comorbidity, symptom, medication or treatment. While patients with mild disease presented mostly anosmia, were treated with antibiotics and did not require oxygen supply, the incidence of dyspnea was significantly higher in the severe and critical groups, many of the latter requiring corticosteroids, hydroxychloroquine, lopinavir/ritonavir. Low-flow oxygen therapies were mainly necessary for severe patients, some of who required high-flow oxygen administration and, a high proportion of critical patients were intubated and required vasopressor administration or dialysis. Please note that COVID-19-related medication (b) was dispensed after blood sample collection, so that is assumed the subsequent analysis are not biased due to exposure to medication at the time of blood collectionThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.