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.

The contribution of endogenous pain modulation dysfunction to clinical and sensory measures of neuropathic pain (NP) has not been fully explored. Habituation, temporal summation, and heterotopic noxious conditioning stimulus-induced modulation of tonic heat pain intensity were examined in healthy noninjured subjects (n = 10), and above the level of spinal cord injury (SCI) in individuals without (SCI-noNP, n = 10) and with NP (SCI-NP, n = 10). Thermoalgesic thresholds, Cz/AFz contact heat evoked potentials (CHEPs), and phasic or tonic (30 seconds) heat pain intensity were assessed within the C6 dermatome. Although habituation to tonic heat pain intensity (0-10) was reported by the noninjured (10 s: 3.5 ± 0.3 vs 30 s: 2.2 ± 0.5 numerical rating scale; P = 0.003), loss of habituation was identified in both the SCI-noNP (3.8 ± 0.3 vs 3.6 ± 0.5) and SCI-NP group (4.2 ± 0.4 vs 4.9 ± 0.8). Significant temporal summation of tonic heat pain intensity was not observed in the 3 groups. Inhibition of tonic heat pain intensity induced by heterotopic noxious conditioning stimulus was identified in the noninjured (-29.7% ± 9.7%) and SCI-noNP groups (-19.6% ± 7.0%), but not in subjects with SCI-NP (+1.1% ± 8.0%; P < 0.05). Additionally, the mean conditioned pain modulation response correlated positively with Cz/AFz CHEP amplitude (ρ = 0.8; P = 0.015) and evoked heat pain intensity (ρ = 0.8; P = 0.007) in the SCI-NP group. Stepwise regression analysis revealed that the mean conditioned pain modulation (R = 0.72) correlated with pain severity and pressing spontaneous pain in the SCI-NP group. Comprehensive assessment of sensory dysfunction above the level of injury with tonic thermal test and conditioning stimuli revealed less-efficient endogenous pain modulation in subjects with SCI-NP.

Cumulative childhood adverse events may be a more relevant risk factor for chronic pain conditions than the experience of a specific type of adverse event. Clinicians and researchers need to evaluate cumulative childhood adversity when assessing its link to chronic pain.

BACKGROUND: Coronavirus disease 2019 (COVID-19) patients present long-lasting physical and neuropsychological impairment, which may require rehabilitation. OBJECTIVES: The current cross-sectional study characterizes post COVID-19 sequelae and persistent symptoms in patients in an outpatient rehabilitation program. METHODS: Thirty patients [16 post-ICU and 14 non-ICU; median age = 54(43.8–62) years; 19 men] presenting sequelae and/or persistent symptoms (>3 months after acute COVID-19) were selected of 41 patients referred for neurorehabilitation. Patients underwent physical, neuropsychological and respiratory evaluation and assessment of impact of fatigue and quality of life. RESULTS: The main reasons for referral to rehabilitation were: fatigue (86.6%), dyspnea (66.7%), subjective cognitive impairment (46.7%) and neurological sequelae (33.3%). Post-ICU patient presented sequelae of critical illness myopathy and polyneuropathy, stroke and encephalopathy and lower forced vital capacity compared to non-ICU patients. Cognitive impairment was found in 63.3% of patients, with a similar profile in both sub-groups. Increased physical fatigue, anxiety and depression and low quality of life were prevalent irrespective of acute COVID-19 severity. CONCLUSIONS: The variability of post COVID-19 physical and neuropsychological impairment requires a complex screening process both in ICU and non-ICU patients. The high impact of persistent symptoms on daily life activities and quality of life, regardless of acute infection severity, indicate need for rehabilitation.