Cardiopulmonary work up of patients with and without fatigue 6 months after COVID-19 (preprint)

The pathogenesis of post-COVID-19 symptoms remains incompletely understood. Therefore, we aimed to determine cardiopulmonary limitations six months after surviving COVID-19 using pulmonary function tests (PFTs), echocardiographic studies to the point of analyses of global-longitudinal-strain (GLS), which describes the cycling myocardium deformation and provides better data on left ventricular (LV) dysfunction than LV ejection fraction (LVEF), and validated questionnaires. Overall, 60 consecutive hospitalized patients were included (61±2 years, 32% treated in the ICU). At follow-up (194±3 days after discharge), fatigue was the most prevalent symptom (28%). Patients with fatigue were more symptomatic overall and characterized by worse quality of life (QoL) scores compared to patients without fatigue (all p<0.05), mainly due to limited mobility and high symptom burden. While PFT variables and LVEF were normal in the vast majority (LVEF=52% (45%-52%)) of patients, GLS was significantly reduced (-15%(-18%_-14%)). However, GLS values were not different between patients with and without fatigue. In conclusion, fatigue was the most prevalent post-COVID-19 symptom in our cohort, which was associated with worse QoL mainly due to limited mobility and the high burden of concomitant symptoms. Patients showed a subtle myocardial dysfunction six months after surviving COVID-19, but this did not relate to the presence of fatigue.

Glycemic Variability Is Associated With All-Cause Mortality In COVID-19 Patients With ARDSFindings From The COVAS Cohort (preprint)

There is high mortality among intensive care unit (ICU) patients with acute respiratory distress syndrome (ARDS) caused by coronavirus disease 19 (COVID-19). Important factors for COVID-19 mortality are diabetes status and elevated fasting plasma glucose (FPG). However, the effect of glycemic variability on survival has not been explored in patients with COVID-19 and ARDS. This single-centre cohort-study compared several metrics of daily glycemic variability (DGV) for goodness-of-fit in patients requiring mechanical ventilation due to COVID-19 ARDS in the ICU at University Hospital Aachen, Germany. 106 patients had moderate to severe ARDS (P/F ratio median [IQR]: 112 [87-148] mmHg). Continuous HRs showed a proportional increase in mortality risk with DGV. Multivariable unadjusted and adjusted Cox-models showed a statistically significant difference in mortality for DGV (HR: 1.02, (P)<0.001, LR(P)<0.001; HR: 1.016, (P)=0.001, LR(P)<0.001, respectively). Kaplan-Meier estimators yielded a shorter median survival (25 vs. 87 days) and higher likelihood of death (75% vs. 31%) in patients with DGV ≥ 25.5mg/dl (P<0.0001). High glycemic variability during ICU admission is associated with significant increase in all-cause mortality for patients admitted with COVID-19 ARDS to the ICU. This effect persisted even after adjustment for clinically predetermined confounders, including diabetes, procalcitonin and FPG levels at baseline.

Diaphragm Dysfunction as a Determinant of Persisting Dyspnoea in Patients One Year after Invasive Mechanical Ventilation Due to COVID-19 Related ARDS (preprint)

Background: Some patients with coronavirus disease 2019 (COVID-19) experience prolonged fatigue and dyspnoea without objective impairment of pulmonary or cardiac function. This study determined diaphragm function and its central voluntary activation as a possible pathophysiological correlate after severe COVID-19 acute respiratory distress syndrome (ARDS).Methods:Ten patients with severe COVID-19 ARDS treated with invasive mechanical ventilation (IMV) (6 female, age 56±14 years, 63±45 days of IMV) and ten matched healthy controls underwent pulmonary function tests (PFTs), 6-minute walk test, echocardiography, diaphragm ultrasound, and invasive recording of twitch transdiaphragmatic pressure (twPdi) following magnetic diaphragm stimulation. Twitch interpolation was used to determine the diaphragm voluntary activation index (DVAI); reflecting central diaphragm activation.Findings: One year post discharge, neither PFTs nor echocardiography were indicative of significant abnormalities in severe COVID-19 survivors. However, six patients reported persisting dyspnoea on exertion (severe in two, moderate in four). On ultrasound, the diaphragm thickening ratio was lower in patients versus controls (1.87±0.37 vs. 2.76±0.72; p<0.01), and diaphragm excursion velocity during a maximum sniff manoeuvre was associated with dyspnoea. TwPdi following cervical magnetic stimulation did not differ between patients and controls overall, but twPdi half relaxation time progressively increased in parallel with dyspnoea severity (ANOVA p=0.03), while sniff Pdi progressively decreased (ANOVA p=0.05). DVAI was lower in patients versus controls (30±27% vs 79±6%, p<0.01) and was associated with dyspnoea (ANOVA p=0.05).Interpretation: Inspiratory muscle dysfunction with impaired central voluntary activation of the diaphragm is present one year after severe COVID-19 ARDS treated with IMV, and relates to dyspnoea.Trial Registration: This prospective case-control study was registered with number, (NCT04854863)Funding: None to declare. Declaration of Interest: The authors have no conflicts of interest to disclose.Ethical Approval: This study was approved by the local ethics committee (Ethikkommission an der Medizinischen Fakultät der Rheinisch-Westfälischen Technischen Hochschule Aachen, CTCA-A-Nr. 20-515, AZ EK 443/20).

New susceptibility loci for severe COVID-19 by detailed GWAS analysis in European populations (preprint)

Due to the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), deepening the host genetic contribution to severe COVID-19 may further improve our understanding about underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany, as well as hypothesis-driven targeted analysis of the human leukocyte antigen (HLA) region and chromosome Y haplotypes. We include detailed stratified analyses based on age, sex and disease severity. In addition to already established risk loci, our data identify and replicate two genome-wide significant loci at 17q21.31 and 19q13.33 associated with severe COVID-19 with respiratory failure. These associations implicate a highly pleiotropic ~0.9-Mb 17q21.31 inversion polymorphism, which affects lung function and immune and blood cell counts, and the NAPSA gene, involved in lung surfactant protein production, in COVID-19 pathogenesis.

Epigenetic clocks are not accelerated in COVID-19 patients (preprint)

Age is a major risk factor for severe outcome of coronavirus disease 2019 (COVID-19), but it remains unclear if this is rather due to increased chronological age or biological age. During lifetime, specific DNA methylation changes are acquired in our genome that act as "epigenetic clocks" allowing to estimate donor age and to provide a surrogate marker for biological age. In this study, we followed the hypothesis that particularly patients with accelerated epigenetic age are affected by severe outcomes of COVID-19. Using four different age predictors, we did not observe accelerated age in global DNA methylation profiles of blood samples of nine COVID-19 patients. Alternatively, we used targeted bisulfite amplicon sequencing of three age-associated genomic regions to estimate donor-age of blood samples of 95 controls and seventeen COVID-19 patients. The predictions correlated well with chronological age, while COVID-19 patients even tended to be predicted younger than expected. Furthermore, lymphocytes in nineteen COVID-19 patients did not reveal significantly accelerated telomere attrition. Our results demonstrate that these biomarkers of biological age are therefore not suitable to predict a higher risk for severe COVID-19 infection in elderly patients.

Clinical course of COVID-19 patients needing supplemental oxygen outside the intensive care unit (preprint)

Purpose: Patients suffering from CVOID-19 mostly experience a benign course of the disease. Approximately 14 % of SARS-CoV2 infected patients are admitted to a hospital. Cohorts exhibiting severe lung failure in the form of acute respiratory distress syndrome (ARDS) have been well characterized. Patients without ARDS but in need of supplementary oxygen have received much less attention. This study describes the diagnosis, symptoms, treatment and outcomes of hospitalized patients with COVID-19 needing oxygen support during their stay on regular ward.Methods: All 133 patients admitted to the RWTH Aachen university hospital with the diagnosis of COVID-19 were included in an observational registry. Clinical data sets were extracted from the hospital information system. This analysis includes all 57 patients requiring supplemental oxygen not admitted to the ICU.Results: 57 patients needing supplemental oxygen and being treated outside the ICU were analyzed. Patients exhibited the typical set of symptoms for COVID-19. Of note, hypoxic patients mostly did not suffer from clinically relevant dyspnea despite oxygen saturations below 92 %. Patients had fever for 7 [2-11] days and needed supplemental oxygen for 8 [5-13] days resulting in an overall hospitalization time of 12 [7-20] days. In addition, patients had persisting systemic inflammation with CRP levels remaining elevated until discharge or death.Conclusion: This description of COVID-19 patients requiring oxygen therapy should be taken into account when planning treatment capacity. Patients on oxygen need long-term inpatient care.