Implementing remote monitoring for COVID-19 patients in primary care (preprint)

Background: In Germany, most patients with coronavirus disease 2019 (COVID-19) are treated in an outpatient setting. To improve assessments of the health status of COVID-19 outpatients, various remote monitoring models have been developed. However, little information exists on experiences acquired with remote monitoring in an outpatient setting, particularly from a patient perspective. The aim of our 'COVID-19@home' study was therefore to implement and evaluate an app-based remote monitoring concept for acute and post-acute COVID-19-patients in primary care. In this paper, we focus on the patients' evaluation of our remote monitoring approach. Methods Patients with acute COVID-19 measured heart rate, blood pressure, oxygen saturation, and body temperature daily for 28 days. Patients with post-acute COVID-19 determined the same parameters for 12 weeks, supplemented by lung parameters and daily step count. The data were documented using the 'SaniQ' smartphone app. COVID-19 symptoms were assessed daily using an app-based questionnaire. Patients' GPs could access the data on the 'SaniQ Praxis' telemedicine platform. We used an app-based questionnaire consisting of 11 questions presented with a 4-point Likert scale to evaluate patient satisfaction. Data were analyzed descriptively. Results Of the 51 patients aged 19-77 years that participated in the study, 42 completed the questionnaire. All patients rated home monitoring as 'very good' or 'rather good' and were able to integrate the measuring processes into their daily routines. Overall, 93% would recommend the app and the measuring devices to their family and friends. About 60% felt that their COVID-19 treatment had benefited from home monitoring. Only few patients were unsettled by the app and use of the measuring devices. During the course of the study, the implementation process was optimized. Conclusions The use of remote monitoring in COVID-19 patients is feasible and was evaluated positively by most study patients. However, it is difficult to imagine how general practices could cope with monitoring patients with acute diseases without any further organizational support. Future research should address cost-effectiveness and changes in such clinical outcomes as hospitalization and mortality.

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.

Validation of a prospective urinalysis-based prediction model for ICU-resources and outcome of Covid-19 disease: A multicenter cohort study (preprint)

Purpose: Identifying preventive strategies in Covid-19 patients helps to improve ICU-resource-allocation and reduce mortality. We recently demonstrated in a post-mortem cohort that SARS-CoV-2 renal tropism was associated with kidney injury, disease severity and mortality. We also proposed an algorithm to predict the need for ICU-resources and the risk of adverse outcomes in Covid-19 patients harnessing urinalysis and protein/coagulation parameters on admission for signs of kidney injury. Here, we aimed to validate this hypothesis in a multicenter cohort. Methods: Patients hospitalized for Covid-19 at four tertiary centers were screened for an available urinalysis, serum albumin (SA) and antithrombin-III activity (AT-III) obtained prospectively within 48h upon admission. The respective presumed risk for an unfavorable course was categorized as “low”, “intermediate” or “high”, depending on a normal urinalysis, an abnormal urinalysis with SA ≥2 g/dl and AT-III ≥70%, or an abnormal urinalysis with at least one SA or AT-III abnormality. Time to ICU or death within ten days served as primary, in-hospital mortality and required organ support served as secondary endpoints.Results: Among a total of N=223 screened patients, N=145 were eligible for enrollment, falling into the low (N=43), intermediate (N=84), and high risk (N=18) categories. The risk for ICU transfer or death was 100% in the high risk group and significantly elevated in the composite of high and intermediate risk as compared to the low risk group (63.7% vs. 27.9%; HR 2.6; 95%-CI 1.4 to 4.9; P=0.0020). Having an abnormal urinalysis was associated with mortality, need for mechanical ventilation, extra-corporeal membrane oxygenation (ECMO) or renal replacement therapy (RRT). Conclusion: Our data confirm that Covid-19-associated urine abnormalities on admission predict disease aggravation and need for ICU. By engaging a simple urine dipstick on hospital admission our algorithm allows for early preventive measures and appropriate patient stratification. (ClinicalTrials.gov number NCT04347824)

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.

Validation of a Prospective Urinalysis-Based Prediction Model for the Outcome of COVID-19 Disease: A Multicenter Cohort Study (preprint)

Background: Identifying preventive strategies in Covid-19 patients will help to improve resource-allocation and reduce mortality. In this Journal, we recently demonstrated in a post-mortem cohort that SARS-CoV-2 renal tropism was associated with kidney injury, disease severity and mortality. We also proposed an algorithm to predict the risk of adverse outcomes in Covid-19 patients harnessing urinalysis and protein/coagulation parameters on admission for signs of kidney injury. Here, we aimed to validate this hypothesis in a multicenter cohort.Methods: Patients hospitalized for Covid-19 at four tertiary centers were screened for an available urinalysis, serum albumin (SA) and antithrombin-III activity (AT-III) obtained prospectively within 48h upon admission. The respective presumed risk for an unfavorable course was categorized as “low”, “intermediate” or “high”, depending on a normal urinalysis, an abnormal urinalysis with SA ≥2 g/dl and AT-III ≥70%, or an abnormal urinalysis with at least one SA or AT-III abnormality. Time to ICU or death within ten days served as primary, in-hospital mortality and required organ support served as secondary endpoints.Findings: Among a total of N=223 screened patients, N=145 were eligible for enrollment, falling into the low (N=43), intermediate (N=84), and high risk (N=18) categories. The risk for ICU transfer or death was 100% in the high risk group and significantly elevated in the composite of high and intermediate risk as compared to the low risk group (63·7% vs. 27·9%; HR 2·6; 95%-CI 1·4 to 4·9; P=0·0020). Having an abnormal urinalysis was associated with mortality, need for mechanical ventilation, extra-corporeal membrane oxygenation (ECMO) or renal replacement therapy (RRT).Interpretation: Our data confirm that Covid-19-associated urine abnormalities on admission predict disease aggravation. This supports the conceptual relevance of Covid-19-associated kidney injury. By engaging a simple urine dipstick our algorithm allows for early preventive measures and appropriate patient stratification. Trial Registration: (ClinicalTrials.gov number NCT04347824)Funding Statement: This work was supported by the DFG (GR 1852/6-1 to OG; CRC1192 to JET, EH and TBH), (HU 1016/8-2, HU 1016/11-1, HU 1016/ 12-1 to TBH) and (GR 1852/6-1 to OG); by the BMBF (STOP-FSGS-01GM1518C and NephrESA-031L0191E to TBH), by the Else-Kröner Fresenius Foundation (Else Kröner-Promotionskolleg –iPRIME to TBH), and by the H2020-IMI2 consortium BEAt-DKD (115974 to TBH). In addition, the UMG Göttingen applied for Government funding (Covid-19 program) by The German Federal Ministry of Education and Research and the application currently is under consideration.Declaration of Interests: All authors report no conflict of interest in relation to this observational cohort-study. Ethics Approval Statement: According to the German Medicines Act, the study was approved by the leading institutional review board (IRB) of the UMG Göttingen (41/4/20), and all others.