Impact of the COVID-19 pandemic on aortic valve replacement procedures in Germany.

BACKGROUND: COVID-19 has caused the deferral of millions of elective procedures, likely resulting in a backlog of cases. We estimate the number of postponed surgical aortic valve replacement (sAVR) and transcatheter aortic valve replacement (TAVR) procedures during the first two waves of the COVID-19 pandemic in Germany. METHODS: Using German national records, all isolated TAVR and sAVR procedures between 2007 and 2020 were identified. Using weekly TAVR and sAVR procedures between 2017 and 2019, we created a forecast for 2020 and compared it with the observed number of procedures in 2020. RESULTS: In Germany, a total of 225,398 isolated sAVR and 159,638 isolated TAVR procedures were conducted between 2007 and 2020 that were included in our analysis. The reduction in all AVR procedures (sAVR and TAVR) for the entire year 2020 was 19.07% (95%CI: 15.19-22.95%). During the first wave of the pandemic (week 12-21), the mean weekly reduction was 32.06% (23.44-40.68%) and during the second wave of the pandemic (week 41-52), the mean weekly reduction was 25.58% (14.19-36.97%). The number of sAVR procedures decreased more than the number of TAVR procedures (24.63% vs. 16.42% for the entire year 2020). CONCLUSION: The first year of the COVID-19 pandemic saw a substantial postponing of AVR procedures in Germany. Postponing was higher for sAVR than for TAVR procedures and less pronounced during the second wave of the COVID-19 pandemic.

Local, collaborative, stepped, and personalized care management for older people with chronic diseases - results from the randomized controlled LoChro-trial.

BACKGROUND: In the aging population of Western societies, an increasing number of older adults have multiple chronic diseases. As multifaceted health problems imply the involvement of several healthcare professionals, multimorbid older people frequently face a fragmentation of health care. Addressing these challenges, we developed a local, collaborative, stepped, and personalized care management approach (LoChro-Care) and evaluated its effectiveness. METHODS: A two-group, parallel randomized controlled trial was conducted comparing LoChro-Care recipients (IG) to participants with usual care (CG). Patients aged 65 + with chronic conditions were recruited at inpatient and outpatient departments of the Medical Center, University of Freiburg. Participants were allocated using block randomization (nIG = 261, nCG = 263). LoChro-Care comprised individualized care provided by chronic care managers with 7 to 13 contacts over 12 months. Questionnaires were given at 3 time points (T0: baseline, T1: after 12 months, T2: after 18 months). The primary outcome was the physical, psychological, and social health status represented by a composite score of functional health and depressive symptoms. Secondary outcomes were the participants' evaluation of their health care situation, health-related quality of life (HRQL), and life-satisfaction (LS). The data were analyzed using linear mixed modelling. RESULTS: We analyzed N = 491 participants (nIG = 244, nCG = 247), aged M = 76.78 years (SD = 6.35). For the composite endpoint, neither a significant difference between IG and CG (p = .88) nor a group-time interaction (p = .52; p = .88) could be observed. Participants in both groups showed a significant decline on the primary outcome between T0 and T2 (p < .001). Post hoc analyses revealed a decline in both functional health (p < .001) and depressive symptoms (p = .02). Both groups did not differ in their evaluation of their health care situation (p = .93), HRQL (p = .44) or LS (p = .32). Relevant confounding variables were female gender and multimorbidity. CONCLUSION: Supporting patients' self-management in coordinating their individual care network through LoChro-Care did not result in any significant effect on the primary and secondary outcomes. A decline of functional health and depressive symptoms was observed among all participants. Potential future intervention adaptations are discussed, such as a more active case management through direct referral to (in-)formal support, an earlier treatment initiation, and the consideration of specific sociodemographic factors in care management planning. TRIAL REGISTRATION: German Clinical Trials Register (DRKS): DRKS00013904 (02.02.2018), https://drks.de/search/de/trial/DRKS00013904.

COVID-19 pandemic affects STEMI numbers and in-hospital mortality: results of a nationwide analysis in Germany.

BACKGROUND: The COVID-19 pandemic led to extensive restrictions in Germany in 2020, including the postponement of elective interventions. We examined the impact on ST-elevation myocardial infarction (STEMI) as an acute and non-postponable disease. METHODS: Using German national records, all STEMI between 2017 and 2020 were identified. Using the number of STEMI cases between 2017 and 2019, we created a forecast for 2020 and compared it with the observed number of STEMI in 2020. RESULTS: From 2017 to 2020, 248,062 patients were treated for STEMI in Germany. Mean age was 65.21 years and 28.36% were female. When comparing forecasted and observed STEMI in 2020, a correlation can be seen: noticeable fewer STEMI were treated in those weeks respectively months with an increasing COVID-19 hospitalization rate (monthly percentage decrease in STEMI: March - 14.85%, April - 13.39%, November - 11.92%, December - 22.95%). At the same time, the crude in-hospital mortality after STEMI increased significantly at the peaks of the first and second waves (relative risk/RR of monthly in-hospital mortality: April RR = 1.11 [95% CI 1.02; 1.21], November RR = 1.13 [1.04; 1.24], December RR = 1.16 [1.06; 1.27]). CONCLUSION: The COVID-19 pandemic led to a noticeable decrease in the number of STEMI interventions in Germany at the peaks of the first and second waves in 2020, corresponding to an increase in COVID-19 hospitalizations. At the same time, in-hospital mortality after STEMI increased significantly in these phases. Impact of the COVID-19 pandemic on STEMI numbers and in-hospital mortality in Germany. Relative difference between forecasted and observed STEMI numbers (above figure), the relative risk of in-hospital mortality (middle figure) as well as number of new hospital admissions for COVID-19 per million inhabitants according to Roser et al.27 (bottom figure).

Myocarditis mortality with and without COVID-19: insights from a national registry.

BACKGROUND: Myocarditis in context of a SARS-CoV-2 infection is vividly discussed in the literature. Real-world data however are sparse, and relevance of the myocarditis diagnosis to outcome in coronavirus disease (COVID-19) is unclear. PATIENTS AND METHODS: Retrospective analysis of 75,304 patients hospitalized in Germany with myocarditis between 2007 and 2020 is reported by DESTATIS. Patients hospitalized between 01/2016 and 12/2019 served as reference cohort for the COVID-19 patients hospitalized in 2020. RESULTS: A total of 75,304 patients were hospitalized between 2007 and 2020 (age 42.5 years, 30.1% female, hospital mortality 2.4%). In the reference cohort, 24,474 patients (age 42.8 years, 29.5% female, hospital mortality 2.2%) were registered. In 2020, annual myocarditis hospitalizations dropped by 19.6% compared to reference (4921 vs. 6119 annual hospitalization), of which 443/4921 (9.0%) were connected to COVID-19. In 2020, hospital mortality of myocarditis in non-COVID-19 patients increased significantly compared to reference (2.9% vs. 2.2%, p = 0.008, OR 1.31, 95% CI 1.08-1.60). In COVID-19 myocarditis, hospital mortality was even higher compared to reference (13.5% vs. 2.2%, p < 0.001, OR 6.93, 95% CI 5.18-9.18). CONCLUSION: The burden of patients with myocarditis and COVID-19 in 2020 was low. Hospital mortality was more than sixfold higher in patients with myocarditis and COVID-19 compared to those with myocarditis but without COVID-19.

Long COVID symptoms in exposed and infected children, adolescents and their parents one year after SARS-CoV-2 infection: A prospective observational cohort study.

BACKGROUND: Long COVID in children and adolescents remains poorly understood due to a lack of well-controlled studies with long-term follow-up. In particular, the impact of the family context on persistent symptoms following SARS-CoV-2 infection remains unknown. We examined long COVID symptoms in a cohort of infected children, adolescents, and adults and their exposed but non-infected household members approximately 1 year after infection and investigated clustering of persistent symptoms within households. METHODS: 1267 members of 341 households (404 children aged <14 years, 140 adolescents aged 14-18 years and 723 adults) were categorized as having had either a SARS-CoV-2 infection or household exposure to SARS-CoV-2 without infection, based on three serological assays and history of laboratory-confirmed infection. Participants completed questionnaires assessing the presence of long COVID symptoms 11-12 months after infection in the household using online questionnaires. FINDINGS: The prevalence of moderate or severe persistent symptoms was statistically significantly higher in infected than in exposed women (36.4% [95% CI: 30.7-42.4%] vs 14.2% [95% CI: 8.7-21.5%]), infected men (22.9% [95% CI: 17.9-28.5%] vs 10.3% [95% CI: 5.8-16.9%]) and infected adolescent girls (32.1% 95% CI: 17.2-50.5%] vs 8.9% [95%CI: 3.1-19.8%]). However, moderate or severe persistent symptoms were not statistically more common in infected adolescent boys aged 14-18 (9.7% [95% CI: 2.8-23.6%] or in infected children <14 years (girls: 4.3% [95% CI: 1.2-11.0%]; boys: 3.7% [95% CI: 1.1-9.6%]) than in their exposed counterparts (adolescent boys: 0.0% [95% CI: 0.0-6.7%]; girls < 14 years: 2.3% [95% CI: 0·7-6·1%]; boys < 14 years: 0.0% [95% CI: 0.0-2.0%]). The number of persistent symptoms reported by individuals was associated with the number of persistent symptoms reported by their household members (IRR=1·11, p=·005, 95% CI [1.03-1.20]). INTERPRETATION: In this controlled, multi-centre study, infected men, women and adolescent girls were at increased risk of negative outcomes 11-12 months after SARS-CoV-2 infection. Amongst non-infected adults, prevalence of negative outcomes was also high. Prolonged symptoms tended to cluster within families, suggesting family-level interventions for long COVID could prove useful. FUNDING: Ministry of Science, Research and the Arts, Baden-Württemberg, Germany.

Robust and durable serological response following pediatric SARS-CoV-2 infection.

The quality and persistence of children's humoral immune response following SARS-CoV-2 infection remains largely unknown but will be crucial to guide pediatric SARS-CoV-2 vaccination programs. Here, we examine 548 children and 717 adults within 328 households with at least one member with a previous laboratory-confirmed SARS-CoV-2 infection. We assess serological response at 3-4 months and 11-12 months after infection using a bead-based multiplex immunoassay for 23 human coronavirus antigens including SARS-CoV-2 and its Variants of Concern (VOC) and endemic human coronaviruses (HCoVs), and additionally by three commercial SARS-CoV-2 antibody assays. Neutralization against wild type SARS-CoV-2 and the Delta VOC are analysed in a pseudotyped virus assay. Children, compared to adults, are five times more likely to be asymptomatic, and have higher specific antibody levels which persist longer (96.2% versus 82.9% still seropositive 11-12 months post infection). Of note, symptomatic and asymptomatic infections induce similar humoral responses in all age groups. SARS-CoV-2 infection occurs independent of HCoV serostatus. Neutralization responses of children and adults are similar, although neutralization is reduced for both against the Delta VOC. Overall, the long-term humoral immune response to SARS-CoV-2 infection in children is of longer duration than in adults even after asymptomatic infection.

Pre-medication with oral anticoagulants is associated with better outcomes in a large multinational COVID-19 cohort with cardiovascular comorbidities.

AIMS: Coagulopathy and venous thromboembolism are common findings in coronavirus disease 2019 (COVID-19) and are associated with poor outcome. Timely initiation of anticoagulation after hospital admission was shown to be beneficial. In this study we aim to examine the association of pre-existing oral anticoagulation (OAC) with outcome among a cohort of SARS-CoV-2 infected patients. METHODS AND RESULTS: We analysed the data from the large multi-national Lean European Open Survey on SARS-CoV-2 infected patients (LEOSS) from March to August 2020. Patients with SARS-CoV-2 infection were eligible for inclusion. We retrospectively analysed the association of pre-existing OAC with all-cause mortality. Secondary outcome measures included COVID-19-related mortality, recovery and composite endpoints combining death and/or thrombotic event and death and/or bleeding event. We restricted bleeding events to intracerebral bleeding in this analysis to ensure clinical relevance and to limit reporting errors. A total of 1 433 SARS-CoV-2 infected patients were analysed, while 334 patients (23.3%) had an existing premedication with OAC and 1 099 patients (79.7%) had no OAC. After risk adjustment for comorbidities, pre-existing OAC showed a protective influence on the endpoint death (OR 0.62, P = 0.013) as well as the secondary endpoints COVID-19-related death (OR 0.64, P = 0.023) and non-recovery (OR 0.66, P = 0.014). The combined endpoint death or thrombotic event tended to be less frequent in patients on OAC (OR 0.71, P = 0.056). CONCLUSIONS: Pre-existing OAC is protective in COVID-19, irrespective of anticoagulation regime during hospital stay and independent of the stage and course of disease.

Influence of immunosuppression in patients with severe acute respiratory distress syndrome on veno-venous extracorporeal membrane oxygenation therapy.

Prognosis of patients suffering from acute respiratory distress syndrome (ARDS) is poor. This is especially true for immunosuppressed patients. It is controverisal whether these patients should receive veno-venous extracorporeal membrane oxygenation (VV ECMO) while evidence on this topic is sparse. We report retrospective data of a single-center registry of patients with severe ARDS requiring ECMO support between October 2010 and June 2019. Patients were analyzed by their status of immunosuppression. ECMO weaning success and hospital survival were analyzed before and after propensity score matching (PSM). Moreover, ventilator free days (VFD) were compared. A total of 288 patients were analyzed (age 55 years, 67% male), 88 (31%) presented with immunosuppression. Survival rates were lower in immunosuppressed patients (27% vs. 53%, P < .001 and 27% vs. 48% after PSM, P = .006). VFD (60 days) were lower for patients with immunosuppression (11.9 vs. 22.4, P < .001), and immunosuppression was an independent predictor for mortality in multivariate analysis. Hospital survival was 20%, 14%, 35%, and 46% for patients with oncological malignancies, solid organ transplantation, autoimmune diseases, and HIV, respectively. In this analysis immunosuppression was an independent predictor for mortality. However, there were major differences in the weaning and survival rates between the etiologies of immunosuppression which should be considered in decision making.

Outcome Prediction in Patients with Severe COVID-19 Requiring Extracorporeal Membrane Oxygenation-A Retrospective International Multicenter Study.

The role of veno-venous extracorporeal membrane oxygenation therapy (V-V ECMO) in severe COVID-19 acute respiratory distress syndrome (ARDS) is still under debate and conclusive data from large cohorts are scarce. Furthermore, criteria for the selection of patients that benefit most from this highly invasive and resource-demanding therapy are yet to be defined. In this study, we assess survival in an international multicenter cohort of COVID-19 patients treated with V-V ECMO and evaluate the performance of several clinical scores to predict 30-day survival. METHODS: This is an investigator-initiated retrospective non-interventional international multicenter registry study (NCT04405973, first registered 28 May 2020). In 127 patients treated with V-V ECMO at 15 centers in Germany, Switzerland, Italy, Belgium, and the United States, we calculated the Sequential Organ Failure Assessment (SOFA) Score, Simplified Acute Physiology Score II (SAPS II), Acute Physiology And Chronic Health Evaluation II (APACHE II) Score, Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) Score, Predicting Death for Severe ARDS on V­V ECMO (PRESERVE) Score, and 30-day survival. RESULTS: In our study cohort which enrolled 127 patients, overall 30-day survival was 54%. Median SOFA, SAPS II, APACHE II, RESP, and PRESERVE were 9, 36, 17, 1, and 4, respectively. The prognostic accuracy for all these scores (area under the receiver operating characteristic-AUROC) ranged between 0.548 and 0.605. CONCLUSIONS: The use of scores for the prediction of mortality cannot be recommended for treatment decisions in severe COVID-19 ARDS undergoing V-V ECMO; nevertheless, scoring results below or above a specific cut-off value may be considered as an additional tool in the evaluation of prognosis. Survival rates in this cohort of COVID-19 patients treated with V­V ECMO were slightly lower than those reported in non-COVID-19 ARDS patients treated with V-V ECMO.

Outcome of acute respiratory distress syndrome requiring extracorporeal membrane oxygenation in Covid-19 or influenza: A single-center registry study.

Veno-venous extracorporeal membrane oxygenation (V-V ECMO) is used to sustain blood oxygenation and decarboxylation in severe acute respiratory distress syndrome (ARDS). It is under debate if V-V ECMO is as appropriate for coronavirus disease 2019 (Covid-19) ARDS as it is for influenza. In this retrospective study, we analyzed all patients with confirmed SARS-CoV-2 or influenza A/B infection, ARDS and V-V ECMO, treated at our medical intensive care unit (ICU) between October 2010 and June 2020. Baseline and procedural characteristics as well as survival 30 days after ECMO cannulation were analyzed. A total of 62 V-V ECMO patients were included (15 with Covid-19 and 47 with influenza). Both groups had similar baseline characteristics at cannulation. Thirty days after ECMO cannulation, 13.3% of all patients with Covid-19 were discharged alive from our ICU compared to 44.7% with influenza (P = .03). Patients with Covid-19 had fewer ECMO-free days (0 (0-9.7) days vs. 13.2 (0-22.1) days; P = .05). Cumulative incidences of 30-day-survival showed no significant differences (48.6% in Covid-19 patients, 63.7% in influenza patients; P = .23). ICU treatment duration was significantly longer in ARDS patients with V-V ECMO for Covid-19 compared to influenza. Thirty-day mortality was higher in Covid-19, but not significant.

Statistical Analysis of Clinical COVID-19 Data: A Concise Overview of Lessons Learned, Common Errors and How to Avoid Them.

By definition, in-hospital patient data are restricted to the time between hospital admission and discharge (alive or dead). For hospitalised cases of COVID-19, a number of events during hospitalization are of interest regarding the influence of risk factors on the likelihood of experiencing these events. The same is true for predicting times from hospital admission of COVID-19 patients to intensive care or from start of ventilation (invasive or non-invasive) to extubation. This logical restriction of the data to the period of hospitalisation is associated with a substantial risk that inappropriate methods are used for analysis. Here, we briefly discuss the most common types of bias which can occur when analysing in-hospital COVID-19 data.

Joint analysis of duration of ventilation, length of intensive care, and mortality of COVID-19 patients: a multistate approach.

BACKGROUND: The clinical progress of patients hospitalized due to COVID-19 is often associated with severe pneumonia which may require intensive care, invasive ventilation, or extracorporeal membrane oxygenation (ECMO). The length of intensive care and the duration of these supportive therapies are clinically relevant outcomes. From the statistical perspective, these quantities are challenging to estimate due to episodes being time-dependent and potentially multiple, as well as being determined by the competing, terminal events of discharge alive and death. METHODS: We used multistate models to study COVID-19 patients' time-dependent progress and provide a statistical framework to estimate hazard rates and transition probabilities. These estimates can then be used to quantify average sojourn times of clinically important states such as intensive care and invasive ventilation. We have made two real data sets of COVID-19 patients (n = 24* and n = 53**) and the corresponding statistical code publically available. RESULTS: The expected lengths of intensive care unit (ICU) stay at day 28 for the two cohorts were 15.05* and 19.62** days, while expected durations of mechanical ventilation were 7.97* and 9.85** days. Predicted mortality stood at 51%* and 15%**. Patients mechanically ventilated at the start of the example studies had a longer expected duration of ventilation (12.25*, 14.57** days) compared to patients non-ventilated (4.34*, 1.41** days) after 28 days. Furthermore, initially ventilated patients had a higher risk of death (54%* and 20%** vs. 48%* and 6%**) after 4 weeks. These results are further illustrated in stacked probability plots for the two groups from time zero, as well as for the entire cohort which depicts the predicted proportions of the patients in each state over follow-up. CONCLUSIONS: The multistate approach gives important insights into the progress of COVID-19 patients in terms of ventilation duration, length of ICU stay, and mortality. In addition to avoiding frequent pitfalls in survival analysis, the methodology enables active cases to be analyzed by allowing for censoring. The stacked probability plots provide extensive information in a concise manner that can be easily conveyed to decision makers regarding healthcare capacities. Furthermore, clear comparisons can be made among different baseline characteristics.