ABSTRACT
Background: COVID-19-Convalescent Plasma (CCP) showed beneficial effects when given early in the treatment course or when it contains high-titre of neutralizing antibodies. Here we present a long-term follow up of patients of the multicentric national randomized CAPSID trial that investigated the effect of CCP in hospitalized COVID-19 patients. CCP donors were also included in the follow up and severed as a control group of patients with mild to moderate disease. Method(s): Patients and donors were invited to participate in the long-term follow up. Data on long-term overall survival (OS) were available for n=52 patients (control group: n=22, high titre CCP: n=16, low-titre CCP: n=14) and n=113 donors. Structured interview and a quality of life (QoL) assessment by questionnaires (FACIT fatigue, FACIT dyspnea and EQ-ED- 5DL) were performed. Visits took place online or on site. Laboratory tests included neutralizing antibody testing by PRNT and inflammation markers. Data are given as median with IQR. Medical events were assessed and graded according to CTCAE. For donors the median follow up time was 517 (483-553) days after the first plasmapheresis and for patients 395 (371-417) days after randomization. Result(s): Medical events during follow up were reported in 27% of donors and 16% of patients (p=0.164) with grade 3 or higher in 9% of donors and 22% of patients. More patients than donors reported a decrease in their socioeconomic status and reported more frequently about GI, pulmonal, pain symptoms or alopecia (p<0.02), but no difference in neurologic symptoms including anosmia was observed. Post COVID-Scale was worse in patients with a trend for better outcome in the CCP group (p=0.089). The trend for better OS in the CCP group became more pronounced during the long-term follow up (p=0.08) and OS remained significantly better in the high dose CCP group (p=0.01). All QoL scores showed a consistent trend towards better outcomes of the CCP group. Conclusion(s): To our knowledge, this is the first long-term follow up from a randomized trial of CCP. CCP-donors with mild to moderate COVID- 19 had a significant smaller long-term disease burden than patients with severe disease. The addition of CCP added to standard treatment in severe COVID-19 showed a trend to better OS and QoL. We had previously reported significant better outcomes in the high-titre CCP subgroup (until day 60). This was even more pronounced during the long-term follow up (> 1 year).
ABSTRACT
Elevated pro-inflammatory cytokines such as interleukin-6 (IL-6) have been observed in patients with COVID-19 and are associated with adverse clinical outcomes. Systemic immune response is co-regulated via the vagally-mediated cholinergic anti-inflammatory reflex. Specifically, a reduced release of pro-inflammatory cytokines such as IL-6 from acetylcholine-synthesizing T-cells in response to Vagus nerve stimulation has been demonstrated in animal and human studies. A known non-invasive and cost-effective way to stimulate efferent vagal activity is slow-paced breathing. The primary aim of this RCT was to determine if high-dose breath-assisted reflex stimulation results in a reduction of systemic inflammatory levels in COVID-19 patients. 48 hospitalized COVID-19 patients with moderate to severe symptoms from two isolation wards were randomized to intervention (3x20min app-assisted slow-paced breathing @6BPM) or TAU control group at the University Medical Center Ulm (Germany) during March & May 2021 (BEAT-COVID-study;DRKS00023971). Morning samples of IL-6, protocol adherence and self-reported total practice time (TPT) were collected bi-daily. Mixed effect linear regression models were used to explore groupXtime differences as well as dose-response analysis. Models were adjusted for age, ward, and TAU protocols. A total of 40 patients (age 55±14;67% male) were included to the final analysis. Feasibility of the applied breathing protocol was good, oxygenation was stable and no adverse events occurred. Adherence was closely monitored and sufficient in 17 out of 25 IG patients. Primary reason for non-adherence was worsening of symptoms with transfer to ICU. Reduction rate in inflammatory markers were not statistically different between IG and CG. Investigating the effect of categorized TPT on next morning IL-6 levels in 25 IG patients from 112 intervention days revealed significant lower IL-6 values when TPT exceeded 40min (b= -0.898ln[pg/ml];p=0.043). This is equivalent to a ratio of 59.3% reduction in circulating IL-6 compared to days with TPT <10min. This is the first clinical RCT to study immediate anti-inflammatory effects of a slow-paced breathing protocol in hospitalized COVID-19 patients. Although no between group differences were found in the reduction rate of systemic inflammatory markers, promising dose-response effects were observed.
ABSTRACT
Background: Several observational studies suggested efficacy of COVID-19 convalescent plasma (CCP) but the results of several randomized clinical trials of CCP are not consistent. The trials differ in treatment schedules in terms of timing, volume and antibody content of CCP as well as enrolled patient populations and endpoints. The CAPSID was designed at the beginning of the pandemic and assessed the efficacy of neutralizing antibody containing high-dose COVID-19 convalescent plasma (CCP) in hospitalized patients with severe COVID-19. Methods: Patients (n=105) in 13 hospitals in Germany were randomized to either receive standard treatment and three units of CCP on days 1, 3 and 5 (total dose 846 ml) (n=53) or standard treatment alone (n=52). Patients in the control group with progress on day 14 could receive CCP (crossover group;n=7) on days 15, 17 and 19. The primary outcome was a dichotomous composite outcome of survival and no longer fulfilling criteria of severe COVID-19 on day 21. For Cross over patients a propensity matching with patients of the plasma group was performed. Results: Neutralizing antibodies were present at baseline in 18.2% of CCP and 19.2% of control group patients. In the ITT analysis the primary outcome occurred in 43.4% of patients in the CCP and 32.7% in the control group (p=0.32). The CCP group showed a trend for shorter times to clinical improvement (40 days, p=0.27) and discharge from hospital (20 days, p=0.24). Among those in the CCP group who received a higher or lower cumulative amount of neutralizing antibodies the primary outcome occurred in 56.0% and 32.1% of patients The high titer group showed significantly shorter intervals to clinical improvement or hospital discharge and a better overall survival (p=0.02). None of the patients in the crossover group (CG) achieved clinical improvement and survived. Comparing the CG to 14 CCP patients matched by baseline characteristics resulted in worse OS in the CG group (p=0.02) while comparison with 6 day 14 matched patients showed equal OS. Interpretation: CCP added to standard treatment did not result in a significant difference in the primary and secondary outcomes. A pre-defined subgroup analysis showed a signal of benefit for CCP among those who received a larger amount of neutralizing antibodies. A progress on day 14 is an indicator for poor outcome in COVID-19. Late administration of CCP is not supported by our results.
ABSTRACT
The number of people in Germany infected with SARS-CoV-2 was increasing for a long time while capacities for inpatient treatment continued to decrease. In order to secure patient safety yet avoiding an excessive expend of limited resources, early differentiation between expected mild and severe courses of COVID-19 is needed. We established a literature-based COVID-19 risk score to identify COVID-19 cases requiring inpatient treatment and conducted a retrospective cohort study with 155 patients to validate our approach. Due to the high predictive value and discriminatory power, the presented COVID-19 risk score can be a valuable tool to support clinicians in their decision-making. © 2021 Cambridge University Press. All rights reserved.
ABSTRACT
INTRODUCTION: Since the early SARS-CoV-2 pandemic, cancer patients have been assumed to be at higher risk for severe COVID-19. Here, we present an analysis of cancer patients from the LEOSS (Lean European Open Survey on SARS-CoV-2 Infected Patients) registry to determine whether cancer patients are at higher risk. PATIENTS AND METHODS: We retrospectively analyzed a cohort of 435 cancer patients and 2636 non-cancer patients with confirmed SARS-CoV-2 infection, enrolled between March 16 and August 31, 2020. Data on socio-demographics, comorbidities, cancer-related features and infection course were collected. Age-, sex- and comorbidity-adjusted analysis was performed. Primary endpoint was COVID-19-related mortality. RESULTS: In total, 435 cancer patients were included in our analysis. Commonest age category was 76-85 years (36.5%), and 40.5% were female. Solid tumors were seen in 59% and lymphoma and leukemia in 17.5% and 11% of patients. Of these, 54% had an active malignancy, and 22% had recently received anti-cancer treatments. At detection of SARS-CoV-2, the majority (62.5%) presented with mild symptoms. Progression to severe COVID-19 was seen in 55% and ICU admission in 27.5%. COVID-19-related mortality rate was 22.5%. Male sex, advanced age, and active malignancy were associated with higher death rates. Comparing cancer and non-cancer patients, age distribution and comorbidity differed significantly, as did mortality (14% vs 22.5%, p value < 0.001). After adjustments for other risk factors, mortality was comparable. CONCLUSION: Comparing cancer and non-cancer patients, outcome of COVID-19 was comparable after adjusting for age, sex, and comorbidity. However, our results emphasize that cancer patients as a group are at higher risk due to advanced age and pre-existing conditions.