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Background. Patients with hematological malignancy or other cancers as well as immunosuppression bear a high risk for severe COVID-19. Monoclonal antibodies (mAb) are efficient at early stages of the disease but may lose potency with new variants. Trials on plasma from convalescent donors in unselected patients have not shown clinical benefit. No randomized trials focussing on patients with underlying disease have been published. Methods. We conducted an open-label, multicenter, randomized controlled trial to evaluate efficacy of plasma (CVP - convalescent or after vaccination) in patients with COVID-19 at high risk for adverse outcome in Germany. We assessed the effect of high-titer CVP (2 units from different donors, 238-337 ml each, on subsequent days). Patients with hematological or other malignancy (group 1), immunosuppression (group 2), age >50 and <=75 years and lymphopenia and/or high D-dimers (group 3) or age >75 years (group 4) who were hospitalized with confirmed SARS-CoV-2 infection and with an oxygen saturation <=94% were included. Primary outcome measure was time to clinical improvement on a seven-point ordinal scale, secondary outcome was mortality (Janssen et al. Trials 2020 Oct 6;21(1):828). Results. Overall, 133 patients were randomized, 68 received CVP with an additional 10 patients as a crossover on day 10. Median age (range) was 68 years (39-95) in the CVP group and 70 (38-90) in controls. For the entire cohort, no significant difference was seen in time to improvement (median days: CVP 12.5 vs. control 18;HR 1.24 (95% confidence interval (CI) 0.83-1.85), p=0.29). Subgroup analysis (group 1+2) revealed shortened time to improvement (median days CVP 13 vs. control 32;HR 2.03 (95%CI 1.17-3.6), p=0.01) and mortality was reduced (mortality CVP n=6 (18%) vs. control n=10 (29%). No significant differences in time to improvement were observed in group 3 or 4 (HR 0.72 (95%CI 0.41-1.28), p=0.26). No relevant adverse events were observed. Conclusion. CVP improves time to clinical improvement and mortality for COVID-19 patients with underlying hematological disease/cancer or other reasons of impaired immune response. Even with new variants, high-titer CVP may offer a widely available and inexpensive therapy option in high-risk groups. Funding. BMBF FKZ 01KI20152;EudraCT 2020-001632-10.
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Background: The administration of modified immune cells (MIC) prior to kidney transplantation led to specific immunosuppression against the allogeneic donor and a significant increase in regulatory B lymphocytes (Breg) (Morath et al., J Clin Invest 2020). We now wanted to investigate how this approach affects the clinical course of treated patients. Method(s): Clinical results of ten patients from a phase I clinical trial who had received MIC infusions before kidney transplantation were compared to results of 15 matched standard-risk recipients. Follow-up was until year five after surgery. Result(s): The 10 MIC patients had an excellent clinical course with stable kidney graft function and showed no donor-specific human leukocyte antigen antibodies (DSA) or acute rejections during follow-up. In contrast, 1 of 15 controls died and 5 of 15 controls developed DSA (log rank P = 0.046) (Figure 1 A, B). While the number of patients with a non-opportunistic infection did not differ significantly between groups (P = 0.36), opportunistic infections were reported more frequently in controls (log rank P = 0.033) (Figure 1 C). Compared to controls, MIC patients were found to have a trend towards a higher COVID-19 anti-S1 IgG index after vaccination with a median of 53 vs. 2 (P = 0.16). Importantly, the four MIC patients who had received the highest MIC cell dose 7 days before surgery and were on low immunosuppression during follow-up, continued to show absent anti-donor T lymphocyte reactivity in vitro and high CD19+CD24hiCD38hi transitional Breg as well as CD19+CD24hiCD27+ memory Breg. Conclusion(s): MIC infusions together with reduced conventional immunosuppression were associated with lower de novo DSA development and lower rates of opportunistic infections. In the future, MIC infusions could contribute to graft protection while reducing the side effects of immunosuppressive therapy. (Figure Presented).
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Introduction Long-Covid or Post-COVID-19 syndrome develops during or after an infection with COVID-19 and continues for more than 12 weeks. The signs and symptoms are not explained by an alternative diagnosis. Neuropsychiatric symptoms are usually manifested as cognitive impairment (brain fog, loss of concentration or memory issues, etc.), headache, sleep disturbance, peripheral neuropathy symptoms (pins and needles and numbness), dizziness, anosmia, symptoms of depression, anxiety and fatigue. Patients complain of reduced quality of life and impairment on daily functioning. Although the burden of disease is high there is until now very few data available, the etiopathology is still unknown and treatment strategies are not established. Objectives The objective of this study is to gather standardized data of patients with long-covid syndrome who suffer from neuropsychiatric symptoms in order to better understand the complexity of this syndrome. Methods Patients were referred from the long-covid outpatient unit of the internal medicine department to our specialized outpatient unit, so that the previous infection was confirmed. A standardized psychiatric interview and a thorough neuropsychological assessment was conducted. Results We will present preliminary data on psychiatric symptoms, neuropsychology and quality of life with patients with long-covid syndrome. Conclusions Potential treatment strategies to improve psychiatric and neurocognitive symptoms as well as improvement of quality of life will be discussed. Disclosure Daniela Roesch Ely and Matthias Weisbrod have a contract with Schuhfried GmbH (development of neurocognitive batteries and training programs)
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Background: Therapy options are limited for COVID-19 patients with hematological disease, cancer, immunosuppression or adanced age. Een though no benefit was obsered for conalescent plasma in unselected patients with COVID-19, retrospectie data suggest that it could be effectie in patients unable to mount a sufficient immune response upon SARS-CoV-2 infection. Plasma from accinated donors has not been systematically assessed for COVID-19 treatment. Aims: We conducted a randomized clinical trial to address plasma efficacy in patients at high risk for an aderse outcome. Methods: COVID-19 patients with confirmed SARS-CoV-2 infections and oxygen saturation <=94% were randomized (NCT05200754). Patients receied conalescent or accinated SARS-CoV-2 plasma in two bags (238 - 337 ml plasma each) from different donors on day 1 and 2 (PLASMA) or standard of care (CONTROL). Randomization was stratified according to four clinical patient groups, hematological/solid cancer (group-1), treatment or disease associated immunosuppression (group 2), high risk disease by standard parameters (group-3) or age >=75 years (group-4). Mechanically entilated patients were not eligible. Plasma was obtained from donors with high leel neutralizing actiity (titer >=1:80) either after SARS-CoV-2 infection (conalescent) or after accination with at least two doses of mRNA accines (accinated). Crossoer for the control group was allowed at day 10. The primary endpoint was time to improement as two points on a seen-point ordinal scale or lie discharge from the Hospital (IMPROVEMENT) with prespecified analyses of subgroups (Janssen M, et al. Trials 2020 Oct 6;21(1):828). Results: A total of 133 patients were randomized with 68 receiing PLASMA with a median age of 68 years (range 36-95) or CONTROL (n=65, of which n=10 (15.4%) crossed oer at day 10) with a median age of 70 years (range 38-90). The distribution of the four predefined groups was group-1, n=53;group-2, n=18;group-3, n=35;and group-4, n=27. The intention to treat analysis reealed a non-significant shorter time to IMPROVEMENT for patients in PLASMA (median 12.5 days, 95%-CI [10;16]) compared to patients in CONTROL (median 18 days, 95%-CI [11;28] ), hazard ratio 1.24, 95% confidence interal [0.83;1.85], p=0.29). Oerall, 27 patients died (PLASMA, n=12;CONTROL, n=15;p=0.80). Predefined subgroup analysis reealed a clinically significant benefit in patients with hematological malignancies, other cancers or immunosuppression (group-1, group-2, n=71). With a median time to improement of 13 days (95%-CI [9;19]) for PLASMA and 32 days (95%-CI [17;57]) for CONTROL(HR 2.03, 95%-CI [1.17;3.6], p=0.01). A sensitiity analysis reealed that IMPROVEMENT appeared to be seen een earlier with accinated (median 10 days, 95%-CI [8;14]) compared to conalescent SARS-CoV-2 plasma (median 13 days, 95%-CI [6;38]) and CONTROL. Within group-1 and group-2, six patients in PLASMA (18.2%) and 10 in CONTROL (28.6%) died. No significant differences in improement were obsered in group-3 and group-4 with a HR of 0.72 (95%-CI [0.41;1.28], p=0.26). Within group-3 and group-4, six patients in PLASMA (18.8%) and fie in CONTROL (16.7%) died. No preiously unknown side effects of plasma therapy emerged within the trial. Summary/Conclusion: Plasma from conalescent and particularly accinated donors improed outcome of COVID-19 patients with an underlying hematological disease /cancer or other reasons of impaired immune response. Plasma did not improe outcome in immune-competent patients with other risk factors and/or older age. (Figure Presented).
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Introduction: Viral infections may trigger diabetes. Clinical data suggest infection with the pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), may impact glucose homeostasis in patients. Notably, cases of new-onset diabetes upon SARS-CoV-2 infection have been reported. However, experimental evidence of pancreatic infection is still controversial. Aims & Methods: Here, we employ cadaveric human pancreatic islets, as well as pancreatic tissue from deceased COVID-19 patients to investigate the impact of SARS-CoV-2 on the pancreas. Results: We show that human β-cells express viral entry proteins ACE2 and TMPRSS2, making them susceptible to SARS-CoV-2 infection and replication. Our data further demonstrates that SARS-CoV-2 infects and replicates in ex vivo cultured human islets and infection. This infection is associated with morphological, transcriptional and functional changes, such as reduction of insulin-secretory granules in β-cells and impaired glucose-stimulated insulin secretion. In COVID-19 post-mortem examinations, we detected SARS-CoV-2 nucleocapsid protein in pancreatic exocrine cells, and in cells that stain positive for the β-cell marker NKX6.1 in all patients investigated. Conclusion: Taken together, our data define the human pancreas as a target of SARS-CoV-2 infection and suggest that β-cell infection might contribute to the metabolic dysregulation observed in patients with COVID- 19.
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Background: The clinical spectrum of coronavirus disease 2019 (COVID-19) ranges from asymptomatic infection to critical illness and death in up to 89% of mechanically ventilated patients. Therefore, new therapeutic strategies are needed. Recent evidence suggests a multi-level inflammatory syndrome in some of the most critically ill patients with overlapping features of other hyperinflammatory or autoimmune diseases. Thus, plasma exchange (PE) has become a subject of controversy as potential therapy in these patients. Here, we report the results of the so far largest cohort of critically ill COVID-19 patients treated with PE. Methods: All critically ill COVID-19 patients treated with PE at Heidelberg University Hospital were analyzed between April and December 2020. Disease course and outcomes were compared with a standard care control group matched for age, sex, and disease severity. Changes in laboratory and clinical parameters were studied longitudinally. Kaplan-Meier and Cox regression analyses were performed. Results: In total, 28 critically ill COVID-19 patients were treated with an average of 3 PE procedures per patient. No relevant complications occurred during PE therapy. Inflammatory markers and biochemical indicators of end-organ damage and endothelial activation were significantly reduced during PE. These laboratory changes were accompanied by normalization of body temperature, improved pulmonary function, and reduced vasopressor demand. Most importantly, the laboratory and clinical improvements were maintained after the last PE. In contrast, most parameters in the control group did not improve significantly over seven days, although baseline clinical and laboratory parameters were comparable in both groups. Kaplan-Meier analysis showed improved 30-day survival in the PE group compared to the control group (67.9% vs. 42.9%, p=0.044). In a multivariable analysis, the hazard ratio for death was 0.27 (95% CI 0.11-0.68, p=0.005) with PE versus standard care. Conclusions: Our data further suggest that PE represents a potential therapeutic strategy for a subset of severe COVID-19 cases. The observed PE-related effects appear to go beyond a purely artificial improvement in blood parameters and may indicate a reversal of the complex COVID-19 immunopathology. Randomized controlled trials are urgently needed.
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In anticipation of the pressure of the rising numbers in COVID-19 cases on the regional health system, an exchange between the actors engaged in handling the pandemic from a medical perspective in the district of Rhein-Neckar/ Heidelberg was initiated in October 2020. The outpatient and inpatient sector as well as the public health office of the district and the Department of Family Medicine and Health Services Research of the University Hospital participated. A mutual online meeting was planned to enable bidirectional exchange at the intersection of primary care. The mutually identified topics, like criteria for admission, therapy and nursing homes were ver-ified via an online survey (n = 63 participants, 76 % family physicians). Additional topics that had been suggested were passed on to the intersectional actors and, wherever possible, included in the meeting. On 11 December 2020, 71 physicians attended the meeting. In addition to the presentations, 53 questions were asked and discussed by the presenters via chat. Demand for a follow-up meeting was high. In January, a follow-up event with n = 115 participants focusing on COVID-19 vaccinations war organized, again with an active participation and a high request for a follow-up meeting. So, the experiences encourage to continue this format, involving all the actors relevant for a medical management of the pan-demic. This could be a component for fostering a bilateral communication, on the one hand engaging the actors of the primary care sector and on the other hand providing continuing medical education in the dynamic pandemic.
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Background: Most data on COVID-19 was collected in hospitalized cases. Much less is known about the spectrum of disease in entire populations including nonhospitalized patients and minors. In this study, we examine a representative cohort in an administrative district in Southern Germany who tested positive for SARS-CoV-2 between February and June of 2020. Methods: We contacted all confirmed SARS-CoV-2 cases in an administrative district in southern Germany. Consenting participants answered a retrospective survey either via a telephone, electronically or via mail. Clinical and sociodemographic features were compared between hospitalized and non-hospitalized patients. Additionally, we assessed potential risk factors for hospitalization and time to hospitalization in a series of regression models. As predictors we assessed age as a continuous variable, sex, smoking as a continuous variable using pack years, living with children (age <18), hypertension (yes/no), coronary heart disease (CHD;yes/no), diabetes (type 1 or type 2;yes/no) and lung conditions (yes/no). Lung conditions were defined as a combined variable of either COPD, asthma treated with medications, any other lung disease or previously performed lung surgery. Secondly, we estimated the influence of the same covariates on the time from symptom onset to hospitalization with a Cox proportional hazard ratio (HR) model. Results: We included 897 participants in our study, 69% out of 1,305 total cases in the district with a mean age of 47 years (range 2-97), 51% of which were female and 47% had a pre-existing illness. The percentage of asymptomatic, mild (symptomatic, no hospitalization), moderate (leading to hospital admission) and critical illness (requiring mechanical ventilation) was 54 patients (6%), 713 (79%), 97 (11%) and 16 (2%), respectively. Seventeen patients (2%) died. The most prevalent symptoms were fatigue (65%), cough (62%) and dysgeusia (60%). The risk factors for hospitalization included older age (OR 1.05 per year increase;95% CI 1.04-1.07) preexisting lung conditions (OR 3.09;95% CI 1.62-5.88). Female sex was a protective factor (OR 0.51;95% CI 0.33-0.77). Conclusion: This population-representative analysis of COVID-19 cases confirms age, male sex and preexisting lung conditions but not cardiovascular disease as risk factors for severe illness. Almost 80% of infection take a mild course, whereas 13% of patients suffer moderate to severe illness.
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The emerging SARS-CoV-2 pandemic entails an urgent need for specific and sensitive high-throughput serological assays to assess SARS-CoV-2 epidemiology. We, therefore, aimed at developing a fluorescent-bead based SARS-CoV-2 multiplex serology assay for detection of antibody responses to the SARS-CoV-2 proteome. Proteins of the SARS-CoV-2 proteome and protein N of SARS-CoV-1 and common cold Coronaviruses (ccCoVs) were recombinantly expressed in E. coli or HEK293 cells. Assay performance was assessed in a COVID-19 case cohort (n = 48 hospitalized patients from Heidelberg) as well as n = 85 age- and sex-matched pre-pandemic controls from the ESTHER study. Assay validation included comparison with home-made immunofluorescence and commercial enzyme-linked immunosorbent (ELISA) assays. A sensitivity of 100% (95% CI: 86-100%) was achieved in COVID-19 patients 14 days post symptom onset with dual sero-positivity to SARS-CoV-2 N and the receptor-binding domain of the spike protein. The specificity obtained with this algorithm was 100% (95% CI: 96-100%). Antibody responses to ccCoVs N were abundantly high and did not correlate with those to SARS-CoV-2 N. Inclusion of additional SARS-CoV-2 proteins as well as separate assessment of immunoglobulin (Ig) classes M, A, and G allowed for explorative analyses regarding disease progression and course of antibody response. This newly developed SARS-CoV-2 multiplex serology assay achieved high sensitivity and specificity to determine SARS-CoV-2 sero-positivity. Its high throughput ability allows epidemiologic SARS-CoV-2 research in large population-based studies. Inclusion of additional pathogens into the panel as well as separate assessment of Ig isotypes will furthermore allow addressing research questions beyond SARS-CoV-2 sero-prevalence.
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Introduction: The spectrum of coronavirus disease 2019 (COVID-19) ranges from asymptomatic infection to respiratory failure and death of patients. Severely affected patients may develop a cytokine storm-like clinical syndrome with multi-organ failure and a mortality rate of up to 90%. Case Description: Here we report on five COVID-19 patients with a median age of 67 years who were treated at the intensive care unit due to respiratory failure. Prophylactic antibiotic, antimycotic, and antiviral/immunomodulatory therapy was initiated in all patients upon admission. During the course of the disease, patients developed circulatory shock and persistent fever together with increased interleukin 6-levels compatible with the cytokine storm-like clinical syndrome. In addition, all patients had multi-organ failure with acute respiratory-distress syndrome (ARDS, 4 severe, 1 moderate) and acute kidney injury of at least KDIGO stage 2. A single PE with a median of 3.39 L of fresh frozen plasma was initiated in all patients followed by one additional treatment in patients 1, 3, and 5. During the PE, striking reduction of inflammatory markers C-reactive protein (-47%, P=0.0078) and interleukin 6 (-74%, P=0.0078), as well as significant reduction of ferritin (-49%, P=0.0078), LDH (-41%, P=0.0078), and D-Dimer (-47%, P=0.016) were observed. Due to circulatory shock, four patients received vasopressor treatment at the start of the PE that could be substantially reduced during treatment (-71%, P=0.031). Biochemical and clinical improvement continued over the following days together with an increase in the oxygenation index in 4 out of 5 patients. These improvements were achieved with only 1 to 2 PE, which might be a possible indication of a direct pathophysiological influence of PE on the COVID-19-associated cytokine storm-like clinical syndrome. Three of the 5 most critically ill patients are alive, while a 71-year-old male and a 76-year-old female patient died after the therapy was limited due to persistent severe ARDS. Discussion: PE improved inflammation, microcirculatory clot formation, and hypotension, thereby improving clinical outcomes. Further studies to test whether (repeated) PE can alter the course of critically ill COVID-19 patients are clearly indicated.
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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.
Subject(s)
COVID-19/prevention & control , Neoplasms/therapy , Registries/statistics & numerical data , SARS-CoV-2/isolation & purification , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/epidemiology , COVID-19/virology , Comorbidity , Europe/epidemiology , Female , Hospital Mortality , Hospitalization/statistics & numerical data , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasms/epidemiology , Outcome Assessment, Health Care/methods , Outcome Assessment, Health Care/statistics & numerical data , Pandemics , Retrospective Studies , SARS-CoV-2/physiology , Young AdultABSTRACT
BACKGROUND: Clinically, coronavirus disease 2019 (COVID-19) is associated with a wide range of symptoms, which can range from mild complaints of an upper respiratory infection to life-threatening hypoxic respiratory insufficiency and multiorgan failure. OBJECTIVE: The initially identified pulmonary damage patterns, such as diffuse alveolar damage in acute lung failure, are accompanied by new findings that draw a more complex scenario. These include microvascular involvement and a wide range of associated pathologies of multiple organ systems. A back-scaling of microstructural vascular changes is possible via targeted correlation of pathological autopsy results with radiological imaging. MATERIAL AND METHODS: Radiological and pathological correlation as well as microradiological imaging to investigate microvascular involvement in fatal COVID-19. RESULTS: The cases of two COVID-19 patients are presented. Patient 1 showed a relative hypoperfusion in lung regions that did not have typical COVID-19 infiltrates; the targeted post-mortem correlation also showed subtle signs of microvascular damage even in these lung sections. Patient 2 showed both radiologically and pathologically advanced typical COVID-19 destruction of lung structures and the case illustrates the damage patterns of the blood-air barrier. The perfusion deficit of the intestinal wall shown in computed tomography of patient 2 could not ultimately clearly be microscopically attributed to intestinal microvascular damage. CONCLUSION: In addition to microvascular thrombosis, our results indicate a functional pulmonary vasodysregulation as part of the pathophysiology during the vascular phase of COVID-19. The clinical relevance of autopsies and the integration of radiological imaging findings into histopathological injury patterns must be emphasized for a better understanding of COVID-19.