Use and effectiveness of remdesivir for the treatment of patients with covid-19 using data from the Lean European Open Survey on SARS-CoV-2 infected patients (LEOSS): a multicentre cohort study.

OBJECTIVES: The use of remdesivir (RDV) as the first drug approved for coronavirus disease 2019 (COVID-19) remains controversial. Based on the Lean European Open Survey on severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infected patients (LEOSS), we aim to contribute timing-focused complementary real-world insights to its evaluation. METHODS: SARS-CoV-2 infected patients between January 2020 and December 2021 treated with RDV were matched 1:1 to controls considering sociodemographics, comorbidities and clinical status. Multiple imputations were used to account for missing data. Effects on fatal outcome were estimated using uni- and multivariable Cox regression models. RESULTS: We included 9,687 patients. For those starting RDV administration in the complicated phase, Cox regression for fatal outcome showed an adjusted hazard ratio (aHR) of 0.59 (95%CI 0.41-0.83). Positive trends could be obtained for further scenarios: an aHR of 0.51 (95%CI 0.16-1.68) when RDV was initiated in uncomplicated and of 0.76 (95% CI 0.55-1.04) in a critical phase of disease. Patients receiving RDV with concomitant steroids exhibited a further reduction in aHR in both, the complicated (aHR 0.50, 95%CI 0.29-0.88) and critical phase (aHR 0.63, 95%CI 0.39-1.02). CONCLUSION: Our study results elucidate that RDV use, in particular when initiated in the complicated phase and accompanied by steroids is associated with improved mortality. However, given the limitations of non-randomized trials in estimating the magnitude of the benefit of an intervention, further randomized trials focusing on the timing of therapy initiation seem warranted.

Rapid selection of sotrovimab escape variants in SARS-CoV-2 Omicron infected immunocompromised patients.

BACKGROUND: Monoclonal antibodies (mAb) targeting SARS-CoV-2 are predominantly less effective against Omicron variants. Immunocompromised patients often experience prolonged viral shedding and are therefore at increased risk for viral escape mutations, when mAbs are used as monotherapy. METHODS: In an observational, prospective cohort, 57 patients infected with Omicron variants receiving sotrovimab alone or in combination with remdesivir were followed. The study endpoints were a decrease in SARS-CoV-2-RNA <106 copies/ml in nasopharyngeal swabs at day 21 and the emergence of resistance mutations at days 7, 14, and 21 after sotrovimab administration. All SARS-CoV-2 samples were analyzed by whole-genome sequencing, individual variants within the quasispecies were subsequently quantified and further characterized by a pseudovirus neutralization assay. RESULTS: 47/57 patients (82.5%) were infected with Omicron/BA.1 and 10/57 (17.5%) with Omicron/BA.2. The vast majority of patients (43/57, 75.4%) were immunodeficient, predominantly due to immunosuppression after organ transplantation or hematologic malignancies. 21 days after sotrovimab administration, 12/43 (27.9%) of immunodeficient patients had prolonged viral shedding compared to 1/14 (7.1%) immunocompetent patients (p = 0.011). Longitudinal sequencing revealed that 14/43 (32.6%) immunodeficient patients had in part Omicron-specific viral spike protein mutations (e.g., P337S and/or E340D/V) that substantially reduced susceptibility to sotrovimab in a pseudovirus neutralization assay. Combination therapy with remdesivir significantly reduced the selection of escape variants. CONCLUSIONS: Immunocompromised patients face a considerable risk of prolonged viral shedding and emergence of escape mutations after early therapy with sotrovimab. These findings underscore the importance of careful monitoring and the need to conduct dedicated clinical trials for this patient population.

Prognostic markers for the clinical course in the blood of patients with SARS-CoV-2 infection.

BACKGROUND: The presentation of peptides and the subsequent immune response depend on the MHC characteristics and influence the specificity of the immune response. Several studies have found an association between HLA variants and differential COVID-19 outcomes and have shown that HLA genotypes are associated with differential immune responses against SARS-CoV-2, particularly in severely ill patients. Information, whether HLA haplotypes are associated with the severity or length of the disease in moderately diseased individuals is absent. METHODS: Next-generation sequencing-based HLA typing was performed in 303 female and 231 male non-hospitalized North Rhine Westphalian patients infected with SARS-CoV2 during the first and second wave. For HLA-Class I, we obtained results from 528 patients, and for HLA-Class II from 531. In those patients, who became ill between March 2020 and January 2021, the 22 most common HLA-Class I (HLA-A, -B, -C) or HLA-Class II (HLA -DRB1/3/4, -DQA1, -DQB1) haplotypes were determined. The identified HLA haplotypes as well as the presence of a CCR5Δ32 mutation and number of O and A blood group alleles were associated to disease severity and duration of the disease. RESULTS: The influence of the HLA haplotypes on disease severity and duration was more pronounced than the influence of age, sex, or ABO blood group. These associations were sex dependent. The presence of mutated CCR5 resulted in a longer recovery period in males. CONCLUSION: The existence of certain HLA haplotypes is associated with more severe disease.

Obesity and lipid metabolism disorders determine the risk for development of long COVID syndrome: a cross-sectional study from 50,402 COVID-19 patients.

PURPOSE: Metabolic disorders have been identified as major risk factors for severe acute courses of COVID-19. With decreasing numbers of infections in many countries, the long COVID syndrome (LCS) represents the next major challenge in pandemic management, warranting the precise definition of risk factors for LCS development. METHODS: We identified 50,402 COVID-19 patients in the Disease Analyzer database (IQVIA) featuring data from 1056 general practices in Germany. Multivariate logistic regression analysis was used to identify risk factors for the development of LCS. RESULTS: Of the 50,402 COVID-19 patients included into this analysis, 1,708 (3.4%) were diagnosed with LCS. In a multivariate regression analysis, we identified lipid metabolism disorders (OR 1.46, 95% CI 1.28-1.65, p < 0.001) and obesity (OR 1.25, 95% CI 1.08-1.44, p = 0.003) as strong risk factors for the development of LCS. Besides these metabolic factors, patients' age between 46 and 60 years (compared to age ≤ 30, (OR 1.81 95% CI 1.54-2.13, p < 0.001), female sex (OR 1.33, 95% CI 1.20-1.47, p < 0.001) as well as pre-existing asthma (OR 1.67, 95% CI 1.39-2.00, p < 0.001) and depression (OR 1.27, 95% CI 1.09-1.47, p = < 0.002) in women, and cancer (OR 1.4, 95% CI 1.09-1.95, p = < 0.012) in men were associated with an increased likelihood of developing LCS. CONCLUSION: Lipid metabolism disorders and obesity represent age-independent risk factors for the development of LCS, suggesting that metabolic alterations determine the risk for unfavorable disease courses along all phases of COVID-19.

Acute cardiac side effects after COVID-19 mRNA vaccination: a case series.

BACKGROUND: Vaccination against SARS-CoV-2 has been the main tool to contain the pandemic. The rush development of the 3 vaccines and their expedited approval have led to inoculation of millions of patients around the world, leading to a containment of the disease. Despite continuous viral mutations and the identification of weaker variants, the severity of the infections has been mild, with many patients being either asymptomatic or recovering at home. Currently the focus has shifted from the host of organ damage related to the infection to potential side effects of the vaccine. Myocarditis has been reported as one of the potential side effects from the mRNA vaccine, affecting young healthy individuals. Up to September 30, 2021, 1.243 cases of myocarditis after vaccination with BNT162b2 Comirnaty© were registered in young adults by the Paul-Ehrlich-Institute in Germany alone. The exact pathophysiology and the risk factors for myocarditis following vaccination remain unclear. We present a case series of eight patients with cardiac symptom shortly after SARS-CoV-2 mRNA vaccination (BNT162b6, Biontech, Comirnaty© or mRNA-1237 Moderna, Spikevax©). PATIENTS AND METHODS: Eight patients between 13 and 56 years of age, vaccinated with either BNT162b2 or mRNA-1273 mRNA vaccine between January and August 2021 developed cardiac side effects shortly after either their first or second dose of the vaccine. Clinical data were retrieved from the clinical information system and analyzed. To support diagnosis of myocarditis or pericarditis, cardiac magnetic resonance imaging (MRI) was performed shortly after the onset of symptoms, with further investigations in severe cases. Symptoms were defined as dyspnea, chest pain and cardiac arrhythmia as determined by electrocardiography. RESULTS: Eight patients (5 males and 3 females) developed cardiac symptoms compatible with myocarditis, according to the CDC criteria, shortly after SARS-CoV-2 mRNA vaccination. Three patients (2 males, 1 female) required hospitalization due to severe chest pain and elevated troponin levels. All patients recovered fully within 7 days from the symptom onset. CONCLUSIONS: Our data suggest that cardiac adverse events such as myocarditis or pericarditis shortly after SARS-CoV-2 mRNA vaccination are rare but possible and occur particularly in male patients.

Delayed skin reaction after mRNA-1273 vaccine against SARS-CoV-2: a rare clinical reaction.

BACKGROUND: The coronavirus disease 2019 (COVID-19) is associated with a wide clinical spectrum of skin manifestations, including urticarial, vesicular, vasculitic and chilblain-like lesions. Recently, delayed skin reactions have been reported in 1% individuals following mRNA vaccination against SARS-CoV-2. The exact pathophysiology and the risk factors still remain unclear. PATIENTS AND METHODS: 6821 employees and patients were vaccinated at our institutions between February and June 2021. Every patient received two doses of the mRNA-1273 vaccine in our hospitals, and reported back in case of any side effects which were collected in our hospital managed database. RESULTS: Eleven of 6821 vaccinated patients (0.16%) developed delayed skin reactions after either the first or second dose of the mRNA-1273 vaccine against SARS-CoV-2. Eight of 11 patients (73%) developed a rash after the first dose, while in 3/11 (27%), the rash occurred after the second dose. More females (9/11) were affected. Four of 11 patients required antihistamines, with two needing additional topical steroids. All the cutaneous manifestations resolved within 14 days. None of the skin reactions after the first dose of the vaccine prevented the administration of the second dose. There were no long-term cutaneous sequelae in any of the affected individuals. CONCLUSION: Our data suggests that skin reactions after the use of mRNA-1273 vaccine against SARS-CoV-2 are possible, but rare. Further studies need to be done to understand the pathophysiology of these lesions.

[Oro- and nasopharyngeal swab for detection of SARS-CoV-2 - step-by-step approach]. / Oro- und nasopharyngealer Abstrich ­ Schritt für Schritt.

Oro- and nasopharyngeal swab specimens by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) to detect SARS-CoV-2 is currently the main diagnostic tool during the ongoing COVID-19 pandemia. Accurate performance of the procedure to avoid false negative results, adequate personal protective equipment and material sparing algorithms are mandatory while obtaining swab specimens. In the current stey-by-step review a feasible approach will be presented.

Measures of infection prevention and incidence of SARS-CoV-2 infections in cancer patients undergoing radiotherapy in Germany, Austria and Switzerland.

PURPOSE: COVID-19 infection has manifested as a major threat to both patients and healthcare providers around the world. Radiation oncology institutions (ROI) deliver a major component of cancer treatment, with protocols that might span over several weeks, with the result of increasing susceptibility to COVID-19 infection and presenting with a more severe clinical course when compared with the general population. The aim of this manuscript is to investigate the impact of ROI protocols and performance on daily practice in the high-risk cancer patients during this pandemic. METHODS: We addressed the incidence of positive COVID-19 cases in both patients and health care workers (HCW), in addition to the protective measures adopted in ROIs in Germany, Austria and Switzerland using a specific questionnaire. RESULTS: The results of the questionnaire showed that a noteworthy number of ROIs were able to complete treatment in SARS-CoV­2 positive cancer patients, with only a short interruption. The ROIs reported a significant decrease in patient volume that was not impacted by the circumambient disease incidence, the type of ROI or the occurrence of positive cases. Of the ROIs 16.5% also reported infected HCWs. About half of the ROIs (50.5%) adopted a screening program for patients whereas only 23.3% also screened their HCWs. The range of protective measures included the creation of working groups, instituting home office work and protection with face masks. Regarding the therapeutic options offered, curative procedures were performed with either unchanged or moderately decreased schedules, whereas palliative or benign radiotherapy procedures were more often shortened. Most ROIs postponed or cancelled radiation treatment for benign indications (88.1%). The occurrence of SARS-CoV­2 infections did not affect the treatment options for curative procedures. Non-university-based ROIs seemed to be more willing to change their treatment options for curative and palliative cases than university-based ROIs. CONCLUSION: Most ROIs reported a deep impact of SARS-CoV­2 infections on their work routine. Modification and prioritization of treatment regimens and the application of protective measures preserved a well-functioning radiation oncology service and patient care.