Anti-SARS-CoV-2 antibody containing plasma improves outcome in patients with hematologic or solid cancer and severe COVID-19 via increased neutralizing antibody activity. A randomized clinical trial

Cancer patients are at high risk of severe COVID-19 with high morbidity and mortality. Further, impaired humoral response renders SARS-CoV-2 vaccines less effective and treatment options are scarce. Randomized trials using convalescent plasma are missing for high-risk patients. Here, we performed a multicenter trial (https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001632-10/DE) in hospitalized patients with severe COVID-19 within four risk groups (1, cancer; 2, immunosuppression; 3, lab-based risk factors; 4, advanced age) randomized to standard of care (CONTROL) or standard of care plus convalescent/vaccinated anti-SARS-CoV-2 plasma (PLASMA). For the four groups combined, PLASMA did not improve clinically compared to CONTROL (HR 1.29; p=0.205). However, cancer patients experienced shortened median time to improvement (HR 2.50, p=0.003) and superior survival in PLASMA vs. CONTROL (HR 0.28; p=0.042). Neutralizing antibody activity increased in PLASMA but not in CONTROL cancer patients (p=0.001). Taken together, convalescent/vaccinated plasma may improve COVID-19 outcome in cancer patients unable to intrinsically generate an adequate immune response.

Prevalence, determinants, and impact on general health and working capacity of post-acute sequelae of COVID-19 six to 12 months after infection: a population-based retrospective cohort study from southern Germany

BackgroundPost-acute sequelae of SARS-CoV-2 infection have commonly been described after COVID-19, but few population-based studies have examined symptoms six to 12 months after acute SARS-CoV-2 infection and their associations with general health recovery and working capacity. MethodsThis population-based retrospective cohort study in four geographically defined regions in southern Germany included persons aged 18-65 years with PCR confirmed SARS-CoV-2 infection between October 2020 and March 2021. Symptom frequencies (six to 12 months after versus before acute infection, expressed as prevalence differences [PD] and prevalence ratios [PR]), symptom severity and clustering, risk factors and associations with general health recovery, and working capacity were analysed. FindingsAmong a total of 11 710 subjects (mean age 44{middle dot}1 years, 59{middle dot}8% females, 3{middle dot}5% previously admitted with COVID-19, mean follow-up time 8.5 months) the most prevalent symptoms with PDs >20% and PRs >5% were rapid physical exhaustion, shortness of breath, concentration difficulties, chronic fatigue, memory disturbance, and altered sense of smell. Female sex and severity of the initial infection were the main risk factors. Prevalence rates, however, appeared substantial among both men and women who had a mild course of acute infection, and PCS considerably affected also younger subjects. Fatigue (PD 37{middle dot}2%) and neurocognitive impairment (PD 31{middle dot}3%) as symptom clusters contributed most to reduced health recovery and working capacity, but chest symptoms, anxiety/depression, headache/dizziness and pain syndromes were also prevalent and relevant for working capacity, with some differences according to sex and age. When considering new symptoms with at least moderate impairment of daily life and [≤]80% recovered general health or working capacity, the overall estimate for post-COVID syndrome was 28{middle dot}5% (age- and sex-standardised rate 26{middle dot}5%). InterpretationThe burden of self-reported post-acute symptoms and possible sequelae, notably fatigue and neurocognitive impairment, remains considerable six to 12 months after acute infection even among young and middle-aged adults after mild acute SARS-CoV-2 infection, and impacts general health and working capacity. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSPrevious studies have shown that post-acute sequelae of COVID-19 are common, in particular among patients who had been admitted to hospital for COVID-19. Post-acute self-reported complaints and symptoms often are diverse, nonspecific and sometimes of unknown severity and functional relevance. We searched PubMed and medRxiv for studies published between January 2021 and February 2022, using search terms describing "long covid, post-acute sequelae of COVID-19, prevalence, and systematic review", with no language restrictions. Searches with the terms "long covid", "post-acute sequelae of COVID-19", "post-covid condition" and "post-covid syndrome" were also done in PROSPERO, and we screened the website of the UK Office for National Statistics (www.ons.gov.uk) for long covid studies. We found more than 20 systematic reviews summarising post-acute symptom patterns among adults and a prevalence of "any" or "defined" symptoms (such as respiratory symptoms or symptoms related to mental health) or of medically assessed functional impairment (pulmonary or cardiac or neurocognitive function). Two reviews reported of health-related quality of life assessments. The prevalence of post-acute sequelae of COVID-19 or long covid/post-covid syndromes ranged between <10 to >70%, in part due to lack of uniform and clear case definitions, variable follow-up times, and non-inclusion of outpatients with initially mild disease. Most papers reviewed presented high heterogeneity and had a short follow-up, and there were very few papers estimating the prevalence of post-covid syndrome beyond six months after acute infection. The studies with the largest number of subjects were either including only patients after hospital admission, used online surveys of subjects with self-reported suspected and confirmed COVID-19 or electronic medical records only. We found one (small but) comprehensive population-based study from Switzerland assessing post-covid syndrome prevalence and associations with quality of life and health recovery with a follow-up time ranging from six to 10 months. Two further population-based studies from Switzerland and Norway investigated long covid symptoms among subgroups with [≥]6 months (n=498) and 11 to 12 months (n=170) of follow-up after acute infection, respectively. Added value of this studyWith this large population-based study, we provide evidence of persistence of new symptom clusters (not present before acute infection) such as fatigue, neurocognitive impairment, chest symptoms, smell or taste disorder, and anxiety/depression beyond six months after acute infection, with a prevalence of >20% for each of these five clusters. We show that the three most frequent clusters (fatigue, neurocognitive impairment, chest symptoms) are often interfering with daily life and activities, often co-occur, and that both fatigue and neurocognitive impairment have the largest impact on working capacity, while long-term smell and taste disorders are reported relatively independent of other complaints. Age in this 18-65-year old adult population was not a major determinant of symptom prevalence, but we confirm severity of the initial infection and female sex as consistent risk factors for various manifestations of medium-term post-COVID syndrome, and age as risk factor for self-reported reduced working capacity, which overall and at population level exceeded 10%. Implications of all the available evidenceFuture research should include the medical validation of the key symptom clusters of post-COVID syndrome, determine the possible causes, and urgently address prognostic factors and therapeutic options. The described key symptom clusters contributed most to reduced general health status and working capacity in middle-aged adults. The findings of this study may also help develop a more consistent and relevant definition of post-COVID syndrome with major implications for research and medical practice.

COVID-19 in-hospital mortality and mode of death in a dynamic and non-restricted tertiary care model in Germany

BackgroundReported mortality of hospitalised COVID-19 patients varies substantially, particularly in critically ill patients. So far COVID-19 in-hospital mortality and modes of death under optimised care conditions have not been systematically studied. MethodsThis retrospective observational monocenter cohort study was performed after implementation of a non-restricted, dynamic tertiary care model at the University Medical Center Freiburg, an experienced ARDS and ECMO referral center. All hospitalised patients with PCR-confirmed SARS-CoV-2 infection were included. The primary endpoint was in-hospital mortality, secondary endpoints included major complications and modes of death. A multistate analysis and a Cox regression analysis for competing risk models were performed. Modes of death were determined by two independent reviewers. ResultsBetween February 25, and May 8, 213 patients were included in the analysis. The median age was 65 years, 129 patients (61%) were male. 70 patients (33%) were admitted to the intensive care unit (ICU), of which 57 patients (81%) received mechanical ventilation and 23 patients (33%) extracorporeal membrane-oxygenation (ECMO) support. According to the multistate model the probability to die within 90 days after COVID-19 onset was 24% in the whole cohort. If the levels of care at time of study entry were accounted for, the probabilities to die were 16% if the patient was initially on a regular ward, 47% if in the ICU and 57% if mechanical ventilation was required at study entry. Age [≥]65 years and male sex were predictors for in-hospital death. Predominant complications - as judged by two independent reviewers - determining modes of death were multi-organ failure, septic shock and thromboembolic and hemorrhagic complications. ConclusionIn a dynamic care model COVID-19-related in-hospital mortality remained substantial. In the absence of potent antiviral agents, strategies to alleviate or prevent the identified complications should be investigated. In this context, multistate analyses enable comparison of models-of-care and treatment strategies and allow estimation and allocation of health care resources. RegistrationGerman Clinical Trials Register (identifier DRKS00021775), retrospectively registered June 10, 2020.

Anosmia in COVID-19 patients

ObjectivesCoronaviruses (CoVs) have a neuroinvasive propensity, and the frequently reported symptoms of smelling and taste dysfunction in many COVID-19 patients may be related to the respective capability of SARS-CoV2, the cause of the current pandemic. In this study we objectified and quantified the magnitude and underreporting of the smelling dysfunction caused by COVID-19 using a standardized test. MethodsWe conducted a prospective cross-sectional study comparing the proportion of anosmia using Sniffin-sticks in those reporting a loss of smell, in those who did not as well as in uninfected controls. The outcome of anosmic versus not anosmic patients were recorded during hospital stay and at day 15 on a six-category ordinal scale. The study was approved by the institutional review board, all participants consented to the study. Results40% of 45 consecutive hospitalized COVID-19 patients and 0% of 45 uninfected controls consenting were diagnosed with anosmia. 44% of anosmic and 50% of hyposmic patients did not report having smelling problems. Anosmia or hyposmia was not predictive of a severe COVID-19 manifestation. ConclusionsThe majority of COVID-19 patients have an objective anosmia and hyposmia, which often occurs unnoticed. These symptoms may be related to the neuroinvasive propensity of SARS-COV-2 and the unusual presentation of COVID-19 disease manifestations.