Within-host evolution of SARS-CoV-2 in an immunosuppressed COVID-19 patient: a source of immune escape variants

The recent emergence of SARS-CoV-2 variants showing increased transmissibility and immune escape is a matter of global concern. Their origin remains unclear, but intra-host virus evolution during persistent infections could be a contributing factor. Here, we studied the long-term SARS-CoV-2 infection in an immunosuppressed organ transplant recipient. Frequent respiratory specimens were tested for variant viral genomes by RT-qPCR, next-generation sequencing (NGS), and virus isolation. Late in infection, several virus variants emerged which escaped neutralization by COVID-19 convalescent and vaccine-induced antisera and had acquired genome mutations similar to those found in variants of concern first identified in UK, South Africa, and Brazil. Importantly, infection of susceptible hACE2-transgenic mice with one of the patients escape variants elicited protective immunity against re-infection with either the parental virus, the escape variant or the South African variant of concern, demonstrating broad immune control. Upon lowering immunosuppressive treatment, the patient generated spike-specific neutralizing antibodies and resolved the infection. Our results indicate that immunocompromised patients are an alarming source of potentially harmful SARS-CoV-2 variants and open up new avenues for the updating of COVID-19 vaccines.

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.