ABSTRACT
Although lung disease is the primary clinical outcome in COVID-19 patients, how SARS-CoV-2 induces lung pathology remains elusive. Here we describe a high-throughput platform to generate self-organizing and commensurate human lung buds derived from hESCs cultured on micropatterned substrates. Lung buds resemble human fetal lungs and display proximodistal patterning of alveolar and airway tissue directed by KGF. These lung buds are susceptible to infection by SARS-CoV-2 and endemic coronaviruses and can be used to track cell type-specific cytopathic effects in hundreds of lung buds in parallel. Transcriptomic comparisons of infected lung buds and postmortem tissue of COVID-19 patients identified an induction of BMP signaling pathway. BMP activity renders lung cells more susceptible to SARS-CoV-2 infection and its pharmacological inhibition impairs infection by this virus. These data highlight the rapid and scalable access to disease-relevant tissue using lung buds that recapitulate key features of human lung morphogenesis and viral infection biology.
Subject(s)
COVID-19 , Humans , SARS-CoV-2 , Lung , Cells, CulturedABSTRACT
Background: The effects of MS disease modifying therapies (DMTs) on COVID-19 morbidity and mortality have been studied in clinician-reported registries, but the true prevalence of SARSCoV-2 infection and its outcomes in the MS population receiving DMTs are unknown. Objectives: To assess the prevalence of SARS-CoV-2 infection and its outcomes, and their association with individual DMTs among all MS patients receiving DMTs in England. Aims: To understand the magnitude of COVID-19's impact on a population of MS patients receiving DMTs. Methods: We analysed merged national databases to ascertain the rate of SARS-CoV-2 positive tests and COVID-19 in-hospital mortality among all MS patients receiving DMTs in England from 1/02/2020 to 27/03/2021. The National Health Service (NHS) England and NHS Improvement collect prescribing and dispensing data on all MS DMTs. Public Health England collects data on all SARS-CoV-2 tests and COVID-19 in-hospital deaths. Further clinical data collection on a random sample of patients who tested positive (cases) or were not tested (controls) for SARS-CoV-2 is ongoing in multiple centres to establish risk factors of adverse COVID-19 outcomes without selection bias. Results: A total of 35556 MS patients had received a DMT. Their mean (standard deviation) age was 44 (12) years. A total of 16,108 patients (45.3%) were tested for SARS-CoV-2, and 2000 (5.6%) tested positive with a mean age of 42 (12) years. Twentysix patients with a positive test (1.3%) died in hospital. Their mean age was 54 (16) years. The age-standardised mortality ratio (95% confidence interval) of the MS versus the general population was 1.2 (0.7-1.7). There was no clear difference between individual DMTs in their rates of positive tests or inhospital mortality. Detailed data on 79 randomly selected patients with a positive test has been collected at two centres so far. Their mean age is 44 (11) years and 55 (69.6%) are women. Five were hospitalised due to COVID-19 out of whom one was admitted to an intensive therapy unit and died. Data will be updated and reanalysed prior to ECTRIMS 2021. Conclusions: So far, COVID-19 does not appear to significantly increase the risk of mortality in MS patients on DMTs compared to the general population, in this large population study.