The effects of sleep disturbance on dyspnoea and impaired lung function following COVID-19 hospitalisation: a prospective multi-centre cohort study

BackgroundSleep disturbance is common following hospitalisation both for COVID-19 and other causes. The clinical associations are poorly understood, despite it altering pathophysiology in other scenarios. We, therefore, investigated whether sleep disturbance is associated with dyspnoea along with relevant mediation pathways. MethodsSleep parameters were assessed in a prospective cohort of patients (n=2,468) hospitalised for COVID-19 in the United Kingdom in 39 centres using both subjective and device-based measures. Results were compared to a matched UK biobank cohort and associations were evaluated using multivariable linear regression. Findings64% (456/714) of participants reported poor sleep quality; 56% felt their sleep quality had deteriorated for at least 1-year following hospitalisation. Compared to the matched cohort, both sleep regularity (44.5 vs 59.2, p<0.001) and sleep efficiency (85.4% vs 88.5%, p<0.001) were lower whilst sleep period duration was longer (8.25h vs 7.32h, p<0.001). Overall sleep quality (effect estimate 4.2 (3.0-5.5)), deterioration in sleep quality following hospitalisation (effect estimate 3.2 (2.0-4.5)), and sleep regularity (effect estimate 5.9 (3.7-8.1)) were associated with both dyspnoea and impaired lung function (FEV1 and FVC). Depending on the sleep metric, anxiety mediated 13-42% of the effect of sleep disturbance on dyspnoea and muscle weakness mediated 29-43% of this effect. InterpretationSleep disturbance is associated with dyspnoea, anxiety and muscle weakness following COVID-19 hospitalisation. It could have similar effects for other causes of hospitalisation where sleep disturbance is prevalent. FundingUK Research and Innovation, National Institute for Health Research, and Engineering and Physical Sciences Research Council.

Nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination.

BackgroundMost studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. MethodsPlasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data. FindingsStrong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months. Nasal and plasma anti-S IgG remained elevated for at least 12 months with high plasma neutralising titres against all variants. Of 180 with complete data, 160 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal. Samples 12 months after admission showed no association between nasal IgA and plasma IgG responses, indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination. InterpretationThe decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity. Research in contextO_ST_ABSEvidence before the studyC_ST_ABSWhile systemic immunity to SARS-CoV-2 is important in preventing severe disease, mucosal immunity prevents viral replication at the point of entry and reduces onward transmission. We searched PubMed with search terms "mucosal", "nasal", "antibody", "IgA", "COVID-19", "SARS-CoV-2", "convalescent" and "vaccination" for studies published in English before 20th July 2022, identifying three previous studies examining the durability of nasal responses that generally show nasal antibody to persist for 3 to 9 months. However, these studies were small or included individuals with mild COVID-19. One study of 107 care-home residents demonstrated increased salivary IgG (but not IgA) after two doses of mRNA vaccine, and another examined nasal antibody responses after infection and subsequent vaccination in 20 cases, demonstrating rises in both nasal IgA and IgG 7 to 10 days after vaccination. Added value of this studyStudying 446 people hospitalised for COVID-19, we show durable nasal and plasma IgG responses to ancestral (B.1 lineage) SARS-CoV-2, Delta and Omicron (BA.1) variants up to 12 months after infection. Nasal antibody induced by infection with pre-Omicron variants, bind Omicron virus in vitro better than plasma antibody. Although nasal and plasma IgG responses were enhanced by vaccination, Omicron binding responses did not reach levels equivalent to responses for ancestral SARS-CoV-2. Using paired plasma and nasal samples collected approximately 12 months after infection, we show that nasal IgA declines and shows a minimal response to vaccination whilst plasma antibody responses to S antigen are well maintained and boosted by vaccination. Implications of all the available evidenceAfter COVID-19 and subsequent vaccination, Omicron binding plasma and nasal antibody responses are only moderately enhanced, supporting the need for booster vaccinations to maintain immunity against SARS-CoV-2 variants. Notably, there is distinct compartmentalisation between nasal IgA and plasma IgA and IgG responses after vaccination. These findings highlight the need for vaccines that induce robust and durable mucosal immunity.

Longitudinal lung function assessment of patients hospitalised with COVID-19 using 1H and 129Xe lung MRI

IntroductionMicrovascular abnormalities and impaired gas transfer have been observed in patients with COVID-19. The progression of pathophysiological pulmonary changes during the post-acute period in these patients remains unclear. MethodsPatients who were hospitalised due to COVID-19 pneumonia underwent a pulmonary 1H and 129Xe MRI protocol at 6, 12, 25 and 51 weeks after hospital admission. The imaging protocol included: ultra-short echo time, dynamic contrast enhanced lung perfusion, 129Xe lung ventilation, 129Xe diffusion weighted and 129Xe 3D spectroscopic imaging of gas exchange. Results9 patients were recruited and underwent MRI at 6 (n=9), 12 (n=9), 25 (n=6) and 51 (n=8) weeks after hospital admission. Patients with signs of interstitial lung damage at 3 months were excluded from this study. At 6 weeks after hospital admission, patients demonstrated impaired 129Xe gas transfer (RBC:M) but normal lung microstructure (ADC, LmD). Minor ventilation abnormalities present in four patients were largely resolved in the 6-25 week period. At 12 week follow up, all patients with lung perfusion data available (n=6) showed an increase in both pulmonary blood volume and flow when compared to 6 weeks, though this was not statistically significant. At 12 week follow up, significant improvements in 129Xe gas transfer were observed compared to 6-week examinations, however 129Xe gas transfer remained abnormally low at weeks 12, 25 and 51. Changes in 129Xe gas transfer correlated significantly with changes in pulmonary blood volume and TLCO Z-score. ConclusionsThis study demonstrates that multinuclear MRI is sensitive to functional pulmonary changes in the follow up of patients who were hospitalised with COVID-19. Impairment of xenon transfer may indicate damage to the pulmonary microcirculation.

Enhanced neutrophil extracellular trap formation in COVID-19 is inhibited by the PKC inhibitor ruboxistaurin.

Neutrophil extracellular traps (NETs) are web-like DNA and protein lattices which are expelled by neutrophils to trap and kill pathogens, but which cause significant damage to the host tissue. NETs have emerged as critical mediators of lung damage, inflammation and thrombosis in COVID-19 and other diseases, but there are no therapeutics to prevent or reduce NETs that are available to patients. Here, we show that neutrophils isolated from hospitalised patients with COVID-19 produce significantly more NETs in response to LPS compared to cells from healthy control subjects. A subset of patients were captured at follow-up clinics (3-4 month post-infection) and while LPS-induced NET formation is significantly lower at this time point, it remains elevated compared to healthy controls. LPS- and PMA-induced NETs were significantly inhibited by the protein kinase C (PKC) inhibitor ruboxistaurin. Ruboxistaurin-mediated inhibition of NETs in healthy neutrophils reduces NET-induced epithelial cell death. Our findings suggest ruboxistaurin could reduce proinflammatory and tissue-damaging consequences of neutrophils during disease, and since it has completed phase III trials for other indications without safety concerns, it is a promising and novel therapeutic strategy for COVID-19.