Enhanced immune ageing associated with increasing COVID-19 disease severity (preprint)

Background The striking increase in COVID-19 severity in older adults provides a clear example of immunesenescence, the age-related remodelling of the immune system. To better characterise the association between convalescent immunesenescence and acute disease severity, we determined the immune phenotype of COVID-19 survivors and non-infected controls.Results We performed detailed immune phenotyping of peripheral blood mononuclear cells isolated from 103 COVID-19 survivors 3–5 months post recovery who were classified as having had severe (n = 56; age 53.12 ± 11.30 years), moderate (n = 32; age 52.28 ± 11.43 years) or mild (n = 15; age 49.67 ± 7.30 years) disease and compared with age and sex-matched healthy adults (n = 59; age 50.49 ± 10.68 years). We assessed a broad range of immune cell phenotypes to generate a composite score, IMM-AGE, to determine the degree of immune senescence. We found increased immunesenescence features in severe COVID-19 survivors compared to controls including: a reduced frequency and number of naïve CD4 and CD8 T cells (p < 0.0001); increased frequency of EMRA CD4 (p < 0.003) and CD8 T cells (p < 0.001); a higher frequency (p < 0.0001) and absolute numbers (p < 0.001) of CD28− ve CD57+ ve senescent CD4 and CD8 T cells; higher frequency (p < 0.003) and absolute numbers (p < 0.02) of PD-1 expressing exhausted CD8 T cells; a two-fold increase in Th17 polarisation (p < 0.0001); higher frequency of memory B cells (p < 0.001) and increased frequency (p < 0.0001) and numbers (p < 0.001) of CD57+ ve senescent NK cells. As a result, the IMM-AGE score was significantly higher in severe COVID-19 survivors than in controls (p < 0.001). Few differences were seen for those with moderate disease and none for mild disease. Regression analysis revealed the only pre-existing variable influencing the IMM-AGE score was South Asian ethnicity (\(\beta\) = 0.174, p= 0.043), with a major influence being disease severity (\(\beta\) = 0.188, p = 0.01).Conclusions Our analyses reveal a state of enhanced immune ageing in survivors of severe COVID-19 and suggest this could be related to SARS-Cov-2 infection. Our data support the rationale for trials of anti-immune ageing interventions for improving clinical outcomes in these patients with severe disease.

Responsive and Resilient Healthcare? Moments of Resilience in post- hospitalisation services for COVID-19 (preprint)

Background COVID-19 caused disruption to healthcare services globally, resulting in high numbers of hospital admissions and with those discharged often requiring ongoing support. Within the UK, post-discharge services typically developed organically and were shaped over time by local need, funding, and government guidance. Drawing on the Moments of Resilience framework, we explore the development of follow-up services for hospitalised patients by considering the links between resilience at different system levels over time. This study contributes to the resilient healthcare literature by providing empirical evidence of how diverse stakeholders developed and adapted services for patients following hospitalisation with COVID-19 and how action taken at one system level influenced another. Methods Qualitative research comprising comparative case studies based on interviews. Across three purposively selected case studies (two in England, one in Wales) a total of 33 semi-structured interviews were conducted with clinical staff, managers and commissioners who had been involved in developing and/or implementing post-hospitalisation follow-up services. The interviews were audio-recorded and professionally transcribed. Analysis was conducted with the aid of NVivo 12. Results Case studies demonstrated three distinct examples of how healthcare organisations developed and adapted their post-discharge care provision for patients, post-hospitalisation with COVID-19. Initially, the moral distress of witnessing the impact of COVID-19 on patients who were being discharged coupled with local demand gave clinical staff the impetus to take action. Clinical staff and managers worked closely to plan and deliver organisations’ responses. Funding availability and other contextual factors influenced situated and immediate responses and structural adaptations to the post-hospitalisation services. As the pandemic evolved, NHS England and the Welsh government provided funding and guidance for systemic adaptations to post-COVID assessment clinics. Over time, adaptations made at the situated, structural, and systemic levels influenced the resilience and sustainability of services. Conclusions This paper addresses understudied, yet inherently important, aspects of resilience in healthcare by exploring when and where resilience occurs across the healthcare system and how action taken at one system level influenced another.  Comparison across the case studies showed that organisations responded in similar and different ways and on varying timescales to a disruption and national level strategies.

Fatigue outcomes following coronavirus or influenza virus infection: A systematic review and meta-analysis (preprint)

ABSTRACT Objectives Fatigue is a pervasive clinical symptom for many infected with respiratory viruses such as influenza or coronaviruses. Prior evidence from influenza and coronavirus epidemics suggest that fatigue symptomology may continue beyond the acute phase, lasting for several months to several years post-discharge. This systematic review aimed to examine long-term fatigue prevalence among survivors and among communities, as well as investigate the current evidence for associated factors. Design Systematic review and meta-analysis. Setting Hospitalised and community samples. Participants Patient populations with a confirmed diagnosis of a named influenza virus or coronavirus. Main outcomes measured Fatigue, fatigue syndromes Results Ten studies met the inclusion criteria for a pooled prevalence analysis and five studies were identified as eligible for a means differences analysis. A fatigue prevalence of 41% (95% CI 0.299-0.488) was found among a total population of 1,310. Using the ‘vitality’ subscale of the SF-36 as a proxy for fatigue, the estimate for means differences indicated a lower mean vitality score for survivors compared to population norms (M -1.523, CI -13.53 – 10.48), although this was not significant (p = 0.803). The most common associations with fatigue were PTSD, depression and anxiety, female gender and higher age. Conclusions This study reveals that a significant proportion of survivors (41%) experienced fatigue following their recovery from novel respiratory viruses such as SARS, MERS, SARS-CoV2 or influenza and that this fatigue can be long-lasting. Also, some factors such as female gender and psychological factors may contribute to continuing fatigue outcomes for this population. Strengths and limitations (a) this study provides support for long-term fatigue outcomes in people with a confirmed influenza, SARS, MERS, SARS-CoV2 virus infection (b) the study suggests individual, psychological and social factors are associated with fatigue, (c) findings are limited by the availability of fatigue data and lack of pre-morbid fatigue information; (d) a meta-analysis on the associations was prohibited by the small number of studies investigating long-term fatigue correlates and (e) the heterogeneity of the studies (>75%) suggests the pooled estimates should be interpreted with caution.

COPD in the time of COVID-19: An analysis of acute exacerbations and reported behavioural changes in patients with COPD (preprint)

IntroductionThe impact of the SARS-CoV-2 pandemic, and lockdown measures, on acute exacerbations of COPD (AECOPD) is unknown. We aimed to evaluate the change in AECOPD treatment frequency during the first six weeks of lockdown in the UK compared with 2019 and assess changes in self-reported behaviour and well-being. MethodsIn this observational study patients with established COPD were recruited. Exacerbation frequency was measured in the first six weeks of COVID lockdown and compared with the same period in 2019 using electronic health records. A telephone survey was used to assess changes in anxiety, inhaler adherence, physical activity, shopping and visitor behaviour during the pre-lockdown and lockdown periods compared to normal. Results160 participants were recruited (mean [SD] age 67.3 [8.1] years, 88 [55%] male, FEV1 34.3 [13] % predicted) and 140 [88%] reported at least one AECOPD in the previous year. Significantly more community treated exacerbations were observed in 2020 compared with 2019 (126 vs 99, p=0.026). The increase was as a result of multiple courses of treatment, with a similar proportion of patients receiving at least one course (34.4% vs 33.8%). During "lockdown" participants reported significantly increased anxiety, adherence to their preventative inhalers, and good adherence to shielding advice (all p<0.001). A significant reduction in self-reported physical activity and visitors was reported (both p<0.001). DiscussionTreatment for AECOPD events increased during the first six weeks of the SARS-CoV-2 pandemic in the UK compared to 2019. This was associated with increased symptoms of anxiety and significant behavioural change. What is the key question?How has the COVID-19 pandemic lockdown affected exacerbation patterns and behaviour in patients with COPD? What is the bottom line?A 38% increase in the number of community treated exacerbations was seen in 2020 compared with 2019. Increased symptoms of anxiety were seen in patients, alongside increased inhaler adherence and reduced physical activity. Why read on?The impact of the COVID-19 pandemic has led to significant changes in treatment for exacerbations of COPD in the community, as well as increased anxiety amongst patients.