Variation in clinical outcomes and immune consequences following two viral infections
Citation:
Townsend, Liam, Variation in clinical outcomes and immune consequences following two viral infections, Trinity College Dublin. School of Medicine,2022Download Item:
Abstract:
Ageing is associated with increasing rates of ill-health. However, the burden of ill-health is not evenly distributed across ageing populations. The term biological age captures the consequences of ageing more effectively than chronological age. Accelerated biological ageing leads to frailty. Frailty, as defined by an increased likelihood of poor health outcomes, is a major burden on health services worldwide. Chronic infection is associated with the development of frailty phenotypes. Patients with chronic viral infections, most notably HIV, demonstrate multimorbidity at an earlier age. This perhaps explains why healthy life years are not increased in all treated HIV patients, who can now expect normal lifespans. Instead, multimorbidity develops, including cardiovascular disease and multisystem symptoms such as fatigue, reduced exercise tolerance and weakness. Frail individuals are also at increased risk of poor outcomes following subsequent viral infection. Abnormalities in immune phenotype, function and regulation are thought to underlie the development of frailty in both infectious and non-infectious conditions, as well as poorer outcomes following viral infection in frail individuals. The precise immunopathological mechanisms of frailty and the effects of frailty on subsequent infections remain poorly understood.
Here we hypothesise that immune dysregulation following viral infection contributes to the development of a frailty phenotype in susceptible individuals. We aimed to assess the development of immune dysregulation and accelerated biological ageing in viral infection, and identify risk factors for their development.
In the first instance, frailty in HIV-negative and virally-suppressed HIV-positive patients was assessed using the Fried frailty phenotype. Circulating lymphocytes, monocytes and pro-inflammatory cytokines were measured, and autophagic flux and mitochondrial ROS production in these immune cell populations was assessed. There were reduced proportions of CD4+ and increased CD8+ lymphocytes in HIV-positive patients, but no association with frailty assessments. Circulating levels of MCP-1, IP-10 and TNFα were increased in the HIV cohort but were not associated with frailty measures. These changes were independent of differences in autophagic flux or mitochondrial ROS in circulating immune cells, where we saw no differences between PLWHIV and their HIV-negative counterparts. There were also no differences between these cohorts in the frailty characteristics assessed.
Frailty characteristics are seen in patients following viral infections other than HIV. The SARS-CoV-2 pandemic demonstrates a large burden of ongoing ill-health, in particular fatigue, in survivors. The impact of frailty and immune dysregulation in acute SARS-CoV-2 patients was assessed. Convalescent immune recovery, including immune population, cytokine and antibody measurements, and the cardinal features of accelerated biological ageing and frailty were measured in convalescent SARS-CoV-2 patients. Dysregulated myeloid function, with immature neutrophils and monocytes, as well as pro-inflammatory cytokine production and blunted type 1 interferon responses were associated with severe disease. Frail individuals were more likely to develop severe disease, driving further frailty risk.
Sustained T cell abnormalities were found 14 weeks post-infection, most marked in those with pre-existing frailty, with expanded activated CD4+ and CD8+ T cells and reduced naïve CD8+ T cells. Fatigue and reduced exercise tolerance were common during the convalescent period and were independent of initial disease severity. While frailty scores at the time of initial infection influenced immune parameters during convalescence, there was no association between measures of ongoing ill-health and immune parameters.
These results demonstrate significant changes in lymphocyte populations and circulating cytokines in chronic well-controlled HIV infection, but no demonstrable association with frailty. However, we demonstrate frailty as a risk factor for immune dysregulation and severe disease in acute SARS-CoV-2 infection. Accelerated biological ageing and frailty features during SARS-CoV-2 convalescence are evident, together with persistent immune dysregulation, but there is no direct relationship between physical sequalae and immune consequences of SARS-CoV-2 infection.
Collectively, these results illustrate the complex interactions between frailty and viral infection, with frailty as a risk factor for severe infection and also a consequence of viral infection. The lack of linear relationship with immunological parameters suggests that the pathogenesis of biological ageing is not solely a direct consequence of immune dysregulation as assessed here. Other factors such as lifestyle, genetics and adverse life events are also likely to contribute to the concomitant development of accelerated biological ageing and dysregulated immune activity. This work emphasises the complexity and multifactorial origin of accelerated biological ageing. Further work will require longitudinal assessment of these patients, with repeated immunological and clinical measurements, to better understand their relationship.
Sponsor
Grant Number
Health Research Board
203930/B/16/Z
Irish Clinical Academic Training (ICAT) Programme
Wellcome Trust
Health Service Executive, National Doctors Training and Planning and the Health and Social Care, Research and Development Division, Northern Ireland
Author: Townsend, Liam
Advisor:
O’Farrelly, ClionaBergin, Colm
Ní Cheallaigh, Cliona
Bourke, Nollaig
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