Characterisation of the pro-inflammatory cytokine signature in severe COVID-19.

Clinical outcomes from infection with SARS-CoV-2, the cause of the COVID-19 pandemic, are remarkably variable ranging from asymptomatic infection to severe pneumonia and death. One of the key drivers of this variability is differing trajectories in the immune response to SARS-CoV-2 infection. Many studies have noted markedly elevated cytokine levels in severe COVID-19, although results vary by cohort, cytokine studied and sensitivity of assay used. We assessed the immune response in acute COVID-19 by measuring 20 inflammatory markers in 118 unvaccinated patients with acute COVID-19 (median age: 70, IQR: 58-79 years; 48.3% female) recruited during the first year of the pandemic and 44 SARS-CoV-2 naïve healthy controls. Acute COVID-19 was associated with marked elevations in nearly all pro-inflammatory markers, whilst eleven markers (namely IL-1ß, IL-2, IL-6, IL-10, IL-18, IL-23, IL-33, TNF-α, IP-10, G-CSF and YKL-40) were associated with disease severity. We observed significant correlations between nearly all markers elevated in those infected with SARS-CoV-2 consistent with widespread immune dysregulation. Principal component analysis highlighted a pro-inflammatory cytokine signature (with strongest contributions from IL-1ß, IL-2, IL-6, IL-10, IL-33, G-CSF, TNF-α and IP-10) which was independently associated with severe COVID-19 (aOR: 1.40, 1.11-1.76, p=0.005), invasive mechanical ventilation (aOR: 1.61, 1.19-2.20, p=0.001) and mortality (aOR 1.57, 1.06-2.32, p = 0.02). Our findings demonstrate elevated cytokines and widespread immune dysregulation in severe COVID-19, adding further evidence for the role of a pro-inflammatory cytokine signature in severe and critical COVID-19.

Vitamin D and COVID-19-Revisited.

Vitamin D, when activated to 1,25-dihydroxyvitamin D, is a steroid hormone that induces responses in several hundred genes, including many involved in immune responses to infection. Without supplementation, people living in temperate zones commonly become deficient in the precursor form of vitamin D, 25-hydroxyvitamin D, during winter, as do people who receive less sunlight exposure or those with darker skin pigmentation. Studies performed pre-COVID-19 have shown significant but modest reduction in upper respiratory infections in people receiving regular daily vitamin D supplementation. Vitamin D deficiency, like the risk of severe COVID-19, is linked with darker skin colour and also with obesity. Greater risk from COVID-19 has been associated with reduced ultraviolet exposure. Various studies have examined serum 25-hydroxyvitamin D levels, either historical or current, in patients with COVID-19. The results of these studies have varied but the majority have shown an association between vitamin D deficiency and increased risk of COVID-19 illness or severity. Interventional studies of vitamin D supplementation have so far been inconclusive. Trial protocols commonly allow control groups to receive low-dose supplementation that may be adequate for many. The effects of vitamin D supplementation on disease severity in patients with existing COVID-19 are further complicated by the frequent use of large bolus dose vitamin D to achieve rapid effects, even though this approach has been shown to be ineffective in other settings. As the pandemic passes into its third year, a substantial role of vitamin D deficiency in determining the risk from COVID-19 remains possible but unproven.

The bi-directional association between loneliness and depression among older adults from before to during the COVID-19 pandemic.

BACKGROUND: Older adults have both the highest risk of contracting SARS-CoV-2 and in many jurisdictions have had additional restrictions placed on the social interactions. As a result, the COVID-19 pandemic has led to increased depression and loneliness among older adults. Using data from an established cohort of older adults, the aims of this study was to describe changes in loneliness and depression and to examine the directionality of the association between depression and loneliness over a 5-year period that included the early months of the pandemic. METHODS: Data were from The Irish Longitudinal Study on Ageing (TILDA), a large cohort of community-dwelling adults aged 54+. We applied an auto-regressive cross-lagged panel modelling approach to estimate the effect of depression on loneliness and vice versa over three time points. RESULTS: Both depression and loneliness increased significantly in the early months of the pandemic. While the association between loneliness and depression was bi-directional, loneliness was a stronger predictor of depression. CONCLUSION: The strength and bi-directionality of the association between loneliness and depression suggests that interventions to alleviate loneliness may also help reduce depressive symptoms and vice versa.

Title: Understanding a Low Vitamin D State in the Context of COVID-19.

While a low vitamin D state has been associated with an increased risk of infection by SARS-CoV-2 in addition to an increased severity of COVID-19 disease, a causal role is not yet established. Here, we review the evidence relating to i) vitamin D and its role in SARS-CoV-2 infection and COVID-19 disease ii) the vitamin D status in the Irish adult population iii) the use of supplemental vitamin D to treat a deficient status and iv) the application of the Bradford-Hill causation criteria. We conclude that reverse causality probably makes a minimal contribution to the presence of low vitamin D states in the setting of COVID-19. Applying the Bradford-Hill criteria, however, the collective literature supports a causal association between low vitamin D status, SARS-CoV-2 infection, and severe COVID-19 (respiratory failure, requirement for ventilation and mortality). A biologically plausible rationale exists for these findings, given vitamin D's role in immune regulation. The thresholds which define low, deficient, and replete vitamin D states vary according to the disease studied, underscoring the complexities for determining the goals for supplementation. All are currently unknown in the setting of COVID-19. The design of vitamin D randomised controlled trials is notoriously problematic and these trials commonly fail for a number of behavioural and methodological reasons. In Ireland, as in most other countries, low vitamin D status is common in older adults, adults in institutions, and with obesity, dark skin, low UVB exposure, diabetes and low socio-economic status. Physiological vitamin D levels for optimal immune function are considerably higher than those that can be achieved from food and sunlight exposure alone in Ireland. A window exists in which a significant number of adults could benefit from vitamin D supplementation, not least because of recent data demonstrating an association between vitamin D status and COVID-19. During the COVID pandemic, we believe that supplementation with 20-25ug (800-1000 IU)/day or more may be required for adults with apparently normal immune systems to improve immunity against SARS-CoV-2. We expect that higher monitored doses of 37.5-50 ug (1,500-2,000)/day may be needed for vulnerable groups (e.g., those with obesity, darker skin, diabetes mellitus and older adults). Such doses are within the safe daily intakes cited by international advisory agencies.

Depressive Symptoms Among Older Adults Pre- and Post-COVID-19 Pandemic.

OBJECTIVES: It is a concern that public health measures to prevent older people contracting COVID-19 could lead to a rise in mental health problems such as depression. The aim of this study therefore is to examine trends of depressive symptoms before and during the COVID-19 pandemic in a large cohort of older people. DESIGN: Observational study with 6-year follow-up. SETTING & PARTICIPANTS: More than 3000 community-dwelling adults aged ≥60 years participating in The Irish Longitudinal Study on Ageing (TILDA). METHODS: Mixed effects multilevel models were used to describe trends in depressive symptoms across 3 waves of TILDA: wave 4 (2016), wave 5 (2018), and a final wave conducted July-November 2020. Depressive symptoms were measured using the 8-item Center for Epidemiologic Studies Depression Scale (CES-D), with a score ≥9 indicating clinically significant symptoms. RESULTS: The prevalence of clinically significant depressive symptoms at waves 4 and 5 was 7.2% [95% confidence interval (CI) 6.5, 7.9] and 7.2% (95% CI 6.5, 8.0), respectively. This more than doubled to 19.8% (95% CI 18.5, 21.2) during the COVID-19 pandemic. There was no change in CES-D scores between waves 4 and 5 (ß = 0.09, 95% CI -0.04, 0.23), but a large increase in symptoms was observed during the pandemic (ß = 2.20, 95% CI 2.07, 2.33). Age ≥70 years was independently associated with depressive symptoms (ß = 0.45, 95% CI 0.18, 0.72) during the pandemic but not from wave 4 to 5 (ß = 0.09, 95% CI -0.18, 0.36). Living with others was associated with a lower burden of symptoms during the pandemic (ß = -0.40, 95% CI -0.71, -0.09) but not between waves 4 and 5 (ß = -0.40, 95% CI -0.71, -0.09). CONCLUSIONS AND IMPLICATIONS: This study demonstrates significant increases in the burden of depressive symptoms among older people during the COVID-19 pandemic, particularly those aged ≥70 years and/or living alone. Even a small increase in the incidence of late life depression can have major implications for health care systems and societies in general. Improving access to age-attuned mental health care should therefore be a priority.

Caring in the time of COVID-19, longitudinal trends in wellbeing and mental health in carers in Ireland: evidence from the Irish longitudinal study on ageing (TILDA)*

BackgroundThe initial public health response to the COVID-19 pandemic in Ireland recommended that older people aged ≥70 years remain at home, and physically isolate from those outside their household. This may have affected both care-receipt and care-provision by the older population as maintaining these activities could be challenging with travel restrictions and recommended physical distancing. This study aimed to determine if prevalence of informal caring changed during the COVID-19 pandemic, and examine longitudinal trends in quality of life, stress, and depressive symptoms in carers.MethodsWe analysed the COVID-19 self-completion questionnaire (SCQ) sub-study (June-November 2020) of The Irish Longitudinal Study on Ageing (TILDA), a nationally representative study of people aged ≥50 years ongoing since 2009. A total of 3,043 participants aged ≥60 years were included. Participants were asked if they cared for someone during the COVID-19 pandemic, their relationship to the recipient, and number of hours/week. Outcome measures collected were CES-D8, Perceived stress Scale (PSS) and CASP12. Change in prevalence of caring from previous waves was examined. Multi-level regression analyses examined longitudinal trends in CED-D8, PSS and CASP12 scores by caring status since Wave 3 (2014), adjusting for sociodemographic variables. Analyses were conducted in Stata 14.ResultsPrevalence of informal caring tripled during the COVID-19 pandemic (15% compared to 5% in 2018). While 26% of carers reported they had stopped caring since the pandemic, most of those providing care were new carers (68% of men and 66% of women carers). Becoming a new carer during the pandemic was associated with lower CASP12 scores (β=-0.582, 95% CI -1.018,-0.146) and higher PSS (β=0.541, 95% CI 0.316,0.765) compared to no caring. Caring for ≥50 hours in the past week was associated with lower CASP12 (β=-0.878, 95%CI -1.345,-0.412), higher PSS scores (β=0.383, 95%CI 0.066,0.700) and higher depressive symptoms (β=0.371, 95% CI 0.251,0.490). This association was moderated by carer status;new carers with increased hours had higher CES-D8 compared to non-carers, with no difference for those who stopped or continued caring.DiscussionThis study demonstrated that the reduction of availability of both formal and informal care for older people during the COVID-19 pandemic, led to increased caring by older household members and was associated with lower wellbeing and mental health. This study provides further evidence of the detrimental indirect effects of the pandemic for older people and emphasizes for policymakers the importance of prioritising formal and informal care arrangements for the older population.

Investigating the Relationship between Vitamin D and Persistent Symptoms Following SARS-CoV-2 Infection.

The emergence of persistent symptoms following SARS-CoV-2 infection, known as long COVID, is providing a new challenge to healthcare systems. The cardinal features are fatigue and reduced exercise tolerance. Vitamin D is known to have pleotropic effects far beyond bone health and is associated with immune modulation and autoimmunity. We hypothesize that vitamin D levels are associated with persistent symptoms following COVID-19. Herein, we investigate the relationship between vitamin D and fatigue and reduced exercise tolerance, assessed by the Chalder Fatigue Score, six-minute walk test and modified Borg scale. Multivariable linear and logistic regression models were used to evaluate the relationships. A total of 149 patients were recruited at a median of 79 days after COVID-19 illness. The median vitamin D level was 62 nmol/L, with n = 36 (24%) having levels 30-49 nmol/L and n = 14 (9%) with levels <30 nmol/L. Fatigue was common, with n = 86 (58%) meeting the case definition. The median Borg score was 3, while the median distance covered for the walk test was 450 m. No relationship between vitamin D and the measures of ongoing ill-health assessed in the study was found following multivariable regression analysis. These results suggest that persistent fatigue and reduced exercise tolerance following COVID-19 are independent of vitamin D.

Fatigue following COVID-19 infection is not associated with autonomic dysfunction.

BACKGROUND: The long-term clinical and physiological consequences of COVID-19 infection remain unclear. While fatigue has emerged as a common symptom following infection, little is known about its links with autonomic dysfunction. SARS-CoV-2 is known to infect endothelial cells in acute infection, resulting in autonomic dysfunction. Here we set out to test the hypothesis that this results in persistent autonomic dysfunction and is associated with post-COVID fatigue in convalescent patients. METHODS: We recruited 20 fatigued and 20 non-fatigued post-COVID patients (median age 44.5 years, 36/40 (90%) female, median time to follow up 166.5 days). Fatigue was assessed using the Chalder Fatigue Scale. These underwent the Ewing's autonomic function test battery, including deep breathing, active standing, Valsalva manoeuvre and cold-pressor testing, with continuous electrocardiogram and blood pressure monitoring, as well as near-infrared spectroscopy-based cerebral oxygenation. 24-hour ambulatory blood pressure monitoring was also conducted, and patients completed the generalised anxiety disorder-7 questionnaire. We assessed between-group differences in autonomic function test results and used unadjusted and adjusted linear regression to investigate the relationship between fatigue, anxiety, and autonomic test results. RESULTS: We found no pathological differences between fatigued and non-fatigued patients on autonomic testing or on 24-hour blood pressure monitoring. Symptoms of orthostatic intolerance were reported by 70% of the fatigued cohort at the time of active standing, with no associated physiological abnormality detected. Fatigue was strongly associated with increased anxiety (p <0.001), with no patients having a pre-existing diagnosis of anxiety. CONCLUSIONS: These results demonstrate the significant burden of fatigue, symptoms of autonomic dysfunction and anxiety in the aftermath of COVID-19 infection, but reassuringly do not demonstrate pathological findings on autonomic testing.

Perspective: Vitamin D supplementation prevents rickets and acute respiratory infections when given as daily maintenance but not as intermittent bolus: implications for COVID-19.

The value of vitamin D supplementation in the treatment or prevention of various conditions is often viewed with scepticism as a result of contradictory results of randomised trials. It is now becoming apparent that there is a pattern to these inconsistencies. A recent large trial has shown that high-dose intermittent bolus vitamin D therapy is ineffective at preventing rickets - the condition that is most unequivocally caused by vitamin D deficiency. There is a plausible biological explanation since high-dose bolus replacement induces long-term expression of the catabolic enzyme 24-hydroxylase and fibroblast growth factor 23, both of which have vitamin D inactivating effects. Meta-analyses of vitamin D supplementation in prevention of acute respiratory infection and trials in tuberculosis and other conditions also support efficacy of low dose daily maintenance rather than intermittent bolus dosing. This is particularly relevant during the current COVID-19 pandemic given the well-documented associations between COVID-19 risk and vitamin D deficiency. We would urge that clinicians take note of these findings and give strong support to widespread use of daily vitamin D supplementation.

The 'Wish to Die' in later life: prevalence, longitudinal course and mortality. Data from TILDA.

BACKGROUND: 'Wish to Die' (WTD) involves thoughts of or wishes for one's own death or that one would be better off dead. OBJECTIVE: To examine the prevalence, longitudinal course and mortality-risk of WTD in community-dwelling older people. DESIGN: Observational study with 6-year follow-up. SETTING: The Irish Longitudinal Study on Ageing, a nationally representative cohort of older adults. SUBJECTS: In total, 8,174 community-dwelling adults aged ≥50 years. METHODS: To define WTD, participants were asked: 'In the last month, have you felt that you would rather be dead?' Depressive symptoms were measured using the CES-D. Mortality data were compiled by linking administrative death records to individual-level survey data from the study. RESULTS: At Wave 1, 3.5% of participants (279/8,174) reported WTD. Both persistent loneliness (OR 5.73 (95% CI 3.41-9.64)) and depressive symptoms (OR 6.12 (95% CI 4.33-8.67)) were independently associated with WTD.Of participants who first reported WTD at Wave 1 or 2, 72% did not report WTD when reassessed after 2 years, and the prevalence of depressive symptoms (-44%) and loneliness (-19%) was more likely to decline in this group at follow-up.Fifteen per cent of participants expressing WTD at Wave 1 died during a 6-year follow-up. CONCLUSIONS: WTD amongst community-dwelling older people is frequently transient and is strongly linked with the course of depressive symptoms and loneliness. An enhanced focus on improving access to mental health care and addressing social isolation in older people should therefore be a public health priority, particularly in the current context of the Covid-19 pandemic.

Mortality risk associated with combinations of loneliness and social isolation. Findings from The Irish Longitudinal Study on Ageing (TILDA).

BACKGROUND: Social distancing and similar measures in response to the coronavirus disease 2019 pandemic have greatly increased loneliness and social isolation among older adults. Understanding the association between loneliness and mortality is therefore critically important. We examined whether combinations of loneliness and social isolation, using a metric named social asymmetry, was associated with increased mortality risk. METHODS: The sample was derived from participants in The Irish Longitudinal Study on Ageing, a nationally representative sample of community-dwelling older adults aged ≥50. Survey data were linked to official death registration records. Cox proportional hazards regressions and competing risk survival analyses were used to examine the association between social asymmetry and all-cause and cause-specific mortality. RESULTS: Of four social asymmetry groups, concordant low lonely (low loneliness, low isolation) included 35.5% of participants; 26.4% were concordant high lonely (high loneliness, high isolation); 19.2% were discordant robust (low loneliness, high isolation) and 18.9% discordant susceptible (high loneliness, low isolation). The concordant high lonely (hazard ratio [HR] = 1.43, 95% confidence interval [CI]: 1.09-1.87) and discordant robust (HR = 1.37, 95% CI: 1.04-1.81) groups had an increased mortality risk compared to those in the concordant low lonely group. The concordant high lonely group had an increased risk of mortality due to diseases of the circulatory system (sub-distribution hazard ratio = 1.52, 95% CI: 1.03-2.25). CONCLUSION: We found that social asymmetry predicted mortality over a 7-year follow-up period. Our results confirm that a mismatch between subjective loneliness and objective social isolation, as well as the combination of loneliness and social isolation, were associated with an increased all-cause mortality risk.

Preventing vitamin D deficiency during the COVID-19 pandemic: UK definitions of vitamin D sufficiency and recommended supplement dose are set too low.

There is growing evidence linking vitamin D deficiency with risk of COVID-19. It is therefore distressing that there is major disagreement about the optimal serum level for 25-hydroxyvitamin D (25(OH)D) and appropriate supplement dose. The UK Scientific Advisory Committee for Nutrition has set the lowest level for defining sufficiency (10 ng/ml or 25 nmol/L) of any national advisory body or scientific society and consequently recommends supplementation with 10 micrograms (400 IU) per day. We have searched for published evidence to support this but not found it. There is considerable evidence to support the higher level for sufficiency (20 ng/ml or 50 nmol/L) recommended by the European Food Safety Authority and the American Institute of Medicine and hence greater supplementation (20 micrograms or 800 IU per day). Serum 25(OH)D concentrations in the UK typically fall by around 50% through winter. We believe that governments should urgently recommend supplementation with 20-25 micrograms (800-1,000 IU) per day.