Although intermittent increases in inflammation are critical for survival during physical injury and infection, recent research has revealed that certain social, environmental and lifestyle factors can promote systemic chronic inflammation (SCI) that can, in turn, lead to several diseases that collectively represent the leading causes of disability and mortality worldwide, such as cardiovascular disease, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease and autoimmune and neurodegenerative disorders. In the present Perspective we describe the multi-level mechanisms underlying SCI and several risk factors that promote this health-damaging phenotype, including infections, physical inactivity, poor diet, environmental and industrial toxicants and psychological stress. Furthermore, we suggest potential strategies for advancing the early diagnosis, prevention and treatment of SCI.

/pdf/chronic-inflammation-in-the-etiology-of-disease-across-the-3ahtzxhxp7.pdf

Chronic inflammation in the etiology of disease across the life span

An overview of systematic reviews on the public health consequences of social isolation and loneliness

The novel coronavirus disease (COVID-19) outbreak, caused by SARS-CoV-2, represents the greatest medical challenge in decades. We provide a comprehensive review of the clinical course of COVID-19, its comorbidities, and mechanistic considerations for future therapies. While COVID-19 primarily affects the lungs, causing interstitial pneumonitis and severe acute respiratory distress syndrome (ARDS), it also affects multiple organs, particularly the cardiovascular system. Risk of severe infection and mortality increase with advancing age and male sex. Mortality is increased by comorbidities: cardiovascular disease, hypertension, diabetes, chronic pulmonary disease, and cancer. The most common complications include arrhythmia (atrial fibrillation, ventricular tachyarrhythmia, and ventricular fibrillation), cardiac injury [elevated highly sensitive troponin I (hs-cTnI) and creatine kinase (CK) levels], fulminant myocarditis, heart failure, pulmonary embolism, and disseminated intravascular coagulation (DIC). Mechanistically, SARS-CoV-2, following proteolytic cleavage of its S protein by a serine protease, binds to the transmembrane angiotensin-converting enzyme 2 (ACE2) -a homologue of ACE-to enter type 2 pneumocytes, macrophages, perivascular pericytes, and cardiomyocytes. This may lead to myocardial dysfunction and damage, endothelial dysfunction, microvascular dysfunction, plaque instability, and myocardial infarction (MI). While ACE2 is essential for viral invasion, there is no evidence that ACE inhibitors or angiotensin receptor blockers (ARBs) worsen prognosis. Hence, patients should not discontinue their use. Moreover, renin-angiotensin-aldosterone system (RAAS) inhibitors might be beneficial in COVID-19. Initial immune and inflammatory responses induce a severe cytokine storm [interleukin (IL)-6, IL-7, IL-22, IL-17, etc.] during the rapid progression phase of COVID-19. Early evaluation and continued monitoring of cardiac damage (cTnI and NT-proBNP) and coagulation (D-dimer) after hospitalization may identify patients with cardiac injury and predict COVID-19 complications. Preventive measures (social distancing and social isolation) also increase cardiovascular risk. Cardiovascular considerations of therapies currently used, including remdesivir, chloroquine, hydroxychloroquine, tocilizumab, ribavirin, interferons, and lopinavir/ritonavir, as well as experimental therapies, such as human recombinant ACE2 (rhACE2), are discussed.

COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options.

Infection-triggered perturbation of the immune system could induce psychopathology, and psychiatric sequelae were observed after previous coronavirus outbreaks. The spreading of the Severe Acute Respiratory Syndrome Coronavirus (COVID-19) pandemic could be associated with psychiatric implications. We investigated the psychopathological impact of COVID-19 in survivors, also considering the effect of clinical and inflammatory predictors. We screened for psychiatric symptoms 402 adults surviving COVID-19 (265 male, mean age 58), at one month follow-up after hospital treatment. A clinical interview and a battery of self-report questionnaires were used to investigate post-traumatic stress disorder (PTSD), depression, anxiety, insomnia, and obsessive-compulsive (OC) symptomatology. We collected sociodemographic information, clinical data, baseline inflammatory markers and follow-up oxygen saturation levels. A significant proportion of patients self-rated in the psychopathological range: 28% for PTSD, 31% for depression, 42% for anxiety, 20% for OC symptoms, and 40% for insomnia. Overall, 56% scored in the pathological range in at least one clinical dimension. Despite significantly lower levels of baseline inflammatory markers, females suffered more for both anxiety and depression. Patients with a positive previous psychiatric diagnosis showed increased scores on most psychopathological measures, with similar baseline inflammation. Baseline systemic immune-inflammation index (SII), which reflects the immune response and systemic inflammation based on peripheral lymphocyte, neutrophil, and platelet counts, positively associated with scores of depression and anxiety at follow-up. PTSD, major depression, and anxiety, are all high-burden non-communicable conditions associated with years of life lived with disability. Considering the alarming impact of COVID-19 infection on mental health, the current insights on inflammation in psychiatry, and the present observation of worse inflammation leading to worse depression, we recommend to assess psychopathology of COVID-19 survivors and to deepen research on inflammatory biomarkers, in order to diagnose and treat emergent psychiatric conditions.

Anxiety and depression in COVID-19 survivors: Role of inflammatory and clinical predictors.

The health and well-being consequences of social isolation and loneliness in old age are increasingly being recognised The purpose of this scoping review was to take stock of the available evidence and to highlight gaps and areas for future research We searched nine databases for empirical papers investigating the impact of social isolation and/or loneliness on a range of health outcomes in old age Our search, conducted between July and September 2013 yielded 11,736 articles, of which 128 items from 15 countries were included in the scoping review Papers were reviewed, with a focus on the definitions and measurements of the two concepts, associations and causal mechanisms, differences across population groups and interventions The evidence is largely US-focused, and loneliness is more researched than social isolation A recent trend is the investigation of the comparative effects of social isolation and loneliness Depression and cardiovascular health are the most often researched outcomes, followed by well-being Almost all (but two) studies found a detrimental effect of isolation or loneliness on health However, causal links and mechanisms are difficult to demonstrate, and further investigation is warranted We found a paucity of research focusing on at-risk sub-groups and in the area of interventions Future research should aim to better link the evidence on the risk factors for loneliness and social isolation and the evidence on their impact on health

/pdf/social-isolation-loneliness-and-health-in-old-age-a-scoping-y5f4s9m2ha.pdf

Social isolation, loneliness and health in old age: a scoping review.

Background The influence of social relationships on morbidity is widely accepted, but the size of the risk to cardiovascular health is unclear.

Objective We undertook a systematic review and meta-analysis to investigate the association between loneliness or social isolation and incident coronary heart disease (CHD) and stroke.

Methods Sixteen electronic databases were systematically searched for longitudinal studies set in high-income countries and published up until May 2015. Two independent reviewers screened studies for inclusion and extracted data. We assessed quality using a component approach and pooled data for analysis using random effects models.

Results Of the 35 925 records retrieved, 23 papers met inclusion criteria for the narrative review. They reported data from 16 longitudinal datasets, for a total of 4628 CHD and 3002 stroke events recorded over follow-up periods ranging from 3 to 21 years. Reports of 11 CHD studies and 8 stroke studies provided data suitable for meta-analysis. Poor social relationships were associated with a 29% increase in risk of incident CHD (pooled relative risk: 1.29, 95% CI 1.04 to 1.59) and a 32% increase in risk of stroke (pooled relative risk: 1.32, 95% CI 1.04 to 1.68). Subgroup analyses did not identify any differences by gender.

Conclusions Our findings suggest that deficiencies in social relationships are associated with an increased risk of developing CHD and stroke. Future studies are needed to investigate whether interventions targeting loneliness and social isolation can help to prevent two of the leading causes of death and disability in high-income countries.

Study registration number CRD42014010225.

/pdf/loneliness-and-social-isolation-as-risk-factors-for-coronary-3kvb4h8gzr.pdf

Loneliness and social isolation as risk factors for coronary heart disease and stroke: systematic review and meta-analysis of longitudinal observational studies

From Greek mythology and the Bible to modern critiques of the digital age, loneliness has been portrayed as part of the human condition. Recognition of the significant adverse consequences for health has come more recently, with much of the interest triggered by a rise in the death rate in Europe in 2003. Unusually high temperatures in the summer of that year were linked with the deaths of more than 40,000 mainly elderly people throughout mainland Europe. Proportionately fewer deaths were recorded among frail and sick older people living in institutions, compared with more able, but less well-supported people living in the community. These deaths stimulated much discussion and reflection on the treatment of elders in society. In France, and later the UK, non-governmental organizations instigated campaigns to address loneliness and isolation among the aged. Such campaigns, along with research from different disciplines linking loneliness and isolation with adverse health outcomes and premature mortality, have focused attention on the problems. But despite acknowledgement of isolation in the UK National Service Framework for Older People in relation to falls and depression,1 concern among care providers and commissioners has never matched the breadth and severity of the consequences of isolation and loneliness. In this article, we present an overview of current evidence and suggest that a renewed research agenda is required for a growing older population.

https://journals.sagepub.com/doi/pdf/10.1258/jrsm.2012.120128

Loneliness, isolation and the health of older adults: do we need a new research agenda?

Objectives We present a novel way of classifying and comparing measures of social relationships to help readers interpret the growing literature on loneliness and social isolation and to provide researchers with a starting point to guide their choice of measuring tool. Methods Measures of social relationships used in epidemiological studies were identified from two systematic reviews—one review on the association between social relationships and health and social care service use, and a second review on the association between social relationships and health. Questions from each measure were retrieved and tabulated to derive a classification of social relationship measures. Results We present a classification of measures according to two dimensions: (1) whether instruments cover structural or functional aspects of social relationships and (2) the degree of subjectivity asked of respondents. We explain how this classification can be used to clarify the remit of the many questionnaires used in the literature and to compare them. Conclusions Different dimensions of social relationships are likely to have different implications for health. Our classification of social relationship measures transcends disciplinary and conceptual boundaries, allowing researchers to compare tools that developed from different theoretical perspectives. Careful choice of measures is essential to further our understanding of the links between social relationships and health, to identify people in need of help and to design appropriate prevention and intervention strategies.

https://bmjopen.bmj.com/content/bmjopen/6/4/e010799.full.pdf

Loneliness, social isolation and social relationships: what are we measuring? A novel framework for classifying and comparing tools

Background There is increasing evidence of an association between social relationships and morbidity in general, and cardiovascular disease in particular. However, recent syntheses of the evidence raise two important questions: is it the perceived quality or the more objective quantity of relationships that matters most; and what are the implications of changes in relationships over time? In this study, we investigate the cumulative effects of loneliness and social isolation on incident cardiovascular disease. Design A secondary analysis of prospective follow-up data from the English Longitudinal Study of Ageing (ELSA). Methods To assess the association between social isolation or loneliness and incident cardiovascular disease, lagged values of exposure to loneliness and isolation were treated as time-varying variables in discrete time survival models controlling for potential confounders and established cardiovascular disease risk factors. Results A total of 5397 men and women aged over 50 years were followed up for new fatal and non-fatal diagnoses of heart disease and stroke between 2004 and 2010. Over a mean follow-up period of 5.4 years, 571 new cardiovascular events were recorded. We found that loneliness was associated with an increased risk of cardiovascular disease (odds ratio 1.27, 95% confidence interval 1.01-1.57). Social isolation, meanwhile, was not associated with disease incidence. There was no evidence of a cumulative effect over time of social relationships on cardiovascular disease risk. Conclusions Loneliness is associated with an increased risk of developing coronary heart disease and stroke, independently of traditional cardiovascular disease risk factors. Our findings suggest that primary prevention strategies targeting loneliness could help to prevent cardiovascular disease.

Nicole Valtorta

Papers

An overview of systematic reviews on the public health consequences of social isolation and loneliness

Loneliness and social isolation as risk factors for coronary heart disease and stroke: systematic review and meta-analysis of longitudinal observational studies

Loneliness, isolation and the health of older adults: do we need a new research agenda?

Loneliness, social isolation and social relationships: what are we measuring? A novel framework for classifying and comparing tools

Loneliness, social isolation and risk of cardiovascular disease in the English Longitudinal Study of Ageing.