Association of frailty with outcomes in individuals with COVID-19: A living review and meta-analysis.

BACKGROUND AND OBJECTIVES: Frailty leaves older adults vulnerable to adverse health outcomes. Frailty assessment is recommended by multiple COVID-19 guidelines to inform care and resource allocation. We aimed to identify, describe, and synthesize studies reporting the association of frailty with outcomes (informed by the Institute for Healthcare Improvement's Triple Aim [health, resource use, and experience]) in individuals with COVID-19. DESIGN: Systematic review and meta-analysis. SETTING: Studies reporting associations between frailty and outcomes in the setting of COVID-19 diagnosis. PARTICIPANTS: Adults with COVID-19. MEASUREMENTS: Following review of titles, abstracts and full text, we included 52 studies that contained 118,373 participants with COVID-19. Risk of bias was assessed using the Quality in Prognostic studies tool. Our primary outcome was mortality, secondary outcomes included delirium, intensive care unit admission, need for ventilation and discharge location. Where appropriate, random-effects meta-analysis was used to pool adjusted and unadjusted effect measures by frailty instrument. RESULTS: The Clinical Frailty Scale (CFS) was the most used frailty instrument. Mortality was reported in 37 studies. After confounder adjustment, frailty identified using the CFS was significantly associated with mortality in COVID-19 positive patients (odds ratio 1.79, 95% confidence interval [CI] 1.49-2.14; hazard ratio 1.87, 95% CI 1.33-2.61). On an unadjusted basis, frailty identified using the CFS was significantly associated with increased odds of delirium and reduced odds of intensive care unit admission. Results were generally consistent using other frailty instruments. Patient-reported, cost and experience outcomes were rarely reported. CONCLUSION: Frailty is associated with a substantial increase in mortality risk in COVID-19 patients, even after adjustment. Delirium risk is also increased. Frailty assessment may help to guide prognosis and individualized care planning, but data relating frailty status to patient-reported outcomes are urgently needed to provide a more comprehensive overview of outcomes relevant to older adults.

High Frequency of Recurrent Falls Among Prefrail and Frail Women With and Without HIV.

BACKGROUND: Frailty may occur at younger ages among HIV+ populations. We evaluated associations of the frailty status with self-reported single and recurrent falls in the Women's Interagency HIV Study (WIHS). METHODS: The frailty status was defined using the Fried Frailty Phenotype (FFP) among 897 HIV+ and 392 HIV- women; median age 53 years. Women were classified as robust (FFP 0), prefrail (FFP 1-2), and frail (FFP 3-5). Stepwise logistic regression models adjusting for the HIV status and study site were fit to evaluate associations of the FFP with self-reported single (1 vs. 0) and recurrent falls (≥2 vs. 0) over the prior 12 months. RESULTS: HIV+ women were less likely to be frail (9% vs. 14% vs. P = 0.009), but frequency of falls did not differ by the HIV status. In multivariate analyses, recurrent falls were more common among prefrail [adjusted odds ratio (AOR) 2.23, 95% confidence interval (CI): 1.40 to 3.57, P = 0.0008] and frail (AOR 3.61, 95% CI: 1.90 to 6.89, P < 0.0001) than robust women. Among HIV+ women, single (AOR 2.88, 95% CI: 1.16 to 7.20, P = 0.023) and recurrent falls (AOR 3.50, 95% CI: 1.24 to 9.88, P = 0.018) were more common among those who were frail; recurrent, but not single falls, were more common among prefrail than robust HIV+ women (AOR 2.00, 95% CI: 1.03 to 3.91, P = 0.042). CONCLUSIONS: HIV+ women were less likely to be frail. Compared with robust women, prefrail and frail women with and without HIV were more likely to experience single or recurrent falls within a 12-month period. Additional studies are needed to develop interventions that decrease development of frailty and reduce risk of recurrent falls among HIV+ women.

Health status is related to testosterone, estrone and body fat: moving to functional hypogonadism in adult men with HIV.

OBJECTIVE: Hypogonadism is common in HIV-infected men. The relationship between health status, sex steroids and body composition is poorly known in HIV. The aim was to investigate the association between health status (comorbidities/frailty), body composition, and gonadal function in young-to-middle-aged HIV-infected men. DESIGN: Prospective, cross-sectional, observational study. METHODS: HIV-infected men aged <50 years and ongoing Highly Active Antiretroviral Therapy were enrolled. Serum total testosterone (TT), estradiol (E2), estrone (E1) were measured by liquid chromatography-tandem mass spectrometry, LH and FSH by immunoassay. Free testosterone (cFT) was calculated by Vermeulen equation. Body composition was assessed by dual-energy X-ray absorptiometry and abdominal CT scan. Multimorbidity (MM) and frailty were defined as ≥3 comorbidities and by a 37-item index, respectively. RESULTS: A total of 316 HIV-infected men aged 45.3 ± 5.3 years were enrolled. Body fat parameters were inversely related to cFT and TT, and directly related to E1 and E2/testosterone (TS) ratio. Patients with MM had lower cFT (P < 0.0001) and TT (P = 0.036), and higher E1 (P < 0.0001) and E2/TS ratio (P = 0.002). Frailty was inversely related to cFT (R2 = 0.057, P < 0.0001) and TT (R2 = 0.013, P = 0.043), and directly related to E1 (R2 = 0.171, P < 0.0001), E2 (R2 = 0.041, P = 0.004) and E2/TS ratio (R2 = 0.104, P < 0.0001). CONCLUSIONS: Lower TT and cFT, higher E1, E2/TS ratio and visceral fat were independently associated to poor health status and frailty, being possible hallmarks of unhealthy conditions in adult HIV-infected men. Overall, MM, frailty and body fat mass are strictly associated to each other and to sex steroids, concurring together to functional male hypogonadism in HIV.

SARS-CoV-2, testosterone and frailty in males (PROTEGGIMI): A multidimensional research project.

Preliminary published data depict a much greater prevalence of males with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) referred for intensive care unit admission and severe sequelae in several countries. In this context, males seem to not only be more susceptible to the infection compared to female subjects, at least in Western countries, but their case fatality rate attributable to SARS-CoV-2 infection is also highest. Therefore, we may speculate that the different hormonal milieu could have a more profound pathophysiological role in association with SARS-CoV-2, with endogenous testosterone leaving men more prone to develop more serious complications related to the SARS-CoV-2 infection. Another option is that SARS-CoV-2 infection per se causes an acute stage of male hypogonadism, the depletion of androgenic action triggering serious or an even fatal course of the disease. Therefore, we strongly advocate the development of a prospective multidimensional andrological translational research project in men, which we called the PROTEGGIMI study. In this Opinion Article, we will not only highlight novel research activity in this area but also invite other researchers and learned scientific societies to join us in our efforts to understand an important and very newly discovered gap in knowledge, which may have serious implications for the lives of millions of men.

Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study.

BACKGROUND: The objective of this quasi-experimental study was to determine whether bolus vitamin D supplementation taken either regularly over the preceding year or after the diagnosis of COVID-19 was effective in improving survival among hospitalized frail elderly COVID-19 patients. METHODS: Seventy-seven patients consecutively hospitalized for COVID-19 in a geriatric unit were included. Intervention groups were participants regularly supplemented with vitamin D over the preceding year (Group 1), and those supplemented with vitamin D after COVID-19 diagnosis (Group 2). The comparator group involved participants having received no vitamin D supplements (Group 3). Outcomes were 14-day mortality and highest (worst) score on the ordinal scale for clinical improvement (OSCI) measured during COVID-19 acute phase. Potential confounders were age, gender, functional abilities, undernutrition, cancer, hypertension, cardiomyopathy, glycated hemoglobin, number of acute health issues at admission, hospital use of antibiotics, corticosteroids, and pharmacological treatments of respiratory disorders. RESULTS: The three groups (n = 77; mean ± SD, 88 ± 5years; 49% women) were similar at baseline (except for woman proportion, p = 0.02), as were the treatments used for COVID-19. In Group 1 (n = 29), 93.1% of COVID-19 participants survived at day 14, compared to 81.2% survivors in Group 2 (n = 16) (p = 0.33) and 68.7% survivors in Group 3 (n = 32) (p = 0.02). While considering Group 3 as reference (hazard ratio (HR) = 1), the fully-adjusted HR for 14-day mortality was HR = 0.07 (p = 0.017) for Group 1 and HR = 0.37 (p = 0.28) for Group 2. Group 1 had longer survival time than Group 3 (log-rank p = 0.015), although there was no difference between Groups 2 and 3 (log-rank p = 0.32). Group 1, but not Group 2 (p = 0.40), was associated with lower risk of OSCI score ≥5 compared to Group 3 (odds ratio = 0.08, p= 0.03). CONCLUSIONS: Regular bolus vitamin D supplementation was associated with less severe COVID-19 and better survival in frail elderly.

The role of Frailty on Adverse Outcomes Among Older Patients with COVID-19.

BACKGROUND: Diagnosis and screening of frailty, a condition characterized by an increased vulnerability to adverse outcomes of COVID-19, has emerged as an essential clinical tool which is strongly recommended by healthcare providers concerned with hospitalized elderly population. The data showing the role of frailty in patients infected with COVID-19 is needed. METHODS: This was a nationwide cohort study conducted at all hospitals in Turkey. All COVID-19 hospitalized patients (≥ 65 years) were included. Patients who were alive and not discharged up to July 20, 2020, were excluded. The frailty was assessed by using the "Hospital Frailty Risk Score" (HFRS). Patients were classified into three risk groups of frailty based on previously validated cut points as low (<5 points), intermediate (5-15 points), and high (>15 points). Additionally, patients who had the HFRS of ≥5 were defined as frail. The primary outcome was in-hospital mortality rates by frailty group. RESULTS: Between March 11, 2020, and June 22, 2020, a total of 18,234 COVID-19 patients from all of 81 provinces of Turkey were included. Totally, 12,295 (67.4%) patients were defined as frail (HFRS of >5) of which 2,801 (15.4%) patients were categorized in the highest level of frailty (HFRS of >15). Observed in-hospital mortality rates were 697 (12.0%), 1,751 (18.2%) and 867 (31.0%) in low, intermediate and high hospital frailty risk, respectively (p<0.001). Compared with low HFRS (<5), the adjusted odds ratios for in-hospital mortality were 1.482 (1.334-1.646) for intermediate HFRS (5-15) and 2.084; 95% CI, 1.799-2.413 for high HFRS (>15). CONCLUSIONS: As a claims-based frailty model, the HFRS provides clinicians and health systems, a standardized tool for an effective detection and grading of frailty in patients in COVID-19. A frailty-based tailored management of the older population may provide a more accurate risk categorization for both therapeutic and preventive strategies.

The association between frailty and severe disease among COVID-19 patients aged over 60 years in China: a prospective cohort study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) has been a pandemic worldwide. Old age and underlying illnesses are associated with poor prognosis among COVID-19 patients. However, whether frailty, a common geriatric syndrome of reduced reserve to stressors, is associated with poor prognosis among older COVID-19 patients is unknown. The aim of our study is to investigate the association between frailty and severe disease among COVID-19 patients aged ≥ 60 years. METHODS: A prospective cohort study of 114 hospitalized older patients (≥ 60 years) with confirmed COVID-19 pneumonia was conducted between 7 February 2020 and 6 April 2020. Epidemiological, demographic, clinical, laboratory, and outcome data on admission were extracted from electronic medical records. All patients were assessed for frailty on admission using the FRAIL scale, in which five components are included: fatigue, resistance, ambulation, illnesses, and loss of weight. The outcome was the development of the severe disease within 60 days. We used the Cox proportional hazards models to identify the unadjusted and adjusted associations between frailty and severe illness. The significant variables in univariable analysis were included in the adjusted model. RESULTS: Of 114 patients, (median age, 67 years; interquartile range = 64-75 years; 57 [50%] men), 39 (34.2%), 39 (34.2%), and 36 (31.6%) were non-frail, pre-frail, and frail, respectively. During the 60 days of follow-up, 43 severe diseases occurred including eight deaths. Four of 39 (10.3%) non-frail patients, 15 of 39 (38.5%) pre-frail patients, and 24 of 36 (66.7%) frail patients progressed to severe disease. After adjustment of age, sex, body mass index, haemoglobin, white blood count, lymphocyte count, albumin, CD8+ count, D-dimer, and C-reactive protein, frailty (HR = 7.47, 95% CI 1.73-32.34, P = 0.007) and pre-frailty (HR = 5.01, 95% CI 1.16-21.61, P = 0.03) were associated with a higher hazard of severe disease than the non-frail. CONCLUSIONS: Frailty, assessed by the FRAIL scale, was associated with a higher risk of developing severe disease among older COVID-19 patients. Our findings suggested that the use of a clinician friendly assessment of frailty could help in early warning of older patients at high-risk with severe COVID-19 pneumonia.

Deep Learning Analysis of Cerebral Blood Flow to Identify Cognitive Impairment and Frailty in Persons Living With HIV.

BACKGROUND: Deep learning algorithms of cerebral blood flow were used to classify cognitive impairment and frailty in people living with HIV (PLWH). Feature extraction techniques identified brain regions that were the strongest predictors. SETTING: Virologically suppressed (<50 copies/mL) PLWH (n = 125) on combination antiretroviral therapy were enrolled. Participants averaged 51.4 (11.4) years of age and 13.7 (2.8) years of education. Participants were administered a neuropsychological battery, assessed for frailty, and completed structural neuroimaging. METHODS: Deep neural network (DNN) models were trained to classify PLWH as cognitively unimpaired or impaired based on neuropsychological tests (Hopkins Verbal Learning Test-Revised and Brief Visuospatial Memory Test-Revised, Trail making, Letter-Number Sequencing, Verbal Fluency, and Color Word Interference), as well as frail, prefrail, or nonfrail based on the Fried phenotype criteria (at least 3 of the following 5: weight loss, physical inactivity, exhaustion, grip strength, walking time). RESULTS: DNNs classified individuals with cognitive impairment in the learning, memory, and executive domains with 82%-86% accuracy (0.81-0.87 AUC). Our model classified nonfrail, prefrail, and frail PLWH with 75% accuracy. The strongest predictors of cognitive impairment were cortical (parietal, occipital, and temporal) and subcortical (amygdala, caudate, and hippocampus) regions, whereas the strongest predictors of frailty were subcortical (amygdala, caudate, hippocampus, thalamus, pallidum, and cerebellum). CONCLUSIONS: DNN models achieved high accuracy in classifying cognitive impairment and frailty status in PLWH. Feature selection algorithms identified predictive regions in each domain and identified overlapping regions between cognitive impairment and frailty. Our results suggest frailty in HIV is primarily subcortical, whereas cognitive impairment in HIV involves subcortical and cortical brain regions.

Veterans Aging Cohort Study Index as a Marker of Bone Disease in HIV-Infected Patients.

People living with human immunodeficiency virus (HIV) infection have higher risk of low bone mineral density (BMD) and fragility fracture than general population. The aim of our retrospective study was to explore if HIV-specific Veterans Aging Cohort Study (VACS) Index and its specific components could help identify patients at risk for low BMD. A total of 195 HIV-infected patients with dual-energy X-ray absorptiometry (DXA) scan between 2007 and 2014 were included and DXA scan results were used to classify patients with osteopenia. VACS Index was calculated for all patients using laboratory values closest to the date of DXA scan. Logistic regression was used to assess the association between VACS Index score or individual components of VACS Index with the presence of low BMD after adjusting for confounding variables. A total of 109 (56%) patients were diagnosed with low BMD. VACS Index score was significantly associated with low BMD, with the odds of low BMD increasing 1.21 times for each 10 unit increase in VACS Index score [confidence interval (95% CI) 1.03-1.42; p = .02]. The two groups differed significantly on patient weights, proportion of white patients, and hepatitis C-coinfected patients. After adjusting for white race and weight, hepatitis C coinfection was significantly associated with increased risk of low BMD (odds ratio 24.4; 95% CI 7.45-80.16). VACS Index score, previously demonstrated to be a marker of frailty in HIV-infected patients, is significantly associated with risk of low BMD and could be used to develop a prediction tool to screen for low BMD in resource-limited setting where DXA scans are not easily available.

HIV Infection-Associated Frailty: The Solution for Now Is Antiretroviral Drugs: A Perspective.

This Perspective article provides a new view of frailty as it relates to HIV-1 infection. We discuss new findings and where our research is going.

Frailty as a predictor of falls in HIV-infected and uninfected women.

BACKGROUND: Frailty and falls occur commonly and prematurely in HIV-infected populations. Whether frailty in middle-age predicts future falls among HIV-infected women is unknown. METHODS: We evaluated associations of frailty with single and recurrent falls 10 years later among 729 HIV-infected and 326 uninfected women in the Women's Interagency HIV Study (WIHS) with frailty measured in 2005 and self-reported falls in 2014-2016. Frailty was defined as ≥3 of 5 Fried Frailty Index components: slow gait, reduced grip strength, exhaustion, unintentional weight loss and low physical activity. Stepwise logistic regression models determined odds of single (versus 0) or recurrent falls (≥2 versus 0) during the 2-year period; separate models evaluated frailty components. RESULTS: HIV-infected women were older (median 42 versus 39 years; P<0.0001) and more often frail (14% versus 9%; P=0.04) than uninfected women. Over 2 years, 40% of HIV-infected versus 39% of uninfected women reported a fall (single fall in 15% HIV+ versus 18% HIV- women; recurrent falls in 25% HIV+ versus 20% HIV- women [overall P=0.20]). In multivariate models, frailty independently predicted recurrent falls (adjusted odds ratio [aOR] 1.84, 95% CI: 1.13, 2.97; P=0.01), but not a single fall. Among frailty components, unintentional weight loss independently predicted single fall (aOR 2.31, 95% CI: 1.28, 4.17; P=0.005); unintentional weight loss (aOR 2.26, 95% CI: 1.32, 3.86; P=0.003) and exhaustion (aOR 1.66, 95% CI: 1.10, 2.50; P=0.02) independently predicted recurrent falls. CONCLUSIONS: Early frailty measurement among middle-aged women with or at-risk for HIV may be a useful tool to assess future fall risk.

Association of Fibroblast Growth Factor-23 (FGF-23) With Incident Frailty in HIV-Infected and HIV-Uninfected Individuals.

BACKGROUND: In the Multicenter AIDS Cohort Study, we examined whether fibroblast growth factor-23 (FGF-23), a bone-derived phosphaturic hormone involved in bone metabolism, is associated with incident frailty. Furthermore, we examined whether this association differs by HIV serostatus and race. METHODS: Of 715 men assessed for frailty and selected for FGF-23 measurements using stored blood samples (2007-2011), 512 men were nonfrail at/before the baseline visit. Frailty was defined by the presence of ≥3 of the following on 2 consecutive 6-month visits within 1 year: unintentional weight loss ≥10 pounds, weakness, slowness, low energy, and low physical activity. We determined the association of FGF-23 levels with incident frailty using proportional hazards models adjusting for sociodemographics, comorbidities, and kidney function. RESULTS: Sixty-five percent were HIV-infected; 29% were black. Median baseline FGF-23 levels were lower in HIV-infected vs. HIV-uninfected men (33.7 vs. 39.9 rU/mL, P = 0.006) but similar by race. During a median follow-up of 6.6 years, 32 men developed frailty; they had higher baseline FGF-23 levels vs. men who remained nonfrail (45 vs. 36 rU/mL, P = 0.02). FGF-23 (per doubling) was associated with a 1.63-fold risk of frailty [95% confidence interval (CI): 1.19 to 2.23]; results did not differ by HIV serostatus. Conversely, FGF-23 was associated with a 2.72-fold risk of frailty among blacks (95% CI: 1.51 to 4.91) but had minimal association among nonblacks (hazard ratio = 1.26, 95% CI: 0.77 to 2.05; p-interaction = 0.024). CONCLUSIONS: Among men with or at-risk of HIV infection, higher FGF-23 was associated with greater risk of frailty, particularly in blacks. The mechanisms by which FGF-23 may contribute to frailty warrant further study.

Association between human herpes virus seropositivity and frailty in the elderly: A systematic review and meta-analysis.

Frailty is an emerging geriatric syndrome characterized by decreased physiologic reserve and increased vulnerability to environmental factors. Several studies have examined the association between persistent cytomegalovirus (CMV) infection and poor clinical outcomes in the elderly, but the results are often contradictory. Here, we performed a systematic review and meta-analysis to analyze the association between human herpesvirus seropositivity [CMV, Epstein-Barr virus (EBV), Varicella zoster virus (VZV), and Herpes simplex virus (HSV)] and frailty in elderly people. Searches were performed in PubMed, SCOPUS, Lilacs, IBECS, and Web of Science databases. We used the odds ratio (OR) as a measure of the association between herpesvirus infections and frailty. Summary estimates were calculated using random-effects models. Six studies were included in the present systematic review. The data from 2559 elderly subjects were analyzed; 1571 of the subjects had ages between 60 and 79 years, and 988 of the subjects were older than 80. We found an association between CMV seropositivity and frailty in the elderly aged 60-79 years (OR 2.33, CI 95% 1.48-3.67) but not in the oldest-old subjects (OR 0.67, CI 95% 0.42-1.05). Moreover, no association was found between EBV, VZV, and HSV infections and frailty. Current evidence suggests an association between CMV seropositivity and frailty in individuals aged 60-79 years old.

DNA methylation signatures of illicit drug injection and hepatitis C are associated with HIV frailty.

Intravenous illicit drug use (IDU) and hepatitis C infection (HCV) commonly co-occur among HIV-infected individuals. These co-occurring conditions may produce interacting epigenetic effects in white blood cells that influence immune function and health outcomes. Here, we report an epigenome-wide association analysis comparing IDU+/ HCV+ and IDU-/HCV- in 386 HIV-infected individuals as a discovery sample and in 412 individuals as a replication sample. We observe 6 significant CpGs in the promoters of 4 genes, NLRC5, TRIM69, CX3CR1, and BCL9, in the discovery sample and in meta-analysis. We identify 19 differentially methylated regions on chromosome 6 harboring MHC gene clusters. Importantly, a panel of IDU+/HCV+-associated CpGs discriminated HIV frailty based upon a validated index with an area under the curve of 79.3% for high frailty and 82.3% for low frailty. These findings suggest that IDU and HCV involve epigenetic programming and that their associated methylation signatures discriminate HIV pathophysiologic frailty.