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Objective: Frailty is a critical aging-related syndrome marked by diminished physiologic reserve and heightened vulnerability to stress, predictive of major adverse clinical outcomes in HIV-infected and uninfected adults. Frailty is a dynamic state, yet little data exist on predictors and consequences of frailty transitions., Design/methods: Frailty was assessed semiannually among HIV-infected and uninfected persons with prior injection drug use using the five Fried phenotype domains. An inflammatory index score was constructed from IL-6 and soluble TNF-α receptor-1 data. Markov transition models assessed determinants of frailty transitions. Cox proportional hazards models estimated mortality risk., Results: Among 1353 AIDS Linked to the IntraVenous Experience participants with 9559 frailty transition assessments, 33% were HIV-infected. Younger age, higher education, employment, reduced comorbidity, HIV virologic suppression, elevated CD4 nadir (>500 cells/μl) and absence of a prior AIDS diagnosis were significantly associated with both reduced frailty progression and greater frailty recovery. Each SD decrease in inflammatory index score was associated with decreased frailty progression [odds ratio 0.78; 95% confidence interval (CI), 0.65, 0.92] and increased frailty recovery (odds ratio 1.29; 95% CI, 1.08, 1.53). Being frail at one of two consecutive visits was associated with increased mortality, compared with maintenance of a nonfrail state. Being frail at both of two consecutive visits demonstrated the highest mortality risk (hazard ratio 3.23; 95% CI, 2.1, 4.96)., Conclusion: Sustained, and to a lesser degree, intermittent frail states are associated with increased mortality. HIV virologic suppression with earlier antiretroviral therapy, reduced comorbidity, and reduced inflammation may prevent frailty progression and promote frailty recovery, consequently improving survival for persons aging with HIV and persons with prior injection drug use.

Frailty is a clinical syndrome initially characterized in geriatric populations with a hallmark of age-related declines in physiologic reserve and function and increased vulnerability to adverse health outcomes. Recently, frailty has increasingly been recognized as a common and important HIV-associated non-AIDS (HANA) condition. This article provides an overview of our current understanding of frailty and its phenotypic characteristics and evidence that they are related to aging and to chronic inflammation that is associated with aging and also with long-term treated HIV infection. The etiology of this chronic inflammation is unknown but we discuss evidence linking it to persistent infection with cytomegalovirus in both geriatric populations and people living with HIV infection.

Frailty is a common and important geriatric syndrome characterized by age-associated declines in physiologic reserve and function across multiorgan systems, leading to increased vulnerability for adverse health outcomes. Two major frailty models have been described in the literature. The frailty phenotype defines frailty as a distinct clinical syndrome meeting three or more of five phenotypic criteria: weakness, slowness, low level of physical activity, self-reported exhaustion, and unintentional weight loss. The frailty index defines frailty as cumulative deficits identified in a comprehensive geriatric assessment. Significant progress has recently been made in understanding the pathogenesis of frailty. Chronic inflammation is likely a key pathophysiologic process that contributes to the frailty syndrome directly and indirectly through other intermediate physiologic systems, such as the musculoskeletal, endocrine, and hematologic systems. The complex multifactorial etiologies of frailty also include obesity and specific diseases. Major clinical applications include risk assessment and stratification. This can be applied to the elderly population in the community and in a variety of care settings. Frailty may also be useful for risk assessment in surgical patients and those with cardiovascular diseases, cancer, or human immunodeficiency virus infection, as well as for assessment of vaccine effectiveness in older adults. Currently, exercise and comprehensive geriatric interdisciplinary assessment and treatment are key interventions for frailty. As understanding of the biologic basis and complexity of frailty further improves, more effective and targeted interventional strategies and innovative geriatric-care models will likely be developed.

Background: Frailty is associated with morbidity and premature mortality among elderly HIV-uninfected adults, but the determinants and consequences of frailty in HIV-infected populations remain unclear. We evaluated the correlates of frailty, and the impact of frailty on mortality in a cohort of aging injection drug users (IDUs)., Methods: Frailty was assessed using standard criteria among HIV-infected and uninfected IDUs in 6-month intervals from 2005 to 2008. Generalized linear mixed-model analyses assessed correlates of frailty. Cox proportional hazards models estimated risk for all-cause mortality., Results: Of 1230 participants at baseline, the median age was 48 years and 29% were HIV-infected; the frailty prevalence was 12.3%. In multivariable analysis of 3,365 frailty measures, HIV-infected IDUs had an increased likelihood of frailty (OR, 1.66; 95% CI, 1.24-2.21) compared to HIV-uninfected IDUs; the association was strongest (OR, 2.37; 95% CI, 1.62-3.48) among HIV-infected IDUs with advanced HIV disease (CD4<350 cells/mm3 and detectable HIV RNA). No significant association was seen with less advanced disease. Sociodemographic factors, comorbidity, depressive symptoms, and prescription drug abuse were also independently associated with frailty. Mortality risk was increased with frailty alone (HR 2.63, 95% CI, 1.23-5.66), HIV infection alone (HR 3.29, 95% CI, 1.85-5.88), and being both HIV-infected and frail (HR, 7.06; 95%CI 3.49-14.3)., Conclusion: Frailty was strongly associated with advanced HIV disease, but IDUs with well-controlled HIV had a similar prevalence to HIV-uninfected IDUs. Frailty was independently associated with mortality, with a marked increase in mortality risk for IDUs with both frailty and HIV infection.

Annual immunization with a trivalent inactivated vaccine (TIV) is considered efficacious for prevention of seasonal influenza in older adults. However, significant controversy exists in the current literature regarding the clinical effectiveness of TIV immunization in this highly heterogeneous population. Frailty is an important geriatric syndrome characterized by decreased physiologic reserve and increased vulnerability to stressors. Using a validated set of frailty criteria, we conducted a prospective observational study to evaluate TIV-induced strain-specific hemagglutination inhibition (HI) antibody titers and post-vaccination rates of influenza-like illness (ILI) and infection in frail and nonfrail older adults. The results indicate that frailty was associated with significant impairment in TIV-induced strain-specific HI titers and increased rates of ILI and laboratory-confirmed influenza infection. These findings suggest that assessing frailty status in the elderly may identify those who are less likely to respond to TIV immunization and be at higher risk for seasonal influenza and its complications., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: neopterin is a monocyte/macrophage-derived immune activation marker and its levels increase with age. Frailty is an important clinical syndrome of old age. Previous studies have shown significant association between elevated interleukin-6 (IL-6) levels and frailty. The objective of this study was to evaluate IL-6-independent association of serum neopterin levels with prevalent frailty., Methods: this is a cross-sectional study in community-dwelling older adults recruited from residential and retirement communities in Baltimore, MD, USA. Frailty was determined using validated screening criteria. Serum neopterin and IL-6 levels were measured using standard enzyme-linked immunosorbent assay. Pearson correlation and multivariate linear regression analysis was performed to assess the relationship between log(neopterin) and log(IL-6). Odds ratios (ORs) for frailty were calculated using log(neopterin) and log(IL-6) as continuous measures and across tertiles of neopterin and IL-6 levels, adjusting for age, race, sex, education and body mass index., Results: one hundred and thirty-three individuals with a mean age of 84 years (range 72-97) completed the study. Neopterin levels were significantly higher in frail older adults than those in non-frail controls [median: 8.94 versus 8.35 nM, respectively, P < 0.001 t-test on log(neopterin)]. Log(neopterin) was significantly associated with prevalent frailty, adjusting for log(IL-6). Participants in the top tertile of neopterin had OR of 3.80 [95% confidence interval (CI) = 1.36-10.6, P < 0.01] for frailty. As expected, participants in the top tertile of IL-6 had OR of 3.29 (95% CI = 1.21-7.86, P < 0.05) for frailty. Log(neopterin) correlated with log(IL-6) (correlation coefficient = 0.19, P < 0.05). Moreover, OR for participants in the top neopterin tertile remained significant after adjusting for IL-6 (OR = 3.97, 95% CI = 1.15-13.72, P < 0.05)., Conclusion: elevated neopterin levels had IL-6-independent association with prevalent frailty, suggesting potential monocyte/macrophage-mediated immune activation in the frail elderly.

Frailty is an important geriatric syndrome that predicts disability and mortality. Substantial evidence suggests that inflammation marked by elevated IL-6 levels and total white blood cell (WBC) counts contribute to this syndrome. However, the relationships of WBC subpopulations, the important inflammatory and immune cells, with frailty have not been investigated. To address this important question, we conducted cross-sectional polytomous logistic regression analyses evaluating associations between baseline WBC differential counts and prevalent frailty (defined by the validated Fried's criteria) of 558 disabled women aged 65-101 years and 548 women aged 70-79 living in the community, both from the Women's Health and Aging Studies. The results showed that high neutrophil and monocyte counts were associated with frailty in disabled older women, albeit these associations did not reach statistical significance in women aged 70-79, adjusting for age, race, education, body mass index, smoking, and antibiotic use. In addition, the identified associations were independent of IL-6. No significant associations of lymphocyte, eosinophil, or basophil counts with frailty were observed. These findings provide initial insight into potential roles of neutrophils and monocytes in the pathogenesis of frailty and a basis for further investigation into their function and regulation in frail older women.

Frailty is an important geriatric syndrome that predicts disability and mortality. Substantial evidence suggests inflammation marked by elevated IL-6 levels as a key pathophysiologic factor that contributes to frailty. CXCL-10, a potent pro-inflammatory chemokine, has increased levels with age and is implicated in several inflammatory conditions. To better understand molecular mechanisms of inflammation activation in frailty, we evaluated monocytic expression of CXCL-10 and other inflammatory pathway genes by pathway-specific gene array analysis and quantitative RT-PCR. Frailty status was determined by the validated criteria. Sixteen pairs of community-dwelling frail and age-, race-, and sex-matched non-frail participants (mean age 83 years, range 72-94) completed the study. Here we report that frail participants had higher CXCL-10 expression levels than matched non-frail controls (1.05+/-0.88 versus 0.53+/-0.39, p=0.04). CXCL-10 expression correlated with IL-6 levels only in frail participants (Spearman correlation coefficient r=0.52, p=0.03). Furthermore, frailty-associated CXCL-10 upregulation was highly correlated with IL-6 elevation, both measured by frail-over-non-frail ratios (r=0.93, p<0.0001). These findings suggest upregulated monocytic expression of CXCL-10 as an important molecular mechanism that contributes to inflammation activation in frail older adults. Therapeutic implications include potential development of CXCL-10-based interventional strategies for the prevention and treatment of frailty in older adults.

Background: Elevated white blood cell (WBC) counts and decreased insulin-like growth factor-1 (IGF-1) levels are individually associated with frailty in older adults. WBC subpopulations are known to produce IGF-1 and express IGF-1 receptors in vitro. However, in vivo relationships between WBC and IGF-1 and their joint contribution to frailty have not been investigated., Methods: Baseline data from 696 community-dwelling older women in the Women's Health and Aging Study I were included in this cross-sectional analysis. Multivariate linear regression analysis was performed to assess the relationship between WBC counts and IGF-1 levels. Odds ratios (ORs) for frailty were evaluated across tertiles of WBC counts and IGF-1 levels, adjusting for age, race, education, body mass index, and smoking., Results: WBC counts correlated with IGF-1 levels (Spearman coefficient: .10, p < .01). Compared with participants in the low WBC and high IGF-1 tertiles (reference group), those in the low WBC and low IGF-1 tertiles had OR of 2.33 for frailty (95% confidence interval [CI]: 1.04-3.65, p < .05), those in the high WBC and high IGF-1 tertiles had OR of 3.86 (95% CI: 1.13-4.07, p < .01), and those in the high WBC and low IGF-1 tertiles had OR of 3.61 (95% CI: 1.64-4.97, p < .01), adjusting for covariates., Conclusions: These findings demonstrate in vivo correlation between WBC and IGF-1. They suggest U-shaped joint associations of WBC and IGF-1 with frailty, with the strongest association at adverse levels of both. They also provide a basis for further investigation into the complex immune-endocrine dysregulations in frailty.

Frailty has been increasingly recognized as an important clinical syndrome in old age. The frailty syndrome is characterized by chronic inflammation, decreased functional and physiologic reserve, and increased vulnerability to stressors, leading to disability and mortality. However, molecular mechanisms that contribute to inflammation activation and regulation in frail older adults have not been investigated. To begin to address this, we conducted a pathway-specific gene array analysis of 367 inflammatory pathway genes by lipopolysaccharide (LPS)-challenged CD14(+) monocytes from 32 community-dwelling frail and age-, race-, and sex-paired nonfrail older adults (mean age 83 years, range 72-94). The results showed that ex vivo LPS-challenge induced average 2.0-fold or higher upregulated expression of 116 genes in frail participants and 85 genes in paired nonfrail controls. In addition, frail participants had 2-fold or higher upregulation in LPS-induced expression of 7 stress-responsive genes than nonfrail controls with validation by quantitative real time RT-PCR. These findings suggest upregulated expression of specific stress-responsive genes in monocyte-mediated inflammatory pathway in the syndrome of frailty with potential mechanistic and interventional implications.

Objectives: To evaluate the frequencies of T-lymphocytes expressing CC chemokine receptor-5 (CCR5(+) T-cells) and their relationship with frailty in older adults., Design: Case-control study with an age-, race-, and sex-matched design., Setting: General Clinical Research Center., Participants: Community-dwelling adults aged 72 and older from Baltimore, Maryland., Methods: Frailty was determined using five validated criteria: weakness, slow walking speed, fatigue, low physical activity, and weight loss. Those meeting three or more of these five criteria were defined as frail and those with none as nonfrail. Complete blood counts were performed to obtain peripheral lymphocyte counts using an automated (Coulter) counter. Peripheral blood was collected for surface immunofluorescent staining of CCR5 and other T-cell markers., Results: Twenty-six frail and matched nonfrail participants (mean age+/-standard deviation 83.8+/-5.3, range 72-94) completed the study. Frail participants had higher CCR5(+), CCR5(+)CD8(+), and CCR5(+)CD45RO(-) T-cell counts than matched nonfrail controls (349+/-160/mm(3) vs 194+/-168/mm(3), P=.02; 208+/-98/mm(3) vs 105+/-62/mm(3), P=.02; and 189+/-149/mm(3) vs 52+/-36/mm(3), P=.01; respectively). Furthermore, there was a trend toward graded increase in these T-cell counts across the frailty scores in frail participants (e.g., CCR5(+)CD8(+) counts of 123+/-52/mm(3), 248+/-115/mm(3), and 360+/-215/mm(3) for those with frailty scores of 3, 4, and 5, respectively)., Conclusion: These initial results suggest an expansion of the CCR5(+) T-cell subpopulation in frailty. They provide a basis for further characterization of CCR5(+) T-cells and their role in frailty, with potential therapeutic implications.

Background: The physiological basis of the geriatric syndrome of frailty, a clinical state of increased vulnerability to adverse outcomes such as disability and mortality, remains to be better characterized. We examined the cross-sectional relationship between hemoglobin (Hb) and a recently-validated measure of frailty in community-dwelling older women, and whether this relationship was modified by cardiovascular disease (CVD) status., Methods: Data were pooled from women 70-80 years old participating in the Women's Health and Aging Studies I and II (Baltimore, MD, 1992-1996) with known frailty status and Hb > or = 10 g/dL (n = 670). Logistic regression was used to model the relationship between frailty and Hb, adjusting for demographics, major chronic diseases, and physiologic and functional impairments., Results: Prevalence of frailty was 14%. Frailty risk was highest at the lowest Hb levels, and lowest at mid-normal Hb levels (e.g., 13-14 g/dL). Mildly low and low-normal Hb concentrations were independently associated with frailty. Compared to an Hb concentration equal to 13.5 g/dL, the adjusted odds of being frail were 1.9 (95% confidence interval: 1.1-3.4) and 1.5 (95% confidence interval: 1.0-2.1) times higher for Hb concentrations equal to 11.5 g/dL and 12 g/dL, respectively. A statistically significant (p <.05) multiplicative interaction between Hb level and CVD status with respect to frailty risk was observed., Conclusion: In community-dwelling older women, mildly low and low-normal Hb levels were independently associated with increased frailty risk. This risk was synergistically modified by the presence of CVD. These results suggest that mild anemia, and even low-normal Hb levels are independent, potentially modifiable risk factors for frailty in community-dwelling older adults.

Objectives: To evaluate the association between asymptomatic chronic cytomegalovirus (CMV) infection and the frailty syndrome and to assess whether inflammation modifies this association., Design: Cross-sectional analysis., Setting: Women's Health and Aging Study I & II, Baltimore, Maryland., Participants: Seven hundred twenty-four community-dwelling women aged 70 to 79 with baseline measures of CMV, interleukin-6 (IL-6), and frailty status., Measurements: CMV serology and IL-6 concentrations were measured using enzyme-linked immunosorbent assay. Frailty status was based on previously validated criteria: unintentional weight loss, weak grip strength, exhaustion, slow walking speed, and low level of activity. Frail women had three or more of the five components, prefrail women had one or two components, and women who were not frail had none of the components. Multinomial logistic regression adjusted for potential confounders., Results: Eighty-seven percent of women were CMV seropositive, an indication of chronic infection. CMV was associated with prevalent frailty, adjusting for age, smoking history, elevated body mass index, diabetes mellitus, and congestive heart failure (CMV frail adjusted odds ratio (AOR)=3.2, P=.03; CMV prefrail AOR=1.5, P=.18). IL-6 interacted with CMV, significantly increasing the magnitude of this association (CMV positive and low IL-6 frail AOR=1.5, P=.53; CMV positive and high IL-6 frail AOR=20.3, P=.007; CMV positive and low IL-6 prefrail AOR=0.9, P=.73; CMV positive and high IL-6 prefrail AOR=5.5, P=.001)., Conclusion: Chronic CMV infection is associated with prevalent frailty, a state with increased morbidity and mortality in older adults; inflammation enhances this effect. Further prospective studies are needed to establish a causal relationship between CMV, inflammation, and frailty.

Background and Aims: Frailty is a geriatric syndrome that predicts increased morbidity and mortality. In order to investigate specific immune system modulations that may contribute to frailty, eleven age- and sex-matched pairs of community-dwelling frail and non-frail older adults were identified., Methods: Peripheral blood mononuclear cells (PBMC) were isolated and PBMC proliferation and production of IL-6, tumor necrosis factor (TNF)-alpha, and IL-10 in the presence and absence of lipopolysaccharide (LPS) were examined., Results: We found that frail subjects had a significantly lower LPS-induced PBMC proliferation ratio compared with non-frail subjects (2.1+/-0.9 vs 3.11+/-1.9, p<0.03). In addition, frail subjects had higher IL-6 production by PBMC at 48 hours after LPS stimulation (35678+/-15637 vs 25178+/-6342 pg/mL, p<0.03). No significant differences were observed in TNF-alpha, and IL-10 production between groups., Conclusions: These results suggest that, compared with non-frail controls, frail older adults have both decreased LPS-induced proliferation and increased IL-6 production by PBMC.

Background and Aims: The geriatric syndrome of frailty has been conceptualized as a loss of physiologic reserve associated with endocrine dysregulation and immune dysfunction. Our prior studies suggest that the frailty syndrome is associated with elevated serum IL-6 levels. In the present study, our aim is to evaluate the possible role of endocrine dysregulation and its relationship with serum IL-6 in the pathogenesis of this syndrome., Methods: Using a recently validated screening algorithm for frailty, we identified 18 frail and 33 non-frail community-dwelling older adults for inclusion in this study. Serum levels of insulin-like growth factor-I (IGF-I), DHEA-S, and IL-6 were measured by immunoassays. The inter-relationships among serum levels of IL-6, DHEA-S, and IGF-I were determined by linear regression analysis., Results: Age-adjusted serum levels of IGF-I (88+/-49 vs 122+/-47 [ng/mL], p<0.023) and DHEA-S (0.30+/-0.21 vs 0.53+/-0.25 [microg/mL], p=0.016) were significantly lower in frail vs non-frail individuals, respectively. There was a trend for IL-6 to be inversely correlated with IGF-I in the frail (r=-0.42; p=0.082) but not the non-frail group (r=0.12, p=0.521)., Conclusions: Frail subjects have lower levels of serum IGF-I and DHEA-S and higher levels of IL-6 than do non-frail, age-matched individuals. The trend toward an inverse correlation between IGF-I and IL-6 in the frail, but not the non-frail group, suggests potential interaction between endocrine and immune/cytokine dysregulation that requires further study in larger cohorts.

Background: Hospitalization events exact a substantial toll across the age spectrum. Frailty is associated with all-cause hospitalization among HIV-uninfected adults aged 65 years and older. Limited data exist on the frailty relationship to hospitalization among HIV-infected persons or those aged less than 65 years. Comparative investigation of the frailty relationship to specific classes of hospitalizations has rarely been reported among adults of any age. This study sought to determine the frailty relationship to three distinct classes of hospitalization events among HIV-infected persons and their uninfected counterparts.Methods: Frailty was ascertained semiannually among persons with prior injection drug use using the five Fried phenotypic domains. Hospitalization events were categorized using Agency for Healthcare Research and Quality clinical classification software into chronic, infectious, and nonchronic, noninfectious conditions. Cox proportional hazards models were used to examine the frailty relationship to time to first hospitalization event.Results: Among 1,303 subjects, mean age was 48 years; 32% were HIV-infected. Adjusting for sociodemographics, comorbidity, substance use, and HIV disease stage, time-updated frailty status was associated with risk for all hospitalization classes. Baseline frailty was significantly associated with all-cause (hazards ratio [HR] 1.41; 95% confidence interval [CI], 1.06, 1.87), chronic (HR 2.13; 95% CI, 1.46, 3.11), and infectious disease hospitalization (HR 2.51; 95% CI, 1.60, 3.91) but not with nonchronic, noninfectious hospitalization risk (HR 1.09; 95% CI, 0.74, 1.61).Conclusion: The frailty phenotype predicts vulnerability to chronic and infectious disease-related hospitalization. Frailty-targeted interventions may mitigate the substantial burden of infectious and chronic disease-related morbidity and health care utilization in HIV-infected and uninfected populations. [ABSTRACT FROM AUTHOR]

Background: Serum markers of inflammation increase with age and have been strongly associated with adverse clinical outcomes among both HIV-infected and uninfected adults. Yet, limited data exist on the predictive and clinical utility of aggregate measures of inflammation. This study sought to evaluate the relationship of a recently validated aggregate inflammatory index with frailty and mortality among aging HIV-infected and uninfected injection drug users.Methods: Frailty was assessed among HIV-infected and uninfected participants in the AIDS Linked to the IntraVenous Experience (ALIVE) cohort study using the five Fried phenotypic criteria: weight loss, exhaustion, low physical activity, decreased grip strength, and slow gait. The aggregate inflammatory index was constructed from serum measures of interleukin-6 and soluble tumor necrosis factor-α receptor-1. Multinomial logistic regression was used to assess the relationship of frailty with inflammation. Cox proportional hazards models were used to estimate risk for all-cause mortality.Results: Among 1,326 subjects, the median age was 48 years and 29% were HIV-infected. Adjusting for sociodemographics, comorbidity, and HIV status, frailty was significantly associated with each standard deviation increase in log interleukin-6 (odds ratio 1.33; 95% CI, 1.09-1.61), log tumor necrosis factor-α receptor-1 (odds ratio 1.25; 95% CI, 1.04-1.51) and inflammatory index score (odds ratio 1.39; 95% CI, 1.14-1.68). Adjusting for sociodemographics, comorbidity, HIV status, and frailty, the inflammatory index score was independently associated with increased mortality (HR 1.65; 95% CI, 1.44-1.89).Conclusion: A recently validated, simple, biologically informed inflammatory index is independently associated with frailty and mortality risk among aging HIV-infected and uninfected injection drug users. [ABSTRACT FROM AUTHOR]