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Increased Peripheral Proinflammatory Cytokines in HIV-1-Infected Patients With Prolonged Viral Suppression Suffering From High Psychological Stress
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JAIDS Journal of Acquired Immune Deficiency Syndromes:
November 2009
Fumaz, Carmina R PhD; Gonzalez-Garcia, Marian MS; Borras, Xavier PhD; Ferrer, Maria Jose MS; Munoz-Moreno, Jose A MS; Pena, Ruth; Perez-Alvarez, Nuria MS; Puig, Jordi RN; Paredes, Roger PhD; Fernandez-Castro, Jordi PhD; Clotet, Bonaventura PhD
"In summary, patients who reported high levels of stress had significantly higher levels of peripheral proinflammatory cytokines, especially IL-6. The levels in our patients who reported stress averaged more than 6 times the standard cut off of 2.5 pg/mL, which has been determined to be predictive of physical decline.12 TNF-α levels were also significantly higher in patients with stress. Despite the limited sample size in this pilot study, the findings suggest that psychological stress could be a cofactor in the comorbidity of HIV-infected patients. This hypothesis requires further investigation."
To the Editor:
Despite the clinical benefits achieved with the use of antiretroviral agents, HIV-infected patients still suffer from high levels of psychological stress1,2 related to multiple inherent disease factors such as HIV nondisclosure,3 the presence of adverse events,4 or the fear of physical impairment.5 Many animal and human studies have demonstrated that stress accelerates HIV-1 disease pathogenesis and impairs the biological impact of antiretroviral treatment.6,7 However, we still know relatively little of the cell-mediated immune regulatory mechanisms that account for the association between psychosocial risk factors and health-related outcomes. Furthermore, the prevalence of concomitant conditions such as neurocognitive dysfunction, bone abnormalities, cardiovascular disease, lymphomas and other neoplasms have increased considerably among HIV-infected patients in recent years.8-11 The role of proinflammatory cytokines in the development of such comorbidity is demonstrated.12-14 Therefore, it seems reasonable to hypothesize that stress-derived immune deregulation could potentially modulate the development of comorbidity in HIV-infected subjects.
Our aim was to evaluate the proinflammatory cytokine profile of HIV-1-infected patients with prolonged viral suppression and different levels of reported psychological stress. For this purpose, we designed a cross-sectional observational study that included patients with documented HIV infection, aged >18 years, with nadir CD4 counts of >200 cells per milliliters, and viral load of <50 copies per milliliters during the last year and on antiretroviral therapy. Exclusion criteria were to have an AIDS-defining event and physical or mental disability that prevented participating in or understanding the study. The objectives and methods were explained to all eligible subjects during routine visits to the HIV clinic between the months of April and June 2008. The ethics committee of Germans Trias i Pujol University Hospital, Badalona, Spain approved the study, and all subjects gave their voluntary written consent before enrollment.
Information was extracted from medical records about route of infection, years since HIV infection diagnosis, years on antiretroviral treatment, and number of antiretroviral regimens and HCV coinfection.
Blood samples were obtained from the participants to determine plasma levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α), CD4 and CD8 cell counts and the CD4/CD8 ratio. Plasma levels of proinflammatory cytokines were determined by cytometric bead array using the human T helper 1/T helper 2 cytokine kit II (BD Biosciences, San Jose, CA) according to the manufacturer's instructions.
Patients then responded to questions on the Perceived Stress Scale (PSS) in a single visit. The PSS is the most widely used psychological instrument for measuring the perception of degree of stress in life situations.15 The reduced version contains 10 items with responses given on 5-point Likert scales (0-4). The scale has been translated and validated in a Spanish population.16
The Kolmogorov-Smirnov test was used to explore the distribution of continuous variables. Variables were described by medians and interquartile ranges (IQR) and compared using a Mann-Whitney nonparametric test or by means and standard deviation and compared using a t test, as appropriate. The PSS score was median split, providing 2 groups of patients with high or low stress, respectively. Cytokine levels were log-transformed to normalize the distribution before analysis. The association between stress and cytokine levels was evaluated with the Pearson correlation test. P values shown represent single-variable comparisons, with statistical significance set at 0.05. All analyses were performed with SPSS 15 (SPSS Inc., Chicago, IL).
Twenty-nine patients who met the inclusion criteria were approached. Eight declined to participate and 21 (72%) gave their written consent to enrollment. The mean age of the subjects was 39.9 ± 3.5 years. Seventeen (80.9%) were men and 14 (66.7%) had acquired the infection through same-sex intercourse. Participants had been diagnosed a mean of 12.0 ± 6.2 years earlier and they had been on antiretroviral therapy for a mean of 8.6 ± 5.0 years. Six subjects (28.6%) were taking first-line antiretroviral therapy and 17 (80.9%) were HCV coinfected. The median CD4 cell count was 564.0 cells per cubic millimeter (IQR, 481.0-882.0 cells/mm3), the median CD8 cell count was 960.0 per cubic millimeter (IQR, 607.2-1260.2 cells/mm3), and the median CD4/CD8 ratio was 0.81 (IQR, 0.49-1.02).
Ten subjects (47.6%) had high psychological stress (PSS score >14). The sociodemographic and clinical variables of patients with and without stress were comparable. Subjects with high stress had significantly higher IL-6 levels (mean, 13.0 ± 23.0 pg/mL) than those with low stress (mean, 1.1 ± 2.4 pg/mL; P = 0.005). Nine subjects (42.9%) had IL-6 levels >2.5 pg/mL. Likewise, subjects with high stress had higher levels of TNF-α (mean, 5.1 ± 2.3 pg/mL) than those with low stress (mean, 2.4 ± 3.4 pg/mL; P = 0.025). A positive correlation was observed between degree of psychological stress and IL-6 concentration (r = .48, P = 0.03). Figure 1 illustrates IL-6 and TNF-α levels in patients with high and low psychological stress.
figure 1
No differences in CD4 and CD8 cell counts or the ratio were observed between subjects with high and low stress (data not shown).
In summary, patients who reported high levels of stress had significantly higher levels of peripheral proinflammatory cytokines, especially IL-6. The levels in our patients who reported stress averaged more than 6 times the standard cut off of 2.5 pg/mL, which has been determined to be predictive of physical decline.12 TNF-α levels were also significantly higher in patients with stress. Despite the limited sample size in this pilot study, the findings suggest that psychological stress could be a cofactor in the comorbidity of HIV-infected patients. This hypothesis requires further investigation.
REFERENCES
1. Siegel K, Karus D, Dean L. Psychosocial characteristics of New York City HIV-infected women before and after the advent of HAART. Am J Public Health. 2004;94:1127-1132.
2. Leserman J, Whetten K, Lowe K, et al. How trauma, recent stressful events, and PTSD affect functional health status and health utilization in HIV-infected patients in the South. Psychosom Med. 2005;67:500-507.
3. Siegel K, Lekas HM, Schrimshaw EW. Serostatus disclosure to sexual partners by HIV-infected women before and after the advent of HAART. Women Health. 2005;41:63-85.
4. Gore-Felton C, Koopman C. Behavioral mediation of the relationship between psychosocial factors and HIV disease progression. Psychosom Med. 2008;70:569-574.
5. Reynolds NR, Neidig JL, Wu AW, et al. Balancing disfigurement and fear of disease progression: patient perceptions of HIV body fat redistribution. AIDS Care. 2006;18:663-673.
6. Cohen S, Janicki-Deverts D, Miller GE. Psychological stress and disease. JAMA. 2007;298:1685-1687.
7. May MT, Sterne JA, Costagliola D, et al. HIV treatment response and prognosis in Europe and North America in the first decade of highly active antiretroviral therapy: a collaborative analysis. Lancet. 2006;368:451-458.
8. Tozzi V, Balestra P, Bellagamba R. Persistence of neuropsychologic deficits despite long-term highly active antiretroviral therapy in patients with HIV-related neurocognitive impairment: prevalence and risk factors. J Acquir Immune Defic Syndr. 2007;45:174-182.
9. Bongiovanni M, Tincati C. Bone diseases associated with human immunodeficiency virus infection: pathogenesis, risk factors and clinical management. Curr Mol Med. 2006;6:395-400.
10. Monsuez JJ, Charniot JC, Escaut L, et al. HIV-associated vascular diseases: structural and functional changes, clinical implications. Int J Cardiol. 2009;133:293-306.
11. Bonnet F, Burty C, Lewden C, et al. Changes in cancer mortality among HIV-infected patients: the Mortalite 2005 Survey. Clin Infect Dis. 2009;48:633-639.
12. Ferrucci L, Harris TB, Guralnik JM, et al. Serum IL-6 level and the development of disability in older persons. J Am Geriatr Soc. 1999;47:639-646.
13. Ershler WB, Keller ET. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med. 2000;51:245-270.
14. Tzoulaki I, Murray GD, Lee AJ, et al. C-reactive protein, interleukin-6, and soluble adhesion molecules as predictors of progressive peripheral atherosclerosis in the general population: Edinburgh Artery Study. Circulation. 2005;112:976-983.
15. Cohen S, Williamson G. Perceived stress in a probability sample of the United States. In: Spacapan S, Oskamp S, eds. The Social Psychology of Health: Claremont Symposium on Applied Social Psychology. Newbury Park, CA: Sage; 1988:31-67.
16. Remor E. Psychometric properties of a European Spanish version of the Perceived Stress Scale (PSS). Span J Psychol. 2006;9:86-93.
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