Feb 17, 2016 - the pathogenesis of neurocognitive dysfunction during HIV infection. ... of HIV- associated neurocognitive disorders are still estimated to affect.
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OBSERVATIONAL STUDY
(1!3)-b-D-Glucan Levels Correlate With Neurocognitive Functioning in HIV-Infected Persons on Suppressive Antiretroviral Therapy A Cohort Study Martin Hoenigl , MD, Michelli Faria de Oliveira, MD, Josue´ Pe´rez-Santiago, PhD, Yonglong Zhang, PhD, Sheldon Morris, MD, Allen J. McCutchan, MD, Malcolm Finkelman, MD, Thomas D. Marcotte, MD, Ronald J. Ellis, MD, and Sara Gianella, MD
Abstract: Microbial translocation from the gut is associated with immune dysfunction, persistent inflammation, and likely plays a role in the pathogenesis of neurocognitive dysfunction during HIV infection. (1!3)-b-D-Glucan (BDG) is a component of most fungal cell walls and might be a useful indicator of gut mucosal barrier impairment. The objective of this study was to evaluate whether higher blood BDG levels correlate with impaired neurocognitive functioning in a cohort of HIVinfected adults with suppressed levels of HIV RNA in blood plasma. In this cross-sectional cohort study, we measured levels of BDG in blood plasma and cerebrospinal fluid (CSF) supernatant samples in a cohort of adults with acute/early HIV infection, who initiated antiretroviral therapy (ART) during the earliest phase of infection and achieved suppressed levels of HIV RNA in blood plasma
(0.5, which is considered at least mild cognitive impairment). Median BDG level in blood plasma was 66 pg/mL (range: 20– 101 pg/mL), whereas median BDG level in CSF supernatant was 5 pg/mL (range: 0–53 pg/mL). Higher levels of plasma BDG were associated with more severe cognitive impairment as measured by the GDS (Spearman r ¼ 0.47, P ¼ 0.042; Pearson [correlation with squareroot-transformed GDS] r ¼ 0.46, P ¼ 0.049; Figure 1 and Table 2]. Of the other biomarkers, a significant correlation with GDS was found for IL-8 (Spearman r ¼ 0.55; P ¼ 0.014), whereas no significant correlations were found for sCD14 (Spearman r ¼ 0.4, n.s.), and nadir CD4þ count (Spearman r ¼ 0.01, n.s.). Also, we found no significant correlation between plasma BDG and both IL-8 (Spearman r ¼ 0.12, n.s.) and sCD14 (Spearman r ¼ 0.38, n.s.). With regard to combinations of BDG, IL-8, and sCD14 and correlation with GDS, BDG þ IL-8 (Spearman r ¼ 0.57; P ¼ 0.01) and BDG þ sCD14 (Spearman r ¼ 0.58, P < 0.01) were the most promising combinations of 2 biomarkers, whereas the combination of all 3 biomarkers (BDG þ IL8 þ sCD14) had the highest correlation with GDS (Spearman r ¼ 0.71; P < 0.01). Plasma BDG levels, levels of other biomarkers including combinations, as well as Spearman correlations with blood BDG and GDS are displayed in Table 2. Using the plasma BDG cut-off recommended by the manufacturer for differentiating negative from intermediate and positive results (ie of 60 pg/mL), the sensitivity for detecting neurocognitive impairment was 78% and the specificity 50%. If BDG cut-off was increased to 70 pg/mL, the sensitivity dropped to 44%, but specificity increased to 90%. Two of 16 CSF samples presented elevated BDG levels (45 and 53 pg/mL; Figure 1), whereas all other samples had BDG levels 80 pg/mL) in patients with mild-to-moderate mucositis.12,24,25 Whether this increase in BDG levels reflects
FIGURE 1. Scatterplots of correlation of blood beta-D-glucan levels (A) and cerebrospinal fluid beta-D-glucan levels (B) with global deficit Scores. Copyright
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TABLE 2. Levels of Investigated Plasma Biomarkers (Median and IQR are Displayed) and Correlations With GDS and Plasma BDG Levels Results, median (IQR) or mean SD
Biomarkers BDG, pg/mL IL-8, pg/mL sCD14, ng/mL BDG IL-8 BDG sCD14/100 IL-8 CD14/10 BDG sCD14 BDG/100
66 2.54 1194 156 672 339 1818
(36–76) (1.72–4.25) (1065–1379) (73–263) (383–1123) (191–513) (845–4253)
Spearman Correlation With GDS 0.47 0.55 0.40 0.57 0.58 0.52 0.71
P 0.04 0.01 n.s 0.01 3)-betaD-glucan, mannan/anti-mannan antibodies, and cand-tec candida antigen as serum biomarkers for candidemia. J Clin Microbiol. 2013;51:1158–1164. 13. Hoenigl M, Anderson CM, Green N, et al. Repeat HIV-testing is associated with an increase in behavioral risk among men who have sex with men: a cohort study. BMC Med. 2015;13:218. 14. Hoenigl M, Weibel N, Mehta SR, et al. Development and validation of the San Diego Early Test (SDET) score to predict acute and early HIV infection risk in men who have sex with men. Clin Infect Dis. 2015;61:468–475. 15. Hoenigl M, Green N, Camacho M, et al. Signs or symptoms of acute HIV infection in a cohort undergoing community-based screening. Emerg Infect Dis. 2016;22:532–534. 16. Hoenigl M, Graff-Zivin J, Little SJ. Costs per diagnosis of acute HIV infection in community-based screening strategies: A comparative analysis of four screening algorithms. Clin Infect Dis. 2016;62:501–511. 17. Hoenigl M, Green N, Mehta SR, et al. Risk factors for acute and early HIV infection among men who have sex with men (MSM) in san diego, 2008 to 2014: a cohort study. Medicine (Baltimore). 2015;94:e1242. 18. Gonzalez R, Heaton RK, Moore DJ, et al. Computerized reaction time battery versus a traditional neuropsychological battery: Detecting HIV-related impairments. J Int Neuropsychol Soc. 2003;9:64–71. 19. Heaton RK, Grant I, Butters N, et al. The HNRC 500–neuropsychology of HIV infection at different disease stages. HIV neurobehavioral research center. J Int Neuropsychol Soc. 1995;1:231–251.
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20. Blackstone K, Moore DJ, Franklin DR, et al. Defining neurocognitive impairment in HIV: Deficit scores versus clinical ratings. Clin Neuropsychol. 2012;26:894–908.
b-D-Glucan Correlates With Global Deficit Score
23. Hoenigl M, Faria de Oliveira M, Pe´rez-Santiago J, et al. Correlation of (1!3)-(-D-glucan with other inflammation markers in chronically HIV infected persons on suppressive antiretroviral therapy. GMS Infect Dis. 2015;3:Doc03.
21. Pruller F, Wagner J, Raggam RB, et al. Automation of serum (1–>3)-beta-D-glucan testing allows reliable and rapid discrimination of patients with and without candidemia. Med Mycol. 2014;52:455–461.
24. Martinez-Jimenez MC, Munoz P, Valerio M, et al. Candida biomarkers in patients with candidaemia and bacteraemia. J Antimicrob Chemother. 2015;70:2354–2361.
22. Sax PE, Komarow L, Finkelman MA, et al. Blood (1->3)-beta-Dglucan as a diagnostic test for HIV-related pneumocystis jirovecii pneumonia. Clin Infect Dis. 2011;53:197–202.
25. Prattes J, Raggam RB, Vanstraelen K, et al. Chemotherapy induced intestinal mucosal barrier damage: a cause of falsely elevated serum 1,3-beta-d-glucan levels? J Clin Microbiol. 2016;54:798–801.
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