Serum (1→3)-β-D-Glucan Levels in HIV-Infected Individuals Are Associated With Immunosuppression, Inflammation, and Cardiopulmonary Function

Abstract

Background Translocation of gastrointestinal bacteria in HIV-infected individuals is associated with systemic inflammation, HIV progression, mortality, and co-morbidities. HIV-infected individuals are also susceptible to fungal infection and colonization, but whether fungal translocation occurs and influences HIV progression or co-morbidities is unknown. Methods Serum (1→3)-β-D-glucan was measured by a Limulus Amebocyte Lysate assay (Fungitell®) in 132 HIV-infected outpatients. Selected plasma cytokines and markers of peripheral T-cell activation were measured. Pulmonary function testing and Doppler-echocardiography were performed. Relationship of high (≥40pg/ml) and low (<40pg/ml) levels of (1→3)-β-D-glucan with HIV-associated variables, inflammation markers, and pulmonary function and pulmonary hypertension measures were determined. Results Forty-eight percent had detectable (1→3)-β-D-glucan, and 16.7% had high levels. Individuals with high (1→3)-β-D-glucan were more likely to have CD4 counts below 200 cells/μl (31.8% vs. 8.4%, p=0.002), had higher log10 HIV viral levels (2.85 vs. 2.13 log copies/ml, p=0.004), and were less likely to use ART (68.2% vs. 90.0%, p=0.006). Plasma IL-8 (p=0.033), TNF-α (p=0.029), and CD8+CD38+ (p=0.046) andCD8+HLA-DR+ (p=0.029) were also increased with high levels. Abnormalities in diffusing capacity (p=0.041) and in pulmonary artery pressures (p=0.006 for pulmonary artery systolic pressure and 0.013 for tricuspid regurgitant velocity) were more common in those with high (1→3)-β-D-glucan. Conclusions We found evidence of peripheral fungal cell wall polysaccharides in an HIV-infected cohort. We also demonstrated an association between high serum (1→3)-β-D-glucan, HIV-associated immunosuppression, inflammation, and cardiopulmonary co-morbidity. These results implicate a new class of pathogen in HIV-associated microbial translocation and suggest a role in HIV progression and co-morbidities.

Correlation of (1→3)-β-D-glucan with other inflammation markers in chronically HIV infected persons on suppressive antiretroviral therapy

“…Our results confirm findings of a previous study, that evaluated BDG levels in a cohort of in HIV-infected outpatients (majority not virologically suppressed) and found that plasma IL-8 (p=0.03), and TNF-α (p=0.03) were increased in those with high BDG levels (i.e. >40 pg/mL), while IL-6 was not significantly different [5]. Another study that evaluated BDG as a marker for cryptococcal meningitis among HIV-infected individuals in cerebrospinal fluid (CSF) (21) found positive correlations between BDG and IL-8 (p<0.01), and also TNF-α (p=0.02), while again no correlation was found with IL-6 [21].…”

“…It has been shown previously that BDG levels were markedly higher (mean 142 pg/mL) in a HIV infected cohort with lower median CD4 counts (26, IQR 10–53, all without opportunistic infections), when compared to the cohort studied here (with a median CD4 count >600 pg/mL) [13]. In another study, high serum BDG levels (>40 pg/mL) were more likely to occur in individuals with CD4 counts less than 200 cells/mL (31.8% vs. 8.4%, p<0.01), higher HIV viral levels (2.85 vs. 2.13 log 10 copies/mL, p<0.01), and those without ART (68.2% vs. 90.0%, p<0.01) [5]. …”

“…In the absence of an active IFI or PJP, serum BDG may be a reasonable indicator of gut mucosal barrier impairment [18], [19] and microbial translocation [20]. The latter was recently reported also for a cohort of HIV-infected subjects [5]. …”

“…Previous reports have indicated that microbial translocation of bacterial and fungal commensals of the gastrointestinal tract into systemic circulation is one important factor, which is associated with immune dysfunction, persistent inflammation and likely also plays a role in the disease progression, and non-AIDS associated comorbidities [4], [5]. The enteropathy associated with HIV infection is characterized by microbial over-growth in the intestinal lumen and disrupted intestinal permeability resulting in increased levels of lipopolysaccharides (LPS) and 16S rRNA in blood plasma.…”

Heart–Lung Interaction via Infection

“…(1→3)-b-D-glucan (BG) is a component of fungal cell walls that is shed into the blood and can be detected in the serum of patients with fungal pneumonia (37,38). We have recently found detectable BG levels in HIVinfected adult outpatients without pneumonia, and BG levels correlate strongly with airway obstruction, DL CO , echocardiographic pulmonary artery pressures, higher inflammatory cytokines, increased sputum neutrophils, and activated peripheral lymphocytes (39). These results indicate that fungal translocation is an unrecognized contributor to inflammation and chronic complications of HIV.…”