Very low levels of 25-hydroxyvitamin D are not associated with immunologic changes or clinical outcome in South African patients with HIV-associated cryptococcal meningitis

Abstract

Background: Vitamin D deficiency is associated with impaired immune responses and increased susceptibility to a number of intracellular pathogens in individuals infected with human immunodeficiency virus (HIV). It is not known whether such an association exists with Cryptococcus neoformans.

Methods: Levels of 25-hydroxyvitamin D (25[OH]D) were measured in 150 patients with cryptococcal meningitis (CM) and 150 HIV-infected controls in Cape Town, South Africa, and associations between vitamin D deficiency and CM were examined. The 25-hydroxyvitamin D levels and cryptococcal notifications were analyzed for evidence of reciprocal seasonality. Associations between 25(OH)D levels and disease severity, immune responses, and microbiological clearance were investigated in the patients with CM.

Results: Vitamin D deficiency (plasma 25[OH]D ≤50 nmol/L) was present in 74% of patients. Vitamin D deficiency was not associated with CM (adjusted odds ratio, 0.93 [95% confidence interval, .6-1.6]; P = .796). Levels of 25(OH)D showed marked seasonality, but no reciprocal seasonality was seen in CM notifications. No significant associations were found between 25(OH)D levels and fungal burden or levels of tumor necrosis factor α, interferon γ, interleukin 6, soluble CD14, or neopterin in cerebrospinal fluid. Rates of fungal clearance did not vary according to vitamin D status.

Conclusions: Vitamin D deficiency does not predispose to the development of CM, or lead to impaired immune responses or microbiological clearance in HIV-infected patients with CM.

Keywords: HIV; South Africa; cryptococcal meningitis; tuberculosis; vitamin D.

Figure 1.

Plasma 25-hydroxyvitamin D (25[OH]D) levels by cryptococcal meningitis status, tuberculosis status, and season. A, Plasma 25(OH)D levels of the whole study population (cases and controls combined), with dashed lines at 75 nmol/L (vitamin D insufficiency), 50 nmol/L (vitamin D deficiency), and 25 nmol/L (severe vitamin D deficiency). B and C, Plasma 25(OH)D levels according to cryptococcal meningitis case status (B) and tuberculosis status (C), with lines at the geometric mean and error bars showing 95% confidence intervals. Levels of 25(OH)D were significantly lower in individuals with tuberculosis than in those without tuberculosis (*34 nmol/L vs 39 nmol/L; P = .029). D, Average number of sunshine hours per month in Cape Town (source: National Oceanic and Atmospheric Administration, available at: www.noaa.gov). E, Levels of 25(OH)D by month (averaged over the 5-year study period) with cosinor regression line. F, Monthly cryptococcal notification rates (averaged over the period 2005–2011) with best-fit regression line. Abbreviations: CM, cryptococcal meningitis; TB, tuberculosis.

Figure 2.

Fungal burden, cerebrospinal fluid (CSF) immune responses, and rate of clearance of infection in cryptococcal meningitis patients with and without vitamin D deficiency. The baseline CSF fungal burden (QCC), rate of clearance of infection (EFA), baseline CSF lymphocyte count, CSF TNF-α concentration, and CSF IFN-γ concentration are shown according to whether patients were vitamin D deficient (plasma 25-hydroxyvitamin D ≤50 nmol/L). Lines indicate the mean in the vitamin D–deficient patients and in those without vitamin D deficiency. No significant differences were present between the vitamin D–deficient and –sufficient groups in any of the variables shown. Abbreviations: CFU, colony-forming units; CSF, cerebrospinal fluid; EFA, early fungicidal activity; IFN, interferon; QCC, quantitative cryptococcal culture; TNF, tumor necrosis factor.