Dexamethasone Slows Fungal Clearance, Results in Poor Outcomes in HIV-Associated Meningitis

According to study findings published in Clinical Infectious Diseases, treatment with the anti-inflammatory steroid dexamethasone is associated with slowed clearance of fungal infections in HIV-associated cryptococcal meningitis. Additionally, the use of dexamethasone in these patients may accelerate the decline rate of TNF-α concentrations, resulting in worsened clinical outcomes. The study was led by Justin Beardsley, PhD, of the Oxford University Clinical Research Unit in Vietnam.

“HIV-associated cryptococcal meningitis (CM) affects approximately 230,000 people annually, mostly in low and low-middle income countries [1]. Even with optimal anti-fungal treatment, outcomes are poor, with ten-week mortality rates of around 30%,” the researchers wrote. “Our data…extended the understanding of the mycological benefits of high baseline concentrations of pro-inflammatory cytokines, by showing that even once established on effective anti-fungal therapy, persistently higher concentrations can be advantageous.”

Individuals from Vietnam, Thailand, and Uganda who carried and HIV-positive diagnosis and presented with a syndrome consistent with cryptococcal meningitis were enrolled. Additional inclusion criteria stipulated that patients had to have had ≥1 of positive CSF India ink stain, positive CSF or blood culture for Cryptococcus, or positive CSF cryptococcal antigen (IMMY CrAg LFA).

All participants had undergone prior randomization to either intravenously administered dexamethasone (n = 133) or placebo (n = 138). Treatment was administered for 2 weeks at 0.3mg/kg/day for the first week then 0.2mg/kg/day for the second week. Additionally, treatment was then given orally at week 3 (0.1mg/kg/day), week 4 (3mg/day), week 5 (2mg/day), and week 6 (1mg/day).

Researchers measured the concentrations of IFN-γ, TNF-α, GM-CSF, IL-6, IL-12p70, IL-8, MCP-1, MIP-1α, IL-4, IL-10, and IL- 17 in cerebrospinal fluid (CSF) from day 1 of treatment to day 7. The main outcome of interest included the change rates of IFN-γ, TNF-α, IL-4, IL-10 and IFN-γ/IL-4 and TNF-α/IL-10 CSF concentration ratios over the 7-day treatment period.

By 10 weeks, patients with good (34%) or intermediate (38%) outcomes were more likely to have IFN-γ concentrations of >30pg/ml compared with those with severe disability (13%) or death (22%) (P=0.02). Over the first 7-day treatment period, patients randomized to dexamethasone demonstrated faster decline rates of TNF-α concentrations vs those randomized to placebo (difference in slope -0.13; 95% CI -0.22 to - 0.06; P=0.03).

In addition, treatment with dexamethasone was significantly associated with greater rapid CSF TNF-α:IL-10 ratio declines compared with placebo (95% CI -0.14 [-0.21 to -0.06]; P<0.001). The faster rate in TNF-α decline was also associated with slower fungal clearance (correlation -0.62; -0.83 to -0.26). The investigators also observed a deleterious effect of dexamethasone on 10-week mortality between 21 and 70 days of treatment for patients with the CC (hazard ratio [HR] 3.24; 95% CI 1.31-8.04) and CT genotypes (HR 3.41; 95% CI 1.07-10.90).

Limitations of the analysis included the unbalanced genotype cohorts as well as the enrollment of patients from Vietnam, Thailand, and Uganda, which limit the generalizability of the findings.

“The body of evidence suggests that, in contrast to TBM and bacterial meningitis, pro- inflammatory immune responses are beneficial in HIV-associated cryptococcal meningitis,” the investigators concluded. “Our data support this conclusion and show that a pro-inflammatory response remains important for fungal clearance even once established on effective anti-fungal therapy.”

Reference:

Beardsley J, Hoang NLT, Kibengo FM, et al. Do intra-cerebral cytokine responses explain the harmful effects of dexamethasone in HIV-associated cryptococcal meningitis? [published August 30, 2018] Clin Infect Dis. doi: 10.1093/cid/ciy725.