Cryptococcal Meningitis Responsible for 1 in 10 HIV-Related Deaths, Study Reports

Cryptococcosis is one of the leading causes of death in sub-Saharan Africa among adults living with HIV. Tuberculosis is the most common cause of AIDS-related morality in adults, but estimates indicate that cryptococcal meningitis is the second most common cause, with a mortality rate of around 15%.

Although complete diagnostic autopsies are the best way to determine a cause of death, the procedure is not frequently performed in low-income settings. In a new study coordinated by the Barcelona Institute for Global Health and published in the journal Scientific Reports, a team of investigators sought to determine the Cryptococcus-associated mortality through autopsies performed in high-prevalence HIV areas.

The study sites were organized at the Department of Pathology of the Maputo Central Hospital in Maputo, Mozambique, and at the Fundaco de Medicine Tropical Doutor Heitor Vieira Dourado in Manaus, Brazil.

According to the investigators, the results were similar despite the differences in the 2 study sites, as they write: “Interestingly, albeit being Maputo and Manaus, 2 sites from different countries in terms of income and climate, some of the results obtained were very similar such as the HIV prevalence in deceased patients (over 60%) and the Cryptococcus-associated mortality in HIV positive patients.”

Between November 2013 and March 2015, autopsies were performed on 284 deceased patients from the 2 study sites. In total, 233 cases were in patients from Mozambique, consisting of 169 cases in adults over the age of 15 years. Of these, 112 were women, 57 of whom were classified as maternal deaths (occurring during pregnancy, post-partum, or within 42 days of termination of pregnancy). The Brazil study site autopsied 61 individuals, 59 of whom were adults, comprising 28 males and 21 females, including 1 maternal death.

Of the 284 autopsies, 163 individuals (57%) tested positive for HIV and a total of 17 (6%) fatal cryptococcal infections were confirmed in the autopsy. In the population of individuals with HIV, cryptococcosis was responsible for 16 deaths. The only death in an individual who did not have HIV was in a 6 year-old child.

Among the Mozambicans, 109 of 169 individuals (64%) had HIV, 11 of these individuals died of cryptococcal infections, including 3 women who were documented as maternal deaths. On the other hand, 37 of the 61 patients from Brazil (61%) were HIV-infected and Cryptococcus was responsible for 5 of these deaths (13%).

Across the population of patients with fatal cryptococcal infections, the median age was 34 years (range 6-44) and 11 of the cases (65%) were detected in men. In 13 of the 16 patients with HIV, a positive HIV test was documented in the clinical records and 4 of these patients were on an antiretroviral therapy regimen, though the duration of therapy was only known for 1 individual.

The investigators report that the mean time from hospital admission to death was 9.3 days (95% Confidence Interval: 2.4-16.2). Cryptococcal infection was considered the first clinical diagnostic option in only 23% of the total confirmed cases, representing a low suspicion of infection among clinicians. Twelve of the 16 patients with HIV died within 1 week of admission with 7 of the patients (41%) dying within 72 hours.

Cryptococcal strains that were isolated from cultures of individuals underwent a consensus multi-locus sequence typing scheme for C neoformans and C gattii as part of the autopsy procedure, with sero-mating types of these strains determined by multiplex polymerase chain reaction (PCR).

The results of the histopathological and microbiological analysis indicate that using PCR, the species was successfully identified in 15 of the 17 cases: 5 were C gattii and the remaining were C neoformans var. grubii. Results note that the most affected organs were the lungs (88%), spleen (76%), liver (71%), bone marrow (59%), and kidney (47%). Additionally, more organs were affected in individuals with C neoformans var. grubii than those with C gattii infections (mean of 6.2 vs 2.8 organs positive), but no specific histopathological difference were observed between the 2 species

“Our study highlights the substantial mortality associated with cryptococcal infections among HIV-infected patients,” the investigators concluded. They further noted that “supporting current recommendations of [Cryptococcus antigen] screening and preemptive therapy, which is even more relevant in settings in which insufficient pre-mortem clinical suspicion is given to this highly prevalent and life-threatening opportunistic infection.”