High Cryptococcal Antigen Titers in Blood are Predictive of Subclinical Cryptococcal Meningitis Among HIV-Infected Patients

Abstract

Background

High mortality rates among asymptomatic cryptococcal antigen (CrAg)-positive patients identified through CrAg screening, despite pre-emptive fluconazole, may be due to undiagnosed cryptococcal meningitis.

Methods

Symptoms were reviewed in CrAg-positive patients identified through screening 19,233 individuals with CD4 cell counts < 100 cells/µL at 17 clinics and 3 hospitals in Johannesburg from September 2012 until September 2015, and 2 of these hospitals until June 2016. Cerebrospinal fluid from 90/254 (35%) asymptomatic patients and 78/173 (45%) with headache only was analyzed for cryptococcal meningitis, present if Cryptococcus was identified by India ink microscopy, culture, or CrAg test. CrAg titers were determined on stored blood samples from 62 of these patients. The associations between blood CrAg titer, concurrent cryptococcal meningitis, and mortality were assessed.

Results

Cryptococcal meningitis was confirmed in 34% (95% confidence interval (CI) 25%-43%, n=31/90) of asymptomatic CrAg-positive patients and 90%, (95% CI 81%-96%, n=70/78) with headache only.Blood CrAg titer was significantly associated with concurrent cryptococcal meningitis in asymptomatic patients (p<0.001) and patients with headache only (p=0.003). The optimal titer for predicting cryptococcal meningitis was >160 (sensitivity 88.2%, specificity 82.1%); odds ratio for concurrent cryptococcal meningitis 34.5 (95% CI 8.3–143.1, p<0.001).

Conclusions

Around a third of asymptomatic CrAg-positive patients have concurrent cryptococcal meningitis. More effective clinical assessment strategies and antifungal regimens are required for CrAg-positive patients, including investigation for cryptococcal meningitis irrespective of symptoms. Where not possible to perform LPs on all CrAg-positive patients, blood CrAg titers should be used to target those most at risk of cryptococcal meningitis.