Determinants of Disease Presentation and Outcome during Cryptococcosis: The CryptoA/D Study

Abstract

Background

Cryptococcosis is a life-threatening opportunistic fungal infection in both HIV-positive and -negative patients. Information on clinical presentation and therapeutic guidelines, derived mostly from clinical trials performed before introduction of highly active antiretroviral therapy in patients with cryptococcal meningoencephalitis, is missing data on extrameningeal involvement and infections by serotype D as opposed to serotype A of Cryptococcus neoformans.

Methods and Findings

The prospective multicenter study CryptoA/D was designed in France (1997–2001) to analyse the factors influencing clinical presentation and outcome without the bias of inclusion into therapeutic trials. Of the 230 patients enrolled, 177 (77%) were HIV-positive, 50 (22%) were female, and 161 (72.5%) were infected with serotype A. Based on culture results at baseline, cryptococcosis was more severe in men, in HIV-positive patients, and in patients infected with serotype A. Factors independently associated with mycological failure at week 2 independent of HIV status were initial dissemination (OR, 2.4 [95% confidence interval (CI), 1.2–4.9]), high (>1:512) serum antigen titre (OR, 2.6 [1.3–5.4]), and lack of flucytosine during induction therapy (OR, 3.8 [1.9–7.8]). The three-month survival was shorter in patients with abnormal neurology or brain imaging at baseline, and in those with haematological malignancy.

Conclusions

Thus sex, HIV status, and infecting serotype are major determinants of presentation and outcome during cryptococcosis. We propose a modification of current guidelines for the initial management of cryptococcosis based on systematic fungal burden evaluation.

Abstract

Françoise Dromer and colleagues report that sex, HIV status, and infecting serotype are major determinants of cryptococcosis presentation and outcome.

Editors' Summary

Background.

For people with a healthy immune system, athletes' foot may be the only fungal infection they ever have. But individuals whose immune system has been damaged by infection with HIV or who are immune-suppressed after organ transplantation or cancer chemotherapy can develop cryptococcosis. This is a life-threatening infection caused by Cryptococcus neoformans, a fungus found in bird droppings that enters the human body through the lungs. The initial infection can go unnoticed, although a pneumonia-like disease sometimes develops. However, if the fungus spreads (disseminates) around the body it can cause other symptoms. The commonest of these is cryptococcal meningitis, a swelling of the membrane around the brain that can cause a stiff neck, headaches, and neurological symptoms such as palsies. For anyone with cryptococcal meningitis or severe pneumonia the current treatment guidelines recommend a two-week induction therapy with the antifungal drugs amphotericin B and flucytosine, followed by fluconazole for ten weeks.

Why Was This Study Done?

Even when these guidelines are followed, cryptococcosis kills some people. The guidelines are based on data from clinical trials of antifungal drugs in HIV-positive patients done before there were effective treatments for HIV infections. Patients without meningitis and those with very severe disease were excluded from these trials. Also, it is known that two variants of C. neoformans cause cryptococcosis: variety grubii (also known as serotype A) and variety neoformans (serotype D). There is very little information about the impact of patient-related factors (such as sex, age, and HIV status) or the variety of C. neoformans on clinical presentation (the symptoms patients have when they first visit a doctor), therapeutic management, or disease outcomes in the real world; this information is needed to improve the treatment guidelines. In this nationwide study across France, the researchers have asked what factors influence clinical presentation and outcomes in HIV-positive and HIV-negative patients with cryptococcosis, and whether infections with the two varieties of C. neoformans behave similarly.

What Did the Researchers Do and Find?

Patients were enrolled in the study when their first episode of cryptococcosis was confirmed by growing C. neoformans from blood, urine, or cerebrospinal fluid. Information was collected about their initial symptoms, which body sites were infected with fungus (their mycological status), and their treatment. Clinical and mycological data were also collected at two weeks and three months, and the blood levels of cryptococcal secreted molecules were measured to provide a “serum antigen titer,” a measure of fungal load. The researchers found that cryptococcosis was more severe at presentation in men, in HIV-positive patients, and in patients infected with C. neoformans variety grubii. Patients whose treatment failed at two weeks (judged by the continued presence of C. neoformans in culture of their body fluids) tended to have disseminated disease at presentation, to have high serum antigen titers, and not to have been given flucytosine during the initial round of therapy. Finally, three-month survival was worse in patients with abnormal neurology or brain imaging at the start of the study, or those with hematological malignancies (cancers that affect immune system cells).

What Do These Findings Mean?

These findings provide new information on what determines the clinical presentation and outcome in patients with cryptococcosis. Because the study was done in France, these results will only apply to other countries where C. neoformans causes cryptococcosis—in some countries C. gattii can cause the disease. In addition, not all of the cryptococcosis cases that occurred in France during the study period were enrolled in the study, so it is possible that the infection might have had different characteristics in the missing patients. Nevertheless, the results of this study suggest that more patients would benefit from a two-week induction therapy with amphotericin B and flucytosine than currently recommended. This treatment, write the researchers, should be given to all patients with a high serum antigen titer, fungus in the blood, or initial infection at two separate body sites (in addition to those with cryptococcal meningitis or severe pneumonia for whom it is currently recommended). They also suggest that the fungal burden should be routinely determined in all patients so that their treatment can be adjusted if necessary.

Additional Information.

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040021

• A related PLoS Medicine Perspective article discusses current management of cryptococcosis

• MedlinePlus has encyclopedia pages on cryptococcosis

• US Centers for Disease Control and Prevention provides information on cryptococcosis

• Aidsmap has information on cryptococcosis and research into the disease provided by the charity NAM

• A Clinical Infectious Diseases article published in 2000 states the current treatment guidelines for the management of cryptococcosis