cryptococcosis
Cryptococcosis, also known as cryptococcal disease, is a potentially fatal fungal disease. It is caused by one of two species; Cryptococcus neoformans and Cryptococcus gattii. These were all previously thought to be subspecies of C. neoformans but have now been identified as distinct species.
Cryptococcosis is believed to be acquired by inhalation of the infectious propagule from the environment. Although the exact nature of the infectious propagule is unknown, the leading hypothesis is the basidiospore created through sexual or asexual reproduction.
Cryptococcosis is a defining opportunistic infection for AIDS, and is the second-most-common AIDS-defining illness in Africa. Other conditions that pose an increased risk include certainlymphomas (e.g., Hodgkin’s lymphoma), sarcoidosis, liver cirrhosis, and patients on long-termcorticosteroid therapy.
Distribution is worldwide in soil.[3] The prevalence of cryptococcosis has been increasing over the past 20 years for many reasons, including the increase in incidence of AIDS and the expanded use of immunosuppressive drugs.
In humans, C. neoformans causes three types of infections:
Cryptococcal meningitis (infection of the meninges, the tissue covering the brain) is believed to result from dissemination of the fungus from either an observed or unappreciated pulmonary infection. Often there is also silent dissemination throughout the brain when meningitis is present. Cryptococcus gattii causes infections in immunocompetent people (fully functioning immune system), but C. neoformans v. grubii, and v. neoformans usually only cause clinically evident infections in persons with some form of defect in their immune systems (immunocompromised persons). People with defects in their cell-mediated immunity, for example, people with AIDS, are especially susceptible to disseminated cryptococcosis. Cryptococcosis is often fatal, even if treated. It is estimated that the three-month case-fatality rate is 9% in high-income regions, 55% in low/middle-income regions, and 70% in sub-Saharan Africa. As of 2009 there were globally approximately 958,000 annual cases and 625,000 deaths within three months after infection.[4]
Although the most common presentation of cryptococcosis is of C. neoformans infection in an immunocompromised person (such as persons living with AIDS), the C. gattii is being increasingly recognised as a pathogen in what is presumed to be immunocompetent hosts,[5] especially in Canada and Australia. This may be due to rare exposure and high pathogenicity, or to unrecognised isolated defects in immunity, specific for this organism.
Dependent on the infectious syndrome, symptoms include fever, fatigue, dry cough, headache, blurred vision, and confusion.[6] Symptom onset is often subacute, progressively worsened over several weeks. The two most common presentations are meningitis (an infection in and around the brain) and pulmonary (lung) infection.
Detection of cryptococcal antigen (capsular material) by culture of CSF, sputum and urine provides definitive diagnosis.[7] Blood cultures may be positive in heavy infections. India ink of the CSF is a traditional microscopic method of diagnosis,[8] although the sensitivity is poor in early infection, and may miss 15-20% of patients with culture-positive cryptococcal meningitis.[9] Unusual morphological forms are rarely seen.[10] Cryptococcal antigen from cerebrospinal fluid is the best test for diagnosis of cryptococcal meningitis in terms of sensitivity.
Cryptococcosis is a very subacute infection with a prolonged subclinical phase lasting weeks to months in persons with HIV/AIDS before the onset of symptomatic meningitis. In Sub-Saharan Africa, the prevalence rates of detectable cryptococcal antigen in peripheral blood is often 4–12% in persons with CD4 counts lower than 100 cells/mcL.[13][14] Cryptococcal antigen screen and preemptive treatment with fluconazole is cost saving to the healthcare system by avoiding cryptococcal meningitis.[15] The World Health Organization recommends cryptococcal antigen screening in HIV-infected persons entering care with CD4<100 cells/?L.[16] This undetected subclinical cryptococcal (if not preemptively treated with anti-fungal therapy) will often go on to develop cryptococcal meningitis, despite receiving HIV therapy.[14][17]Cryptococcosis accounts for 20-25% of the mortality after initiating HIV therapy in Africa. What is effective preemptive treatment is unknown, with the current recommendations on dose and duration based on expert opinion. Screening in the United States is controversial, with official guidelines not recommending screening, despite cost-effectiveness and a 3% U.S. cryptococcal antigen prevalence in CD4<100 cells/?L.[18][19]
Treatment options in persons without HIV-infection have not been well studied. Intravenous Amphotericin B combined with flucytosine by mouth is recommended.[20]
Persons living with AIDS often have a greater burden of disease and higher mortality (30-70% at 10-weeks), but recommended therapy is with amphotericin B and flucytosine. Where flucytosine is not available (many low and middle income countries), fluconazole should be used with amphotericin.[16] Amphotericin-based induction therapy has much greater microbiologic activity than fluconazole monotherapy with 30% better survival at 10-weeks.[7][21] Based on a systematic review of existing data, the most cost-effective induction treatment in resource-limited settings appears to be one week of amphotericin B coupled with high-dose fluconazole.[21] After initial induction treatment as above, typical consolidation therapy is with oral fluconazole for at least 8 weeks used with secondary prophylaxis with fluconazole thereafter.[16]