Epidemiology

Many opportunistic fungal pathogens such as Candida species and Cryptococcus neoformans cause disease worldwide. In contrast, the endemic mycoses such as histoplasmosis and coccidioidomycosis, and, to a lesser extent, Cryptococcus gattii, are confined to certain geographical areas.[8][9][10][11][12][13]C neoformans is a phenotypically heterogeneous pathogen and genetic lineage plays an important role in cryptococcal virulence during human infection.[14]

Cryptococcal meningitis

In the 1980s, C neoformans emerged as an important opportunistic infection in the US, Europe, and Australia, occurring in 5% to 10% of all people with AIDS.[15] Since the 1990s, the incidence of HIV-associated cryptococcosis has decreased in the US, largely due to early and effective antiretroviral therapy. The annual incidence in people with AIDS in Atlanta decreased from 66 per 1000 in 1992 to 7 per 1000 in 2000.[16]

Cryptococcosis remains a major cause of morbidity and mortality in people with AIDS in developing countries.[17][18][1] In one study of patients with HIV-associated cryptococcal meningitis (in Thailand, Uganda, Malawi, and South Africa), mortality was 17% at 2 weeks and 34% at 10 weeks.[19] Risk of death was associated with low body weight, older age, anaemia (haemoglobin <75 g/L [<7.5 g/dL]), high peripheral white cell count, high fungal burden, and altered mental status.[19]

HIV-associated cryptococcal meningitis carries a significant burden in sub-Saharan Africa and is considered as a measure of HIV treatment programme failure.[1] In 2014, an estimated 73% of all cryptococcal meningitis cases were reported in sub-Saharan Africa.[1] Tuberculosis and cryptococcosis co-infection causing dual meningitis has been reported in China, and could be easily overlooked or misdiagnosed.[20]

Organ transplantation and developments in immunosuppressive therapies for cancer and other systemic diseases have contributed to the increasing incidence of fungal meningitis. An estimated 8% of invasive fungal infections in solid organ transplant recipients are due to cryptococcosis.[21] Fungal meningitis causes complications in up to 10% of patients with cancer, although they may not develop typical symptoms of meningitis.[22] Risk of cryptococcosis is higher in haematological malignancies than solid tumours.[23]

Between 1999 and the 2004, an outbreak of over 100 cases of C gattii infection occurred on Vancouver Island, Canada, predominantly in immunocompetent individuals.[24][25]

Histoplasmal meningitis

Histoplasmosis is endemic to Ohio and the Mississippi Valley in the US. However, it also occurs widely in Central and South America, Africa, Asia, and parts of southern Europe.[8] Studies using histoplasmin skin tests in tuberculin-negative individuals to determine areas of endemicity have concluded that more than 80% of young adults from states bordering the Ohio and Mississippi rivers have been previously infected with Histoplasma capsulatum.[26] Low-level exposure to H capsulatum in healthy individuals is largely asymptomatic. Central nervous system (CNS) involvement is clinically recognised in 5% to 10% of cases of progressive disseminated histoplasmosis, for which HIV infection is a risk factor.[27]

Coccidioidal meningitis

Coccidioidomycosis is found only in the Western hemisphere, predominantly the southwest of the US and northwest Mexico.[10][28][29] An estimated 100,000 to 150,000 cases of coccidioidomycosis occur annually in the US. The incidence of primary disease and consequent dissemination continues to increase, in part due to population growth, migration and increasing numbers of immunocompromised hosts.[30][31][32] The advent of early, potent antiretroviral therapy has reduced the incidence of HIV-associated coccidioidomycosis.[33][34]

Candidal meningitis

The prevalence of all types of invasive candidiasis is increasing. Candidal meningitis is a relatively common cause of meningitis in premature infants and infants younger than 1 month of age.[35][36] Neonatal candidal meningitis represented 0.4% of admissions to a neonatal intensive care unit in a 10-year retrospective US study.[37] Candidaemia in adults is rarely associated with meningitis, and meningeal involvement has been found in less than 15% of cases of disseminated candidiasis in autopsy series.[38][39] Candidal meningitis is the most common fungal meningitis following CNS shunt or ventriculostomy placement.[40][41] The highest rates are seen in infants less than 1 year old. Neurosurgery-related CNS candidiasis may be increasing,[42] perhaps related to prescription of prophylactic antibiotics for neurosurgical procedures.

Exserohilum rostratum meningitis

An outbreak of fungal infections and fatal fungal meningitis, due to E rostratum from therapeutic use of contaminated pharmaceutical product (vials of methylprednisolone), was reported in the US from September 2012.[43] This was investigated by the Centers for Disease Control and Prevention and local health departments. The investigation traced the primary fungal pathogen, E rostratum, isolated from patient specimens, to three lots of contaminated methylprednisolone acetate produced by a single compounding pharmacy. A total of 753 cases have been reported in 20 states, with 64 deaths.[44]

Aspergillus and mucormycosal meningitis

Aspergillus meningitis is rare and much more frequently observed among immunocompetent patients.[45] Mucormycosal meningitis occurs rarely, as a manifestation of rhinocerebral mucormycosis.[46]

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