Wednesday, December 11, 2013

Cryptococcus: When Yeast Attacks


A scanning electron microscope
view of Cryptococcus yeast cells.
The genus Cryptococcus consists of fungal pathogens that can be found naturally in the environment. Outbreaks of Cryptococcus are rare, but lately have been appearing in areas where the climate was thought to be unsuitable for survival of the unicellular yeast. Some species, such as Cryptococcus neoformans, tend to only cause cryptococcosis in immunocompromised patients, such as people who are HIV positive. On the other hand, the closely related Cryptococcus gattii infects primarily immunocompitent persons. Infection with either species can cause meningitis and respiratory distress, which can be fatal (1). Historically, Cryptococcus infection has been associated with tropical climates. However, recently cases have been reported in the Pacific Northwest and elsewhere within the US.

Cryptococcus infections occur through inhalation of fungal spores. These spores are found in nature, usually in tropical climates, in places such as soil or trees. Infection with Cryptococcus can cause pneumonia-like symptoms, such as trouble breathing, coughing, and fever. In some people, the infection is latent and patients are asymptomatic. However, in the most severe cases, Cryptococcus can spread to the nervous system and cause meningitis. When this occurs, symptoms intensify to include nausea, neck pain, and confusion. With proper treatment, the risk of fatality is about 10-30%. Untreated, meningitis is nearly always fatal (2).

Each year, about one million people globally develop cryptococcal meningitis. The majority of cases are found in sub-Saharan Africa. This is due to not only the climate being conducive to the survival of Cryptococcus, but also the prevalence of HIV. Astoundingly, before the development of HIV protease inhibitors, 5-10% of HIV positive patients could expect to contract cryptococcal meningitis (1). Since the poorer parts of Africa that are being hit hardest by the AIDS epidemic generally do not have access to the most cutting edge HIV therapies, they have not had the amazing decline in cryptococcal infections that has been seen in first world nations.

In treating Cryptococcal meningitis, two angles have to be considered-elimination of Cryptococcus from the body, and relieving the symptoms of meningitis. To clear the body of Cryptococcus, antifungal drugs are used. These can include fluconazole, amphotericin b, and flucytosine. However, no extremely effective antifungal currently exists-from the beginning of treatment, it can take up to two weeks to clear Cryptococcus from the cerebral spinal fluid. Because of this, new treatments are being evaluated, such as combination drug therapy. A recent study of the three drugs mentioned earlier showed that a combination of amphotericin b and flucytosine was more effective in the treatment of cryptococcal meningitis than any one of the three drugs on its own. Interestingly, this combination was also more effective than all three drugs given together (3). However, as mentioned earlier, clearing Cryptococcus is only one half of the problem. Meningitis leads to elevated cerebral spinal fluid pressure, which is a dangerous situation-symptoms include risk of seizures, blindness, and death. This is treated by relieving the pressure-an easy concept with difficult execution. This can either be done medicinally, using chemicals such as mannitol, or physically, by performing a ventricular drainage (2). Even with these various treatments, as stated earlier, cryptococcal meningitis is very deadly, with a 10-30% fatality rate, even in first world populations.

A schematic of a ventricular drainage.

An unlikely outbreak
Cryptococcus gattii cases started appearing on Vancouver Island in 1999, and spread to mainland British Columbia shortly thereafter. Luckily, it did not spread quickly or infect a massive amount of people-the yearly incidence of infection was found to be between 8.7 and 34 cases per million residents. However small this number may seem, it was troubling to health officials because the incidence was found to be ten times higher in Australia, where Cryptococcus is endemic (4). Additionally, because Cryptococcus was found in a place where nobody expected to find it-Vancouver isn’t exactly the tropics-the source of the infection was a huge mystery. So, researchers set out to sample soil, air, and trees to locate its origin.

In a study of the initial outbreak on Vancouver Island, researchers took samples from 347 different types of trees, in addition to numerous soil and air samples. All this work resulted in the discovery of 58 different isolates from 25 different trees. These 25 trees contained representatives from 10 different species, showing a wide range of sources. Interestingly, all but one of these trees were found in Rathtrevor Beach Provincial park. Additional research has found sources of C. gattii elsewhere on Vancouver island, but 46% of the patients infected during this period had visited Rathtrevor park (4).
Rathtrevor Beach Park: the source of the outbreak.

A new threat?
More recently, concern about the spread of Cryptococcus has increased, as it seems that Vancouver Island may not be the only region C. gattii is able to survive. Begininng in 2006, animal and human cases of cryptococcosis started showing up in Washington state and Oregon. Through genotype analysis, it was discovered that the strain infecting people in the American Pacific Northwest was the same strain that caused the Vancouver Island outbreak in 1999 (4). Only 22 cases of human and animal infection combined were reported between 2006 and 2008, but I think more frightening is the ability of Cryptococcus to spread. If a single strain can migrate from Vancouver to Oregon, what's stopping it from spreading to the American south, where the climate is more suitable for Cryptococcus? Additionally, Cryptococcus can be contracted from seemingly innocuous places, such as from trees and soil. Due to this, it seems like a large outbreak would likely be difficult to contain. If a significant movement of spores occurs, the potential danger of cryptococcosis as an emerging infectious disease may be greater than we realize.

Works Cited
1-CDC, 2013, “Cryptococal meningitis: a deadly fungal disease among people living with HIV/AIDS,” National Center for Emerging and Zoonotic Infectious Diseases.

2-Graybill, J, et al 2000, “Diagnosis and Management of Increased Intracranial Pressure in Patients with AIDS and Cryptococcal Meningitis,” Clinical Infectious Diseases, 30:47-54.

3-Brouwer, A, et al 2004, “Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial,” Lancet, 363: 1764-67.

4-Byrnes, E, et al 2007, “Molecular Evidence That the Range of the Vancouver Island Outbreak of Cryptococcus Cryptococcus Infection Has Expanded into the Pacific Northwest in the United States,”  The Journal of Infectious Diseases, 199:1081-6

5-Kidd, S, et al 2004, “A rare genotype of Cryptococcus gattii caused the cryptococcosis outbreak on Vancouver Island,”  PNAS,101: 17258-63.

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