Cryptococcosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Cryptococcosis is an infection acquired by inhalation of soil contaminated with the encapsulated yeast (fungus) Cryptococcus neoformans. The immune response to cryptococcal infection is highly dependent on host T-cell function, interferon-γ and TNF-α signaling is impaired in immunocompromised patients, resulting in disease. The overall incidence of cryptococcosis is estimated to be 0.4 to 1.3 cases per 100,000 persons yearly in the United States. C. neoformans can cause no infection, latent infection, or symptomatic disease. C. neoformans enters the body through the respiratory route, and infection can present as pneumonia-like illness with symptoms such as cough, fever, chest pain, and weight loss. If left untreated, C. neoformans can disseminate to the central nervous system, causing meningoencephalitis. Prognosis is poor without treatment, with a mortality rate reaching 10 to 30% within 3 weeks of presentation. The standard regimen of treatment in non-AIDS patients is intravenous amphotericin B combined with oral flucytosine. AIDS patients often have a reduced response to amphotericin B and flucytosine, therefore, after initial treatment as above, oral fluconazole can be used.

Cryptococci, initially thought to be of the Saccharomyces genus, were first identified in 1894 by German pathologist Otto Busse in a patient with chronic periostitis of the tibia. In 1901, Jean Paul Vuillemin, a French mycologist, moved the yeast-like fungus to the genus Cryptococcus due to the absence of ascospores in its life cycle, a defining feature of Saccharomyces.

Cryptococcosis may be classified based on the site of infection. The clinical syndrome can be classified as pulmonary, CNS, or disseminated cryptococcosis. Another approach to the classification involves the species or variety of the Cryptococcus causative organism, including Cryptococcus neoformans, Cryptococcus gattii, and other, rare species.

Infective cryptococcal species are ubiquitous and natural exposure by inhalation is very common. Cryptococci are intracellular pathogens. Once they are phagocytosed, they germinate and multiply within the macrophages. The immune response to cryptococcal infection is highly dependent on host T-cell function, interferon-γ and TNF-α signaling. Microscopically, Cryptococci are characterized by a thick mucopolysaccharide capsule with a refractile center.

Cryptococcosis is an infection acquired by inhalation of soil contaminated with the encapsulated yeast (fungus) Cryptococcus neoformans.

Cryptococcosis is more common among immunocompromised patients who are at high risk for other fungal, bacterial, and viral infections. Cryptococcal meningitis can be indistinguishable from bacterial or viral meningitis. Cryptococcosis must be differentiated from diseases that cause symptoms of lower respiratory tract infection (fever, dyspnea, cough) and meningitis (fever, headache, neck stiffness, focal neurological deficits) such as coccidioidomycosis, histoplasmosis, tuberculosis, and community/hospital-acquired pneumonia. Cutaneous cryptococcosis in HIV/AIDS patients must be differentiated from molluscum contagiosum and Kaposi’s sarcoma.

The prevalence of cryptococcal antigenemia among patients with HIV in the United States is approximately 2900 per 100,000 patients. The overall annual incidence is estimated to be 0.4 to 1.3 cases per 100,000 individuals in the United States. Cryptococcosis has no age, gender, or racial predilection.

Risk factors for the development of cryptococcal infection include being immunocompromised and inhalational exposure (most commonly from dry bird droppings).

Asymptomatic cryptococcal antigenemia is very common in areas with endemic HIV/AIDS, and is associated with increased mortality and incidence of cryptococcal meningitis. Screening is not recommended for HIV/AIDS patients in the United States or Europe. However, screening may be beneficial in countries with limited HAART availability, high levels of antiretroviral drug resistance, and a high burden of disease. In the absence of symptoms, positive cryptococcal antigenemia should be treated with oral fluconazole.

C. neoformans can cause no infection, latent infection, or symptomatic disease. C. neoformans enters the body through the respiratory route. Infection can present as pneumonia-like illness with symptoms such as cough, fever, chest pain, and weight loss. If left untreated, C. neoformans can disseminate to the central nervous system and cause meningoencephalitis. Prognosis is poor without treatment, with a mortality rate reaching 10 to 30% within 3 weeks of presentation.

The symptoms of cryptococcosis depend on the site of infection/clinical syndrome, the virulence of the yeast strain, and the immune status of the host. Patients may be completely asymptomatic, have latent infection, or have symptomatic disease. Cryptococcus enters the body through the respiratory route. Infection can present as pneumonia-like illness with fever, cough, sputum production, and chest pain. Cryptococcus can also disseminate to the central nervous system and cause meningoencephalitis presenting with headache, nausea, vomiting, altered sensorium, and focal neurological deficits.

Physical examination findings in patients with cryptococcal meningitis include fever, nystagmus, papilledema, and cranial nerve deficits. Cutaneous cryptococcal infection presents with erythematous papules, pustules, nodules, and ulcers. Rales can be heard on auscultation of the chest in pulmonary cryptococcus infection.

Cryptococcal disease can be diagnosed through culture, CSF microscopy, or by cryptococcal antigen (CrAg) detection.

Chest radiography in a patient with pulmonary cryptococcosis may demonstrate interstitial infiltrates, pleural effusion, or hilar lymphadenopathy.

The most common CT findings in patients with pulmonary cryptococcosis are pulmonary nodules and pulmonary opacities that range from a perihilar interstitial pattern to an area of dense alveolar consolidation.

Common MRI findings in patients with cryptococcal meningitis include Virchow-Robin dilatation, hydrocephalus, intracerebral nodules, and pseudocysts.

There are no associated other imaging findings with cryptococcal infection.

Other diagnostic studies helpful diagnosing cryptococcal infection include demonstration of the budding yeast on an India ink stain, staining the polysaccharide cell wall using mucicarmine stain, detection of cryptococcal antigen in CSF, and a positive culture for Cryptococcus neoformans.

The standard regimen of treatment in non-AIDS patients is intravenous amphotericin B combined with oral flucytosine. AIDS patients often have a reduced response to amphotericin B and flucytosine, therefore, after initial treatment as above, oral fluconazole can be used.

Surgical excision of cryptococcoma is recommended if the lesions are larger than 3 cm, accessible lesions have a mass effect or compress vital structures, or the size of the cryptococcoma fails to decrease after 4 weeks of medical therapy.

It is recommended that patients with CD4 counts ≤ 100 cells/μl should have routine cryptococcal antigen screening and patients with positive results should be offered preemptive anti-fungal therapy.

Secondary preventive measures for cryptococcal infection are the same as primary prevention measures.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Serge Korjian M.D.; Yazan Daaboul, M.D.

Cryptococci, initially thought to be of the Saccharomyces genus, were first identified in 1894 by German pathologist Otto Busse in a patient with chronic periostitis of the tibia. In 1901, Jean Paul Vuillemin, a French mycologist, moved the yeast-like fungus to the genus Cryptococcus due to the absence of ascospores in its life cycle, a defining feature of Saccharomyces.

• Cryptococci were first identified in 1894 by German pathologist Otto Busse in a patient with chronic periostitis of the tibia. He described the isolated organism as a “Saccharomyces-like” pathogen.^[1]
• The infection was referred to as “Busse-Buschke” disease named after Busse and his colleague, dermatologist Abraham Buschke.^[2]
• Busse later named the organism Saccharomyces hominis.
• During the same time period, Francesco Sanfelice reported isolating a similar organism from fermenting peach juice. Because of its unique colony form, he referred to the species as Saccharomyces neoformans.
• In 1901, Jean Paul Vuillemin, a French mycologist, transferred the yeast-like fungus to the genus Cryptococcus due to the absence of ascospores in its life cycle, a defining feature of Saccharomyces.^[3]
• In the 1950s, four capsule serotypes (A through D) were identified using rabbit antisera. This classification was later improved by DNA sequencing, epidemiology, and pathobiology.^[1][4]
• Until 1999, Cryptococcus gattii was known as Cryptococcus neoformans var gattii, until it was recognized as separate species with distinct epidemiological patterns and clinical manifestations.^[5]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Serge Korjian M.D.; Yazan Daaboul, M.D.

Cryptococcosis may be classified based on the site of infection. The clinical syndrome can be classified as pulmonary, CNS, or disseminated cryptococcosis. Another approach to the classification is based upon the variety of species of the Cryptococcus causative organism, including Cryptococcus neoformans, Cryptococcus gattii, and other, rarer species.

Cryptococcosis may be classified based on the site of infection (the clinical syndrome), or the species of the Cryptococcus causative organism.

• Pulmonary Cryptococcosis

• The most common clinical syndrome associated with Cryptococcus, but may be asymptomatic.^[1]
• Related to the mode of transmission via aerosolized basidiospores.^[2]
• Extra-pulmonary infections are thought to be secondary to a primary pulmonary infection, even in cases where the latter is not evident.

• Central Nervous System (CNS) Cryptococcosis

• Classically seen in patients with AIDS and low CD4 counts (below 100).^[3]
• Secondary to dissemination of inhaled spores in patients who are severely immunocompromised.
• Cryptococcosis is one of the leading causes of meningitis in adults worldwide.^[4]

• Disseminated Cryptococcosis

• Most often involves the skin, soft tissue, and the medulla of the bone in addition to the lungs and CNS.^[5]
• Also associated with a severely immunocompromised status.

• Cutaneous Cryptococcosis
  • Papules, pustules, nodules, and ulcers are common skin lesions.^[6]

(a) Cryptococcus neoformans

• The most common cryptococcal species associated with human disease.
• Variety includes:

• Cryptococcus neoformans v. neoformans (serotype D)

• The major causative agent of cryptococcosis in Europe.^[7]

• Cryptococcus neoformans v. grubii (serotype A)

• The major causative agent of cryptococcosis in Asia and the U.S.^[8]

(b) Cryptococcus gattii

• Previously a variant of C. neoformans, currently classified as a separate species.
• Emerging as a common fungal pathogen in the Pacific Northwest of the U.S.^[9]

(c) Cryptococcus uniguttulatus

• Very rare
• Associated with ventriculitis^[10]
• First isolated from a human nail

(d) Cryptococcus laurentii

• Rare
• Associated with fungemia, lung abscesses, and meningitis.^[11]

(e) Cryptococcus albidus

• Very rare
• Associated with ocular infections and meningitis.^[12]

• Although other species of Cryptococci exist, they are not known to be infectious to humans.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Serge Korjian M.D.; Yazan Daaboul, M.D.

Infective cryptococcal species are ubiquitous and natural exposure by inhalation is very common. Cryptococci are intracellular pathogens. Once they are phagocytosed, they germinate and multiply within the macrophages. The immune response to cryptococcal infection is highly dependent on host T-cell function, interferon-γ and TNF-α signaling. Microscopically, Cryptococci are characterized by a thick mucopolysaccharide capsule with a refractile center.

• Infective cryptococcal species are ubiquitous and natural exposure is very common.^[1]
• Infection occurs by inhalation of aerosolized, dessicated basidiospores.^[2]

• Cryptococcus polysaccharide capsule, phospholipase activity and extracellular vesicles play key roles in the survival of the organism within the host.^[3]

• Once these spores reach the alveoli, they are phagocytosed by the alveolar macrophages without prior opsonization (usually required for yeast forms).
• Cryptococci are intracellular pathogens. Once they are phagocytosed, they germinate and multiply within the macrophages.^[4]
• Activated macrophages are capable of destroying the yeast forms that develop; however, non-activated macrophages act as germination centers for cryptococci.^[5]
• Cryptococci have the ability to form giant cells that resist phagocytosis and have been hypothesized to play a role in latent infections, and reactivation.^[5]
• Cryptococci also have the ability to change the number of sets of chromosomes they have during infection; this has been associated with heteroresistance to certain antifungal agents.^[6]

• After exposure to desiccated yeast cells or spores, patients may clear the infection, contain it within granulomata as a latent infection, or the infection may disseminate. This depends on the host’s immune status or other, less well-understood mechanisms.

• Disseminated disease occurs among patients with compromised cell-mediated immunity.
• The immune response to cryptococcal infection is highly dependent on host T-cell function, interferon-γ and TNF-α signaling.
• Granuloma formation can be seen and may also be responsible for reactivation in patients presenting with immunocompromised states.^[7][8]

• Cryptococcus exists in yeast form.
• It is round/ovoid and approximately 5-15 μm (resembles Histoplasma or Candida, but often larger).
• It is characterized by a thick mucopolysaccharide capsule with a refractile center.
• India ink staining is used for easy visualization of the capsule in cerebrospinal fluid.^[9]
• It has a tear drop-shaped budding pattern which is useful for differentiating Cryptococcus from Blastomyces and Histoplasma.
• Cryptococcal infections are usually accompanied by very little inflammation.
• Cryptococcus stain positive with methenamine silver, Alcian blue, and PAS (may be confused with corpora amylacea in the CNS).^[10]

{{#ev:youtube|ZG0AcmtBLe4}}

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]

Cryptococcus neoformans is an encapsulated yeast and an obligate aerobe that can live in both plants and animals.^{[1] [2]}It is often found in bird excrement. It is the causative agent of cryptococcosis (cryptococcal pneumonia and meningitis).

Cryptococcus neoformans is composed of two varieties (v.): C. neoformans v. neoformans and C. n. v. grubii. A third variety, C. n. v. gattii, is now considered a distinct species, Cryptococcus gattii. C. n. v. grubii and C. n. v. neoformans have a worldwide distribution and are often found in soil contaminated by bird excrement. The genome sequence of C. neoformans v. neoformans was published in 2005.^[3] Recent studies suggest colonies of C. neoformans and related fungi growing on the ruins of the melted down reactor of the chernobyl nuclear power plant may be able to use the energy of radiation (primary beta radiation) for “radiotrophic” growth.^[4]

C. neoformans grows as a yeast (unicellular) and replicates by budding. It makes hyphae during mating, and eventually creates basidiospores at the end of the hyphae before producing spores. Under host-relevant conditions, including low glucose, serum, 5% carbon dioxide, and low iron, among others, the cells produce a characteristic polysaccharide capsule.^[5] The recognition of C. neoformans in Gram-stained smears of purulent exudates may be hampered by the presence of the large gelatinous capsule which apparently prevents definitive staining of the yeast-like cells. In such stained preparations, it may appear either as round cells with Gram-positive granular inclusions impressed upon a pale lavender cytoplasmic background or as Gram-negative lipoid bodies.^[6] When grown as a yeast, C. neoformans has a prominent capsule composed mostly of polysaccharides. Under the microscope, the India ink stain is used for easy visualization of the capsule in cerebrospinal fluid.^[7] The particles of ink pigment do not enter the capsule that surrounds the spherical yeast cell, resulting in a zone of clearance or “halo” around the cells. This allows for quick and easy identification of C. neoformans. Unusual morphological forms are rarely seen.^[8] For identification in tissue, mucicarmine stain provides specific staining of polysaccharide cell wall in C. neoformans. Cryptococcal antigen from cerebrospinal fluid is thought to be the best test for diagnosis of cryptococcal meningitis in terms of sensitivity, though it might be unreliable in HIV-positive patients.^[9]

Infection with C. neoformans is termed cryptococcosis. Most infections with C. neoformans occur in the lungs.^[10] However, fungal meningitis and encephalitis, especially as a secondary infection for AIDS patients, are often caused by C. neoformans, making it a particularly dangerous fungus. Infections with this fungus are rare in those with fully functioning immune systems.^[11] So, C. neoformans is sometimes referred to as an opportunistic fungus.^[11] It is a facultative intracellular pathogen.^[12] Cryptococcus neoformans was the first intracellular pathogen for which the non-lytic escape process termed vomocytosis was observed.^[13][14]

In human infection, C. neoformans is spread by inhalation of aerosolized basidiospores, and can disseminate to the central nervous system, where it can cause meningoencephalitis.^[15] In the lungs, C. neoformans cells are phagocytosed by alveolar macrophages.^[16] Macrophages produce oxidative and nitrosative agents, creating a hostile environment, to kill invading pathogens.^[17] However, some C. neoformans cells can survive intracellularly in macrophages.^[16] Intracellular survival appears to be the basis for latency, disseminated disease, and resistance to eradication by antifungal agents. One mechanism by which C. neoformans survives the hostile intracellular environment of the macrophage involves upregulation of expression of genes involved in responses to oxidative stress.^[16]

Traversal of the blood–brain barrier by C. neoformans plays a key role in meningitis pathogenesis.^[18] However, precise mechanisms by which it passes the blood-brain barrier are still unknown; one recent study in rats suggested an important role of secreted serine proteases.^[19] The metalloprotease Mpr1 has been demonstrated to be critical in blood-brain barrier penetration.^[20]

The vast majority of environmental and clinical isolates of C. neoformans are mating type a. Filaments of mating type a have haploid nuclei ordinarily, but these can undergo a process of diploidization (perhaps by endoduplication or stimulated nuclear fusion) to form diploid cells termed blastospores. The diploid nuclei of blastospores are able to undergo meiosis, including recombination, to form haploid basidiospores that can then be dispersed.^[21] This process is referred to as monokaryotic fruiting. Required for this process is a gene designated dmc1, a conserved homologue of genes recA in bacteria, and rad51 in eukaryotes (see articles recA and rad51). Dmc1 mediates homologous chromosome pairing during meiosis and repair of double-strand breaks in DNA.^[22] One benefit of meiosis in C. neoformans could be to promote DNA repair in the DNA-damaging environment caused by the oxidative and nitrosative agents produced in macrophages.^[21] Thus, C. neoformans can undergo a meiotic process, monokaryotic fruiting, that may promote recombinational repair in the oxidative, DNA-damaging environment of the host macrophage, and this may contribute to its virulence.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Serge Korjian M.D.; Yazan Daaboul, M.D.

Cryptococcosis is more common among immunocompromised patients who are at high risk for other fungal, bacterial and viral infections. Cryptococcal meningitis can be indistinguishable from bacterial or viral meningitis. Cryptococcosis must be differentiated from diseases that cause symptoms of lower respiratory tract infection (fever, dyspnea, cough) and meningitis (fever, headache, neck stiffness, focal neurological deficits) such as coccidioidomycosis, histoplasmosis, tuberculosis, and community/hospital-acquired pneumonia. Cutaneous cryptococcosis in HIV/AIDS patients must be differentiated from molluscum contagiosum and Kaposi’s sarcoma.

Cryptococcosis is more common among immunocompromised patients who are at high risk for other fungal, bacterial, and viral infections. It should be differentiated from the following diseases which all may cause neurological dysfuntion in an immunocompromised patient:

Cutaneous Cryptococcosis must be differentiated from the following diseases:

• Molluscum contagiosum^[11]
  • Is very similar in appearance to disseminated cryptococcosis manifesting on the skin (umbilicated lesions).
  • Patients are usually less sick, as molluscum is restricted to the skin.
• Kaposi’s Sarcoma^[12][13]
  • Cutaneous cryptococcosis may also present with violaceous papules.
  • It can only be differentiated by biopsy.
• Blastomycosis^[14]
  • CNS involvement is much less common with blastomyces.
  • Cutaneous manifestations may resemble cutaneous cryptococcosis.
  • Not ubiquitous, more common in endemic areas in North America.

Cryptococcal meningitis may be differentiated from other causes of meningitis by cerebrospinal fluid examination as shown below:^{[15][16][17][18][19]}

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Serge Korjian M.D., Yazan Daaboul, M.D.

The prevalence of cryptococcal antigenemia among patients with HIV in the United States is approximately 2900 per 100,000 patients. The overall incidence is estimated to be 0.4 to 1.3 cases per 100,000 persons yearly in the United States. Cryptococcosis has no age, gender, or racial predilections.^[1]

• The prevalence of cryptococcal antigenemia in the general population is unknown. Given the low incidence in the general population, it is thought to be very low.
• Among HIV patients in the United States, the prevalence of cryptococcal antigenemia is approximately 2900 per 100,000 patients with HIV, indicating that the prevalence of cryptococcal infection may be high enough to consider targeted screening for HIV patients.^[1]

• Worldwide, the annual incidence of cryptococcosis in HIV/AIDS patients has been estimated to be 220,000 cases.^[2]

• Nationally, representative estimates for the incidence of cryptococcosis are difficult to establish because cryptococcosis is only reportable in a few states.
• Results from active, population-based surveillance in two U.S. locations in the year 2000 indicated that the annual incidence of cryptococcosis among persons with AIDS ranged from a low of 200 cases per 100,000 patients to a high of 700 cases per 100,000 patients.
• The overall annual incidence in the U.S. ranges from a low of 0.4 per 100,000 individuals to a high of 1.3 cases per 100,000 individuals in the United States.^[3]
• C. neoformans is a major cause of meningitis in people living with HIV/AIDS, with an estimated 1 million cases of cryptococcal meningitis occurring worldwide each year.^[1][4]

Cryptococcosis has no age, gender, or racial predilection.^[1]

The geographical distribution of endemic fungi causing meningitis are shown below:^[5]

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Serge Korjian M.D.; Yazan Daaboul, M.D.

Risk factors for the development of cryptococcal infection include being immunocompromised and inhalational exposure (most commonly from dry bird droppings).

Risk factors for the development of cryptococcal infection include:

• Being immunocompromised, such as having advanced HIV/AIDS (CD4 <100 cells/mm), organ transplantation, invasive cancer, or intake of corticosteroids or other immunosuppressive medications.^[1][2][3]
• Cryptococcus is ubiquitous in the environment, but inhalational exposure to dry bird droppings or guano (excrement of seabirds or cave-dwelling bats) increases the risk of contracting the disease if a patient is immunocompromised.
• Smoking and outdoor occupations are considered risk factors for inhalational exposure.^[4]
• Taking high-dose corticosteroids, monoclonal antibodies such as alemtuzumab or infliximab, or other immunosuppressive agents.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Serge Korjian M.D.; Yazan Daaboul, M.D.

Asymptomatic cryptococcal antigenemia is very common in areas with endemic HIV/AIDS, and is associated with increased mortality and incidence of cryptococcal meningitis. Screening is not recommended for HIV/AIDS patients in the United States or Europe. However, screening may be beneficial in countries with limited HAART availability, high levels of antiretroviral drug resistance, and a high burden of disease. In the absence of symptoms, positive cryptococcal antigenemia should be treated with fluconazole 400 mg orally, once daily.

• The majority of studies on cryptococcal screening have used cryptococcal antigen, also known as CrAg.^[1]
• A dipstick test that requires a small blood sample can detect silent antigenemia with high sensitivity in less than 10 minutes and for a small cost (less than $2).^[2][3]

• Cryptococcal meningitis commonly affects patients with a CD4 count of ≤ 100 cells/μl. Cryptococcal meningitis is a major cause of mortality and morbidity in individuals affected by HIV. It is recommended that patients with a CD4 count of ≤ 100 cells/μl should have routine cryptococcal antigen screening. Patients with a positive result should be offered preemptive anti-fungal therapy.^[4][5]
• Given that the efficacy of such an approach has not been thoroughly studied, the Infectious Disease Society of America does not recommend routine screening for asymptomatic antigenemia in HIV-infected patients in the United States and Europe.
• However, the Infectious Disease Society of America recommends that areas with limited HAART availability, high levels of antiretroviral drug resistance, and a high burden of disease should consider screening.
• In the case of asymptomatic antigenemia, a lumbar puncture and a blood culture are recommended.
• Positive results should warrant treatment as symptomatic meningoencephalitis and/or disseminated disease, if any signs/symptoms are present.
• However, without evidence of meningoencephalitis, patients should be treated with fluconazole 400 mg orally, once daily.^[6]
• Early studies demonstrated that asymptomatic cryptococcal antigenemia can be detected in up to 12% of patients with HIV/AIDS in endemic regions.
• Cryptococcus neoformans was also demonstrated by direct microscopy and culture in the cerebrospinal fluid of approximately 2/3 of patients.^[7]
• Further studies conducted in endemic regions in Africa (south Africa, Uganda) demonstrated that asymptomatic cryptococcal antigenemia ranged from 7 to 38%.^[8][9]
• Asymptomatic antigenemia was also demonstrated to be an independent predictor of mortality among these patients, and, during the first year of ART. An antigen titer greater than 1:8 was 100% sensitive and 96% specific for predicting the incidence of cryptococcal meningitis.^[9]
• These alarming findings raised a question about the possibility of developing screening programs among high risk HIV/AIDS patients and providing patients with fluconazole prophylaxis that decreases the risk of active infections.
• The limited body of evidence suggests that screening and treatment reduces the incidence of cryptococcal meningitis and death in patients with AIDS.^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

C. neoformans can cause no infection, latent infection, or symptomatic disease. C. neoformans enters the body through the respiratory route. Infection can present as pneumonia-like illness with symptoms such as cough, fever, chest pain, and weight loss. If left untreated, C. neoformans can disseminate to the central nervous system and cause meningoencephalitis. Prognosis is poor without treatment, with a mortality rate reaching 10 to 30% within 3 weeks of presentation.

Depending on the virulence of the yeast strain and the immune status of the host, C. neoformans can cause no infection, latent infection, or symptomatic disease. C. neoformans can present as pneumonia-like illness, with symptoms such as cough, fever, chest pain, and weight loss. If left untreated, C. neoformans can disseminate to the central nervous system and cause meningoencephalitis.^[1]

Cryptococcosis may lead to the following complications:^[2]

• Meningitis
• Disseminated cryptococcal infection
• Treatment of fungal meningitis in HIV-infected patients receiving HAART, organ transplantation, and pregnancy may result in immune reconstitution syndrome.^[3][4][5][6]

Prior to the introduction of amphotericin B therapy, cryptococcal meningitis was almost always fatal. Now, although most of these patients can be cured with a course of intravenous amphotericin B, the optimum duration of therapy is often unclear, and there is still a significant percentage of early deaths and late treatment failure.^[7][8][9]

• The mortality of cryptococcal meningitis is high (10-30%).^[10]
• Increasing levels of the following worsens the prognosis of HIV-negative cryptococcal meningitis patients with acute/subacute onset:
  • Ratio of CSF glucose/blood glucose
  • Impaired consciousness
  • Hospitalization duration