Cryptococcosis

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Cryptococcosis
Classification and external resources

Micrograph of cryptococcosis showing the characteristically thick capsule of cryptococcus. Field stain.
ICD-10B45
ICD-9117.5
DiseasesDB3213
MedlinePlus001328
eMedicinemed/482
MeSHD003453
 
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Cryptococcosis
Classification and external resources

Micrograph of cryptococcosis showing the characteristically thick capsule of cryptococcus. Field stain.
ICD-10B45
ICD-9117.5
DiseasesDB3213
MedlinePlus001328
eMedicinemed/482
MeSHD003453

Cryptococcosis, or 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.

Contents

Cause

Cryptococcosis is a defining opportunistic infection for AIDS. Other conditions which pose an increased risk include certain lymphomas (e.g. Hodgkin's lymphoma), sarcoidosis, liver cirrhosis and patients on long-term corticosteroid therapy.

Distribution is worldwide in soil.[1] 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 (those having a functioning immune system), but C. neoformans v. grubii, and v. neoformans usually only cause clinically evident infections in persons who have some form of defect in their immune systems (immunocompromised persons). People who have defects in their cell-mediated immunity, for example, people with AIDS, are especially susceptible to disseminated cryptococcosis. Cryptococcosis is often fatal, even if treated. The 10-week survival averages near 70% with optimal therapy.

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 presumptively immunocompetent hosts, 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.

Diagnosis

Dependent on the infectious syndrome, symptoms include fever, fatigue, chest pain, dry cough, swelling of abdomen, headache, blurred vision and confusion.[2]

Detection of cryptococcal antigen (capsular material) by culture of CSF, sputum and urine provides definitive diagnosis.[3] Blood cultures may be positive in heavy infections. India ink of the CSF is a traditional microscopic method of diagnosis, although the sensitivity is poor in early infection, and may miss up to >=20% of patients with culture-positive cryptococcal meningitis.

Cryptococcosis can rarely occur in the immunocompetent person without HIV, when it usually goes undiagnosed. Less than 250 cases in all are reported in the medical literature, the majority diagnosed postmortem.[4]

Treatment

Treatment options in non-AIDS patients who have reduced immune-system function is not well studied. Intravenous Amphotericin B combined with oral flucytosine may be effective. Every attempt should be made to reduce the amount of immunosuppressive medication until the infection is resolved.

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 (0.7-1.0 mg/kg/day) and flucytosine. Where flucytosine (5FC) is not available, fluconazole 800-1200mg/day should be used adjunctively with amphotericin.[5] Amphotericin-based induction therapy has much greater microbiologic activity than fluconazole monotherapy with 30% better survival at 10-weeks.[3][6] 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 1mg/kg/day coupled with high dose fluconazole 1200mg/day.[6] After initial treatment as above, oral fluconazole can be used.[5] The decision on when to start treatment for HIV is not yet settled, although one small, under-powered trial (when restricting to a "per protocol analysis") suggested that delaying the start of treatment for several weeks may be beneficial in avoiding deaths from Immune reconstitution inflammatory syndrome (IRIS).[7] A larger multisite trial, the Cryptococcal Optimal ART Timing (COAT) Trial, will be completed in spring 2013.

Prevention of Cryptococcosis

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 perpheral blood is often 4-12% in persons with CD4 counts lower than 100 cells/mcL.[8] Cryptococcal antigen screen and preemptive treatment with fluconazole is cost saving to the health care system by avoiding cryptococcal meningitis.[9] The World Health Organization recommends cryptococcal antigen screening in HIV-infected persons entering care with CD4<100 cells/μL.[5] This undetected subclinical cryptococcal (if not preemptively treated with anti-fungal therapy) will often go on to develop cryptococcal meningitis, despite receiving HIV therapy.[10] [8] Cryptococcosis accounts for 20-25% of the mortality after initiating HIV therapy in Africa.

IRIS in immunocompetent hosts

The immune reconstitution inflammatory syndrome (IRIS) has been described in immunocompetent hosts who have meningitis caused by C. gattii and C. grubii. Several weeks or even months into appropriate treatment, there is a sudden onset deterioration with worsening meningitis symptoms and progression or development of new neurological symptoms. IRIS is however much more common in immunocompromised hosts.

Magnetic resonance imaging shows increase in the size of brain lesions, and CSF abnormalities (white cell count, protein, glucose) increase. CSF culture is sterile, and there is no increase in CSF cryptococcal antigen titre.

The increasing inflammation can cause brain injury or be fatal.[11][12][13]

The mechanism behind IRIS in cryptococcal meningitis is primarily immunologic. With reversal of immunosuppression, there is paradoxical increased inflammation as the recovering immune system recognises the fungus. In severe IRIS cases, treatment with systemic corticosteroids has been utilized.

In other animals

Cryptococcosis is also seen in cats and occasionally dogs. It is the most common deep fungal disease in cats, usually leading to chronic infection of the nose and sinuses, and skin ulcers. Cats may develop a bump over the bridge of the nose from local tissue inflammation. It can be associated with FeLV infection in cats. Cryptococcosis is most common in dogs and cats but cattle, sheep, goats, horses, wild animals and birds can also be infected. Soil, fowl manure and pigeon droppings are among the sources of infection.[14][15]

References

  1. ^ "Meningitis: cryptococcal: Overview". Medical Reference: Encyclopedia. University of Maryland Medical Center. September 2010. http://www.umm.edu/ency/article/000642.htm.
  2. ^ Barron MA and Madinger NE (November 18, 2008). "Opportunistic Fungal Infections, Part 3: Cryptococcosis, Histoplasmosis, Coccidioidomycosis, and Emerging Mould Infections". Infections in Medicine. 
  3. ^ a b Rhein, J; Boulware DR, (2012). "Prognosis and management of cryptococcal meningitis in patients with HIV infection". Neurobehavioral HIV Medicine 4: 45. doi:10.2147/NBHIV.S24748. 
  4. ^ Cryptococcosis at eMedicine
  5. ^ a b c World Health Organization. "Rapid advice: Diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children". http://www.who.int/hiv/pub/cryptococcal_disease2011/en/. Retrieved 1 August 2012.
  6. ^ a b Rajasingham, Radha; Rolfes, M.A.; Birkenkamp, K.E.; Meya, D.B.; Boulware, D.R. (2012). "Cryptococcal Meningitis Treatment Strategies in Resource-Limited Settings: A Cost-Effectiveness Analysis". In Farrar, Jeremy. PLoS Medicine 9 (9): e1001316. doi:10.1371/journal.pmed.1001316. PMC 3463510. PMID 23055838. Retrieved 26 September 2012. 
  7. ^ Makadzange AT, Ndhlovu CE, Takarinda K, Reid M, Kurangwa M, Gona P, Hakim JG (2010). "Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-saharan Africa". Clin Infect Dis 50 (11): 1532–8. doi:10.1086/652652. |pmid= 20415574}
  8. ^ a b Meya DB, Manabe YC, Castelnuovo B, Cook BA, Elbireer AM, Kambugu A, Kamya MR, Bohjanen PR, Boulware DR. who start HIV therapy in resource-limited settings. (2010). "Cost-effectiveness of serum cryptococcal antigen screening to prevent deaths among HIV-infected persons with a CD4+ cell count < or = 100 cells/microL". Clin Infect Dis 51 (4): 448–455. doi:10.1086/655143. PMC 2946373. PMID 20597693. 
  9. ^ Rajasingham, R; Meya, DB; Boulware, DR (2012 Apr 15). "Integrating cryptococcal antigen screening and pre-emptive treatment into routine HIV care". Journal of Acquired Immune Deficiency Syndromes 59 (5): e85–91. doi:10.1097/QAI.0b013e31824c837e. PMC 3311156. PMID 22410867. 
  10. ^ Jarvis, JN; Harrison, TS; Govender, N; Lawn, SD; Longley, N; Bicanic, T; Maartens, G; Venter, F; Bekker, LG; Wood, R; Meintjes, G (2011). "Routine cryptococcal antigen screening for HIV-infected patients with low CD4+ T-lymphocyte counts--time to implement in South Africa?". South African Medical Journal 101 (4): 232–4. doi:10.7196/samj.4752. PMID 21786721. 
  11. ^ Lane M, McBride J, Archer J (August 2004). "Steroid responsive late deterioration in Cryptococcus neoformans variety gattii meningitis". Neurology 63 (4): 713–4. doi:10.1212/01.WNL.0000134677.29120.62. PMID 15326249. 
  12. ^ Einsiedel L, Gordon DL, Dyer JR (October 2004). "Paradoxical inflammatory reaction during treatment of Cryptococcus neoformans var. gattii meningitis in an HIV-seronegative woman". Clin. Infect. Dis. 39 (8): e78–82. doi:10.1086/424746. PMID 15486830. 
  13. ^ Ecevit IZ, Clancy CJ, Schmalfuss IM, Nguyen MH (May 2006). "The poor prognosis of central nervous system cryptococcosis among nonimmunosuppressed patients: a call for better disease recognition and evaluation of adjuncts to antifungal therapy". Clin. Infect. Dis. 42 (10): 1443–7. doi:10.1086/503570. PMID 16619158. 
  14. ^ Deep fungal infections
  15. ^ Malik (2003), "Feline Cryptococcosis"

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