Affects: Cats, Dogs
Cryptococcosis is a potentially fatal fungal infection of mainly the lungs, presenting as a pneumonia, and in the brain, where it appears as a meningitis. Coughing, difficulty breathing, chest pain and fever are seen when the lungs are infected. When the brain is infected, symptoms include headache, fever, neck pain, nausea and vomiting, light sensitivity and confusion or changes in behavior. It can also affect other parts of the body including skin, where it may appear as several fluid-filled nodules with dead tissue.
It is caused by the fungi Cryptococcus neoformans or less commonly Cryptococcus gattii, and is acquired by breathing in the spores from the air. These fungi are found globally in soil, decaying wood, pigeon droppings, and in the hollows of some species of trees. Whereas C. neoformans generally infects people with HIV/AIDS and those on immunosuppressant drugs and does not usually affect fit and healthy people, C. gattii (found in some parts of Canada and the US) does. Once breathed in, the dried yeast cells colonize the lungs, where they are either cleared by immune cells, lie dormant, or cause infection and spread.
Diagnosis is by isolating Cryptococcus from a sample of affected tissue or direct observation of the fungus by using staining of body fluids. It can be cultured from a cerebrospinal fluid, sputum, and skin biopsy. Characteristic neuroimaging findings include dilated Virchow-Robin spaces, the 'dirty CSF sign', hydrocephalus, cryptococcomas and hazy brain base sign. Many of these findings are non-specific, but the presence of basal meningeal enhancement is significant as it is associated with the future development of cerebral infarct. Treatment is with fluconazole or amphotericin B.
Signs And Symptoms: Cough, shortness of breath, chest pain, and fever are seen when the lungs are infected, resembling pneumonia. There may also be feeling of tiredness. When the brain is infected, symptoms include headache, fever, neck pain, nausea and vomiting, light sensitivity, confusion, or changes in behaviour. It can also affect other parts of the body, including skin, eyes, bones, and prostate. In the skin, it may appear as several fluid-filled nodules with dead tissue. Depending on the site of infection, other features may include loss of vision, blurred vision, inability to move an eye, and memory loss.
Symptom onset is often sudden when lungs are infected and gradual over several weeks when the central nervous system is affected.
Signs and symptoms of cryptococcal infection may be delayed in those with HIV or AIDS. A positive cryptococcal antigen test may precede symptoms by 3 weeks in those with HIV/AIDS. Others may have reactivation of latent cryptococcal disease years later. In those with HIV, approximately 50% of people have a fever, but fever is rare in previously healthy and immunocompetent people with cryptococcosis.
Cause: Cryptococcosis is a common opportunistic infection for AIDS and is particularly common among people living with AIDS in Africa. Other conditions that pose an increased risk include certain malignancies (such as lymphoma), liver cirrhosis, organ transplants, and long-term corticosteroid therapy.
Distribution is worldwide in soil. The prevalence of cryptococcosis has been increasing over the past 50 years for many reasons, including the increase in incidence of AIDS and the expanded use of immunosuppressive drugs.
In humans, C. neoformans chiefly infects the skin, lungs, and central nervous system (causing meningitis). Less commonly, it may affect other organs such as the eye or prostate.
Diagnosis: Symptom onset is often subacute, progressively worsens over several weeks, and delays in diagnosis are associated with increased mortality.
Cerebrospinal fluid (CSF) or blood antigen testing by lateral flow assay for cryptococcal antigens has a sensitivity and specificity greater than 99% for cryptococcosis. A CSF fungal culture can tell if there is a microbiological failure (failure of the fungal infections to treat the infection). CSF fungal culture has a 90% sensitivity and 100% specificity for the diagnosis of cryptococcal meningitis. CSF cell analysis is characterized by increased lymphocytes, reduced protein, and reduced glucose. For any person who has cryptococcosis at a site outside of the central nervous system (e.g., pulmonary cryptococcosis), a lumbar puncture is indicated to evaluate the cerebrospinal fluid (CSF) for evidence of cryptococcal meningitis, even if they do not have signs or symptoms of CNS disease. Detection of cryptococcal antigen (capsular material) by culture of CSF, sputum, and urine provides a definitive diagnosis. 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 15–20% of patients with culture-positive cryptococcal meningitis. Rapid diagnostic methods to detect cryptococcal antigen include latex agglutination testing, lateral flow immunochromatographic assay (LFA), or enzyme immunoassay (EIA). Polymerase chain reaction (PCR) has been used on tissue specimens, with PCR having a sensitivity of 82% and a specificity of 98% for cryptococcal infection.
Treatment: Treatment options for persons without HIV infection have not been well studied. Intravenous amphotericin B combined with flucytosine by mouth is recommended for initial treatment (induction therapy).
People living with AIDS often have a greater burden of disease and higher mortality (30–70% at 10 weeks). Recommended therapy is with amphotericin B and flucytosine. Adding flucytosine to amphotericin B is associated with earlier fungal clearance and increased survival; however, it is not readily available in many lower-income regions. Where flucytosine is not available, fluconazole should be used with amphotericin. Amphotericin-based induction therapy has much greater microbiologic activity than fluconazole monotherapy with 30% better survival at 10 weeks. Based on a systematic review, the most cost-effective induction treatment in resource-limited settings appears to be one week of amphotericin B coupled with high-dose fluconazole. 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.
The decision on when to start treatment for HIV appears to be very different than other opportunistic infections. A large multi-site trial supports deferring ART for 4–6 weeks was overall preferable with 15% better 1-year survival than earlier ART initiation at 1–2 weeks after diagnosis. A 2018 Cochrane review also supports the delayed starting of treatment until cryptococcosis starts improving with antifungal treatment.
Increased intracranial pressure is seen in about 50% of those with HIV-associated cryptococcal meningitis and is usually associated with a high fungal burden. Regular (often daily) lumbar punctures to lower the intracranial pressure by draining CSF is associated with reduced mortality in those with cryptococcal meningitis (with or without HIV). But in those with suspicion of non-communicating hydrocephalus (which may present as focal neurologic symptoms or impaired mentation), a CT or MRI of the brain is required before lumbar puncture to rule out hydrocephalus, due to the risk of brain herniation with lumbar puncture. Non-communicating hydrocephalus is rare in those with HIV-associated cryptococcal meningitis.
Prevention: 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 rate of detectable cryptococcal antigen in peripheral blood is often 4–12% in persons with CD4 counts lower than 100 cells/mcL.
Cryptococcal antigen screen and preemptive treatment with fluconazole are cost-saving to the healthcare system by avoiding cryptococcal meningitis. The World Health Organization recommends cryptococcal antigen screening in HIV-infected persons entering care with CD4<100 cells/μL. This undetected subclinical cryptococcal (if not preemptively treated with anti-fungal therapy) will often go on to develop cryptococcal meningitis, despite receiving HIV therapy. 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/μL.
Antifungal prophylaxis such as fluconazole and itraconazole reduces the risk of contracting cryptococcosis in those with low CD4 cell count and high risk of developing such disease in a setting of cryptococcal antigen screening tests are not available.