Cryptococcosis

Busse-Buschke disease, European blastomycosis, torulosis, Malade signal

Cryptococcus neoformans is the only one of the 19 cryptococci species to infect humans. It is an encapsulated yeast. It is usually a harmless commensal but is opportunistic if there is immunocompromise.

With the spread of AIDS, cryptococcosis is increasing and now represents a common cause of infection and death in these patients.

There are 2 varieties called C. neoformans var neoformans and C. neoformans var gattii. The former is more common in Europe and North America.

It occurs throughout the world. In sub-Saharan Africa, 15 to 30% of patients with AIDS develop cryptococcal disease. In Zimbabwe, 88% of patients with AIDS have cryptococcal infection as their AIDS-defining illness.

The principal vector of Cryptococcus neoformans var neoformans is the pigeon. Pigeon excreta contaminated with Cryptococcus neoformans var neoformans may remain infectious for as long as 2 years.

Cryptococcus neoformans var gattii is not associated with pigeon excreta. It occurs in tropical and subtropical areas and is associated with exposure to the river red gum tree and the forest red gum tree. During the flowering seasons of November to February, this organism is present in the air around these trees. Epidemiological evidence suggests that eucalyptus trees are not the only environmental source.

• T cell compromise is the underlying pathological factor.
• Immunoglobulin deficiency is not a risk factor.
• Associated conditions include:
  • AIDS
  • Hodgkin's disease
  • Other malignancies of the reticuloendothelial system
  • Transplant recipients
  • Sarcoidosis
• Patients with AIDS now represent about 80% of infections with Cryptococcus.
• In patients with leukaemia, systemic fungal infections account for 25% of deaths.¹

The presentation will depend upon the site involved.

Associated with HIV

Patients with HIV and Cryptococcus present with

• Fever (84%)
• Cough (63%)
• Dyspnoea (50%)
• Headache (41%)
• Weight loss (47%)

Physical findings can be remarkably limited as this encapsulated yeast produces little immune response, even with normal immunity.

Pulmonary Cryptococcosis

• Patients may be asymptomatic or present with acute respiratory distress syndrome in the immunocompromised patient. Less than 15% of pulmonary infection presents as pneumonia.
• A third of immunocompetent patients who develop lung infection have no symptoms or the symptoms are so mild that they do not seek medical attention.
• Symptoms in the immunocompetent include:
  • Dry cough (54%)
  • Cough with the production of scant mucoid sputum (32%)
  • Pleuritic chest pain (46%)
  • Haemoptysis is rare
• Immunocompetent patients usually have spontaneous regression of both clinical and x-ray signs.
• In HIV patients with pulmonary Cryptococcus, 5 to 25% present with cough and dyspnoea.
• Low-grade fever, dyspnoea, weight loss, and malaise may be present. More specific and unusual findings include rales or pleural rub. Pleural effusions may be present but are uncommon.

Meningitis and Meningoencephalitis

• They are the commonest manifestations and usually are subacute or chronic. Death occurs from 2 weeks to several years and is inevitable without treatment if immunity is impaired.
• The commonest symptoms are headache and altered mental status, including personality changes, confusion, lethargy, and coma. Nausea and vomiting are frequent but fever and neck stiffness are rare.
• HIV patients may have minimal or nonspecific symptoms at presentation. They are often afebrile or have mild pyrexia.
• Symptoms include blurred vision, photophobia, and diplopia.
• Findings include hearing defects, epilepsy, ataxia, aphasia, and choreoathetoid movements.
• Dementia may indicate hydrocephalus as a late complication.

Skin

• Dermatological features occur in 10 to 15% of the cases in the form of papules, pustules, nodules, ulcers, or draining sinuses.
• Skin infection occurs in 10 to 15% of patients. It may be the only site if immunity is normal but in the immunosuppressed, especially with AIDS, skin involvement must be considered evidence of disseminated disease.²
• Lesions include nodules, ulcers, papules, and vasculitis.

Rarer Forms

• In cryptococcal infection, 5 to 10% have bone involvement with osteomyelitis.
• Myocarditis
• Chorioretinitis: eye involvement presents with loss of vision from optic neuritis. Rapid diagnosis and treatment are essential to preserve sight.
• Hepatitis
• Peritonitis
• Renal abscess
• Prostatitis: eradication of cryptococci from the prostate is difficult and it can be a reservoir for systemic infections relapse.
• Myositis
• Adrenal involvement

• Tuberculosis
• Pneumocystis carinii

In the CNS

• Tumours, abscesses and other space occupying lesions

Skin Lesions

• They may be mistaken for acne, syphilis, lipoma, tuberculosis, molluscum contagiosum, or basal cell carcinoma

Bone Lesions

• They may be mistaken for cold abscesses from tuberculosis or neoplasm

Obtain urine and sputum cultures even if no clinical evidence of renal or pulmonary disease is present.

Skin Biopsy

• This should include fungal stains and cultures

Blood

• Even with widespread disease, FBC may be remarkably normal.
• Positive blood cultures indicate extensive infection, and the organism may be observed within peripheral leukocytes or bone marrow macrophages in these patients.
• Obtain a latex agglutination test to detect cryptococcal polysaccharide in serum or CSF. This is a very important part of diagnosis.
• In patients with meningitis, cryptococcal antigen is positive in CSF in more than 90%, and serum is positive in approximately 75%.
• Confirm positive test results by cultures before definitely diagnosing cryptococcosis.
• Anticryptococcal antibodies are not important, and low concentrations develop in a significant percentage of healthy people.
• In patients unexpectedly proven to have the disease, consider HIV testing after counselling.

CSF

• Lumbar puncture may show elevated pressure that is associated with a poor prognosis. Glucose is reduced, protein is raised and leukocyte counts are 20/mm³ or more, with more lymphocytes than neutrophils. CSF can be normal in patients with AIDS who are unable to mount an adequate inflammatory response or in early asymptomatic infection.
• Cryptococcus can be cultured from the CSF.
• Smear and culture of CSF.
• An India ink preparation³ is often used to identify the organism in CSF. It can demonstrate the organism in 25 to 50% of cases. Positive smears must be confirmed by culture.
• Cultured centrifuged CSF specimens on 3 or more occasions increase the yield.

Histopathology

• In tissue specimens, routine H&E stains are unsatisfactory to detect the pathogen.
• Methenamine silver or periodic acid-Schiff (PAS) stains are much better.

Imaging Studies

• A chest x-ray in asymptomatic and immunocompetent patients may show patchy pneumonitis, granulomas ranging from 2 to 7 cm, or miliary disease that looks like tuberculosis.
• CT scan or MRI scan of the brain in patients with focal neurological deficits or history compatible with slowly progressive meningitis is essential before lumbar puncture. If a mass is present, avoid lumbar puncture and consult a neurosurgeon.

It is more prevalent in the immunocompromised, especially with AIDS.

Drugs

Management depends upon the group in which the patient fits.

• Pulmonary cryptococcosis with normal immunity usually requires no treatment so long as CSF is normal.
• For cryptococcal infection with HIV infection, the aim is to control infection followed by life-long anti-fungal therapy.⁴
• Without HIV the aim is to achieve a permanent cure of the fungal infection.

Patients with AIDS

• AIDS and cryptococcal meningitis account for more than 80% of the patients with cryptococcosis. An aggressive course of treatment is recommended.
• Amphotericin B for 2 weeks, with or without 2 weeks of flucytosine, is followed by fluconazole for a minimum of 10 weeks. This is followed by lifetime maintenance with fluconazole. Other regimens are available.
• Fluconazole appears to be superior to intraconazole and life-long suppression with fluconazole is superior to weekly injections of amphotericin B.

Patients without AIDS

• Amphotericin B alone or in combination with flucytosine for 6 to 10 weeks or in conjunction with flucytosine for 2 weeks, followed by fluconazole for a minimum of 10 weeks.
• Examine CSF weekly until culture is negative and remains negative for 4 weeks. In most cases, 6 to 10 weeks of therapy is adequate.
• At the end of therapy, most patients have normal CSF glucose but protein abnormalities may persist for years.
• Positive cultures persist or recur during active antifungal therapy in some patients.

Disseminated Cryptococcosis outside Lungs or CNS

• For patients without AIDS, treat cryptococcal lesions of the skin, bone, or other organs with amphotericin B plus flucytosine or with amphotericin B alone.
• Fluconazole enters the prostate better than amphotericin B and can eradicate infection at this site.
• Control of prostatic foci is important because relapses may occur from this site.
• Flucytosine should not be used alone as resistance rapidly develops
• The "azoles" such as itraconazole and ketoconazole do not cross the blood-brain barrier adequately although fluconazole is better than the others.

Surgical

• Surgery is usually unnecessary.
• Occasionally high intracranial pressure requires a shunt.

In patients with AIDS and other causes of immunosuppression cure is often impossible and patients need life-long suppressive therapy.

In patients who are immunocompromised, the mortality from cryptococcal meningitis is 25 to 30%. Those patients who survive have a 40% chance of significant neurological deficits, including loss of vision, impaired mental function, hydrocephalus, and cranial nerve palsies.

Relapse occurs in 20 to 25% of patients.

With early diagnosis, infections from Cryptococcus, including CNS and disseminated infections, usually respond to therapy. With normal immunity therapy controls or eradicates infection in 70 to 75% of cases. In patients with cryptococcaemia and immune deficiency from various causes, mortality is high, especially with cirrhosis.⁵ Modern management of antiretroviral therapy has improved the outcome for patients who are HIV positive.⁶

In patients with AIDS, amphotericin B usually can control the disease but life-long suppression with fluconazole is required to prevent relapse. Fluconazole given once a week is useful in primary prevention of fungal infection in AIDS.⁷

A Cochrane review suggests that cotrimoxazole prophylaxis may be helpful in preventing morbidity and mortality in adults with both early and advanced HIV disease. Further work needs to be done on the applicability of implementing this finding, particularly in areas of high cotrimoxazole resistance.⁸

There are a number of obstacles to producing a vaccine against Cryptococcus,⁹ not least being that many of the target group are immunologically incompetent.