17 States in the early 1990s (65.5 infections per million per year) and has progressively declined since due to the widespread use of fluconazole and the successful treatment of the HIV infection with new antiretroviral drugs.25 Cryptococcosis may present as a pneumonic process or, more often, as a CNS infection secondary to hematogenous and lymphatic spread from a primary pulmonary focus. A more widely disseminated form of the infection may also occur with cutaneous, mucocutaneous, osseous, and visceral involvement. Pulmonary cryptococcosis is variable in presentation ranging from an asysmptomatic process to a more fulminant bilateral pneumonia. Nodular infiltrates, usually without cavitation, may be either unilateral or bilateral becoming more diffuse in severe infections. C. neoformans is highly neurotropic and the most common form of the disease is cerebromeningeal. The course of the disease is variable and may be quite chronic; however, it is inevitably fatal if untreated. Both meninges and the underlying brain tissue are involved and the presentation clinically is that of fever, headache, meningismus, visual disturbances, altered mental status, and seizures. The clinical picture is highly dependent upon the patient’s immune status and tends to be very severe in AIDS patients and other severely compromised patients treated with steroids or other immunosuppressive agents.23 Although both C. neoformans var. neoformans (and var. grubii) and var. gattii can cause meningoencephalitis, var. neoformans (and var. grubii) causes infection primarily in immunocompromised patients (e.g. AIDS), whereas var. gattii infections tend to occur in normal healthy hosts.19–22 Worse prognosis is usually associated with var. gattii.22,26 When compared with var. neoformans, infections caused by var. gattii are associated with cerebral or pulmonary cryptococcomas, papilledema, and high serum/CSF antigen titers.
Microbiology C. neoformans is a ubiquitous encapsulated soil yeast that reproduces asexually by budding. The perfect or sexual stage of C. neoformans can be produced by mating the fungus in vitro; however, the role of this stage in infectivity and pathogenesis is unknown. The yeast cell may vary from 4–20 µm in diameter and is surrounded by a polysaccharide capsule ranging from 1–30 µm. The narrow-based buds are usually single. The capsule may be visualized indirectly by the India ink or nigrosin technique and more specifically in clinical material with mucicarmine, which stains capsular mucopolysaccharide. In tissue, cryptococci stain poorly with hematoxylin and eosin but well with methenamine silver and periodic acid-Schiff. C. neoformans grows well on most bacterial and fungal media used in the routine clinical microbiology laboratory. A rapid presumptive identification of an encapsulated yeast as C. neoformans may be accomplished by demonstration of urease and phenoloxidase enzyme activity.17 C. neoformans is strongly urease positive and possesses a membrane-bound phenoloxidase enzyme that converts phenolic compounds to melanin. Phenoloxidase activity is readily demonstrated on media such as birdseed agar or caffeic acid agar, which contains 3,4-dihydroxycinnamic acid. Oxidation of the Odiphenol in medium produces dark colonies suggestive of C. neoformans. Confirmatory identification is accomplished by employing standard biochemical and physiological tests. Standard laboratory tests do not differentiate among the different serotypes. Media have been proposed for separating serotypes A and D from B and C but are not available commercially.
Diagnosis The clinical presentation of pulmonary cryptococcosis may mimic a number of acute and chronic infectious processes as well as malignancies. Signs and symptoms include fever, malaise, pleuritic pain, cough, scanty sputum, and hemoptysis. Chest roentgenograms may reveal lobar infiltrates, single or multiple nodules, or tumor-like masses. Sputum cultures are positive in only 20% of cases, and the diagnosis is frequently made at thoracotomy for suspected malignancy. Patients with pulmonary cryptococcosis should be thoroughly
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evaluated for systemic infection, with cultures of blood, urine, and cerebrospinal fluid (CSF). Central nervous system cryptococcosis may present as either meningitis (most common), encephalitis, or a more focal process suggestive of malignancy. Signs and symptoms in patients without AIDS include fever, headache, mental status changes, ocular symptoms, meningismus, nausea, vomiting, cranial nerve palsies, and seizures. Aside from fever and headache these signs and symptoms may be significantly less common in patients with AIDS. The chest roentgenogram may or may not be abnormal in patients with central nervous system or systemic cryptococcosis. Extraneural dissemination may present as cryptococcemia or focal involvement of one of several target organs. The laboratory diagnosis of cryptococcosis requires the isolation of cryptococci from normally sterile body fluids, histopathology showing encapsulated organisms, or detection of cryptococcal antigen in serum or CSF. A rapid diagnosis of extraneural infection may be facilitated by biopsy and staining with methenamine silver and mucicarmine. Examination of the CSF in patients with meningitis usually suggests a chronic lymphocytic meningitis with a low-grade (less than 500/mm3) lymphocytic pleocytosis, elevated protein, and low glucose. Microscopic examination of CSF mixed with India ink or nigrosin may reveal encapsulated organisms in approximately 50% of cases. Cultures of CSF and other clinical material are usually positive. Occasionally repeated lumbar punctures, cisternal taps, or sampling of large volumes (up to 10 mL) of CSF may be necessary to establish the diagnosis. In patients with AIDS, cryptococci are present in large numbers, but the CSF shows fewer abnormalities. Detection of cryptococcal antigen in serum and CSF is extremely valuable in the diagnosis of cryptococcal infection. Antigen titers are particularly high in patients with AIDS. Both latex agglutination (LA) and enzyme immunoassays (EIA) are commercially available and are rapid, sensitive, and specific.27 Antigen is detected in the serum in approximately 50% and in CSF in more than 90% of patients with cryptococcal meningitis. High titers of cryptococcal antigen in CSF or serum are associated with a poor prognosis. False-positive results are rare but may be due to rheumatoid factor or cross-reactivity in patients infected with Trichosporon beigelii. The newer EIA methods lack reaction with rheumatoid factor and are more specific than the LA methods.27
Therapy Pulmonary cryptococcosis may not require therapy as long as the process appears to be resolving and the patient is intact immunologically. Long-term follow-up is necessary in patients whose infection is diagnosed at thoracotomy, because there is a 3–10 risk of meningitis for up to three years after surgery. Patients with progressive pulmonary infection, particularly those who are immunocompromised, and all patients with extrapulmonary infection require systemic antifungal therapy. At present, such therapy consists of intravenous amphotericin B. Fluconazole may also be used although the efficacy of this agent in the treatment of pulmonary cryptococcosis has not been documented in clinical trials. Cryptococcal meningitis and extrapulmonary cryptococcosis always require systemic antifungal therapy.28 Cryptococcal meningitis is almost universally fatal without therapy, but approximately 80–90% of patients (non-AIDS) can be cured with current therapeutic regimens. Current therapeutic recommendations are amphotericin B plus 5-fluorocytosine acutely for two weeks (induction therapy), followed by 8-week consolidation with oral fluconazole.28 AIDS patients generally require life-long therapy with fluconazole. In patients without AIDS, treatment may be discontinued after the consolidation therapy; however, relapse may be seen in up to 26% of these patients within 3–6 months after discontinuation of therapy.23,28 Thus, a prolonged consolidation treatment with an azole for up to one year may be advisable even with patients without AIDS. Infections caused by C. neoformans var. gattii demonstrate slower response to antifungal therapy than those caused by var. neoformans. Neurological and visual sequelae are often present despite prolonged amphotericin B therapy and placement of intraventicular shunts.26