Cryptococcosis is an invasive fungal disease primarily caused by Cryptococcus neoformans, which mainly affects the central nervous system but can also disseminate to the lungs, skin, mucous membranes, bones, joints, and other internal organs. The disease can manifest as either acute or chronic and occurs across all age groups.
Etiology and Pathogenesis
Cryptococcus neoformans is widely distributed in the environment and can be found in soil, dried pigeon droppings, fruits, vegetables, and on the skin and in the feces of healthy individuals. It can survive in dried pigeon droppings for several years and serves as a primary source of infection for humans.
Cryptococcus neoformans belongs to the group of yeast-like fungi. In cerebrospinal fluid, sputum, or lesion tissues, the fungus appears as round or oval cells with a thick gelatinous capsule, measuring approximately 5–20 μm in diameter. The organism reproduces by budding, does not produce pseudohyphae, and the mature budding spores separate into individual cells.
The fungus consists of three variants and is classified into five serotypes: A, B, C, D, and AD. A small number of unclassified serotypes also exist. Potential routes of infection include:
- Inhalation of airborne spores, which is the primary route. The spores reach the lungs, causing pulmonary infection, and may subsequently disseminate throughout the body.
- Traumatic contact with the skin.
- Ingestion of contaminated food, leading to systemic infection via the gastrointestinal tract.
In about 80% of cases, the central nervous system is affected. This may occur as the fungus spreads from the nasal cavity to the meninges through the olfactory nerves and lymphatic vessels.
The fungus employs several mechanisms to evade the host's immune defense. Through its polysaccharide capsule, it produces sialic acid and mannitol and secretes enzymes such as phospholipase and superoxide dismutase, which inhibit phagocytosis by alveolar macrophages. This allows the fungus to enter the bloodstream and disseminate hematogenously to other tissues, particularly the central nervous system, resulting in meningitis and encephalitis.
Clinical Manifestations
Cryptococcal Meningitis
Cryptococcal meningitis is the most common form of fungal meningitis. The disease typically has a gradual onset, presenting with varying degrees of fever, episodic headache that progressively worsens, nausea, vomiting, and dizziness. After several weeks or months, symptoms of increased intracranial pressure and involvement of cranial nerves may emerge, often accompanied by fundoscopic findings of retinal exudates and changes suggestive of exudative retinopathy.
Psychiatric symptoms, such as depression, apathy, or irritability, may occasionally occur. In advanced stages, patients may present with hemiplegia, ataxia, seizures, or coma. The clinical presentation can resemble tuberculous meningitis but may exhibit intermittent spontaneous remission. If the disease forms localized cryptococcal granulomas in specific areas of the brain, the clinical picture may mimic brain abscesses or tumors.
Pulmonary Cryptococcosis
Pulmonary cryptococcosis often coexists with central nervous system involvement but may also occur independently. The disease presents insidiously, often with no obvious symptoms and is easily overlooked. If symptoms develop, they can resemble those of pulmonary tuberculosis, such as low-grade fever, fatigue, mild cough, night sweats, and weight loss. Cases are generally self-limiting.
In a few patients, the disease may manifest as an acute pneumonia-like condition. Lesions involving the pleura can cause pleuritic chest pain and pleural effusion. Pulmonary cryptococcal infection may result in subpleural fibrous nodules, cryptococcal nodules, or larger granulomas, which can present as peribronchial and pulmonary parenchymal infiltrates. These findings are often accompanied by mediastinal or hilar lymphadenopathy, mimicking pulmonary tuberculosis. Other findings may include pulmonary and subpleural nodules, diffuse miliary dissemination in both lungs, and in rare cases, cavitation. Calcification and caseous necrosis are uncommon, and the manifestations may vary within the same patient. The prognosis for pulmonary involvement is generally favorable.
Mucocutaneous Cryptococcosis
Mucocutaneous involvement is rare as an isolated condition but can occur as a localized manifestation of systemic cryptococcosis, potentially originating from meninges, lungs, or other lesions.
Cutaneous cryptococcosis primarily presents as acneiform rashes, papules, indurations, or granulomas. Central necrosis may occur, leading to the formation of ulcers and fistulas. Mucosal lesions typically affect the oral cavity and nasopharynx, manifesting as nodules, ulcers, or granuloma-like lesions covered by adherent exudative films.
Diagnosis
Pathogen Examination
India Ink Staining Method
This is a rapid, simple, and reliable diagnostic technique. Depending on the site of infection, fresh specimens such as cerebrospinal fluid, sputum, lesion tissue, or exudates are collected for analysis. A drop of India ink is added to the specimen on a glass slide, covered with a coverslip, and examined under a microscope using a dark field. Cryptococcus appears as round cells surrounded by a thick transparent capsule with refractile spores inside, but no hyphae are present. Repeated examinations yield a high positivity rate. For cerebrospinal fluid, centrifugation is performed, and the sediment is used for smears.
Fungal Culture
Specimens such as cerebrospinal fluid, sputum, or bone marrow are inoculated onto Sabouraud agar medium and incubated at room temperature or 37°C for 3–4 days, during which fungal colonies may appear.
Serological Testing
Detection of Cryptococcus neoformans antigens is commonly performed. The latex agglutination test offers high sensitivity, specificity, and utility in assessing prognosis and treatment efficacy. This rapid and specific diagnostic method is particularly important for the early diagnosis of cryptococcosis.
Treatment
Amphotericin B
Amphotericin B remains the first-line treatment for cryptococcosis. The method of intravenous infusion and associated side effects are similar to previous descriptions.
Intrathecal or Intraventricular Injection
This route is reserved for patients with severe cryptococcal meningitis or those who fail intravenous infusion. For children, the initial intrathecal dose is 0.01 mg, diluted with distilled water (not 0.9% sodium chloride solution) to a concentration not exceeding 0.25 mg/mL (preferably more diluted). Alternatively, the medication can be mixed with 3–5 mL of cerebrospinal fluid obtained during lumbar puncture and slowly injected. Subsequent doses are administered daily with gradual dose escalation, reaching 0.1 mg within approximately one week. Thereafter, the dose is increased by 0.1 mg every 1–3 days, up to a maximum of 0.5 mg per dose, and not exceeding 0.7 mg. The total treatment course generally consists of approximately 30 injections. Dose reduction or temporary discontinuation is indicated if adverse effects occur.
Excessive drug dosage in cerebrospinal fluid may result in arachnoiditis, leading to an increased cerebrospinal fluid cell count, transient radiculitis, sensory loss, urinary retention, paralysis, or seizures. Most of these complications resolve upon timely discontinuation of the drug.
Other Medications
5-Fluorocytosine (5-FC)
This drug has significant inhibitory effects against Cryptococcus and can be combined with amphotericin B for the treatment of systemic cryptococcosis. The dosage remains consistent with previous recommendations.
Fluconazole
This drug achieves therapeutic concentrations in cerebrospinal fluid and is used as described earlier.
Other Azole Antifungals
Agents such as voriconazole and itraconazole can also be employed in the treatment of Cryptococcus neoformans infections.