Cryptococcosis: causes, symptoms, diagnosis, treatment, and prognosis

Cryptococcosis is a pulmonary or disseminated infectious disease caused by human inhalation of dust contaminated by Cryptococcus neoformans or Cryptococcus gatti. Clinically, pneumonia or meningitis may occur, and skin, bones, or internal organs may be involved.


Causes

The pathogens are Cryptococcus, which are widely distributed in nature and can be isolated from soil, fruits, milk, and human body, and are about 6 - 20μm in size and are round. The pathogens growing in tissues and in culture medium are with a wide polysaccharide capsule, with reflective particles inside the fungi. The pathogens can grow rapidly at room temperature and 37 ℃, and can infect animals.

The routes of transmission have not been elucidated. When the pathogens invade the human body and the body resistance declines, the pathogens can spread directly and can be disseminated through blood circulation. Therefore, patients with leukemia, lymphoma, or long-term application of high-dose glucocorticoids or immunosuppressive agents are susceptible to this disease.

Cryptococcus gattii is mainly associated with trees, especially eucalyptus, and is more likely to cause infection in individuals with normal immune functions, while Cryptococcus neoformans is associated with birds.


Signs and Symptoms

Cryptococcal meningitis is the most common fungal meningitis. Chronic onset, varying degrees of fever, paroxysmal headache with gradual exacerbation, nausea, vomiting, and vertigo are present. Symptoms of increased intracranial pressure and cranial nerve involvement may appear in weeks or months, and fundus exudation and retinal exudation may be present. Sometimes, patients may present with mental symptoms, such as depression, apathy, and irritability. In the late stage, hemiplegia, ataxia, spasm, and coma may occur. The clinical manifestations are quite similar to those of tuberculous meningitis, but there are intermittent natural remissions. If cryptococcal granulomas are localized to a certain area of the brain, the clinical manifestations are similar to those of cerebral abscess or cerebral tumor.

Neuroimaging manifestations mainly include Virchow-Robin (VR) spaces expansion, gelatinous pseudocysts, meningeal enhancement, hydrocephalus, granuloma, brain atrophy, and vasculitis. The basal ganglia region and meninges are the most common sites of involvement. In patients with immune insufficiency, pseudocysts, granulomas, and meningeal enhancement are relatively rare due to immunosuppression and absent immunocompetence of polysaccharide capsules.

Figure 1 VR spaces expansion in the basal ganglia region and periventricular white matter area

Figure 2 gelatinous pseudocysts, low signal on T1WI (left) and high signal on T2WI (right)

Figure 3 soap bubble appearance, multiple, small, round or oval gelatinous pseudocysts in the paraventricular white matter area (A, B), basal ganglia (C), midbrain (D), and cerebellum (E) high signal on T2WI, absent space occupying effect, mild enhancement in the head of caudate nucleus (F).

Figure 4 cryptococcal meningitis with the formation of gelatinous pseudocysts in the bilateral basal ganglia, T1WI low signal (A), T2WI high signal (B), DWI absent restricted diffusion (C), ADC high signal (D), patchy enhancement of the basal ganglia area and meningeal enhancement in enhanced T1 (E),Cryptococcus seen in Indian ink stain (F)

Figure 5 cryptococcus infection of central nervous system in HIV patients, Cryptococcus in electron microscopy, thick capsules containing water (A), T2WI punctate hyperintensity in the basal ganglia (B), absent obvious enhancement in T1 enhancement (C), DWI restricted diffusion (D)

Figure 6 meningeal enhancement with hydrocephalus in T1 enhancement

Figure 7 cryptococcal granuloma

Pulmonary cryptococcosis is often concurrent with central nervous system infections, and can also occur alone. Chronic onset is present, and the illness is often neglected due to absence of obvious symptoms. Symptoms are low fever, fatigue, mild cough, night sweats, and weight loss. The disease is difficult to be differentiated from tuberculosis, but can heal spontaneously. Few patients present acute pneumonia. If the pleura is involved, there may be chest pain and pleural effusion. X-ray examination can indicate unilateral or bilateral massive lesions, extensive infiltration, peribronchial infiltration, or miliary lesions. The hilum of lung and mediastinal lymph nodes are not invaded. Good prognosis is generally present.

Figure 8 imaging manifestations in pulmonary cryptococcosis

Mucocutaneous cryptococcosis rarely occurs alone, is often a localized manifestation of systemic cryptococcosis, and may be disseminated from lesions in the meninges, lungs, or other areas. Skin lesions are mainly acneiform eruptions, papules, indurations, and granulomas. Central necrosis can be seen and can result in ulcers or fistulas. Mucosal lesions are nodules, ulcers, and granulomas in the oral cavity and nasopharynx, covered with sticky, exudative membrane.

Figure 9 cutaneous cryptococcosis

Osseous cryptococcosis occurs in 5% - 10% of patients, mostly in the skull and spines, rarely in joints. Osseous lesions are often chronic, multiple, scattered, destructive lesions, without periosteal hyperplasia, but there may be swelling and pain. There are no specific performances in X-ray examinations.

Visceral cryptococcosis is caused by dissemination. The heart, testicles, prostate, and eyes can often be involved, but the kidney, liver, spleen, and lymph nodes are not affected. Gastrointestinal and urogenital infections are similar to tuberculosis in clinical manifestations. Sometimes, the uvea, retina, and lens can be invaded. Occasionally, the heart can be invaded, and endocarditis occurs.


Diagnosis

On the basis of clinical presentations, laboratory examinations, isolation and culture, and Cryptococcus found in mucicarmine stain, India ink stain, or Fontana-Masson stain, the disease can be diagnosed.


Treatment

Cryptococcosis in non-HIV patients

For focal, asymptomatic, pulmonary cryptococcosis, if the cerebrospinal fluid examination is normal, the cerebrospinal fluid and urine culture are negative, and there is no evidence of skin, bone, or other extrapulmonary tissue involvement, no treatment is required. However, it is also recommended that fluconazole can be administered to prevent the disease from dissemination through bloodstream and shorten the duration. Symptomatic pulmonary cryptococcosis should be treated with fluconazole 200 – 400 mg/d orally for 6 - 12 months.

If there is no cryptococcal meningitis, the localized lesions of skin, bone, and other areas require systemic antifungal treatment, usually fluconazole 400 mg/d orally for 6 - 12 months. Severe patients can be treated with amphotericin B 0.5 - 1.0 mg/kg intravenously in combination with flucytosine 25 mg/kg orally once every 6 hours for several weeks.

For patients with cryptococcal meningitis, the standard treatment regimen is amphotericin B 0.7 mg/(kg.d) intravenously in combination with flucytosine 25 mg/kg orally once every 6 hours for 2 - 4 weeks, followed by a consolidation therapy of fluconazole 400 mg/d orally for 8 weeks, followed by maintenance therapy of fluconazole 200 mg/d orally for 6 - 12 months. Repeated lumbar puncture is important for control of intracranial hypertension.

Cryptococcosis in HIV-infected patients

All patients require treatment. For patients with cryptococcal meningitis or severe pulmonary cryptococcosis, the standard treatment regimen is amphotericin B 0.7 mg/(kg.d) intravenously in combination with flucytosine 25 mg/kg orally once every 6 hours for 2 weeks (if the clinical response is slow or the culture is still positive, the induction treatment should be extended), followed by fluconazole 400 mg/d orally for 10 weeks. Long-term maintenance treatment should be given after induction treatment. Repeated lumbar puncture is important for control of intracranial hypertension. If cerebrospinal fluid examinations are normal, cerebrospinal fluid and urine culture are negative, and there are no indications of skin, bone, or other extrapulmonary tissue involvement, mild to moderate pulmonary cryptococcosis can be treated with fluconazole 400 mg/d orally for 6 - 12 months.

Almost all patients need antifungal maintenance therapy until CD4 cell count is > 150/μL. Fluconazole 200 mg/d is recommended for maintenance treatment.


Prognosis

Pulmonary cryptococcosis patients without obvious immunodeficiency often heal spontaneously. Cryptococcal encephalopathy cannot be cured in about 30% of patients after antifungal treatment. Cryptococcal meningitis patients with AIDS is rarely cured and usually requires lifelong medication.