Version July 2025
INTRODUCTION —
Cryptococcus neoformans is a cause of central nervous system (CNS) disease in both immunocompromised and immunocompetent patients. It can also cause pneumonia and other infections outside the CNS.
This topic will review nonmeningeal infections due to C. neoformans. The microbiology and epidemiology of C. neoformans infection are presented separately. C. neoformans meningoencephalitis and Cryptococcus gattii infection are also discussed elsewhere. (See "Microbiology and epidemiology of Cryptococcus neoformans infection" and "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV" and "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in patients without HIV" and "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention" and "Cryptococcus neoformans: Treatment and prevention of meningoencephalitis and disseminated infection in patients without HIV" and "Cryptococcus gattii infection: Microbiology, epidemiology, and pathogenesis" and "Cryptococcus gattii infection: Clinical features and diagnosis" and "Cryptococcus gattii infection: Treatment".)
CLINICAL MANIFESTATIONS
Pulmonary disease — Clinical manifestations of pulmonary cryptococcosis range from asymptomatic pneumonia to acute respiratory failure [1-4].
Humans likely become infected with C. neoformans by inhaling the basidiospore form of the fungus or small, poorly encapsulated yeasts. Basidiospores are smaller than the yeast forms obtained from clinical samples and have much smaller polysaccharide capsules, facilitating deposition in the alveoli and terminal bronchioles after inhalation [5]. (See "Cryptococcus gattii infection: Microbiology, epidemiology, and pathogenesis".)
Following inhalation, C. neoformans likely causes a focal pneumonitis that may or may not be symptomatic. The immune status is the most important determinant of the subsequent course of the infection (eg, whether the pneumonitis resolves or progresses to symptomatic dissemination) [6,7]. The factors that determine whether an exposed person develops symptomatic infection are uncertain but may include the inoculum of fungi (eg, burden of exposure) and/or virulence factors of the infecting strain.
Postmortem studies on immunocompetent persons without antecedent respiratory complaints have demonstrated small areas of granulomatous inflammation in the lung parenchyma and/or hilar lymph nodes due to C. neoformans [8,9]. The foci are generally smaller than those seen in tuberculosis and do not appear to calcify as frequently as seen with histoplasmosis.
Infection can persist in a latent state; if the host immune system becomes compromised, yeasts may be liberated from the granulomatous complexes and cause active infection.
Immunocompromised adults — In immunocompromised patients, most cases of pulmonary cryptococcosis are due to reactivation of latent infection. However, primary infection in a naïve host or reinfection with a new strain is also possible.
Conditions that increase risk for pulmonary cryptococcosis include HIV infection, malignancies, stem cell and solid organ transplantation, cirrhosis, renal failure, chronic lung disease, diabetes, Cushing syndrome, sarcoidosis, and treatment with glucocorticoids or tumor necrosis factor-alpha antagonists [2,3,10-16]. Cryptococcal pneumonia in a lung transplant patient due to asymptomatic C. neoformans carriage in the donor lung has also been reported [17].
Symptoms typically include fever, chest pain, dyspnea, and cough [3,14,18-20]; headache and hemoptysis have also been reported. Immunocompromised patients with pulmonary cryptococcosis generally have more symptoms than immunocompetent hosts and are more likely to present with extrapulmonary disease (eg, meningeal disease). (See 'Patients with disease involving more than one organ system' below.)
In persons with HIV, the presentation of pulmonary cryptococcosis can be acute and severe. The severity of symptoms and extent of dissemination are inversely proportional to the CD4 lymphocyte count; most symptomatic cases occur in patients with CD4 counts less than 100/microL. Other opportunistic infections with manifestations similar to pulmonary cryptococcosis include those due to Pneumocystis jirovecii, Mycobacterium avium complex, Mycobacterium tuberculosis, cytomegalovirus, and Histoplasma capsulatum [14,20].
In immunocompromised patients without HIV, cryptococcal pneumonia and acute respiratory distress syndrome (ARDS) occur more frequently among organ transplant recipients than other hosts [1,21,22]. In this setting, ARDS is often associated with disseminated infection; mortality is high, and urgent treatment is required [1,4].
Dissemination from the lungs to the central nervous system (CNS) commonly occurs in immunocompromised patients. In a study of 34 immunocompromised patients with cryptococcal pneumonia, 28 developed extrapulmonary disease [3]. In persons with human immunodeficiency virus (HIV), dissemination to the CNS is seen in 65 to 94 percent of cases of pulmonary cryptococcosis [14,18-20]. (See 'Additional evaluation' below.)
Immunocompetent adults — Pulmonary cryptococcosis can occur in apparently immunocompetent patients [23,24]. Common symptoms include cough, sputum production, hemoptysis, dyspnea, chest pain, fever, malaise, night sweats, and weight loss [2,23,25,26]. Rare manifestations include obstruction of the superior vena cava, Pancoast syndrome due to granulomatous inflammation from the host response to C. neoformans, eosinophilic pneumonia, and extension from the lung to the chest wall [27-30].
However, asymptomatic infections can be detected. In a review of 90 immunocompetent hosts with pulmonary cryptococcosis, 32 percent of the patients were asymptomatic, and pulmonary infection was discovered as an incidental finding [23]. Asymptomatic patients with chest radiograph findings suspicious of malignancy who undergo biopsy are occasionally found to have cryptococcosis.
Pregnant persons — There have been cases of cryptococcal pneumonia described in pregnancy, although there are insufficient epidemiologic data to implicate pregnancy as a predisposing condition [31]. Immune reconstitution inflammatory syndrome (IRIS) can occur in the postpartum period [32-34]. Indeed, nearly half of the Cryptococcus cases reported in pregnancy presented with symptomatic disease in the third trimester or postpartum period [31]. (See "Overview of immune reconstitution inflammatory syndromes".)
Imaging findings — Radiographic features of pulmonary cryptococcosis in immunocompetent patients are variable. The most common findings are solitary or few well-defined, noncalcified nodules that are often pleural-based (image 1) [35-37]. Other radiographic findings include lobar infiltrates, hilar and mediastinal adenopathy, and pleural effusions [38-43]. In a case series of 12 immunocompetent hosts, 10 patients had nodules and masses (eight were peripheral); three had cavitation [44].
Radiographic findings are usually more severe than those seen in apparently immunocompetent patients. In patients with HIV, alveolar infiltrates, lymphadenopathy, mass lesions, and small pleural effusions have been described [14]. Interstitial infiltrates may mimic the radiographic presentation of P. jirovecii pneumonia [14,45]. (See "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV".)
Cryptococcomas can appear in the lung and/or brain with lesions that can be ≥3 cm in diameter.
Other nonmeningeal infections — Nonmeningeal nonpulmonary cryptococcosis can be seen at several sites. This generally reflects disseminated infection, even if clinical manifestations are confined to a single anatomic site.
Skin lesions — Cryptococcal skin lesions are seen in up to 15 percent of patients with disseminated infection; they manifest as papules (picture 1), plaques, purpura, ulcers, cellulitis, superficial plaques, abscesses, and sinus tracts [46,47]. Patients with advanced HIV infection may have umbilicated papules resembling molluscum contagiosum; in transplant patients, cellulitis may occur without evidence of dissemination. Although the majority of cryptococcal skin lesions result from disseminated infection, primary cryptococcal skin infections by direct inoculation may occur [48].
Skeletal disease — Cryptococcal lesions of the skeletal system occur in <10 percent of patients with disseminated disease [49]. The vertebrae are the most common site of osteoarticular infection. Radiography typically demonstrates a well-circumscribed osteolytic lesion resembling malignancy. Septic arthritis is rare.
Other sites — Cryptococcal infection can involve any body site or structure following dissemination, including the liver, lymph nodes, peritoneum, urogenital tract, adrenal glands, and eyes. Involvement of the eyes frequently reflects CNS infection, which should be sought in all cases [50]. The prostate may serve as a reservoir of infection [51]. (See "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in patients without HIV".)
Among 175 solid organ transplant recipients with cryptococcosis, nine patients (5 percent) presented very early following transplantation (defined as ≤30 days post-transplant; mean 5.7 days post-transplant) [52]. Patients who presented very early were more likely to have disease at unusual locations, including in the transplanted allograft or in the surgical fossa. These locations suggest that the infections were donor derived. Five of the nine patients (56 percent) with very early-onset disease were liver transplant recipients compared with 43 of 166 patients (26 percent) with disease occurring >30 days post transplant [52], suggesting that some of these patients may have had unrecognized infection prior to transplantation as a result of the impaired host defenses that accompany cirrhosis [53].
EVALUATION AND DIAGNOSIS —
Diagnostic tools for cryptococcosis include fungal culture, histology, and serum cryptococcal antigen. In some patients (eg, immunocompromised patients), additional evaluation is needed to assess for the presence of central nervous system (CNS) disease.
Culture and histology — The diagnosis of cryptococcus is best established by culturing the organism.
●Respiratory or tissue specimen – Patients with possible cryptococcal infection should have diagnostic testing so the organism can be identified via culture or histology. As an example, for those with possible pulmonary disease after chest x-ray and/ or computed tomography (CT) scan of chest, sputum, or bronchoalveolar lavage (BAL) should be obtained whenever possible. In most cases, biopsy is only necessary if malignancy is suspected.
Visualization of encapsulated yeast forms in sputum, bronchoalveolar lavage, or other tissue specimens is suggestive of cryptococcal infection. Culture of expectorated sputum samples is often positive in immunocompromised patients. C. neoformans in respiratory tract specimens from transplant patients should be considered to represent a true pathogen.
Associated pleural effusions are usually exudative [38,39]. Yeast forms may be seen in the pleural effusion, and cultures are usually positive.
If a tissue specimen is obtained, histology can help to establish the diagnosis by demonstrating encapsulated yeast forms (picture 2), but the culture may be negative.
●Blood cultures – Routine blood cultures should be obtained for patients who are immunocompromised. They should also be obtained for immunocompetent patients with symptoms (eg, fever) once the diagnosis of pulmonary or nonpulmonary disease has been established.
Testing for serum cryptococcal antigen — Serum cryptococcal antigen testing should be performed in all patients with cryptococcosis to help assess the severity of disease and possibly the approach to treatment. In addition, for immunocompromised patients, it can be used as a screening test if a different specimen is difficult to obtain (eg, respiratory or bone). There is no role for monitoring serum cryptococcal antigen titers to determine the duration of therapy in either immunosuppressed or immunocompetent hosts.
●Role in immunocompromised patients – Given the high rate of extrapulmonary disease in immunocompromised patients with cryptococcal pneumonia, a positive serum cryptococcal antigen should prompt investigation for disseminated infection with blood cultures, cerebrospinal fluid (CSF) cryptococcal antigen assay, and CSF culture [54]. (See 'Culture and histology' above and 'Additional evaluation' below.)
In solid organ transplant recipients with pulmonary cryptococcosis, a positive serum cryptococcal antigen test frequently reflects advanced lung involvement and/or extrapulmonary disease, such as fungemia or CNS infection [55]. In one series including solid organ transplant recipients, a positive serum cryptococcal antigen titer was documented in 38 percent of patients with pulmonary cryptococcosis [56]. In a prospective study of 60 solid organ transplant recipients with pulmonary cryptococcosis, positive serum cryptococcal antigen results were observed in 84 percent of those with any pulmonary involvement; the test was positive in 73 percent of those with disease limited to the lungs [55]. However, a negative cryptococcal antigen result does not exclude the diagnosis of cryptococcosis.
In immunocompromised patients, cryptococcal antigen testing is also an excellent screening test for cryptococcal disease. As an example, in patients with respiratory symptoms, it may be helpful for supporting the diagnosis if a pulmonary specimen cannot be obtained. The serum cryptococcal antigen is positive in virtually all patients with HIV infection and pulmonary cryptococcosis and in 56 to 70 percent of patients with other underlying immunocompromising conditions [2,12,13,18,57]. False-positive serum cryptococcal antigen tests can occur in the setting of infections due to the fungus Trichosporon asahii (formerly T. beigelii) or the bacterial genera Stomatococcus or Capnocytophaga [58-60]. False-negative serum cryptococcal antigen tests can occur with samples that contain a large amount of antigen (the prozone phenomenon) if the laboratory is using a latex agglutination assay and doesn't pretreat the sample with pronase [61].
●Immunocompetent patients – In immunocompetent patients with cryptococcal disease, the presence of antigen supports the need for additional evaluation to rule out CNS infection and may impact the approach to treatment. (See 'Additional evaluation' below and 'Treatment' below.)
However, unlike immunocompromised patients, antigen detection is not a sensitive test for diagnosis of pulmonary infection due C. neoformans in immunocompetent patients. It may be more useful for diagnosis of cryptococcal pneumonia due to C. gattii in regions where C. gattii is endemic (eg, Australia) or has caused outbreaks of disease (eg, the United States Pacific Northwest and British Columbia). (See "Cryptococcus gattii infection: Clinical features and diagnosis", section on 'Cryptococcal antigen'.)
Additional evaluation — Additional evaluation depends upon the immune status of the patient.
●Immunocompromised patients – Immunocompromised patients with cryptococcosis (pulmonary or nonpulmonary) should be evaluated for disseminated infection; this includes blood and CSF cultures as well as blood and CSF cryptococcal polysaccharide antigen testing [54].
CT or magnetic resonance imaging (MRI) scan of the brain and a lumbar puncture to rule out CNS disease should be performed even in the absence of neurologic signs or symptoms. Such patients appear to have a higher burden of infection with risk for extrapulmonary spread and seeding of the CNS. (See "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in patients without HIV".)
●Immunocompetent patients – Immunocompetent patients with a very high serum cryptococcal antigen titer (≥1:512) should be evaluated for CNS disease; such patients appear to have a higher burden of infection with risk for extrapulmonary spread and seeding of the CNS. Similar to immunocompromised patients, this includes CT or MRI scan of the brain and a lumbar puncture.
Evaluation for CNS disease should also be performed in those with neurologic symptoms or an underlying condition that predisposes to dissemination (eg, cirrhosis, receipt of high dose glucocorticoids), regardless of the serum cryptococcal antigen titer. In a study of HIV-seronegative patients with pulmonary cryptococcal disease, those with disseminated disease were more likely to have cirrhosis, headache, weight loss, fever, altered mental status, and/or to be receiving high-dose glucocorticoids [62].
However, a lumbar puncture is not needed for most other immunocompetent patients since dissemination to the CNS is rare [62].
TREATMENT —
The approach to treatment depends upon the severity of disease and the presence of dissemination.
Isolated pulmonary disease — For patients with isolated pulmonary disease, the goal of treatment is to control signs and symptoms of cryptococcal pneumonia and minimize risk of dissemination to the central nervous system (CNS) [63]. Literature for management of pulmonary cryptococcal infection consists of retrospective reports; the approach is also extrapolated from literature describing management of patients with HIV infection and CNS disease [1-3,18,56].
Treatment considerations for special populations, including those who are pregnant, are discussed below. (See 'Special populations' below and 'Patients with disease involving more than one organ system' below.)
Severe disease — Severe disease includes patients with diffuse pulmonary infiltrates, multiple pulmonary nodules, lesions ≥2 cm, or a cryptococcal antigen titer ≥1:512 (a known poor prognostic factor [54]).
●Antifungal therapy – For non-pregnant adults with severe pulmonary disease, we suggest an induction regimen that includes a lipid formulation of amphotericin B plus flucytosine, as described in the table (table 1).
In patients without large cryptococcomas (eg, <2 cm), the duration of induction therapy is two weeks. If large cryptococcomas are present, the duration should be extended to four to six weeks.
Induction therapy is followed by consolidation therapy with fluconazole 400 to 800 mg for eight weeks; the higher dose is preferred for those with cryptococcomas. Consolidation therapy is followed by maintenance therapy with fluconazole 200 mg/day. The total duration of antifungal therapy is typically 12 months. The approach to discontinuing maintenance therapy in persons with HIV are discussed below. (See 'Preventing recurrence in Immunocompromised patients' below.)
●Additional interventions – Pleural effusions rarely require drainage [38,39]. Surgical excision of infected pulmonary tissue may be indicated in cases where the masses impinge on adjacent structures [27,28] or the patient is not responding to medical therapy [63].
Mild disease — For patients with mild disease (eg, minimal symptoms and/or cryptococcoma <2 cm), we suggest fluconazole (400 mg [6 mg/kg] orally daily) for 6 to 12 months [63]. Factors that influence the duration within that range include the presence of underlying cirrhosis and/or receipt of high-dose glucocorticoids or other immunocompromising therapies. There is no role for monitoring serum cryptococcal antigen titers to guide duration of therapy.
If fluconazole is not available or is contraindicated, acceptable alternatives include itraconazole (loading doses of 200 mg orally three times daily for three days, then 200 mg orally twice daily); voriconazole (loading doses of 6 mg/kg intravenously [IV] twice daily or 400 mg orally twice daily on the first day, then 200 mg orally twice daily); posaconazole delayed-release tablets (loading doses of 300 mg orally twice daily on the first day, then 300 mg orally once daily) [64,65]; or isavuconazole (200 mg three times per day for two days, then 200 mg orally once daily) [66], although there are minimal data available regarding the latter agents.
The efficacy of this approach was illustrated in a study of 39 solid organ transplant recipients with extraneural cryptococcosis who received fluconazole or a regimen containing amphotericin B; the mortality was comparable (10 to 11 percent) [67]. Among 109 immunocompromised patients without HIV who had pulmonary cryptococcosis treated with fluconazole, the 12-month survival was 95 percent [2]. In a retrospective review of 14 solid organ transplant recipients with extraneural cryptococcosis who received fluconazole as primary therapy for a median of 60 days, no therapeutic failures were observed [54]
Asymptomatic disease — Immunocompromised patients with asymptomatic disease (eg, lesion found incidentally on imaging) should be treated with antifungal therapy to reduce the risk of developing severe disease. The approach to treatment is the same as for those with mild disease. (See 'Mild disease' above.)
We also suggest antifungal therapy for immunocompetent patients who are asymptomatic and have a detectable serum cryptococcal antigen. Although these patients probably have a very low likelihood of symptomatic systemic dissemination, treatment with fluconazole is appropriate since it is likely to be curative and the risk of adverse effects is low [63].
We do not treat immunocompetent patients who are asymptomatic, have cryptococcal infection diagnosed incidentally in the setting of pulmonary nodule resection to rule out malignancy, and have negative tissue cultures and negative cryptococcal antigen titers. For such patients, we monitor clinical symptoms and get a repeat chest x-ray in six months.
There are reports of asymptomatic immunocompetent patients who improved radiographically with observation alone in the absence of antifungal therapy [2,3,56,68]. As an example, in retrospective review that included 23 apparently immunocompetent patients who underwent surgical lung resection and were found to have histologically diagnosed pulmonary Cryptococcus lesions, 15 did not receive antifungal treatment and none had a known clinical recurrence within a minimal follow-up period of 15 months [68]. In this study, serum antigen titers and fungal culture were not available.
Special populations
Persons with HIV — Patients with HIV should continue chronic suppressive therapy with fluconazole (200 mg/day) after they have finished their initial treatment course. In those receiving antiretroviral therapy, it is reasonable to discontinue maintenance fluconazole after one year of treatment if they have CD4 count >100 cells/microL, a suppressed viral load, and a cryptococcal antigen titer ≤1:512 that is not increasing [69].
Some patients may be diagnosed with HIV when they present with cryptococcal disease. For those with isolated pulmonary disease, antiretroviral therapy should be initiated within two weeks of their diagnosis. However, for those with CNS involvement, antiretroviral therapy (ART) should be delayed by several weeks to reduce the risk of developing a severe immune reconstitution syndrome. This is discussed in detail separately. (See "When to initiate antiretroviral therapy in persons with HIV", section on 'Patients with opportunistic infections' and "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention", section on 'When to initiate antiretroviral therapy (ART)'.)
Pregnant patients — Pregnant persons with cryptococcal disease should be managed in conjunction with an infectious diseases specialist given concerns for teratogenicity with azoles, especially during the first trimester. As an example, an asymptomatic person without CNS disease who requires treatment can typically be followed closely, and therapy with fluconazole can begin following delivery [63].
Isolated nonmeningeal, nonpulmonary disease — There are minimal data to support a specific strategy for treatment of isolated, nonmeningeal, nonpulmonary cryptococcal disease.
We suggest fluconazole (400 mg [6 mg/kg] orally once daily) for immunocompetent patients who meet all of the following criteria [63,70,71]:
●Infection is present in a single non-CNS organ system
●Serum cryptococcal antigen must be <1:512
●There is absence of fungemia
●No risk factors for immunosuppression (eg, plans for immunosuppressive therapy)
The duration of treatment is 6 to 12 months.
All other patients should be managed with a regimen that includes induction therapy with lipid formulation of amphotericin B and flucytosine, followed by consolidation and maintenance therapy with fluconazole, similar to the treatment of CNS or severe pulmonary disease (table 1).
Patients with ocular infections must be managed in consultation with ophthalmologic expertise and tailored to individual circumstances depending on the extent of eye structure involvement and whether CNS involvement has been documented. Therapeutic possibilities include systemic therapy with high penetration into the eye such as fluconazole or flucytosine and/or adjunctive intravitreal amphotericin B deoxycholate.
Patients with disease involving more than one organ system — Patients with cryptococcal infection involving more than one organ system should be treated with an induction regimen that includes lipid formulation of amphotericin B and flucytosine, followed by consolidation and maintenance therapy with fluconazole, similar to the treatment of CNS or severe pulmonary disease (table 1). (See 'Evaluation and diagnosis' above.)
For patients with CNS disease, there are additional treatment considerations based on the results of follow-up cerebrospinal fluid (CSF) cultures and intracranial pressure. This is discussed in detail in separate topic reviews. (See "Cryptococcus neoformans: Treatment and prevention of meningoencephalitis and disseminated infection in patients without HIV" and "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention".)
PREVENTING RECURRENCE IN IMMUNOCOMPROMISED PATIENTS —
Some immunocompromised patients will have been successfully treated for cryptococcal infection but subsequently require reinitiating or intensifying their immunosuppressive therapy (eg, if they must subsequently undergo chemotherapy or intensive therapy for graft rejection). When this occurs within two years of the initial diagnosis, we suggest that antifungal therapy be reinitiated. Patients should be treated with fluconazole (200 to 400 mg/day) while receiving such therapy to prevent recurrent cryptococcal infection.
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cryptococcosis".)
SUMMARY AND RECOMMENDATIONS
●Clinical manifestations – Cryptococcus neoformans is a cause of central nervous system (CNS) disease. It can also cause pneumonia and other infections outside the CNS.
•Pulmonary infection – Clinical manifestations of pulmonary cryptococcosis range from asymptomatic pneumonia to acute respiratory failure. Common symptoms include cough, sputum production, hemoptysis, dyspnea, chest pain, fever, malaise, night sweats, and weight loss. Imaging typically reveals one or more noncalcified nodules that may be pleural-based. (See 'Pulmonary disease' above.)
Immunocompromised patients are typically more symptomatic than immunocompetent patients and are more likely to present with extrapulmonary disease (eg, meningeal disease). In addition, on imaging, alveolar infiltrates, lymphadenopathy, mass lesions, and small pleural effusions may be seen. (See 'Immunocompromised adults' above.)
•Other nonpulmonary manifestations – Nonmeningeal, nonpulmonary cryptococcosis typically presents as skin, soft tissue, or osteoarticular infection. (See 'Other nonmeningeal infections' above.)
●Evaluation and diagnosis
•Culture and histology – The diagnosis of cryptococcus is best established by culturing the organism (eg, from sputum or BAL for pulmonary disease). Visualization of encapsulated yeast forms in sputum, bronchoalveolar lavage, or other tissue specimens is also suggestive of cryptococcal infection (See 'Culture and histology' above.)
•Cryptococcal antigen testing – Serum cryptococcal antigen testing should be performed in all patients with cryptococcosis to help assess the severity of disease and possibly the approach to treatment. For immunocompromised patients, it can be used as a screening test if a specimen is difficult to obtain. (See 'Testing for serum cryptococcal antigen' above.)
•Additional testing – Additional evaluation depends upon the immune status of the patient. As an example, in immunocompromised patients, a lumbar puncture should be performed to rule out CNS disease, even in the absence of neurologic signs or symptoms. By contrast, for immunocompetent patients, lumbar puncture is typically reserved for those with neurologic symptoms or a very high serum cryptococcal antigen titer (≥1:512). (See 'Additional evaluation' above.)
●Treatment of isolated pulmonary disease – Treatment of isolated pulmonary disease depends upon the severity of disease and is extrapolated from literature describing management of CNS infection in patients with HIV. (See 'Treatment' above.)
•Whom to treat – All patients with symptomatic pulmonary disease require treatment. For patients who are asymptomatic (eg, lesion found incidentally on imaging), we treat those who are immunocompromised since they are at high risk for developing severe infection. (See 'Asymptomatic disease' above.)
We also suggest treatment for asymptomatic immunocompetent patients who have a detectable serum cryptococcal antigen (Grade 2C). Although these patients have a low likelihood of developing symptomatic disease or dissemination, treatment with fluconazole is likely to be curative and the risk of adverse effects is low. (See 'Asymptomatic disease' above.)
•Regimens for patients with severe pulmonary disease – For patients with severe pulmonary disease (eg, diffuse pulmonary infiltrates, multiple pulmonary nodules, lesions ≥2 cm, or a cryptococcal antigen titer ≥1:512 ), we suggest induction therapy with a lipid formulation of amphotericin B plus flucytosine followed by consolidation and maintenance therapy with fluconazole (Grade 2C). Specific regimens are described in the table (table 1). (See 'Severe disease' above.)
•Regimens for patients with mild or asymptomatic pulmonary disease – For those with mild disease and those with asymptomatic disease who require treatment, we suggest fluconazole (400 mg/daily) rather than an amphotericin B-containing regimen (Grade 2B). Available data suggest that amphotericin B and fluconazole have similar efficacy in this setting, but amphotericin B has more side effects. A different azole is a reasonable alternative if fluconazole cannot be used and the organism is susceptible. (See 'Mild disease' above.)
The typical duration of treatment is 6 to 12 months. (See 'Mild disease' above and 'Asymptomatic disease' above.)
●Treatment of isolated nonmeningeal, nonpulmonary disease – For immunocompetent patients with nonmeningeal, nonpulmonary infection, we suggest fluconazole rather than an amphotericin B-containing regimen if infection is present at a single non-CNS site, the serum cryptococcal antigen is < 1:512, there is no fungemia, and there are no risk factors for immunosuppression (Grade 2C). These patients are at low risk for dissemination to the CNS. Fluconazole (400 mg [6 mg/kg] orally once daily) should be administered for 6 to 12 months.
For all other patients, we treat with an induction regimen that includes lipid formulation of amphotericin and flucytosine, followed by consolidation and maintenance therapy with fluconazole (similar to the treatment of severe pulmonary or CNS disease) (table 1).
●Treatment if disease at more than one organ system – For patients with disease at ≥2 organ systems, we suggest induction therapy with lipid formulation of amphotericin B and flucytosine, followed by consolidation and maintenance therapy with fluconazole (table 1) (Grade 2C). (See 'Patients with disease involving more than one organ system' above.)
For patients with CNS disease, there are additional treatment considerations based on the results of follow-up cerebrospinal fluid (CSF) cultures and intracranial pressure. This is discussed in detail in separate topic reviews. (See "Cryptococcus neoformans: Treatment and prevention of meningoencephalitis and disseminated infection in patients without HIV" and "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention".)
●Preventing recurrences – Some immunocompromised patients will have been successfully treated for cryptococcal infection but subsequently require reinitiating or intensifying their immunosuppressive therapy.
If this occurs within two years of the initial diagnosis, we suggest that antifungal therapy be reinitiated (Grade 2C). Patients should be treated with fluconazole (200 to 400 mg/day) until immunosuppressive therapy has been completed. (See 'Preventing recurrence in Immunocompromised patients' above.)
