Cryptococcus neoformans infection outside the central nervous system

INTRODUCTION — Cryptococcus neoformans pneumonia and infection outside the central nervous system in immunocompetent and immunocompromised patients will be reviewed here.

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 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".)

PULMONARY INFECTION IN IMMUNOCOMPETENT ADULTS

Clinical manifestations — 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 [1]. Following inhalation, C. neoformans likely cause 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) [2,3].

A large segment of the population has been exposed to C. neoformans [4]. Subclinical primary infections are common and most are asymptomatic. 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 [5,6]. 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, organisms may be liberated from the granulomatous complexes and cause active infection.

There are also descriptions of pulmonary cryptococcosis in apparently immunocompetent patients [7,8]. In a review of approximately 90 immunocompetent hosts with pulmonary cryptococcosis, 32 percent of the patients were asymptomatic, and pulmonary infection was discovered as an incidental finding [7]. Asymptomatic patients with chest radiograph findings suspicious for malignancy who undergo biopsy are occasionally found to have cryptococcosis.

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. Common symptoms include cough, sputum production, hemoptysis, dyspnea, chest pain, fever, malaise, night sweats, and weight loss [7,9-11]. Less common symptoms include rash and gastrointestinal complaints. 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 [12-15].

Diagnosis — Diagnostic tools for pulmonary cryptococcosis include histology, fungal culture, serum cryptococcal antigen, and radiography.

Culture and histology — Visualization of encapsulated yeast forms in sputum, bronchoalveolar lavage or tissue specimens is suggestive of cryptococcal pulmonary infection. The diagnosis is established by culturing the organism from sputum or another specimen. Biopsy specimens of asymptomatic nodules may have yeast on histopathologic inspection but the culture may be negative.

Associated pleural effusions are usually exudative [16,17]. Yeast forms may be seen in the pleural effusion, and cultures are usually positive.

Routine blood cultures are appropriate for patients who have extensive infiltrates and/or systemic symptoms.

Cryptococcal antigen — Serum cryptococcal antigen should be performed. Although positive results are often found in immunocompromised hosts with C. neoformans pneumonia, antigen detection is not a sensitive test for diagnosis of pulmonary infection in immunocompetent patients. However, antigen testing may be more useful for diagnosis of cryptococcal pneumonia due to C. gattii among immunocompetent hosts 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'.)

There is no role for monitoring serum cryptococcal antigen titers to determine duration of therapy in either immunosuppressed or immunocompetent hosts.

Radiography — 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) [18-20]. Other radiographic findings include lobar infiltrates, hilar and mediastinal adenopathy, and pleural effusions [16,17,21-24]. In a case series of 12 immunocompetent hosts, 10 patients had nodules and masses (eight were peripheral); three had cavitation [25].

Lumbar puncture — Dissemination from the lungs to the central nervous system (CNS) in immunocompetent patients is rare, and routine lumbar puncture to evaluate for cryptococcal meningoencephalitis is generally not necessary [26]. Immunocompetent hosts with no CNS symptoms and low serum cryptococcal antigen titer (<1:512) need not undergo lumbar puncture. However, lumbar puncture is warranted for patients with neurologic symptoms or an underlying condition that predisposes to dissemination. Lumbar puncture is also appropriate for immunocompetent patients with a very high serum cryptococcal antigen titer (>1:512); such patients appear to have a higher burden of infection with risk for extrapulmonary spread and seeding of the central nervous system.

Treatment — The goal of treatment is to control signs and symptoms of cryptococcal pneumonia and minimize risk of dissemination to the central nervous system [27]. Literature for management of pulmonary cryptococcal infection consists of retrospective reports; the approach is extrapolated from literature describing management of patients with HIV infection and CNS disease [9,28-31].

Pleural effusions rarely require drainage [16,17]. Surgical excision of infected pulmonary tissue is only indicated in cases of masses that impinge on adjacent structures [12,13].

The management of C. gattii infection is discussed separately. (See "Cryptococcus gattii infection: Treatment".)

Antifungal therapy — Patients with severe pulmonary disease (eg, diffuse pulmonary infiltrates) or disseminated disease (eg, at least two noncontiguous sites) or a cryptococcal antigen titer ≥1:512 (a known poor prognostic factor [32]) should be managed as outlined separately. (See "Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in patients without HIV".)

Based on extrapolation from literature describing management of patients with HIV infection, treatment for immunocompetent patients with mild to moderate pulmonary cryptococcosis in the absence of diffuse pulmonary infiltrates or disseminated infection consists of fluconazole (400 mg [6 mg/kg] orally daily ) for 6 to 12 months (table 1) [27]. 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); or isavuconazole (200 mg three times per day for two days, then 200 mg orally once daily) [33], although there are minimal data available regarding the latter agents.

Asymptomatic patients who have cryptococcal infection diagnosed incidentally in the setting of pulmonary nodule resection to rule out malignancy and who have negative cultures and cryptococcal antigen titers may not require antifungal therapy. There are reports of immunocompetent, asymptomatic patients with positive culture, serology, and/or histopathology who improved radiographically with observation alone in the absence of antifungal therapy [9,29,31,34]. 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 [34]. In this study, serum antigen titers and fungal culture were not available.

Asymptomatic patients with detectable serum cryptococcal antigen probably have a very low likelihood of symptomatic systemic dissemination. However, treatment with fluconazole is appropriate since it is likely to be curative and the risk of adverse effects is low [27].

There is no role for monitoring serum cryptococcal antigen titers to guide duration of therapy.

Surgery — Occasionally, localized cryptococcal infections of the lung not responding to medical therapy may need surgical resection for cure [27].

PULMONARY INFECTION IN IMMUNOCOMPROMISED ADULTS — Most cases of pulmonary cryptococcosis in the immunocompromised host are likely due to reactivation of latent infection. However, primary infection in a naïve host or reinfection with a new strain is also possible. Immunocompromised hosts with pulmonary cryptococcosis generally have more symptoms than immunocompetent hosts and are more likely to present with extrapulmonary disease.

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's syndrome, sarcoidosis, and treatment with glucocorticoids or tumor necrosis factor-alpha antagonists [9,31,35-41]. Cryptococcal pneumonia in a lung transplant patient due to asymptomatic C. neoformans carriage in the donor lung has also been reported [42].

Clinical manifestations

HIV-negative patients — Clinical manifestations due to pulmonary cryptococcosis range from asymptomatic pneumonia to acute respiratory failure [9,28,31,43]. Among 34 immunocompromised patients with cryptococcal pneumonia, 28 developed extrapulmonary disease [31]. The most common symptoms were fever (63 percent), chest pain (44 percent), dyspnea (27 percent), cough (17 percent), and hemoptysis (7 percent).

Cryptococcal pneumonia and acute respiratory distress syndrome (ARDS) occur more frequently among organ transplant recipients than other hosts [28,44,45]. In this setting, ARDS is often associated with disseminated infection; mortality is high and urgent treatment is required [28,43]. Such patients should be managed as outlined separately for cryptococcal meningoencephalitis. (See "Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in patients without HIV".)

HIV-positive patients — The presentation of pulmonary cryptococcosis in patients with HIV is more acute and severe than in other hosts. 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.

Clinical manifestations include fever (81 to 94 percent), cough (63 to 71 percent), dyspnea (5 to 50 percent), and headache (41 percent) [39]. Some patients are hypoxic; some present with ARDS. Dissemination from the lungs to the central nervous system occurs in 65 to 94 percent of cases of HIV-associated pulmonary cryptococcosis [30,39,46,47].

Other opportunistic infections with manifestations similar to pulmonary cryptococcosis include those due to Pneumocystis jirovecii, Mycobacterium avium complex, Mycobacterium tuberculosis, cytomegalovirus, and Histoplasma capsulatum [39,47].

Diagnosis — Diagnostic tools for pulmonary cryptococcosis include histology, fungal culture, serum cryptococcal antigen, and radiography.

Evaluation of immunocompromised patients with pulmonary cryptococcosis should include evaluation for disseminated infection; this includes blood and cerebrospinal fluid (CSF) cultures as well as blood and CSF cryptococcal polysaccharide antigen testing [32].

Cryptococcal antigen — 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 [9,30,37,38,48]. Therefore, it is an excellent screening test in immunocompromised patients with respiratory symptoms. 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 [49-51]. 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 [52].

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 central nervous system infection [53]. In one series including solid organ transplant recipients, a positive serum cryptococcal antigen titer was documented in 38 percent of patients with pulmonary cryptococcosis [29]. 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 [53]. However, a negative cryptococcal antigen result does not exclude the diagnosis of cryptococcosis.

Given the high rate of extrapulmonary disease among immunocompromised patients with cryptococcal pneumonia, a positive serum cryptococcal antigen result should prompt investigation for disseminated infection with blood culture, CSF cryptococcal antigen assay, and CSF culture [32]. Positive results should prompt management as outlined separately. (See "Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in patients without HIV" and "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV".)

Culture and histology — 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. Bronchoscopy may be indicated in patients with advanced HIV infection to rule out other opportunistic infections [54].

Biopsy is necessary only if malignancy is suspected. Histology can help to establish the diagnosis by demonstrating encapsulated yeast forms (picture 1).

Routine blood cultures are appropriate for patients with severe immunosuppression, extensive infiltrates, and/or systemic symptoms.

Radiography — Radiographic findings are usually more severe than those seen in apparently immunocompetent patients. (See 'Radiography' above.)

In patients with HIV, alveolar infiltrates, lymphadenopathy, mass lesions, and small pleural effusions have been described [39]. Interstitial infiltrates may mimic the radiographic presentation of P. jirovecii pneumonia [39,55]. (See "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV".)

Lumbar puncture — Lumbar puncture to evaluate for cryptococcal meningoencephalitis is warranted for patients with neurologic symptoms or an underlying condition that predisposes to dissemination. 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 [26].

Although the definition of the immunocompromised state is imprecise, a lumbar puncture to rule out central nervous system disease should be performed in those with pulmonary cryptococcosis who are considered to be immunosuppressed 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 central nervous system. (See "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in patients without HIV".)

Treatment

Antifungal therapy — Patients with severe pulmonary disease (eg, diffuse pulmonary infiltrates) or disseminated disease (eg, at least two noncontiguous sites) or a serum cryptococcal antigen titer ≥1:512 (a known poor prognostic factor [32]) should be managed as outlined separately. (See "Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in patients without HIV".)

The optimal treatment of cryptococcal pneumonia is uncertain; management is extrapolated from literature describing management of patients with HIV infection and central nervous system disease [9,29,30]. In general, treatment for immunocompromised patients with mild to moderate pulmonary cryptococcosis in the absence of diffuse pulmonary infiltrates or disseminated infection consists of fluconazole (400 mg [6 mg/kg] orally daily) for 6 to 12 months (table 1) [27]. If fluconazole is not available or 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 twice daily or 400 mg orally twice daily on the first day, then 200 mg orally twice daily); posaconazole delayed-release tables (loading doses of 300 mg orally twice daily on the first day, then 300 mg orally once daily) [56,57]; or isavuconazole (200 mg three times per day for two days, then 200 mg once per day) [33], although there are minimal data for 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) [58]. Among 109 HIV-negative immunocompromised patients with pulmonary cryptococcosis treated with fluconazole, the 12-month survival was 95 percent [9]. 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 [58].

HIV-infected patients should continue chronic suppressive therapy with 200 mg per day of fluconazole. In patients with HIV who are receiving highly active antiretroviral therapy and have CD4 count >100 cells/microL, suppressed viral load, and a cryptococcal antigen titer ≤1:512 that is not increasing, it may be reasonable to discontinue maintenance fluconazole after one year of treatment [59].

Patients who have responded to therapy for pulmonary cryptococcosis and subsequently must undergo chemotherapy or intensive therapy for graft rejection within two years of the diagnosis should be treated with fluconazole while receiving such therapy to prevent recurrent cryptococcal infection.

There is no role for monitoring serum cryptococcal antigen titers to determine duration of therapy.

Surgery — Occasionally, localized cryptococcal infections of the lung not responding to medical therapy may need surgical resection for cure [27].

PULMONARY INFECTION IN PREGNANT WOMEN — There have been cases of cryptococcal pneumonia described in pregnancy, although there are insufficient epidemiologic data to implicate pregnancy as a predisposing condition [60].

Patients with severe pulmonary disease (eg, diffuse pulmonary infiltrates) or disseminated disease (eg, at least two noncontiguous sites or cryptococcal antigen titer ≥1:512) should be managed as outlined separately.

Pregnant women with stable pulmonary cryptococcosis should be followed closely, and therapy with fluconazole can begin following delivery [27]. Immune reconstitution inflammatory syndrome can occur in the postpartum period [61-63]. Indeed, nearly half of the Cryptococcus cases reported in pregnancy presented with symptomatic disease in the third trimester or postpartum period [60]. (See "Immune reconstitution inflammatory syndrome".)

PULMONARY INFECTION IN CHILDREN — Cryptococcus has been reported in children with primary immunodeficiencies such as hyperimmunoglobulin M syndrome and severe combined immunodeficiency syndrome, as well as children with HIV, connective tissue diseases, and solid organ transplant recipients. Cryptococcosis has also been described in children with no recognized immunodeficiency.

Patients with severe pulmonary disease (eg, diffuse pulmonary infiltrates) or disseminated disease (eg, at least two noncontiguous sites or serum cryptococcal antigen titer ≥1:512) should be managed as outlined separately.

Treatment of children with mild to moderate pulmonary cryptococcosis consists of fluconazole (6 to 12 mg/kg per day orally) for 6 to 12 months [27].

NONMENINGEAL, NONPULMONARY CRYPTOCOCCOSIS

Clinical manifestations — Nonmeningeal, nonpulmonary cryptococcosis generally reflects disseminated infection, even if clinical manifestations are confined to a single anatomic site (such as skin, soft tissue, or osteoarticular infection).

Cryptococcal skin lesions are seen in up to 15 percent of patients with disseminated infection; they manifest as papules (picture 2), plaques, purpura, ulcers, cellulitis, superficial plaques, abscesses, and sinus tracts [64,65]. 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 [66].

Cryptococcal lesions of the skeletal system occur in <10 percent of patients with disseminated disease [67]. The vertebrae are the most common site of osteoarticular infection. Radiography typically demonstrates a well-circumscribed osteolytic lesion resembling malignancy. Septic arthritis is rare.

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 central nervous system (CNS) infection, which should be sought in all cases [68]. The prostate may serve as a reservoir of infection [69]. (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) [70]. 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 [70], 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 [71].

Treatment — Patients with severe pulmonary disease (eg, diffuse pulmonary infiltrates) or disseminated disease (eg, at least two noncontiguous sites or cryptococcal antigen titer ≥1:512) should be managed as outlined separately. (See "Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in patients without HIV".)

There are no studies evaluating treatment of cryptococcal infection involving sites other than lungs and CNS. In general, infection at a single site in the absence of CNS disease, fungemia or risk factors for immunosuppression may be managed with fluconazole (400 mg [6 mg/kg] orally once daily) for 6 to 12 months [27,72,73].

Management of 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.

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

●A large segment of the population has been exposed to Cryptococcus neoformans. Subclinical primary infections are common, and most are asymptomatic. Infection can persist in a latent state; if the host immune system becomes compromised, organisms may be liberated from the granulomatous complexes and cause active infection. Symptomatic pulmonary cryptococcosis can also occur in apparently immunocompetent patients. (See 'Pulmonary infection in immunocompetent adults' above and 'Pulmonary infection in immunocompromised adults' above.)

●Clinical manifestations due to cryptococcal pneumonia range from asymptomatic pneumonia to acute respiratory failure. The presentation of pulmonary cryptococcosis in patients with HIV is more acute and severe than in other hosts. Most symptomatic cases occur in patients with CD4 counts less than 100 cells/microL. (See 'HIV-positive patients' above.)

●The diagnosis of cryptococcal pneumonia in immunocompetent hosts is established by culturing the organism from sputum or another specimen. Visualization of encapsulated yeast forms in sputum, bronchoalveolar lavage, or tissue specimens is suggestive of cryptococcal pulmonary infection. The most common radiographic findings are solitary or few well-defined, noncalcified nodules. Lumbar puncture is warranted for patients with neurologic symptoms and for patients with serum cryptococcal antigen titer >1:512. (See 'Diagnosis' above.)

●The serum cryptococcal antigen titer is often positive in immunocompromised patients with cryptococcal pneumonia. Culture of respiratory specimens is also a useful tool. A lumbar puncture to rule out central nervous system disease should be performed in those with pulmonary cryptococcosis who are considered to be immunosuppressed even in the absence of neurologic signs or symptoms.(See 'Diagnosis' above.)

●We suggest that patients with mild to moderate pulmonary cryptococcosis in the absence of diffuse pulmonary infiltrates or disseminated infection be treated with fluconazole (Grade 2B). Dosing is fluconazole 400 mg (6 mg/kg) orally once daily for 6 to 12 months (table 1). (See 'Antifungal therapy' above.)

●Patients with severe pulmonary disease (eg, diffuse pulmonary infiltrates) or disseminated disease (eg, at least two noncontiguous sites or cryptococcal antigen titer ≥1:512) should be managed as outlined separately. (See "Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in patients without HIV".)