key: cord-0006685-9c6r65cx authors: Khawcharoenporn, T.; Apisarnthanarak, A.; Mundy, L. M. title: Non-neoformans Cryptococcal Infections: a Systematic Review date: 2007 journal: Infection DOI: 10.1007/s15010-007-6142-8 sha: 36cdc7abbd11ee6db477e0b6fcdbc7eac4e1fb18 doc_id: 6685 cord_uid: 9c6r65cx Non-neoformans cryptococci have been generally regarded as saprophytes and rarely reported as human pathogens. However, the incidence of infection due to these organisms has increased over the past 40 years, with Cryptococcus laurentii and Cryptococcus albidus, together, responsible for 80% of reported cases. Conditions associated with impaired cell-mediated immunity are important risks for non-neoformans cryptococcal infections and prior azole prophylaxis has been associated with antifungal resistance. The presence of invasive devices was a significant risk factor for Cryptococcus laurentii infection (adjusted OR = 8.7; 95% CI = 1.48–82.9; p = 0.003), while predictors for mortality included age ≥45 years (aOR = 8.4; 95% CI = 1.18–78.82; p = 0.004) and meningeal presentation (aOR = 7.0; 95% CI = 1.85–60.5; p= 0.04). Because clinical manifestations of non-neoformans cryptococcal infections are most often indistinguishable from Cryptococcus neoformans, a high index of suspicion remains important to facilitate early diagnosis and prompt treatment for such infections. Cryptococcal infections are serious and life-threatening, with presentations most often caused by Cryptococcus neoformans in immunocompromised hosts [1] . Other cryptococcal species have traditionally been considered non-pathogenic; however, there has been an incremental rise in non-neoformans cryptococcal infections over the past four decades [2] [3] [4] [5] . This increase may reflect enhanced awareness of such infections, improved laboratory detection of non-neoformans species in the Cryptococcus genus and a rise in the number of at-risk patients. We conducted a systematic review of the literature to characterize the epidemiology, risk factors, pathogenesis, clinical manifestations and treatment of non-neoformans cryptococcal infection in humans. A comprehensive search was performed for cases reported in the English literature using the Pubmed databases from inception through April 2006. Search terms included "fungus", "infection", "Cryptococcus", "non-neoformans", "adeliensis", "albidus", "curvatus", "humicolus", "laurentii", "luteolus", "macerans" and "uniguttulatus". References in each manuscript were reviewed to identify additional cases of non-neoformans cryptococcal infection. Thirty-eight articles were identified, reporting a total of 44 human cases of non-neoformans cryptococcal infection. Categorical variables were compared using Chi-square or Fisher's exact test, as appropriate. Continuous variables were compared using the Mann-Whitney U Test. Multivariate analysis was used to adjust for confounders of risk factors and mortality. All tests were two-tailed, with p value < 0.05 considered significant. Non-neoformans species have generally been identified from various environmental sources and are widely distributed geographically, inclusive of the Caribbean, Antarctic and the Himalaya regions (Table 1) . Some non-neoformans species, such as Cryptococcus laurentii and Cryptococcus uniguttulatus, had been reported to colonize humans [3, 6] . The prevalence of cryptococcal infection, in particular C. neoformans infection, increased during the acquired immune deficiency syndrome (AIDS) pandemic. After the first report of Cryptococcus luteolus in a child with measles [7] , more sporadic non-neoformans cases were reported. However, the overall prevalence of non-neoformans cryptococcal infection, in comparison to C. neoformans, remains relatively low. Cryptococcus laurentii Complex C. laurentii has been reported to have a high degree of intraspecies heterogeneity and has been divided into phylogenetic groups I and II [8] . The physiologic and biochemical characteristics of the various species in the complex are very similar. However, the species in phylogenetic group I, such as Cryptococcus flavescens and Cryptococcus aureus, can be distinguished from phylogenetic group II, by their combination of assimilation patterns of D-glucosamine, Nacetyl-D-glucosamine, DL-lactic acid, 1,2-propanediol and sodium nitrite and vitamin requirements [8] . There is general agreement that most cryptococcal infections are acquired by inhalation of infectious propagules. Notably, two cases of healthcare-associated infections have been reported with transmission either from direct inhalation of airborne yeast in close geographic proximity or through respiratory care procedures with contaminated instruments by medical personnel [9, 10] . In addition, one case of mother-to-child transmission of C. neoformans has been reported [11] . The virulence factors of Cryptococcus spp. have been ascribed to capsule formation against phagocytosis, the expression of the laccase enzyme, and production of melanin [12] [13] [14] . The presence of the polysaccharide capsule in non-neoformans cryptococci shares common features with that of C. neoformans [3] . The process of melanin deposition observed in non-neoformans cryptococci is responsible for the alteration in cell wall integrity, immune evasion and decreased susceptibility to antifungal therapy [14] . However, the level of laccase activity expressed in these non-neoformans cryptococci is lower than that seen in C. neoformans [3, 14] . Once the yeast enters the human host, macrophages are responsible for phagocytosis and the production of proinflammatory cytokines for recruitment of inflammatory cells [13, 15] . T-cell lymphocytes, especially Th-1 subtypes, then produce cytokines to activate fungicidal activity of macrophages and the transformation of alveolar macrophages into giant cells from which the ingestion of large encapsulated yeast cells occur as part of granuloma formation [13, 15] . The likelihood of neoformans cryptococcal infection rises dramatically in individuals with impaired cell-mediated immunity, inclusive of lymphoproliferative disorders, advanced HIV infection (CD4 counts < 100 cells/μl) and hematologic malignancies [13, 16, 17] . Other recognized risk factors include use of steroid or chemotherapeutic agents, organ transplantation [13] , impaired humoral immunity such as hyper-IgM syndrome [18] [19] [20] , non-HIV lymphopenia [21] , and direct or indirect exposures to pigeon excreta [22, 23] . The majority (48%) of non-neoformans cryptococcal cases had impaired cell-mediated immunity (i.e., neutropenia, hematologic malignancy, steroid or immunosuppressive drug use, or organ transplantation) while 16% had comorbid HIV infection with a mean CD4 count < 100 cells/µl. From our analysis, the presence of invasive devices (aOR = 8.7; 95% CI = 1.48-82.9; p = 0.003) was a significant risk factor associated with C. laurentii infection. Clinical presentations for patients with C. laurentii and C. albidus were similar (Table 2 ), yet patients with C. laurentii infection were younger (p = 0.01) and more likely to survive (p = 0.01). Non-neoformans cryptococci has been reported to cause infection in many organ systems ( Seventeen patients with non-neoformans cryptococcemia presented with either fever, hypothermia or septic shock [2, 4, 5, 9, [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] . Risk factors included the presence of an invasive device (9/17; 53%), neutropenia (7/ With the exception for one case that had acute respiratory distress syndrome (ARDS) [30] , most cases manifested as chronic, indolent illnesses [9, 25, [44] [45] [46] . The type and extent of pulmonary involvement included pneumonia, lung abscess and empyema [9, 26, [44] [45] [46] . The diagnoses were confirmed by positive culture results from different sources including bronchial swab or biopsy, sputum, or fluid from abscess and pleural space. Chest radiograph findings included localized opacities, disseminated nodular infiltration mimicking miliary patterns, cavity lesions, hilar node enlargement, pleural fluid and diffuse bilateral opacification with or without a pattern similar to that seen in ARDS. Notable, the investigators of one report suggested that C. albidus may be an etiologic agent of summer-type hypersensitivity pneumonitis [47] . Non-neoformans cryptococci can infect other organ systems such as skin, eyes, the gastrointestinal (GI) tract and lymph nodes [25] . Skin infections included cutaneous nodules, erythematous patches and plaque [23, 27, 30, 48, 49] . Ocular manifestations included deteriorating vision, painless scleral ulcer and corneal infiltrates [50] [51] [52] [53] . Two patients receiving chronic ambulatory peritoneal dialysis had peritonitis [25, 54, 55] . The choices and duration of treatment for non-neoformans cryptococci infections depend on the anatomical sites of involvement, the host-immune status and the severity of infection. Recommendations regarding the treatment for non-neoformans cryptococcal infections are limited to date due to the small number of empirically treated cases and lack of controlled trial data. Amphotericin B alone was used for treatment of fungemia, meningitis, lung abscess, cutaneous infection and peritonitis with 100% cure in nine cases. The mean induction period was 14 days followed by fluconazole treatment for meningitis [5] . In patients with fungemia, the mean duration of treatment was 25 days (ranged 14-33 days) [31] [32] [33] [34] [35] , while it was longer for lung abscess (42 days) [46] and peritonitis (60 days) [54] . In one patient with peritonitis, successful treatment was restricted to removal of the peritoneal catheter followed by peritoneal irrigation with saline solution [55] . In one patient with fungemia, a 14-day course of amphotericin B plus flucytosine was successful [4] . Fluconazole was successfully used in six patients with fungemia (mean duration 17 days) [4, 35] , meningitis (mean duration 36 days) [18, 42] and endophthalmitis (150 days) [52] . Amphotericin B alone was used in pneumonia, empyema, meningitis and fungemia cases with 86% treatment success (6/7 cases). The mean duration of treatment for meningitis was 60 days [22] , with 17 days (ranged 14-20 days) for fungemia [28, 29] and 90 days for empyema [47] . One patient developed leukopenia and anemia as side effects of conventional amphotericin B (1 mg/kg/day) and therapy was switched to itraconazole [52] . A non-pharmacological intervention involving removal of infected tissue was used successfully in a patient with keratitis after corneal transplantation. Fluconazole was used successfully in all patients with cutaneous infections with a 56-day mean treatment period [48] . Overall, spontaneous recovery of non-neoformans cryptococcal infection may occur in less severe cases with non-CNS infections. In these cases, non-pharmocologic treatments, such as catheter or infected-tissue removal, were successful alone or in combination with antifungal agents [51, 54, 55] . Amphotericin B, at the similar dose and duration recommended for C. neoformans infection, [56] seemed effective for non-neoformans cryptococcal infection. Fluconazole has been used as initial therapy in selected patients with non-CNS infection. However, longer duration of treatment, drug susceptibility, and the hostimmune status are factors to consider for optimal CNS treatment. Newer azoles, such as, voriconazole and posaconazole has been shown to be active against C. neoformans in in-vitro studies [57] [58] [59] [60] , although their clinical efficacy has not been well studied in clinical trials. Echinocandins, such as caspofungin, micafungin and anidulafungin have demonstrated potent antifungal activity toward a variety of fungi but not Cryptococcus spp. [61] [62] [63] . Characteristics of patients with non-neoformans cryptococcal infection, stratified by survival, are compared in table 3. However, the attributable mortality could not be determined due to limited clinical data for each report. Predictors for overall mortality included age ≥ 45 years (adjusted OR = 8.4; 95% CI = 1.18-78.82; p = 0.004) and CNS infection (aOR = 7.0; 95% CI = 1.85-60.5; p = 0.04). Table 3 Factors associated with overall mortality among patients with non-neoformans cryptococcal infection. Non-survival (n = 6) Survival (n = 37) P value Host comorbidities, drug intolerance, poor drug compliance and pharmacokinetic issues can each contribute to anticryptococcal drug resistance. For most C. neoformans clinical isolates, primary drug resistance to the standard antifungal agents, such as the polyenes and azoles, was uncommon while drug resistance to flucytosine has been increasingly observed [64] . The widespread use of azoles in immunocompromised hosts has contributed to the apparent azole resistance [64] . For non-neoformans cryptococci, antifungal susceptibility testing has been reported for 16/44 (36%) cases, 15 (94%) of whom had clinical isolates susceptible to amphotericin B. The exception was a case with C. laurentii who had two subsequences episodes of C. neoformans meningitis followed by C. laurentii meningoencephalitis. Prior exposure to amphotericin B for the treatment of C. neoformans meningitis may have contributed to the emergence of amphotericin B-resistant C. laurentii [42] . For non-neoformans cryptococci, primary resistance was most frequent for fluconazole and flucytosine [4, 32, 37-39, 46-39, 50] . Fluconazole resistance was more common in patients who previously received azole prophylaxis (83%) than azole-naive patients (50%). Itraconazole, ketoconazole and voriconazole susceptibility testing was reported for only a few cases [2, 32, 34, 37, 38] . In a small subset of cases with available data, amphotericin B was active against non-neoformans cryptococci. Hence, in patients with prior azole exposure, fluconazole susceptibility testing seems prudent. Three general strategies have been recommended for prevention of C. neoformans infection: (1) avoidance of close contact with pathogen-rich environments, (2) improvement of host defenses, i.e., by using granulocyte-macrophage colonystimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF) or use of combination antiretroviral therapy in HIV-infected patients and (3) antifungal prophylaxis. Data relevant to antifungal prophylaxis for non-neoformans cryptococci is sparce. There are no guideline recommendations for non-neoformans cryptococcal prophylaxis in HIV-infected patients. Until additional data become available, we suggest that the prophylaxis of non-neoformans cryptococcal infections in HIV-infected persons be similar to that for C. neoformans infections. For high-risk patients without HIV infection, precise recommendations for primary prophylaxis of nonneoformans cryptococcal infections are non-existent. In this systematic review, six patients who received primary prophylaxis for fungal infections developed non-neoformans cryptococcal infections (Table 4 ). The reasons for failure were possibly due to drug intolerance, reduced suscepti-bility or resistance to the prophylactic agents. Large comparative clinical trials would help characterize the "high risk" patients most likely to benefit from anti-cryptococcal prophylaxis. With the increase in immunocompromised patients worldwide and the widespread use of immunosuppressive agents, non-neoformans cryptococci have been increasingly recognized as human pathogens. Epidemiological studies suggest that non-neoformans cryptococci have a diverse geographic distribution and that persons with impaired cell-mediated immunity or invasive devices are predisposed to these infections. Infection can involve many organ systems with clinical manifestations similar to C. neoformans infection. Amphotericin B remains the mainstay of the treatment and azole agents are reasonable alternatives for patients with less severe, non-disseminated infection. Drug susceptibility testing should guide treatment. Patients with advanced age and meningitis may have higher risk for mortality and should be promptly diagnosed and treated. Avoidance of organism-rich environments, improvement of host defenses and antifungal prophylaxis may help prevent non-neoformans cryptococcal disease. 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