Human immune polymorphisms associated with the risk of cryptococcal disease.

Cryptococcus neoformans is an opportunistic fungal pathogen that can cause lethal cryptococcal meningitis in immunocompromised individuals such as those with HIV/AIDS. In addition, cryptococcal infections occasionally arise in immunocompetent individuals or those with previously undiagnosed immunodeficiencies. The course of cryptococcosis is highly variable in both patient groups, and there is rapidly growing evidence that genetic polymorphisms may have a significant impact on the trajectory of disease. Here, we review what is currently known about the nature of these polymorphisms and their impact on host response to C. neoformans infection. Thus far, polymorphisms in Fc gamma receptors, mannose-binding lectin, Dectin-2, Toll-like receptors and macrophage colony-stimulating factor have been associated with susceptibility to cryptococcal disease. Notably, however, in some cases the impact of these polymorphisms depends on the genetic background of the population; for example, the FCGR3A 158 F/V polymorphism was associated with an increased risk of cryptococcal disease in both HIV-positive and HIV-negative white populations, but not in Han Chinese patients. In most cases, the precise mechanism by which the identified polymorphisms influence disease progression remains unclear, although impaired fungal recognition and phagocytosis by innate immune cells appears to play a major role. Finally, we highlight outstanding questions in the field and emphasize the need for future research to include more diverse populations in their genetic association studies.

Transcriptional Changes in Pulmonary Phagocyte Subsets Dictate the Outcome Following Interaction With The Fungal Pathogen Cryptococcus neoformans.

With over 220,000 cases and 180,000 deaths annually, Cryptococcus neoformans is the most common cause of fungal meningitis and a leading cause of death in HIV/AIDS patients in Sub-Saharan Africa. Either C. neoformans can be killed by innate airway phagocytes, or it can survive intracellularly. Pulmonary murine macrophage and dendritic cell (DC) subsets have been identified in the naïve lung, and we hypothesize that each subset has different interactions with C. neoformans. For these studies, we purified murine pulmonary macrophage and DC subsets from naïve mice - alveolar macrophages, Ly6c- and Ly6c+ monocyte-like macrophages, interstitial macrophages, CD11b+ and CD103+ DCs. With each subset, we examined cryptococcal association (binding/internalization), fungicidal activity, intracellular fungal morphology, cytokine secretion and transcriptional profiling in an ex vivo model using these pulmonary phagocyte subsets. Results showed that all subsets associate with C. neoformans, but only female Ly6c- monocyte-like macrophages significantly inhibited growth, while male CD11b+ DCs significantly enhanced fungal growth. In addition, cytokine analysis revealed that some subsets from female mice produced increased amounts of cytokines compared to their counterparts in male mice following exposure to C. neoformans. In addition, although cells were analyzed ex vivo without the influence of the lung microenviroment, we did not find evidence of phagocyte polarization following incubation with C. neoformans. Imaging flow cytometry showed differing ratios of cryptococcal morphologies, c-shaped or budding, depending on phagocyte subset. RNA sequencing analysis revealed the up- and down-regulation of many genes, from immunological pathways (including differential regulation of MHC class I in the antigen processing pathway and the cell adhesion pathway) and pathways relating to relating to metabolic activity (genes in the Cytochrome P450 family, genes related to actin binding, calcium voltage channels, serine proteases, and phospholipases). Future studies gaining a more in-depth understanding on the functionality of individual genes and pathways specific to permissive and non-permissive pulmonary phagocytes will allow identification of key targets when developing therapeutic strategies to prevent cryptococcal meningitis.

Cryptococcus gattii Species Complex as an Opportunistic Pathogen: Underlying Medical Conditions Associated with the Infection.

The Cryptococcus gattii species complex has often been referred to as a primary pathogen due to its high infection frequency among apparently immunocompetent patients. In order to scrutinize the immune status of patients and the lineages of etiologic agents, we analyzed patient histories and the molecular types of etiologic agents from 135 global C. gattii cases. Eighty-six of 135 patients had been diagnosed as immunocompetent, although some of them had underlying medical issues, and 49 were diagnosed as immunocompromised with risk factors similar to those seen in Cryptococcus neoformans infection. We focused on the 86 apparently immunocompetent patients and were able to obtain plasma from 32 (37%) to analyze for the presence of autoantibodies against the granulocyte-macrophage colony-stimulating factor (GM-CSF) since these antibodies have been reported as a hidden risk factor for C. gattii infection. Among the 32 patients, 25 were free from any known other health issues, and 7 had various medical conditions at the time of diagnosis for cryptococcosis. Importantly, plasma from 19 (76%) of 25 patients with no recognized underlying medical condition showed the presence of GM-CSF autoantibodies, supporting this antibody as a major hidden risk factor for C. gattii infection. These data indicate that seemingly immunocompetent people with C. gattii infection warrant detailed evaluation for unrecognized immunologic risks. There was no relationship between molecular type and underlying conditions of patients. Frequency of each molecular type was related to its geographic origin exemplified by the overrepresentation of VGIV in HIV-positive (HIV+) patients due to its prevalence in Africa. IMPORTANCE The C. neoformans and C. gattii species complex causes cryptococcosis. The C. neoformans species complex is known as an opportunistic pathogen since it primarily infects immunocompromised patients. C. gattii species complex has been referred to as a primary pathogen due to its high infection frequency in apparently immunocompetent people. We analyzed 135 global cases of C. gattii infection with documented patient history. Eighty-six of 135 patients were originally diagnosed as immunocompetent and 49 as immunosuppressed with similar underlying conditions reported for C. neoformans infection. A significant number of C. gattii patients without known underlying conditions possessed autoantibodies against granulocytes-macrophage colony-stimulating factor (GM-CSF) in their plasma, supporting the presence of GM-CSF antibodies as a hidden risk factor for C. gattii infection. No relationship was found between C. gattii lineages and the underlying conditions except for overrepresentation of the molecular type VGIV among HIV+ patients due to the prevalence of VGIV in Africa.

X-linked immunodeficient (XID) mice exhibit high susceptibility to Cryptococcus gattii infection.

Cryptococcosis is an opportunistic disease caused by the fungus Cryptococcus neoformans and Cryptococcus gattii. It starts as a pulmonary infection that can spread to other organs, such as the brain, leading to the most serious occurrence of the disease, meningoencephalitis. The humoral response has already been described in limiting the progression of cryptococcosis where the B-1 cell seems to be responsible for producing natural IgM antibodies, crucial for combating fungal infections. The role of the B-1 cell in C. neoformans infection has been initially described, however the role of the humoral response of B-1 cells has not yet been evaluated during C. gattii infections. In the present study we tried to unravel this issue using XID mice, a murine model deficient in the Btk protein which compromises the development of B-1 lymphocytes. We use the XID mice compared to BALB/c mice that are sufficient for the B-1 population during C. gattii infection. Our model of chronic lung infection revealed that XID mice, unlike the sufficient group of B-1, had early mortality with significant weight loss, in addition to reduced levels of IgM and IgG specific to GXM isolated from the capsule of C. neoformans. In addition to this, we observed an increased fungal load in the blood and in the brain. We described an increase in the capsular size of C. gattii and the predominant presence of cytokines with a Th2 profile was also observed in these animals. Thus, the present study strongly points to a higher susceptibility of the XID mouse to C. gattii, which suggests that the presence of B-1 cells and anti-GXM antibodies is fundamental during the control of infection by C. gattii.

Donor-derived Cryptococcus gattii sensu stricto infection in two kidney transplant recipients, southeastern United States.

Cryptococcus gattii infection is a rare cause of severe pulmonary disease and meningoencephalitis that has only recently been detected in the southeastern United States. We describe an organ transplant-associated outbreak of C. gattii infection involving an HIV-negative immunosuppressed donor in this region who died following new-onset headache and seizure of unknown cause. Retrospective cryptococcal antigen (CrAg) testing of donor serum was positive. Two of the three transplant recipients developed severe C. gattii infection 11 and 12 weeks following transplantation. One recipient died from severe pulmonary infection, identified on autopsy, and the other ill recipient survived following treatment for cryptococcal meningitis. This outbreak underscores the importance of considering cryptococcosis in patients with clinical findings suggestive of subacute meningitis or other central nervous system (CNS) pathology, and the potential benefit of routine pre-transplant donor CrAg screening using lateral flow assay to guide recipient antifungal prophylaxis. The case also adds to emerging evidence that C. gattii is a potential threat in the southeastern United States.

High prevalence of Cryptococcal antigenemia using a finger-prick lateral flow assay in individuals with advanced HIV disease in Santarém Municipality, Brazilian Amazon Basin.

There is scarce information about HIV-related cryptococcosis in the Brazilian Amazon basin where laboratory infrastructure is limited. The serum cryptococcal antigen (CrAg) lateral flow assay (LFA) has simplified diagnosis of cryptococcosis and is recommended for screening in advanced HIV disease. We evaluated the prevalence of cryptococcal antigenemia using finger-prick CrAg LFA in the Brazilian Amazon basin. We enrolled a prospective cohort of outpatients and hospitalized individuals with advanced HIV disease at two centers in Santarém Municipality, Northern Brazil. All individuals were > 18 years old with advanced HIV disease, regardless of antiretroviral therapy (ART) status and with no prior or current history of confirmed cryptococcal meningitis. We tested CrAg LFA on finger-prick whole blood using an exact volume transfer pipette. From August 2018 to October 2019, 104 individuals were enrolled (outpatients 62 [60%] and hospitalized 42 [40%]). Median age was 38 years (interquartile range [IQR] 30-46), and 84 (81%) were male. Sixty-five (63%) individuals were ART-naïve. Prevalence of finger-prick CrAg LFA-positive was 10.6%; 95% CI, 5.4 to 18.1%. Prevalence of finger-prick CrAg LFA-positive among individuals without neurological symptoms was 6.0%; 95% CI, 1.7-14.6%. The number needed to test to detect one CrAg-positive individual was 9.4 persons (95% CI, 5.5-18.5). Prevalence of cryptococcal antigenemia using finger-prick whole blood CrAg LFA was high. Point-of-care approach was important for the diagnosis and screening of cryptococcosis in resource-limited settings. Screening and preemptive therapy strategy should be urgently implemented in individuals with advanced HIV disease in the Brazilian Amazon basin.

This prospective cohort study was carried-out in the Brazilian Amazon basin. We used a cryptococcal rapid test in patients with AIDS. We included 104 participants, and 11 (10.6%) of them had positive results showing a high prevalence of cryptococcal antigenemia.

An unusual case of reactivated latent pulmonary cryptococcal infection in a patient after short-term steroid and azathioprine therapy: a case report.

BACKGROUND: Cryptococcus is one of the major fungal pathogens infecting the lungs. Pulmonary cryptococcal infection is generally considered a community-acquired condition caused by inhalation of dust contaminated with fungal cells from the environment. Here, we report a case developing pulmonary cryptococcosis 3 months after hospital admission, which has rarely been reported before. CASE PRESENTATION: A 73-year-old female patient who was previously immunocompetent experienced persistent dry cough for 2 weeks, 3 months after admission. Chest computed tomography (CT) showed a new solitary pulmonary nodule developed in the upper lobe of the left lung. Staining and culture of expectorated sputum smears were negative for bacteria, acid-fast bacilli, or fungus. The patient then underwent biopsy of the lesion. Histopathology findings and a positive serum cryptococcal antigen titer (1:8) indicated pulmonary cryptococcosis. Daily intravenous 400 mg fluconazole was administered initially followed by oral fluconazole therapy. Follow-up chest CT after 3 months of antifungal therapy showed complete disappearance of the pulmonary nodule. Respiratory symptoms of the patient also resolved. A complete investigation excluded the possibility of a patient-to-patient transmission or primarily acquiring the infection from the hospital environment. Based on the patient's history of exposure to pigeons before admission and recent steroid and azathioprine use after admission for the treatment of myasthenic crisis, reactivation of a latent pulmonary cryptococcal infection acquired before admission, in this case, is impressed. CONCLUSIONS: Although rarely reported, pulmonary cryptococcal infection should be included in the differential diagnosis of hospitalized patients with respiratory symptoms, especially in those with predisposing risk factors. Chest image studies and further surgical biopsy are needed for confirmation.

A study for precision diagnosing and treatment strategies in difficult-to-treat AIDS cases and HIV-infected patients with highly fatal or highly disabling opportunistic infections: Study protocol for the optimal early intervention for cryptococcal antigenemia in HIV-infected patients.

BACKGROUND: Asymptomatic cryptococcal antigenemia is a state of cryptococcal infection commonly seen in immunocompromised HIV-infected persons. Without early intervention, a proportion of HIV-infected persons with cryptococcal antigenemia may go on to develop cryptococcosis, especially cryptococcal meningitis, which is associated with high mortality. The benefits of antifungal intervention and optimal therapeutic intervention regimens for HIV-infected persons with cryptococcal antigenemia remain controversial. We therefore designed the present study in order to investigate the necessity of, and the optimal regimens for antifungal intervention in the clinical management of cryptococcal antigenemia in HIV-infected populations. METHODS/DESIGN: This study will be an open-labeled, multi-center, prospective, randomized controlled trial, and 450 eligible participants will be randomized into a control arm and 2 intervention arms at a 1:1:1 ratio, with 150 subjects in each arm. Participants in the control arm will not receive antifungal treatment during the study period. Participants in intervention arm 1 will receive oral fluconazole 800 mg/day for 2 weeks, followed by 400 mg/day for 8 weeks and 200 mg/day for 42 weeks, and participants in intervention arm 2 will receive oral fluconazole 400 mg/day for 52 weeks. The primary outcome is the incidence of CM among the 3 groups during the study period. The secondary outcomes include the differences in all-cause mortality, proportion of patients reverting to blood CrAg negativity, change of CrAg titers, and adverse events among the 3 groups during the follow-up period. DISCUSSION: We envisage that the results of this study will reveal the necessity of, and the optimal therapeutic regimens for, antifungal intervention in clinical management of HIV-infected patients with cryptococcal antigenemia. TRIAL REGISTRATION: The study was registered as one of the 12 clinical trials under a general project at the Chinese Clinical Trial Registry on February 1, 2019, and the registration number of the general project is ChiCTR1900021195.

Correlation between clinical outcome and tissue inflammatory response in kidney transplant recipients with cryptococcosis.

Cryptococcosis is the second most common invasive fungal infection reported in renal transplant recipients. Tissue granulomatous inflammation is necessary to contain Cryptococcus infection. This study aims to analyze the granuloma patterns and in situ expression of regulatory T (Treg) immune response in tissue samples from 12 renal transplant recipients with cryptococcosis. Fungal isolates were molecularly identified as Cryptococcus neoformans species complex. A detailed characterization of granulomas in tissue samples from 12 kidney transplant recipients with cryptococcosis was described by checking six lung and six skin biopsies by conventional histology and for immunohistochemical detection of CD4 and Treg markers: forkhead box P3 (FoxP3), interleukin (IL)-10 and transforming-growth factor (TGF)-ß. Granulomas were classified as compact, loose or mixed. Patients with mixed (n = 4) and compact (n = 3) granulomatous inflammation patterns were associated with a better prognosis and presented a higher number of CD4+FoxP3+T cells compared to the group of patients with loose granulomas. In counterpart, three out of five patients with loose granulomas died with cryptococcosis. We suggest that Treg may have a protective role in the tissue response to Cryptococcus infection given its association with compact and mixed granulomas in patients with better clinical outcomes.

Umbilicated papules on the bilateral upper and lower extremities.

Cryptococcosis is a rare opportunistic infection with morphologically diverse cutaneous presentations. Primary infection typically occurs in the lungs with subsequent hematogenous dissemination to other organ systems, especially in immunocompromised patients. Herein, we report a woman in her 70's who presented with pruritic, umbilicated papulonodules of the bilateral upper and lower extremities present for many weeks. She was diagnosed with disseminated Cryptococcus and subsequently evaluated for potential pulmonary and meningeal disease involvement. She died as a result of multiple medical comorbidities.

Disseminated cryptococcal disease during treatment with idelalisib and corticosteroids for follicular lymphoma.

A patient on a regimen of idelalisib and corticosteroids for a relapse of follicular lymphoma presented to our emergency ward with a fever of unknown origin. Despite the initiation of broad-spectrum antibiotics and fluids, the patient's clinical condition deteriorated. Eventually, a diagnosis of disseminated cryptococcosis was established and immunophenotyping revealed complete absence of circulating B and CD4+-T lymphocytes, and a markedly diminished CD8+-T lymphocyte count. In this case, treatment with idelalisib and corticosteroids likely resulted in profound lymphopenia and the first reported instance of disseminated cryptococcosis under this regimen. After the withdrawal of idelalisib and steroids and initiation of antifungal therapy, lymphocyte counts partially recovered. After clinical improvement, the patient could be discharged from the hospital. This case highlights that the combination of idelalisib and corticosteroids can cause significant immunocompromise and opportunistic infections. Additionally, we illustrate the rate of lymphocyte reconstitution after withdrawal from idelalisib and corticosteroids.

Early Cardiopulmonary Cryptococcus neoformans Infection After Liver Transplant: A Case Report.

Cryptococcal infection (CI) is an uncommon fungal disease that poses a particular fatal risk to liver transplant (LT) recipients because of the potential rapid development and dissemination of the disease. Depending on the pathophysiology, CI may manifest with a wide range of clinical presentations that may delay early diagnosis and timely treatment. Additionally, most anticryptococcal therapies may threaten LT recipients owing to the associated hepatotoxicity of these medications. We report a case of a 25-year-old woman who received an LT for cryptogenic cirrhosis and developed rapidly progressive CI with pulmonary, myocardial, and cerebral involvement within a month of transplantation. She presented with severe pulmonary hypertension refractory to medical management and subsequently died despite our efforts. Herein, we review the etiology of cryptococcosis, the natural history of cryptococcal disease, and standard treatments for CI, and we highlight peculiarities of Cryptococcus neoformans infection in solid organ transplant recipients.

Landmark clinical observations and immunopathogenesis pathways linked to HIV and Cryptococcus fatal central nervous system co-infection.

Cryptococcal meningitis remains one of the leading causes of death among HIV-infected adults in the fourth decade of HIV era in sub-Saharan Africa, contributing to 10%-20% of global HIV-related deaths. Despite widespread use and early induction of ART among HIV-infected adults, incidence of cryptococcosis remains significant in those with advanced HIV disease. Cryptococcus species that causes fatal infection follows systemic spread from initial environmental acquired infection in lungs to antigenaemia and fungaemia in circulation prior to establishment of often fatal disease, cryptococcal meningitis in the CNS. Cryptococcus person-to-person transmission is uncommon, and deaths related to blood infection without CNS involvement are rare. Keen to the persistent high mortality associated with HIV-cryptococcal meningitis, seizures are common among a third of the patients, altered mental status is frequent, anaemia is prevalent with ensuing brain hypoxia and at autopsy, brain fibrosis and infarction are evident. In addition, fungal burden is 3-to-4-fold higher in those with seizures. And high immune activation together with exacerbated inflammation and elevated PD-1/PD-L immune checkpoint expression is immunomodulated phenotypes elevated in CSF relative to blood. Lastly, though multiple Cryptococcus species cause disease in this setting, observations are mostly generalised to cryptococcal infection/meningitis or regional dominant species (C neoformans or gattii complex) that may limit our understanding of interspecies differences in infection, progression, treatment or recovery outcome. Together, these factors and underlying mechanisms are hypotheses generating for research to find targets to prevent infection or adequate therapy to prevent persistent high mortality with current optimal therapy.

Anastrozole-induced pulmonary cryptococcosis in a patient with early breast cancer: A case report.

INTRODUCTION: Estrogen is a key factor in breast cancer carcinogenesis, and reductions in its synthesis can decrease breast cancer risk. Anastrozole can reduce plasma estrogen levels by inhibiting the enzyme aromatase, and is approved for adjuvant treatment of breast cancer. We report a case of pulmonary cryptococcosis in a patient who was treated with anastrozole for an early-stage tumor. This case is of special interest because the patient achieved a better curative effect after the administration of anastrozole was discontinued. PATIENT CONCERNS: A 61-year-old woman was found to have multiple pulmonary nodules on chest computed tomography (CT) after being treated for 5 months with anastrozole as an adjuvant breast cancer therapy. A biopsy of the largest lesion of the right lung showed cryptococcus fungal bodies with granulomatous inflammation, so the patient was diagnosed with pulmonary cryptococcosis. She was treated with fluconazole (400 mg/day) for 1 month, but a follow-up CT scan of chest showed no improvement. DIAGNOSIS: Pulmonary cryptococcosis. INTERVENTIONS: Because the pulmonary cryptococcosis was not improving, the administration of anastrozole was discontinued. Fluconazole was continued. OUTCOMES: The pulmonary lesions diminished in size 2 months after discontinuing anastrozole. The patient continued taking fluconazole for a total of 6 months without re-administration of anastrozole, and the lesions of pulmonary cryptococcosis almost disappeared. CONCLUSION: This case of pulmonary cryptococcosis may have been induced by a decrease in estrogen level caused by the aromatase inhibitor, anastrozole. Treatment of pulmonary cryptococcosis with concurrent anastrozole use may be ineffective, and it may be better to discontinue the aromatase inhibitor.

Cryptococcus albidus Fungemia in an Immunosuppressed Child: Case Report and Systematic Literature Review.

Cryptococcus albidus, synonymous with Naganishia albida, rarely causes opportunistic infection in immunocompromised individuals. Its clinical features, particularly in children, are not well defined. Here, we report a case of C albidus fungemia in an immunosuppressed child; we also present results of a systematic review, for which we searched PubMed, Embase, and Web of Science using the keywords "cryptococcus" and "albidus." Our goal was to describe the spectrum of disease, diagnostic approaches, therapies, and outcomes. We identified 20 cases of invasive infection, only 2 of which involved children, and 7 cases of noninvasive infection. The reports originated in the Americas, Europe, and Asia. Of those with invasive infection, 16 (80%) patients had an underlying chronic disorder or had received immunosuppressive therapy, 8 (40%) had fungemia, and 6 (30%) had a central nervous system infection. The attributable case fatality rate was 40%. C albidus is an opportunistic yeast that can rarely cause life-threatening fungemia and central nervous system infection in individuals of any age, especially those who are immunocompromised.

Serum Cryptococcal Antigen Testing in Immunosuppressed HIV-positive Children and Adolescents.

OBJECTIVES: Describe the epidemiology of immunocompromised HIV-infected pediatric (children and adolescents ≤ 19 years) and adults (> 19 years) with positive serum cryptococcal antigen lateral flow assay (CrAg-LFA) in KwaZulu-Natal. DESIGN: Retrospective review of laboratory-based database and clinical charts. METHODS: A review of the National Health Laboratory Services database of all serum CrAg-LFA performed in KwaZulu-Natal between June 2015 and December 2016 and comparison of the epidemiology of pediatric and adult patients was conducted. A reflex serum CrAg-LFA (IMMY CrAg-LFA) was performed on samples with CD4 counts < 100 cells/µL. Charts of all pediatric patients with a positive CrAg-LFA at Prince Mshiyeni Memorial Hospital were reviewed and 1-year outcome assessed. RESULTS: A total of 22,741 laboratory records were retrieved, and 1140 records were removed because of duplicate entries (1074) and insufficient data (64). There was a statistically significant difference in the incidence of positive CrAg-LFA in pediatrics and adults, respectively [40 (3.5%) versus 1194 (5.8%), P = 0.001]. The incidence of positive CrAg-LFA in Ethekwini district was 59 and 56 cases per 100,000 persons in adolescents 10-14 years and 15-19 years, respectively. Six of the 8 patients with available treatment history were on antiretroviral treatment (ART) with immune failure at the time of CrAg-LFA testing. CONCLUSIONS: Severe immune suppression in adolescents on ART is a risk factor for cryptococcal antigenemia. A concerted effort to timeously manage ART failure in adolescents with appropriate changing of ART regimens is urgently warranted.

Cryptococcosis in Patients following Kidney Transplantation: A 9-Year Retrospective Clinical Analysis at a Chinese Tertiary Hospital.

BACKGROUND: Cryptococcosis following kidney transplantation (KT) is rare but is associated with considerably increased risk of mortality. At present, data on the association between cryptococcosis and KT in mainland China remain relatively limited. OBJECTIVES: This study aims to review our experience related to the management of cryptococcosis following KT at a Chinese tertiary hospital. METHODS: All patients with cryptococcosis following KT admitted to our hospital from January 2010 to December 2018 were reviewed. RESULTS: A total of 37 patients with cryptococcosis were enrolled (males: 62.2%). The mean age of the patients was 49.5 ± 9.38 (20-64) years. The average time to infection following KT was 7.0 ± 5.50 years (5 months to 21 years), and 30 patients (81.1%) had cryptococcosis onset >2 years following transplantation. The most common site of infection was the central nervous system, followed by the pulmonary system and skin. Most patients received fluconazole or voriconazole with or without flucytosine as their initial treatment regimen at our hospital. The 2-week mortality rate was 8.1% (3/37), and five patients (13.5%) died within 6 months of being diagnosed with cryptococcosis. Remarkably, all patients who received high-dose fluconazole (800 mg daily) or voriconazole ± flucytosine survived. CONCLUSIONS: Cryptococcosis in kidney transplant recipients is typically a late-occurring infection, with most patients having cryptococcosis onset >2 years following KT at our hospital. The central nervous system, pulmonary system, and skin are the main sites of infection. Voriconazole or high-dose fluconazole can be used as an alternative therapy for post-KT cryptococcosis.

Pulmonary nodules: An unusual onset of HIV infection belatedly diagnosed.

BACKGROUND: Cryptococcosis is a generally systemic and potentially lethal fungal infection. Although HIV infection is a predisposing condition, especially if the CD4+ lymphocyte count is less than 100cells/mm3, other forms of immunosuppression may be associated with this opportunistic fungal condition, such as prolonged steroid therapy or solid organ transplantation. Pulmonary presentation must be included in the differential diagnosis of pneumonia or pulmonary neoplasia in the immunosuppressed patient. CASE REPORT: We report a case of pulmonary cryptococcosis in a non-diagnosed HIV patient. In a 44 year-old male suffering from dyspnea and chest pain the image of a pulmonary nodule was observed in a radiological finding. In the histopathological study, intracellular structures suggestive of fungal conidia, and morphologically compatible with Cryptococcus, were observed. HIV serology and cryptococcal antigen detection in serum were requested, given the possibility of cryptococcosis. Cryptococcus neoformans var. grubii was isolated from the culture of the pulmonary biopsy. The patient was finally diagnosed with pulmonary cryptococcosis and HIV-1 infection. With a proper antifungal treatment the patient evolved satisfactorily. CONCLUSIONS: The best strategy to avoid opportunistic infections such as cryptococcosis in HIV-infected patients consists of an early diagnosis and a highly active antiretroviral treatment. In our case, the diagnosis of a pulmonary infection by C. neoformans var. grubii allowed a late diagnosis of HIV-1 infection.

Incidence of and risk factors for cryptococcosis in kidney transplant recipients in Taiwan-A nationwide population-based study.

OBJECTIVES: The aim of this study was to determine the long-term incidence of cryptococcosis in kidney transplant recipients (KTRs) and to analyze its risk factors. METHODS: This retrospective population-based cohort study analyzed data obtained from Taiwan's National Health Insurance Research Database for KTRs during 2000-2012 and matched cohorts. Both populations were followed until death, development of cryptococcosis, or December 2013. RESULTS: A total of 4,933 KTRs and 49,930 matched patients were included. The cryptococcosis incidence rates for the KTR cohort and matched cohort were 10.59 and 0.4 per 10,000 person-years, respectively. The hazard ratio for cryptococcosis among KTRs was 26.65 (p<0.001); and 43.77 (p<0.001) for cryptococcosis affecting the central nervous system (CNS). The Kaplan-Meier method confirmed an elevated cumulative incidence of cryptococcosis among KTRs (1.00% vs. 0.04%). Predictors for cryptococcosis were advanced age (OR 1.39, 95% CI 1.02-1.89, P=0.038) and cancer (OR 2.63, 95% CI 1.22-5.67, P=0.013), but not the use of any particular class of immunosuppressants. CONCLUSIONS: KTRs are at dramatically higher risk of developing cryptococcosis, especially with CNS involvement, relative to a non-KTR matched cohort. Older KTRs and those with cancer are at even higher risk of developing cryptococcosis.