Cryptococcosis in HIV-negative Patients with Renal Dialysis: A Retrospective Analysis of Pooled Cases

Cryptococcosis is a lethal fungal infection mainly caused by Cryptococcus neoformans/C. gattii species. Currently, our understanding of cryptococcosis episodes in HIV-negative patients during renal dialysis remains scarce and fragmented. Here, we performed an analysis of pooled cases to systemically summarize the epidemiology and clinical characteristics of cryptococcosis among HIV-negative patients with renal dialysis. Using pooled data from our hospital and studies identified in four medical databases, 18 cases were identified and analyzed. The median duration time of renal dialysis for peritoneal renal dialysis and hemodialysis cases was 8 months and 36 months, respectively. Several non-neoformans/gattii species were identified among the renal dialysis recipients with cryptococcosis, particularly Cryptococcus laurentii and Cryptococcus albidus, which share similar clinical manifestations as those caused by C. neoformans and C. gattii. Our analyses suggest that physicians should consider the possibility of the occurrence of cryptococcosis among renal dialysis recipients even when cryptococcal antigen test result is negative. The timely removal of the catheter is crucial for peritoneal dialysis patients with cryptococcosis. In addition, there is a need for optimized antifungal treatment strategy in renal dialysis recipients with cryptococcal infections.     

Choroiditis in a HIV-infected patient with disseminated cryptococcal infection: A case report and literature review

BackgroundOcular involvement in AIDS patients is a common event mainly caused by inflammation or infection. Despite the high prevalence rate of cryptococcosis in these individuals, ocular features have been occasionally described.Case reportA 20-year-old Brazilian female with HIV infection recently diagnosed was admitted with a respiratory profile presumptively diagnosed as Pneumocystis jirovecii pneumonia; an ophthalmologic exam suggested choroiditis by this agent as well. She was complaining of headaches and blurred vision which led to cryptococcal meningitis diagnosis by a CSF positive India ink stain and Cryptococcus neoformans positive culture. Despite therapy based on amphotericin B plus fluconazole, her clinical state progressively worsened and the patient died one week later. At necropsy, disseminated cryptococcal infection was evidenced in several organs including eyes, which presented bilateral chorioretinitis.ConclusionsCryptococcal ocular involvement in AIDS patients has been occasionally proved among the cases already reported. Thus, the post mortem exam is still pivotal to improve the quality of the clinical diagnosis, especially in limited-resource settings.     

Cavitary pneumonia in an AIDS patient with cryptococcosis

Pulmonary cryptococcosis is an unusual fungal infection that is most often found in AIDS or in organ transplant recipients. Although in immunocompromised patients, cryptococcal infection often causes pulmonary infections, the diagnosis of lung involvement is generally difficult. The presentation of pulmonary cryptoccosis in HIV-infected patients appears to be more acute and severe than in other immunocompromised patients, probably related with the severe immunosuppression. Diffuse infiltrates, mediastinal and hilar lymph nodes enlargement are the most common radiological findings in AIDS-associated pulmonary cryptococcosis. Cavitation is a rare form of and includes only 10% to 15% of all cases. Only a few case reports or studies with small number of patients of pulmonary cryptococcosis have been published over the past two decades. We report a case of an AIDS patient who developed cavitary pneumonia as the only clinical expression of cryptococcosis.     

Recovery of Cryptococcus neoformans from the nasopharynx of AIDS patients

Nasopharyngeal swabbings, obtained from AIDS patients, were plated onto Niger seed agar containing antibiotics. Cryptococcus neoformans was isolated from 35 out of 84 patients (41.7%) diagnosed as primary cryptococcal cases before antifungal administration, and 8 out of 86 (9.3%) cryptococcosis patients on antifungal therapy. The fungus could not be isolated from any of 447 samples from 194 AIDS patients not diagnosed with cryptococcosis. These findings are novel in that the presence of C. neoformans in AIDS patients at this site has never been looked at previously. This revised version was published online in June 2006 with corrections to the Cover Date.     

Clinical, epidemiological and outcome features of patients with cryptococcosis in Uberaba, Minas Gerais, Brazil

Nearly one million of cryptococcosis cases occur yearly around the world, involving mainly HIV-infected patients who are not receiving antiretroviral therapy (ART) or present poor adherence. This study aims to evaluate epidemiological, clinical and outcome aspects of patients with cryptococcosis from 1998-2010. Patients were prospectively recruited, and their medical and laboratory records were reviewed. A total of 131 cases were included, and of these, 119 (90.83%) had AIDS, 4 received a renal transplant, 2 presented systemic lupus erythematosus and 6 (4.6%) were apparently immunocompetent. Ninety-one (69.46%) were men, and the median age was 38.7?years. Cryptococcal meningitis (CM) was diagnosed in 103 (78.62%), whereas 28 (21.38%) had cryptococcal infection in other sites. Of patients with CM, 94 (91.26%) had AIDS being cryptococcosis the first defining illness in 61 (64.9%), while 37 (60.65%) of them presented simultaneously both diagnosis. Headache, altered mental status, papilledema and seizures at admission were significatively associated with a poor outcome. Of 163 different isolates, 155 (95.09%) were Cryptococcus neoformans and eight (4.88%) Cryptococcus gattii. Antifungal therapy was warranted in 8 (87.4%) patients with CM, but 46 (51.1%) died during the first days or weeks. Of 28 patients without CM, 21?(75%) received treatment, but 6 (28.6%) died. The poor outcome among this case series was similar to that reported from other developing countries, but it is paradoxal in Brazil where the ART is at free disposal in the public health services. Despite, at least 60-70% of patients present advanced immunosuppression when they receive the AIDS diagnosis.     

Cryptococcosis in China (1985–2010): Review of Cases from Chinese Database

Background

Cryptococcosis is a potential fatal disease, especially in immunocompromised patients. In China, the profile of cryptococcosis is unclear. Therefore, we summarize the epidemiology and therapy of cryptococcosis in china.

Methods

All cases reports about cryptococcosis in China were collected from CBMdisk database (China Biology and Medicine data disc) with key words of cryptococcosis, or cryptococcal infection, or cryptococcus, and case. The features of the cryptococcosis were retrospectively analyzed.

Results

There were 1,032 reports about cryptococcosis, including 8,769 cases. Among them, there were 16% patient with AIDS/HIV, and 17% ones without underlying diseases. There were 2,371 cases of CNS infection. Among them of 2,068 cases, the treatment protocols and outcome were clearly described. The percentages of patients who received intrathecal treatment of amphotericin B(AmB), AmB?+?5-FC(5-fluorocytosine), AmB?+?FCZ(fluconazole), and AmB?+?5-FU?+?FCZ in each medication group were 10, 43, 53, and 33%, respectively. The mortalities were significantly lower in the AmB, Amb?+?5-FC, AmB?+?FCZ intrathecal treatment groups compared with their non-intrathecal treatment controls (6% vs. 23%, 25% vs. 35%, 20% vs. 30%, respectively, P?P?>?0.05).

Conclusion

The Chinese cryptococcosis had its own special clinical features, such as more patients without identifiable underlying diseases. Intrathecal injection of amphotericin B was effective treatment method for cryptococcal CNS infection in China.     

Cryptococcal Meningitis in Senegal: Epidemiology, Laboratory Findings, Therapeutic and Outcome of Cases Diagnosed from 2004 to 2011

Background

Cryptococcal meningitis is one of the most important opportunistic infection and a major contributor to early mortality. In sub-Saharan Africa, particularly in Senegal, prevalence of cryptococcal meningitis remains high. This study aimed to describe the epidemiology, laboratory profile, therapeutic and outcome of cases diagnosed in Dakar.

Methods

We analyzed the cryptococcosis cases diagnosed at the department of parasitology–mycology in Fann Teaching Hospital in Dakar from 2004 to 2011. The diagnosis was confirmed by culture on Sabouraud’s dextrose agar and/or by India ink preparation and/or by cryptococcal antigen detection. The diagnosis methods were assessed by using culture as reference.

Results

A total of 106 cases of cryptococcal meningitis were diagnosed. The prevalence of cryptococcal meningitis was 7.8 %. The mean age of the patients was 40.17 ± 9.89 years. There were slightly more male (53.8 %) than female (46.2 %) patients; 89.6 % were found to be infected with HIV, and the median CD4+ count was 27/mm³. Approximately 79.5 % of the patients had <100 CD4+ lymphocytes/mm³. India ink staining presented sensitivity at 94.11 % and specificity at 100 %. Sensitivity and specificity of cryptococcal antigen detection in cerebrospinal fluid were, respectively, 96.96 and 15.78 %. The most frequently used antifungal drug was fluconazole (86.7 %), and the mortality rate was 62.2 % (66 deaths).

Conclusion

Early diagnosis is essential to control cryptococcosis, and countries should prioritize widespread and reliable access to rapid diagnostic cryptococcus antigen assays. But it is important to make available conventional methods (India ink and culture) in the maximum of laboratory in regional health facilities.     

Pulmonary nodules: An unusual onset of HIV infection belatedly diagnosed

BackgroundCryptococcosis 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 100 cells/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 reportWe 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.ConclusionsThe 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.     

Genotypes of Cryptococcus neoformans and Cryptococcus gattii as agents of endemic cryptococcosis in Teresina, Piauí (northeastern Brazil)

Throughout Brazil, Cryptococcus neoformans is the cause of cryptococcosis, whereas Cryptococcus gattii is endemic to the northern and northeastern states. In this study, the molecular types of 63 cryptococcal isolates recovered from the cerebrospinal fluid of meningitis patients diagnosed between 2008-2010 in Teresina, Piauí, Brazil, were analysed. Out of the 63 patients, 37 (58.7%) were human immunodeficiency virus (HIV)-positive and 26 (41.3%) were HIV-negative. URA5-restriction fragment length polymorphism analysis identified 37/63 (58.7%) isolates as the C. neoformans VNI genotype, predominantly in HIV-positive patients (32/37, 86.5%), and 24/63 (38.1%) as the C. gattii VGII genotype, mostly in HIV-negative patients (21/26, 80.8%). The occurrence of C. gattii VGII in six apparently healthy children and in seven adolescents/young adults in this region reaffirms the endemic occurrence of C. gattii VGII-induced primary cryptococcosis and early cryptococcal infection. Lethality occurred in 18/37 (48.6%) of the HIV-positive subjects and in 13/26 (50%) of the HIV-negative patients. Our results provide new information on the molecular epidemiology of C. neoformans and C. gattii in Brazilian endemic areas.     

Development of an enzyme immunoassay for cryptococcal antibody

An enzyme immunoassay (ELISA) for measurement of cryptococcal Ig G antibody in human serum is described. Clinical studies indicate that the assay is a useful addition to the currently available techniques for measuring antibodies in cryptococcosis. IgG-specific antibody (titers 4 to 1,024) was detected in the serum of 78 % of the cryptococcosis patients tested and in 61 % of the serum from healthy individuals with positive delayed skin hypersensitivity to cryptococcin. The micro-ELISA for cryptococcal antibody is of potential value in patient management, and in epidemiological studies.     

Evaluation of a New Cryptococcal Antigen Lateral Flow Immunoassay in Serum,Cerebrospinal Fluid and Urine for the Diagnosis of Cryptococcosis: A Meta-Analysis and Systematic Review

BackgroundA new lateral flow immunoassay (LFA) for the detection of cryptococcal antigen was developed.ObjectiveWe aimed to systematically review all relevant studies to evaluate the diagnostic accuracy of the cryptococcal antigen LFA on serum, CSF and urine specimens.MethodsWe searched public databases including PubMed, Web of Science, Elsevier Science Direct and Cochrane Library for the English-language literature published up to September 2014. We conducted meta-analyses of sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratios (DOR) and SROC of LFA in serum and CSF, respectively. The sensitivity of LFA in urine was also analyzed. Subgroup analyses were carried out to analyze the potential heterogeneity.Results12 studies were included in this study. The pooled sensitivity and specificity values of LFA in serum were 97.6% (95% CI, 95.6% to 98.9%) and 98.1% (95% CI, 97.4% to 98.6%), respectively. The average PLR of LFA in serum was 43.787 (95% CI, 22.60–84.81) and the NLR was 0.03 (95% CI, 0.01–0.09). The pooled DOR was 2180.30 (95% CI, 868.92–5471.00) and the AUC was 0.9968. The pooled sensitivity and specificity values of LFA in CSF were 98.9% (95% CI, 97.9% to 99.5%) and 98.9% (95% CI, 98.0% to 99.5%), respectively. The average PLR of LFA in serum was 48.83 (95% CI, 21.59–110.40) and the NLR was 0.02 (95% CI, 0.01–0.04). The pooled DOR was 2931.10 (95% CI, 1149.20–7475.90) and the AUC was 0.9974. The pooled sensitivity value of LFA in urine was 85.0% (95% CI, 78.7% to 90.1%)ConclusionsThe study demonstrates a very high accuracy of LFA in serum and CSF for the diagnosis of cryptococcosis in patients at risk. LFA in urine can be a promising sample screening tool for early diagnosis of cryptococcosis.     

Pulmonary cryptococcosis: A rare but emerging disease

Pulmonary cryptococcosis occurs primarily in immunocompromised hosts as an isolated infection or as a precursor to disseminated disease. Recent studies indicate that patients with isolated pulmonary cryptococcosis may be asymptomatic or, if symptomatic, will often have very low serum cryptococcal antigen, distinguishing them from patients with disseminated disease. Amphotericin B plus flucytosine is the initial treatment for disseminated cryptococcosis or severe symptomatic pulmonary cryptococcosis, followed by fluconazole once symptoms have improved. Fluconazole is recommended for asymptomatic or mild disease. Targeted immunotherapies and vaccines are being studied and offer exciting new prevention and treatment strategies.     

Opportunistic invasive mycoses in AIDS. An autopsy study of 211 cases.

The opportunistic mycoses are an important cause of morbidity-mortality among patients with severe immunosuppression provoked by HIV. We present a study of 211 serial autopsies of patients with HIV/AIDS infection carried out by our service in a period of 10 years, observing frequency of invasive mycoses of the 44.1%. Pneumocystis carinii infection was the most frequent (32%) with a prevalence of lung affection. Candidiasis follows it in order of frequency with 31.1%, predominantly the oropharyngeal manifestation. Systemic or cerebromeningeal cryptococcosis were serious and common disorder (29%). Diseminated histoplasmosis occurred in 9.6% and in three cases (3.2%) pulmonary aspergillosis was diagnosed as a postmortem discovery in cavity lesions. In our series, other less common HIV-associated were not identified.     

Pulmonary cryptococcosis in late pregnancy and review of published literature

Naturally occurring maternal immunosuppression increases the risk of infection by a variety of pathogens during pregnancy and the postpartum period. Pulmonary cryptococcosis during pregnancy is relatively rare. Here, we report on two cases of pulmonary cryptococcosis during pregnancy and puerperium. Both cases were successfully treated using oral fluconazole after parturition to avoid fetal toxicity. For the two patients, the placentas were checked and found to be pathologically normal, and the cryptococcal serum antigen in both infants was negative. Pulmonary cryptococcosis should be considered during differential diagnosis as a possible cause of abnormal chest shadow in pregnant patients.     

Epidemiological Profile of Cryptococcal Meningitis Patients in Rio Grande do Sul,Brazil

Cryptococcosis is a major opportunistic mycosis which has meningitis as its most frequent clinical presentation and can be fatal in the absence of antifungal therapy. The aetiological agents are Cryptococcus neoformans, which affects mainly immunocompromised subjects, and C. gattii, the aetiologic agent for cryptococcosis in healthy individuals. A recent outbreak of cryptococcosis on Vancouver Island, Canada, raised the level of concern about the epidemiology of this disease. In Brazil, between 1980 and 2002, six per cent of AIDS patients had cryptococcosis in course at the time of diagnosis. To identify the profile of cryptococcal meningitis patients in Rio Grande do Sul (RS), Brazil, a retroactive study was realized using data from patients registered at Laboratório Central de Saúde Pública IPB-LACEN/RS from 2000 to 2005. Most of the patients were men (77.12%), Caucasian (83.5%), median age between thirty and thirty-nine years old (46.24%) and HIV positive (95%).     

浆细胞样树突状细胞在宿主抵御隐球菌肺部感染中的作用及机制研究进展

肺隐球菌病是由隐球菌感染引起的常见真菌病,由于症状的非特异性,临床上诊断较为困难。作为条件致病性真菌感染,肺隐球菌病的结局主要与宿主免疫力有关。目前肺隐球菌病免疫学发病机制研究主要局限在T细胞和巨噬细胞。近年研究表明,作为树突状细胞亚群之一的浆细胞样树突细胞,由于其激活后可以产生大量的I型干扰素并活化相关的T细胞,所以在机体抵抗病毒和细菌免疫中发挥着重要的作用。但是浆细胞样树突细胞在真菌病,尤其是在隐球菌病的发生发展中发挥的作用尚不明确。本文将介绍肺隐球菌病的临床表现、诊治及T细胞和巨噬细胞在肺隐球菌病中的免疫机制,并通过介绍肺隐球菌病和浆细胞样树突细胞及二者之间已有报道的联系,初步阐述浆细胞样树突细胞在肺隐球菌病免疫学发病机制中的相关作用。     

The changing face of AIDS-related opportunism: cryptococcosis in the highly active antiretroviral therapy (HAART) era. Case reports and literature review

Only nine cases of AIDS-related cryptococcosis have been reported until now in patients receiving highly active antiretroviral therapy (HAART), all of them with abnormal clinical features. Two HIV-infected patients who experienced an atypical relapse of cryptococcosis shortly after the start of HAART and despite maintenance antifungal treatment, are described. Six different relapses of cryptococcal meningitis were observed in a 28-month period in a patient who obtained a poor immune recovery after HAART (as shown by a CD4+ lymphocyte count ranging from 78 to 149 cells/microL, opposed to a baseline level of 98 cells/microL). On the other hand, a patient with favorable immunological response to HAART (as expressed by a CD4+ count growing from 7 to 186 cells/microL), experienced isolated multiple indolent cryptococcal abscesses involving head, neck, the anterior thoracic wall, and regional lymph nodes, with repeatedly negative cultures, and diagnosis obtained by both histopathologic study and positive serum antigen assay. Both our case reports are representative of novel correlations between opportunistic pathogens and immune reactivity, descending from the introduction of HAART. The first episode describes an exceedingly elevated number of disease relapses despite HAART and antifungal maintenance treatment, which may descend from an incomplete immune response to antiretroviral therapy, possibly responsible for failure in obtaining eradication of yeasts, but also for lack of disease dissemination (usually leading to a lethal multivisceral involvement in the pre-HAART era). The abnormal disease course and localization of second reported patient well depicts an "immune reconstitution syndrome" probably representing a flare-up of a latent fungal infection, caused by a rapidly effective HAART. In patients treated with HAART, AIDS-related cryptococcosis cannot therefore be ruled out by the absence of neurological involvement, and by persistingly negative cultures.     

Induction of Protective Immunity Against Cryptococcosis

Cryptococcus neoformans, the predominant etiological agent of cryptococcosis, is an encapsulated fungal pathogen that can cause life-threatening infections of the central nervous system in immune compromised individuals resulting in high morbidity and mortality. Consequently, several studies have endeavored to understand those mechanisms that mediate resistance and susceptibility to Cryptococcus infection. In this review, we will examine the contributions of various components of the innate and adaptive immune response toward protection against cryptococcosis. We will focus our discussion on studies presented at the 8th International Conference on Cryptococcus and Cryptococcosis (ICCC). Remarkable progress has been made toward our understanding of host immunity and susceptibility to cryptococcal infection and the potential for vaccine development.     

新生隐球菌感染流行病学现状及耐药机制相关研究进展

新生隐球菌是一种广泛存在于环境中的酵母类真菌,主要侵犯中枢神经系统引起隐球菌性脑膜炎。HIV感染是导致隐球菌感染的主要危险因素之一,但近年来关于非HIV患者隐球菌感染的报道不断增加。体外药敏试验证实大部分新生隐球菌对棘白菌素类药物具有内在抗性。两性霉素B和氟康唑是用于隐球菌感染治疗的一线药物,而长期广泛用药引起新生隐球菌对氟康唑的耐药率逐年升高,患者临床治疗失败率居高不下。为进一步加深对新生隐球菌的认识,本文结合国内外流行病学报道及相关研究,从感染现状、生物学特征、诊治方法和耐药性等方面进行综述,以期为新生隐球菌性脑膜炎的临床诊治提供参考。     

The granuloma in cryptococcal disease

Although we have recognized cryptococcosis as a disease entity for well over 100 years, there are many details about its pathogenesis which remain unknown. A major barrier to better understanding is the very broad range of clinical and pathological forms cryptococcal infections can take. One such form has been historically called the cryptococcal granuloma, or the cryptococcoma. These words have been used to describe essentially any mass lesion associated with infection, due to their presumed similarity to the quintessential granuloma, the tubercle in tuberculosis. Although clear distinctions between tuberculosis and cryptococcal disease have been discovered, cellular and molecular studies still confirm some important parallels between these 2 diseases and what we now call granulomatous inflammation. In this review, we shall sketch out some of the history behind the term “granuloma” as it pertains to cryptococcal disease, explore our current understanding of the biology of granuloma formation, and try to place that understanding in the context of the myriad pathological presentations of this infection. Finally, we shall summarize the role of the granuloma in cryptococcal latency and present opportunities for future investigations.