Study of some epidemiological aspects of 253 cases of cryptococcosis.

Some epidemiological characteristics of 253 cases of cryptococcosis (CRY) diagnosed between 1981 and 1993 in the Mu?iz Hospital (MH) of Buenos Aires City, were studied. The incidence of CRY associated with AIDS (CRY+AIDS) in the MH during 1983-1993, could be divided into 3 periods: between 1983 and 1988 1-3 cases a year were diagnosed; during 1989-91, the number of cases dopubled annually and in 1992-93 the annual increment was lower. CRY associated with predisposing causes other than AIDS (CRY+non AIDS) exhibited an annual incidence of 0-3 cases during the whole period studied. CRY was more frequent in males (86%). The difference between sexes was more evident in CRY+AIDS patients (88% males) than CRY+non AIDS ones (65% males). The median age (MA) of the studied population was 28 (range 10-71) years; 27 (10-48) in women and 29 (17-71) in men. CRY+AIDS and CRY+non AIDS patients exhibited a MA of 29 (17-51) and 40 years (10-71), respectively. AIDS was the predisposing factor in 92% of patients; 65% of them were intravenous drug abusers and 22% homosexual males, with a MA of 27 (17-40) and 33 (23-55) years, respectively. Cryptococcus neoformans var. neoformans was isolated from all CRY+AIDS and 79% of CRY+non AIDS patients and the gattii variety (Serotype B) produced 4 (21%) cases of CRY+non AIDS.     

Survey of Cryptococcus neoformans in the respiratory tract of patients with bronchopulmonary disorders and in the air.

Cryptococcus neoformans was cultured from 9 (1%) of 835 clinical specimens examined from the respiratory tract of patients. These isolations came from 3 (0.4%) of the760 patients; 8 isolates were from sputum and one from urine. The fungus was not demonstrable in the air at a selected site during a 2-year study although other species of Cryptococcus, namely, C. albidus, C. ater, C. flavus, C. laurentii, C. magnus, C. terreus and C. uniguttulatus were isolated. The three C. neoformans positive patients were males, with pulmonary tuberculosis as the primary disease and history of repeated exposure to pigeon excreta in two. None of these patients manifested any overt signs and symptoms specificially attributable to cryptococcosis, nor did they receive any antifungal therapy. Repeated isolations of C. neoformans from sputum, a positive urine culture and demonstration of cryptococcal antibodies in a serum specimen, followed by negative cultures and serology, suggested that patient 1 had spontaneously recovered from an episode of benign, minimal pulmonary cryptococcosis. Patients 2 and 3 probably carried the fungus as a transient resident of the respiratory tract. The results suggest that C. neoformans is of uncommon occurrence in the respiratory tract of patients with bronchopulmonary disorders and that the isolation of the fungus from this site may not necessarily imply an etiologic relationship.     

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%).     

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.     

Molecular diversity of serial Cryptococcus neoformans isolates from AIDS patients in the city of São Paulo, Brazil

Despite highly active anti-retroviral therapy, cryptococcal meningoencephalitis is the second most prevalent neurological disease in Brazilian AIDS patients, being frequently a defining condition with several episodes. As knowledge of Cryptococcus neoformans isolates in the same episode is critical for understanding why some patients develop several episodes, we investigated the genotype characteristics of C. neoformans isolates in two different situations. By pulsed field gel electrophoresis and random amplified polymorphic DNA analysis, 54 isolates from 12 patients with AIDS and cryptococcosis were analyzed. Group 1 comprised 39 isolates from nine patients with a single episode and hospitalization. Group 2 comprised 15 isolates from three patients with two episodes and hospitalizations. Except for three patients from group 1 probably infected with a single C. neoformans isolate, the other nine patients probably were infected with multiple isolates selected in different collection periods, or the infecting isolate might have underwent mutation to adapt and survive the host immune system and/or the antifungal therapy. However, the three patients from group 2 presented genetic diversity among isolates collected in both hospitalizations, possibly having hosted the initial isolate in both periods. These data, emphasize that Cryptococcus diversity in infection can contribute to strategies of treatment and prevention of cryptococcosis.     

Disseminated cryptococcosis in an AIDS patient with unusual clinical presentation

Disseminated cryptocococcosis is a rare and often fatal disease. Here in we report an unusual fatal case of disseminated cryptococcosis. The patient presented with a past history of postmenopausal bleeding with loss of consciousness, altered mental status, few seizures and a low grade fever. Lumbar puncture revealed elevated pressure, lymphocytic pleocytosis, elevated protein and markedly reduced glucose level. Cryptococcus neoformans was isolated from cerebrospinal fluid and blood. Serological assay revealed the presence of human immunodeficiency virus. The patient was treated with antifungal agents intravenously without any signs of improvement and the patient passed away after two weeks of therapy. This is the first case report of disseminated cryptococcosis in an AIDS patient suffering from cryptoccoccal vaginitis.     

Respiratory cryptococcosis in HIV positive patients.

Although the lungs are the portal of entry of the infection, respiratory manifestations of AIDS related cryptococcosis have not been very well studied. The lack of typical findings in clinical and roentgenographic studies and the difficulties in the interpretation of the isolation of Cryptococcus neoformans from bronchial secretions, is probably the explanation for the lack of interest on this subject. The clinical and microbiological findings of 22 HIV positive patients, who presented C. neoformans in their respiratory tract clinical samples, are presented. Seventeen were males and 5 females, their age average was 30.8 years (21-50 years) and the following risk factors for HIV infection were detected: intravenous drug abuse 18, heterosexuals with several sexual partners two, one female prostitute and 1 homosexual man. All patients, except three, showed less than 100 CD4+ cells per microl. The following symptoms were observed: fever, cough, mucoid expectoration and chest ache. Roengenographic studies presented diffuse infiltrative patches in eleven cases, pulmonary cavities in three, pseudotumoral nodules in two, pneumonic infiltration in two and pleural effusion in four patients. C. neoformans was observed and/or isolated from sputum in nine patients, from bronchoalveolar lavage in seven, from lung biopsy in one and from pleural effusion in four cases. Blood cultures for C. neoformans were positive in 13 cases, urine cultures in 10 and in 11 patients C. neoformans was isolated from C.S.F. The latex agglutination tests for C. neoformans capsular polysaccharide rendered positive results in serum samples from 19 patients and from C.S.F. in 14 cases. Seven cases also presented active tuberculosis. According to these findings, it seems that the isolation of C. neoformans from bronchial secretion of HIV positive patients is a signal of disseminated cryptococcosis. It is important to isolate C. neoformans or detect its capsular antigen from other clinical samples in order to confirm the diagnosis of disseminated cryptococcosis. As observed in other studies, pleuropulmonary cryptococcosis does not present a typical clinical pattern.     

Pathogenicity of Cryptococcus neoformans: virulence factors and immunological mechanisms

Cryptococcus neoformans is the causative agent of cryptococcosis and cryptococcal meningitis, which are serious pathological conditions affecting up to 10% of patients with AIDS. Mechanisms of pathogenicity of C. neoformans and the host defenses against this fungus are reviewed, incorporating recent data and perspectives.     

Fluconazole Non-susceptible <Emphasis Type="Italic">Cryptococcus neoformans</Emphasis>, Relapsing/Refractory Cryptococcosis and Long-term Use of Liposomal Amphotericin B in an AIDS Patient

The treatment of cryptococcosis is hampered by inefficacy or intolerance to the recommended antifungal agents. A patient diagnosed with AIDS had multiple relapses of cryptococcal infection, which became refractory to antifungal agents during the course of therapy. During the follow-up, the patient developed renal toxicity due to amphotericin B use and non-susceptibility of isolated Cryptococcus neoformans to fluconazole was detected. Thereafter, antifungal treatment was performed exclusively with liposomal amphotericin B, reaching a cumulative dose of 19,180 mg over 46 months. The final relapse of cryptococcosis occurred during the maintenance phase with liposomal formulation in a once-weekly dose. Measurement of the minimum serum concentrations of amphotericin B, determined sequentially before and after this relapse, suggested the importance of monitoring drug levels when the liposomal formulation is used for a long period.     

Cryptococcosis due to Cryptococcus neoformans var. gattii in Brazilian patients with AIDS. Report of three cases

Three cases of Cryptococcus neoformans var. gattii infection in AIDS patients observed in Rio Grande do Sul (Brazil) are related. A brief comment on the epidemiology of cryptococcosis in Brazil is also made.     

Cryptococcosis in Patients with Nephrotic Syndrome: A Pooled Analysis of Cases

Cryptococcosis is an infection that may be lethal in patients with nephrotic syndrome (NS). However, there is relatively limited epidemiological and clinical data about cryptococcosis in NS patients. We performed a pooled analysis to systemically summarize the epidemiology, risk factors, clinical and laboratory characteristics, treatments and outcomes of cryptococcosis in NS patients. Using data pooled from our hospital and studies identified via searches of three literature databases, 17 cases were identified for inclusion in this analysis. The prevalence of cryptococcosis in NS was 0.3%, with a higher rate in more recent years. Most patients were Asian (94%) and from upper-middle to high-income countries (76%). The median time interval from NS diagnosis to cryptococcosis diagnosis among the cryptococcosis patients was 16 months, and 46% of the identified cryptococcal infections were diagnosed within the first year of NS diagnosis. Cutaneous cryptococcosis was frequently diagnosed among the included patients (35%), 58% received an erroneous diagnosis and inappropriate treatment, 90% of whom had a cryptococcal infection mistaken for a bacterial infection. The mortality rate was 35%. Standard therapeutic strategies should be emphasized for both antifungal treatment and renal disease control. Further studies conducted in various medical centers are warranted to confirm our conclusions.     

Epidemiological study of cryptococcosis in Spain: first results

The study constitutes an approach to the knowledge of the epidemiology of cryptococosis in Spain. For detection of cases 167 Spanish hospitals were contacted. All cases included were accompanied by the correspondent isolate of Cryptococcus neoformans, together with clinical, demographic and mycological data. Results obtained from January 1998 to end of December 1999 are analysed and presented here. Fifty-six Spanish hospitals reported 58 cases of cryptococcosis; only 43 of them were adequately documented and accompanied by the clinical isolate. The results showed a higher incidence in males (88.4%) than in females (11.6%); being most frequently affected those between 30 and 40 years old (48.8%). The 84.6% (33) corresponded to new cases and 15.4% (6) to relapses of the disease. The HIV infection was the most frequent risk factor reported (86%) and, for 29.7% (11) of them, cryptococcosis was the AIDS defining disease. For the diagnosis, CSF analysis showed the best results (India ink; culture and antigen detection). All strains collected (100%) corresponded to C. neoformans variety neoformans. Serotypes distribution was 45.5% for serotype A and 22.7% for each of serotypes D and AD.     

Molecular analysis of 311 Cryptococcus neoformans isolates from a 30-month ECMM survey of cryptococcosis in Europe

During a European Confederation of Medical Mycology (ECMM) prospective survey of cryptococcosis in Europe (from July 1997 to December 1999) 655 cases were reported from 17 countries; 565 of the completed questionnaires were evaluable. Cryptococcosis was associated with HIV infection in 77% of cases (range 57.5-94%). Assessment of the laboratory data highlighted the lack of defined standard procedures for the diagnosis of cryptococcosis: the antigen test was not usually used for screening, the disease was mainly recognised when meningitis occurred (65% of patients) and, with the exception of a few cases, the extent of the infection was not investigated. Cryptococcus neoformans was the etiological agent in all of the cases except for six caused by C. gattii and four by other Cryptococcus species. A total of 311 C. neoformans strains were serotyped by Crypto Check latex agglutination, genotyped by PCR-fingerprinting using the (GACA)4 oligonucleotide as a single primer, and their mating type was determined by PCR of the STE20 alleles. Serotype A was the most represented (51% of the isolates), followed by serotype D (30%) and serotype AD (19%). PCR-fingerprinting analysis significantly increased the percentage of hybrid strains to 30%, as 6% of the serotype A and 28% of the serotype D isolates were of the VN3 or VN4 hybrid genotype. In addition, the mating type determinations revealed the MATa serotype A allele in one haploid strain and 28 hybrids, and hybrid isolates with a single mating type (four Aalpha and two Dalpha) were also identified. This is the first prospective survey to be carried out in Europe which has attempted to investigate the epidemiology of cryptococcosis and the population structure of C. neoformans, and the results obtained thus far show the widespread involvement of AD hybrid strains in C. neoformans infections.     

55例社区获得性肺隐球菌病病例分析

本文旨在通过研究社区获得性肺隐球菌病的临床特点,提高医务人员对肺隐球菌病的认识,做到早期诊断和治疗.采用回顾性病例分析研究,统计2003年1月~2009年12月入住复旦大学附属中山医院的55例确诊及临床诊断为肺隐球菌病患者的临床资料.55例患者中,男性34例,女性21例;年龄17~75岁,平均(44.8±13.4)岁....     

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.     

Identification and characterization of the Cryptococcus neoformans phosphomannose isomerase-encoding gene, MAN1, and its impact on pathogenicity

The polysaccharide capsule surrounding Cryptococcus neoformans comprises manose, xylose and glucuronic acid, of which mannose is the major constituent. The GDP-mannose biosynthesis pathway is highly conserved in fungi and consists of three key enzymes: phosphomannose isomerase (PMI), phosphomannomutase (PMM) and GDP-mannose pyrophosphorylase (GMP). The MAN1 gene, encoding for the PMI enzyme, was isolated and sequenced from C. neoformans, and a disruption of the MAN1 gene was generated. One MAN1 disruption mutant, man1, which showed poor capsule formation, reduced polysaccharide secretion and morphological abnormalities, was chosen for virulence studies. In both the rabbit and the mouse models of invasive cryptococcosis, man1 was shown to be severely impaired in its virulence, with complete elimination of the yeast from the host. A reconstituted strain of man1 was constructed using gene replacement at the native locus. The wild-type and reconstituted strains were significantly more virulent than the knock-out mutant in both animal models. Our findings reveal that PMI activity is essential for the survival of C. neoformans in the host. The fact that the man1 mutant was not pathogenic suggests that blocking mannose synthesis could be fungicidal in the mammalian host and thus an excellent target for antifungal drug development.     

Cryptococcosis in Colombian children and literature review

Cryptococcosis is reported in adults and is often acquired immune deficiency syndrome (AIDS)-associated; however, its frequency in children is low. Based on the National Survey on Cryptococcosis conducted in Colombia, an epidemiological and clinical analysis was performed on cases of the disease observed in children less than 16 years old between 1993-2010. We found 41 affected children (2.6% prevalence) from the 1,578 surveys received. The country mean annual incidence rate was 0.017 cases/100,000 children under 16 years, while in Norte de Santander the incidence rate was 0.122 cases/100,000 (p < 0.0001). The average age of infected children was 8.4 and 58.5% were male. In 46.3% of cases, a risk factor was not identified, while 24.4% had AIDS. The most frequent clinical manifestations were headache (78.1%), fever (68.8%), nausea and vomiting (65.6%), confusion (50%) and meningeal signs (37.5%). Meningitis was the most frequent clinical presentation (87.8%). Amphotericin B was given to 93.5% of patients as an initial treatment. Positive microbiological identification was accomplished by India ink (94.7%), latex in cerebrospinal fluid (100%) and culture (89.5%). Out of 34 isolates studied, Cryptococcus neoformans var. grubii (VNI 85.3%, VNII 8.8%) was isolated in 94.1% of cases and Cryptococcus gattii (VGII) was isolated in 5.9% of cases. These data are complemented by a literature review, which overall suggests that cryptococcosis in children is an unusual event worldwide.     

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.     

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.