Histopathological aspects of neurocryptococcosis in HIV-infected patients: autopsy report of 45 patients

The authors describe the histopathological necropsy findings of 45 human immunodeficiency virus (HIV)-infected patients with neurocryptococcosis. Systemic cryptococcosis with involvement of multiple organs such as spleen, liver, and lungs was present in all patients. Predominant diffuse meningoencephalitis predominantly in the basal ganglia, thalamus, and mid-brain, with minimal inflammatory infiltrate was seen in 30 AIDS patients (70%). We frequently observed in those patients the presence of multiple gelatinous pseudocysts with abundant Cryptococcus neoformans in the Virchow-Robin spaces and adjacent brain caused by the dissemination of the meningeal infection along the perivascular spaces. Isolated meningeal and cerebral involvement with minimal inflammatory infiltrate with numerous fungal organisms, and occasionally with granulomatous reaction and necrosis, was seen in 15 patients (30%). In addition to involvement of multiple organs by C. neoformans, HIV-infected patients with clinical manifestations of neurocryptococcosis frequently present a widespread involvement of the brain.     

The management and outcome of cryptococcosis in patients with different immune statuses and treatment protocols: A multicenter real-world study in Jiangsu Province - China

ObjectiveThe incidence of cryptococcosis is increasing in non-immunocompromised patients. However, the evidence on proper management is inadequate in this population. We conducted this multi-center real-world study in pulmonary cryptococcosis patients with different immune statuses, so as to provide practical evidence for optimized clinical management of cryptococcosis, especially for mild-to-moderate immunodeficient diseases patients.MethodsThis is a prospective observational study. The clinical data of patients with proven cryptococcosis were collected and analyzed from 7 tertiary teaching hospitals in Jiangsu Province, China from January, 2013 to December, 2018. Proven cases include pulmonary cryptococcosis, cryptococcal meningitis, cryptococcemia and cutaneous cryptococcosis. Patients were followed up over 24 months. According to their immune status, patients with cryptococcosis were divided into three groups, namely immunocompetent group (IC), mild-to-moderate immunodeficient diseases group (MID), severe immunodeficient diseases group (SID). Meanwhile, pulmonary crypotococcosis (PC) and extrapulmonary crypotococcosis (EPC) were also classified and analyzed.Results255 proven cases of cryptococcosis were enrolled. Finally, 220 cases completed the follow-up. 143 proven cases (65.0%) were immunocompetent (IC), 41 cases (18.6%) were MID, and 36 cases (16.4%) were SID. 174 cases (79.1%) were PC and 46 cases (20.9%) were EPC. The mortality was significantly higher in SID and MID patients [47.2% (SID) vs. 12.2% (MID) vs. 0.0% (IC), p<0.001]. The mortality was also significantly higher in EPC patients [45.7% vs. 0.6% (PC), p<0.001]. Patients with alternative initial antifungal treatment had higher mortality than patients with guideline recommended initial treatment [23.1% vs. 9.5%, p=0.041]. In MID group, the mortality of receiving alternative initial antifungal treatment was significantly higher than recommended initial treatment [2/3 vs. 3/34(8.8%), p=0.043]. In pulmonary cryptococcosis patients with MID, the mortality was very similar to IC group [0.0% vs. 0.0% (IC)], lower than SID group [0.0% vs. 11.1% (SID), p=0.555]. However, in extrapulmonary cryptococcosis patients with MID, the mortality was significantly higher than that in IC [62.5% vs. 0.0% (IC)], and similar to SID patients [62.5% vs. 59.3% (SID)].ConclusionThe immune status exert a significant influence on the management and prognosis of cryptococcosis patients. The mortality of cryptococcosis patients with MID is higher than that of immunocompetent patients. For MID patients with pure pulmonary cryptococcosis, it is acceptable to take the treatment recommended as IC patients. For the MID patients with extrapulmonary cryptococcosis, the mortality is high and the initial treatment should follow the regimen for SID patients. Following the recommended treatment regimen in the IDSA guideline can reduce mortality in patients with cryptococcosis. Starting on alternative initial antifungal treatment may bring worse outcomes.     

Generalized cryptococcosis in HIV infection

Two cases of generalized cryptococcosis in patients who died of HIV infection are described. The course of the disease was masked by other diseases and final diagnosis was established after necropsy. Leukemia was a clinical "mask" in one case and generalized tuberculosis in the other. Numerous cryptococci were found in different organs histologically with positive Shiff-reaction. Ultrastructurally, cryptococci were of variable forms this probably reflecting different stages of interaction between microorganisms and the host.     

Pathogenesis of Cryptococcus neoformans in congenitally immunodeficient beige athymic mice.

Mortality after intravenous challenge with 10(4) Cryptococcus neoformans demonstrated that doubly immunodeficient beige athymic (bg/bg nu/nu) mice were more susceptible to systemic cryptococcosis than either bg/bg or nu/nu mice. Infected bg/bg nu/nu mice also had a shortened lifespan compared with their bg/bg nu/+ littermates. Beige athymic (bg/bg nu/nu) but not bg/bg nu/+mice developed cryptococcal lesions in the skin, demonstrating that C. neoformans is dermatotropic in a T-cell-deficient host. Higher numbers of C. neoformans were isolated from the lungs and spleen of infected bg/bg nu/nu than bg/bg nu/+ mice as early as day 3 after challenge, indicating that in lymphoid-rich organs, T cells can alter the course of systemic cryptococcosis early in the infection. Despite extensive abscess formation in the brains of bg/bg nu/+ mice, dissemination and growth rate of C. neoformans in the brain was similar in both genotypes. The primary histopathological feature in tissues from bg/bg nu/nu mice infected with C. neoformans consisted of foci of encapsulated yeast cells with minimal to no inflammatory response. In contrast to bg/bg nu/nu mice, bg/bg nu/+ mice mounted a vigorous inflammatory response to C. neoformans that progressed from acute to chronic inflammation. Beige athymic mice are a new animal model that will be useful in clarifying the innate and acquired immune factors important in resistance to cryptococcosis.     

Cryptococcosis in HIV-AIDS patients from Southern Brazil: Still a major problem

IntroductionCryptococcus neoformans is an opportunistic pathogen that causes ∼15% mortality in AIDS patients. Rio Grande City, Rio Grande do Sul (RS), Brazil, has the highest national rate of HIV/AIDS, considering cities with population more than 100,000 habitants.ObjectiveWe aimed to evaluate the clinical and epidemiological profile of cryptococcosis in a reference service for HIV-AIDS patients in the South region of Brazil, over seven years. Material and methods A retrospective study was performed including all cryptococcosis cases diagnosed at the University Hospital, Federal University of Rio Grande (UH-FURG) between January 2010 and December 2016.ResultsSeventy cases of cryptococcosis were diagnosis from 2010 to 2016 in the UH-FURG in the seven years of the study. These numbers were responsible for 2.1% to 8.1% of the hospitalizations/year for HIV patients. All were caused by C. neoformans infection (95% C. neoformans var. grubii VNI and 5% C. neoformans var. grubii VNII). Neurocryptococcosis was the major clinical manifestation and cryptococcosis was the HIV- defining condition in 40% of patients. The period of hospitalization was an average of 39.3 days (SD = 31.3), and more than half of patients (53%; 37/70) died after a mean of 82 days.DiscussionThe present study showed the importance of cryptococcosis as an AIDS-defining disease in HIV-AIDS patients in a tertiary hospital from Southern Brazil. More investment is necessary to reduce the impact of this opportunistic mycosis in HIV-AIDS patients from southern Brazil.     

First case of cryptococcosis in a new species of bandicoot (Bandicota indica) caused by Cryptococcus neoformans var. grubii.

The first case of cryptococcosis caused by Cryptococcus neoformans var. grubii in a new species of bandicoot (Bandicota indica) is described. The animal was trapped in a bamboo thicket in a park located in the city of Jabalpur, India. On necropsy, pathological lesions were seen in the lungs and liver and C. neoformans var. grubii was isolated from the lungs, liver, kidneys, spleen and brain but not the heart or intestine. The soil of the animal's burrow and bamboo debris around it also revealed the presence of C. neoformans var. grubii. We hypothesize that the bandicoots may potentially act as sentinel animals for environmental human pathogenic Cryptococcus species.     

Role of natural killer cells in resistance to systemic cryptococcosis

These studies demonstrate that Cryptococcus neoformans infection induced a dose-dependent augmentation of splenic natural killer (NK) cell activity by bg/+, but not bg/bg mice. To directly assess the role of NK cells in resistance to C. neoformans, bg/+ and bg/bg mice were treated with anti-NK-1.1 monoclonal antibody (mAb). Anti-NK-1.1-treatment abrogated the augmented NK cell activity observed during C. neoformans infection in bg/+ mice. Anti-NK-1.1-treated bg/+ mice had higher C. neoformans colony forming units (CFU) in their lungs on days 3 and 7 after intravenous (i.v.) challenge than control bg/+ mice. Moreover, the number of C. neoformans CFU in the lungs of anti-NK-1.1-treated bg/+ mice on days 3 and 7 were similar to those observed for infected bg/bg mice. By day 14, however, no differences in C. neoformans CFU were evident in the lungs of anti-NK-1.1-treated and control bg/+ mice. Anti-NK-1.1-treatment did not alter either the growth of C. neoformans in the spleens, livers, kidneys, or brain of bg/+ mice or the susceptibility of bg/bg mice to systemic cryptococcosis. These studies suggest that NK cells do not play a role in resistance to systemic cryptococcosis in the spleen, but do appear to play an early, but transient role in resistance to C. neoformans in the lungs. Overall, congenital defects in polymorphonuclear neutrophils (PMNs) and macrophages (M phi s), in addition to defects in NK cells, contribute to the enhanced susceptibility of bg/bg mice to systemic cryptococcosis.     

Experimental systemic infection with Cryptococcus neoformans var. grubii and Cryptococcus gattii in normal and immunodeficient mice.

Cryptococcus neoformans (Cn) var. grubii or Cryptococcus neoformans var. neoformans infection is usually associated with immunocompromised hosts, whereas Cryptococcusgattii more frequently causes disease in immunocompetent hosts. We examined the effects of immunodeficiency and glucocorticoid-induced immunosuppression on systemic murine infection induced by i.v. inoculation with these pathogens. SCID and immunocompetent BALB/c and C57BL/6 mice were infected with 相似文献   

Cryptococcosis outbreak in psittacine birds in Brazil.

An outbreak of cryptococcosis occurred in a breeding aviary in S?o Paulo, Brazil. Seven psittacine birds (of species Charmosyna papou, Lorius lory, Trichoglossus goldiei, Psittacula krameri and Psittacus erithacus) died of disseminated cryptococcosis. Incoordination, progressive paralysis and difficulty in flying were seen in five birds, whereas superficial lesions coincident with respiratory alterations were seen in two birds. Encapsulated yeasts suggestive of Cryptococcus sp. were seen in faecal smears stained with India ink in two cases. Histological examination of the birds showed cryptococcal cells in various tissues, including the beak, choana, sinus, lungs, air sacs, heart, liver, spleen, kidneys, intestines and central nervous system. High titres of cryptococcal antigen were observed in the serum of an affected bird. In this case, titres increased during treatment and the bird eventually died. Yeasts were isolated from the nasal mass, faeces and liver of one bird. Cryptococcus neoformans var. gattii serovar B was identified based on biochemical, physiological and serological tests. These strains were resistant (minimum inhibitory concentration 64 microg/ml) to fluconazole. This is the first report of C. neoformans var. gattii occurring in psittacine birds in Brazil.     

Comparison of protective efficacy of subcutaneous versus intranasal immunization of mice with a Brucella melitensis lipopolysaccharide subunit vaccine

Groups of mice were immunized either subcutaneously or intranasally with purified Brucella melitensis lipopolysaccharide (LPS) or with LPS as a noncovalent complex with Neisseria meningitidis group B outer membrane protein (LPS-GBOMP). Control mice were inoculated with sterile saline. Two doses of vaccine were given 4 weeks apart. Mice were challenged intranasally with virulent B. melitensis strain 16M 4 weeks after the second dose of vaccine. Sera, spleens, lungs, and livers of mice were harvested 8 weeks after challenge. The bacterial loads in the organs were determined by culture on brucella agar plates. Protective efficacy was determined by comparing the clearance of bacteria from organs of immunized mice with the clearance of bacteria from organs of control mice. At 8 weeks postchallenge there was significant protection from disseminated infection of spleens and livers of mice intranasally immunized with either vaccine compared to infection of control mice (P < 0.01). There was no significant difference in clearance of bacteria from the lungs of immunized mice and control mice. However, mice immunized subcutaneously with either LPS or LPS-GBOMP vaccine showed significant protection against infection of the spleen (P < 0.001), liver (P < 0.001), and lungs (P < 0.05). These results show that intranasal immunization of mice with either vaccine provided significant protection against disseminated infection of the spleen and liver but subcutaneous immunization of mice with the vaccines conferred significant protection against infection of the spleen, liver, and lungs.     

Comparative study of the distribution of 7,12-dimethylbenz(a)anthracene in pregnant rats and their fetuses

On the 21st day of pregnancy rats were given an intravenous injection of 7,12-dimethylbenz(a)anthracene (DMBA) in a dose of 15 mg/kg, and its concentration in the organs of the mothers (liver, kidneys, lungs, brain, spleen, and placenta) and of their fetuses (liver, kidneys, lungs, brain, intestine, carcass, and whole fetus) was determined by a fluorescence-spectral method 30, 60, and 180 min later. The highest concentration of DMBA in the mothers at all times was found in the lungs. With an increase in the time of injection the DMBA concentration fell in all organs of the pregnant rats, except in the brain, in which it rose. In the fetuses an irregular distribution of the carcinogen in the organs was found only 60 min after injection of DNBA, when the highest concentration was detected in the liver. In all fetal organs the maximal concentration was found after 60 min. Accumulation of DMBA in the various fetal organs did not correlate with the observed highest frequency of tumors in the kidney and nervous system of rat fetuses following transplacental exposure to DMBA in the same dose.Laboratory of Biophysics and Laboratory of Experimental Tumors, N. N. Petrov Research Institute of Oncology, Ministry of Health of the USSR, Leningrad. (Presented by Academician of the Academy of Medical Sciences of the USSR L. M. Shabad.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 89, No. 3, pp. 334–335, March, 1980.     

Cryptococcus neoformans IV. The Not-So-Encapsulated Yeast

Nonencapsulated cells of Cryptococcus neoformans which may have a diameter of less than 4 μm are capable of producing experimental cryptococcosis in mice. It has been established that this relatively small, nonencapsulated yeast can exist in soil. In this form, the organism could be more readily disseminated by air currents, and it is more likely to be inhaled into the lungs than the larger encapsulated yeast. Nonencapsulated cells produce sufficient capsular material to inhibit phagocytosis by 50% when incubated for 5 to 10 hr with human lung tissue in vitro. The general assumption that the encapsulated cells are the etiological agent of naturally acquired cryptococcosis may have to be revised.     

Serologic evidence for reactivation of cryptococcosis in solid-organ transplant recipients

Cryptococcosis is a significant infection with a high mortality in solid-organ transplant recipients. Nonetheless, the pathogenesis of this disease is poorly understood. It has been hypothesized that cryptococcosis may result from either primary infection or reactivation of a latent infection. Sera were obtained from transplant recipients prior to transplantation and at the time they developed cryptococcosis. Control sera were obtained before and after transplant from patients who did not develop cryptococcosis. Sera were tested for antibodies against Cryptococcus neoformans by using an immunoblot assay. Antibody responses were also compared with those observed in sera from rats with experimental pulmonary cryptococcosis. In all, 52% of the transplant recipients who developed cryptococcosis exhibited serologic evidence of cryptococcal infection before transplantation. These patients developed cryptococcosis significantly earlier after transplant than patients without preexisting reactivity did (5.6 ± 3.4 months compared to 40.6 ± 63.8 months, respectively [P = 0.0011]). The results from our study suggest that a substantial proportion of transplant-associated cryptococcosis cases result from the reactivation of a latent infection. These findings also highlight the potential utility of serologic studies in identifying patients at risk for the development of cryptococcosis after transplantation.     

TISSUE REACTIONS TO ASPERGILLUS IN CASES OF HODGKIN'S DISEASE AND LEUKAEMIA

Five cases of aspergillosis complicating Hodgkin's disease and leukaemia are reported. The organs involved were: lungs (all five cases), stomach (Case 3); brain and meninges (Case 4); heart, kidneys, spleen, thyroid, and liver (Case 2). Cultures of Aspergillus fumigatus were obtained from the post-mortem tissues of three patients.     

Evaluation of the detection of melanin by the Fontana-Masson silver stain in tissue with a wide range of organisms including Cryptococcus

It is not uncommon for surgical pathologists to encounter yeast and yeast-like organisms in tissue sections, and correct identification is imperative for guiding therapy. The Fontana-Masson silver stain for detecting melanin has been accepted as a relatively specific stain for diagnosing cryptococcosis in tissue based on few studies with limited numbers of organisms. This study was designed to test the value of the Fontana-Masson silver by investigating a large collection of tissues with infections that may mimic cryptococcosis. Cases of cryptococcosis and other infections that can morphologically mimic it were identified in the pathology archives of The Johns Hopkins Hospital and The Armed Forces Institute of Pathology. Overall, Fontana-Masson silver was positive in 25 (56%) of 45 cases, including infections caused by Cryptococcus neoformans (9/9), Coccidioides immitis (7/7), Blastomyces dermatitidis (4/10), Paracoccidioides brasiliensis (2/2), Lacazia loboi (1/1), and Rhinosporidium seeberi (1/1). The percentage of organisms staining varied widely, from less than 1% to 100%. Fontana-Masson silver was negative in all infections caused by Histoplasma capsulatum (n = 10), Histoplasma duboisii (n = 1), Sporothrix schenckii (n = 1), and the alga genus Prototheca (n = 2). Fontana-Masson silver was 100% sensitive for cryptococcosis. The specificity was low, however, with 5 of 9 noncryptococcal species being positive in some cases. These results need to be confirmed and extended to other isolates and species but it is clear that many organisms in the morphological differential diagnosis of cryptococcosis can be Fontana-Masson silver stain positive. Accordingly, results of the Fontana-Masson silver stain, especially a positive, should be interpreted cautiously and only in the context of the organism's morphological features and host factors.     

广州地区围产儿脏器重量及大小测量的研究

目的　探讨广州地区围产儿脏器重量及大小的发育规律 .方法　选择 6 2 5例胎龄准确的单胎 ,除外明显浸软、IUGR、水肿儿、巨大胎、有胸腹水者 ,新生儿除外先天性心脏病及有明显疾病的脏器 .根据胎龄分为 6组 ,分别测量围产儿体重、身长和各脏器重量、长度 .进行统计分析 .结果　胰腺、肺发育最早 ,肾脏与肺发育最快 ,出生后脑增长最少而胰腺增长最快 ,肠变异最大等规律 .结论　围产儿脏器资料用于围产儿病理研究有一定意义     

Influence of gender and age on course of infection and cytokine responses in mice with disseminated Cryptococcus neoformans infection

Objective   To study the influence of gender and age on the course of infection and the cytokine response in a murine model of disseminated cryptococcosis.
Methods   The course of the infection (survival and fungal load in blood and tissues) as well as pro-inflammatory and anti-inflammatory cytokine responses in plasma and organs were compared according to gender and age in outbred mice previously infected with Cryptococcus neoformans NIH52D.
Results   Although survival and fungal load were similar in male and female mice, the expression of all cytokines in plasma and of tumour necrosis factor- α and interferon- γ in spleen was significantly increased in female mice compared to male mice in two independent experiments. Young male mice had a significantly shortened survival, were significantly more infected and had predominant tumour necrosis factor- α and interferon- γ responses in comparison with older male mice.
Conclusion   Host factors should be taken into account when studying the immune response to experimental C. neoformans infection. Our data support epidemiological and clinical data showing differences in susceptibility to cryptococcosis according to gender and age.     

Fungal infections in HIV-infected patients]

Recent situation of HIV-related mycosis was discussed in this paper, with the analysis of 1) annual report of HIV trends in Japan by the AIDS epidemiology committee, 2) report of HIV-related opportunistic infections (OIs) collected by the AIDS-OIs research group funded by the Ministry of Health, Labour and Welfare, and 3) 17 cases of HIV-related aspergillosis collected by the author. Annual AIDS cases were increasing, and their major diseases were included with the following mycosis: pneumosystis pneumonia 35.7%, candidiasis 19.1%, and cryptococcosis 2.4%. There were two foreigner's cases of histoplasmosis and no coccidioidosis. Candidiasis was likely to be shown in Japanese patients and cryptococcosis was in foreigners. Outcome of cryptococcosis was very poor as 32.7% of patients died. There were 17 HIV-related aspergillosis, which consisted of 13 cases of lung diseases, 2 of brain lesions, and one each of sinus and stomach disease. Remarkable risk factor of HIV-related aspergillosis was decrease of CD4 cell count less than 10/microl, in addition to the usual risk factors of aspergillosis. Outcome of aspergillosis was very poor, as all treated cases died except one recent case treated with voriconazole.     

Fine-needle aspiration diagnosis of primary cutaneous cryptococcosis in an immunocompetent patient: a case report

We report a case of a primary cutaneous cryptococcosis (PCC) in immunocompetent man diagnosed by fine-needle aspiration (FNA) and confirmed by special stains and culture study. The patient presented with a 2-wk history of two separate skin nodules over the forehead and the left lumbar region. FNA smears revealed a necrotizing suppurative granulomatous inflammation with numerous yeasts of Cryptococcus surrounded by clear halos, which were present within multinucleated giant cells and in the intercellular spaces. This was confirmed subsequently by special stains and a culture of the aspirated material. This case report reemphasizes the role of FNA as a useful modality in the early diagnosis of cutaneous cryptococcosis, especially in clinically unsuspected cases.