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Lipid-based amphotericin B in the treatment of cryptococcosis.

Amphotericin B is the only antifungal drug which, despite its dose-limiting toxicity, can be given intravenously when an aggressive treatment is required. In an attempt to reduce the drug toxicity while retaining its therapeutic efficacy, new formulations of amphotericin B have been developed. The most promising have employed lipid vehicles such as liposomes. Three lipid-based amphotericin B formulations have been developed by pharmaceutical companies and are under active clinical investigation. Efficacy and safety data of these derivatives in animals and humans are reviewed, with particular concern to cryptococcal infection. The authors' experience with a small unilamellar liposomal amphotericin B formulation, AmBisome, in the primary therapy of cryptococcosis is reported. Nine AIDS patients affected with cryptococcosis, seven of whom had meningitis, were given AmBisome (3 mg/kg/day) for 3-6 weeks. Complete response was obtained in six patients, marked improvement in two, and failure in one. AmBisome was well tolerated and shortened the time to clinical and mycological response suggesting a further improvement in the management of cryptococcosis in AIDS patients.

AIDS-Related Opportunistic Infections↗

A case of necrotizing glomerulonephritis presenting with nephrotic syndrome associated with pulmonary cryptococcosis.

We describe a 68-year-old man with necrotizing glomerulonephritis who presented with nephrotic syndrome accompanied by pulmonary cryptococcosis. He developed rheumatoid arthritis in July 1999 and was treated with low-dose prednisolone. He was admitted to our hospital on November 22 following the appearance of bilateral leg edema in October 2000. Laboratory tests at presentation revealed nephrotic syndrome with renal impairment. Renal biopsy specimens revealed necrotizing glomerulonephritis with crescent, but immunofluorescence study showed lack of staining for immunoglobulins or complement components. Chest X-ray and CT showed abnormal shadows in the right upper lung field, and Cryptococcus neoformans was isolated in a transbronchial lung biopsy. After the diagnosis of pulmonary cryptococcosis was made, the patient was treated with 200 mg/day fluconazole. The pulmonary abnormal shadows immediately improved and urinary protein excretion dramatically decreased. A second renal biopsy, performed about 2 months after the first biopsy, showed disappearance of crescent. Electron microscopic examination of the second renal biopsy showed partial effacement of foot processes without electron-dense deposits. Our findings suggest that necrotizing glomerulonephritis with nephrotic syndrome in this patient represented pauci-immune T-cell-mediated injury related to pulmonary cryptococcosis.

Aged↗

Cryptococcosis of the colon resembling Crohn's disease in a patient with the hyperimmunoglobulinemia E-recurrent infection (Job's) syndrome.

A 29-yr-old woman presenting with granulomatous colitis and a chronic perirectal abscess was found to have localized cryptococcosis associated with the hyperimmunoglobulinemia E-recurrent infection (Job's) syndrome. Similarity to previous cases of esophageal cryptococcosis and ileocecal histoplasmosis suggests an association between the hyperimmunoglobulinemia E-recurrent infection syndrome and localized fungal infections of the alimentary tract. To our knowledge, this is the first well-documented case of cryptococcosis confined to the colon and perirectal tissues.

Adult↗

Oral fluconazole therapy for patients with acquired immunodeficiency syndrome and cryptococcosis: experience with 22 patients.

PURPOSE: Cryptococcus neoformans causes infections in up to 10 percent of patients with the acquired immunodeficiency syndrome (AIDS). Nearly 50 percent of AIDS patients with previously treated cryptococcal meningitis will experience a relapse within six months. To reduce the likelihood of relapse, a maintenance regimen of amphotericin B is often administered weekly. However, the drug's intravenous route of administration and considerable toxicity have led to a search for alternative antifungal agents. In this report, we document our experience with fluconazole, a new oral triazole antifungal agent. PATIENTS AND METHODS: Twenty-two patients with AIDS and various forms of cryptococcosis were treated in an open-label study with 50 to 400 mg/day of fluconazole. The following laboratory studies were done on a monthly basis: complete blood cell count, liver function tests, serum creatinine level, serum cryptococcal antigen level, and serum fluconazole level. Lumbar puncture was performed in patients with meningitis every four to eight weeks to evaluate cerebrospinal fluid cryptococcal antigen, India ink preparation findings, fungal culture, fluconazole level, and protein, glucose, and cell count. RESULTS: Of seven patients with active culture-positive infections, four showed clinical and microbiologic responses (three of four with meningitis, one of three with extraneural cryptococcosis). Fifteen patients who had already undergone successful amphotericin B therapy for either meningitis (n = 14) or pneumonia (n = 1) received fluconazole as prophylaxis against relapse. Fourteen patients remained free of infection during 11 to 64 weeks of suppressive therapy; one patient with meningitis experienced relapse after 26 weeks of treatment. Reverse reactions were limited to increases in hepatic enzyme levels in four patients. CONCLUSION: These results appear sufficiently encouraging to warrant further trials of this oral agent in the suppression of chronic cryptococcosis and perhaps in the treatment of acute infection.

Acquired Immunodeficiency Syndrome↗

Isolated pulmonary cryptococcosis in pregnancy.

BACKGROUND: Isolated pulmonary cryptococcosis in an immunocompetent parturient host is a rare event. Little is known about this condition, its prognosis, and its treatment in the immunocompetent pregnant woman. CASE: A 28-year-old woman, para 3, was diagnosed with isolated pulmonary cryptococcosis postpartum. She had delivered a healthy neonate at term who revealed no clinical features compatible with maternal-fetal transmission. The woman was monitored closely throughout the course of her disease and radiogic, clinical, and serologic resolution was achieved after treatment with fluconazole. CONCLUSION: Patients with pulmonary cryptococcosis present with clinical pictures similar to other well-known diseases such as septic pulmonary emboli or choriocarcinoma. Treatment with triazole antifungal therapy yielded favorable results in our patient with this rare condition.

Adult↗

Experience with itraconazole in cryptococcosis and aspergillosis.

Cryptococcosis and aspergillosis in immunocompromised patients are extremely difficult clinical conditions to manage and treatment with available antifungal drugs often fails. Itraconazole, R-51211, Janssen Pharmaceutica, a new orally absorbed triazole, is a possible alternative drug which is potentially effective and nontoxic. Preliminary experience with 28 patients, eight with cryptococcosis and 20 with aspergillosis, is reported. Of these patients, 16 were immunocompromised (seven with the acquired immune-deficiency syndrome (AIDS), five heart transplant recipients and four with leukaemia or lymphoma). Overall, results of treatment were good (18 in remission, four markedly improved, four moderately improved and two failed). Prevention of relapses of cryptococcosis was obtained in all patients with AIDS on long-term itraconazole monotherapy (3 mg/kg). Treatment of invasive aspergillosis required a higher dosage (about 5 mg/kg) and prolonged administration. Besides its efficacy this antifungal agent allowed outpatient management.

Acquired Immunodeficiency Syndrome↗

Treatment of non-meningeal cryptococcosis in patients with AIDS. Centre d'Informations et de Soins de l'Immunodéficience Humaine de l'Est Parisien.

Amphotericin B, alone or combined with flucytosine, is the reference curative treatment for neuromeningeal cryptococcosis associated with the acquired immune deficiency syndrome (AIDS). Treatment of non-meningeal forms is less well standardized. Out of 75 human immunodeficiency virus (HIV)-infected patients with cryptococcosis, 16 had no meningeal involvement. One died before receiving any treatment, another received amphotericine B and recovered, and the remaining 14 received curative therapy with fluconazole (200-400 mg/day); 11 of the latter entered complete remission, while three deteriorated during the first week of treatment but recovered on amphotericin B combined, in two cases, with fluconazole. Only one relapse occurred during maintenance treatment with low-dose fluconazole (100 mg/day). No adverse effects of fluconazole treatment were observed. One of the patients on amphotericin B developed acute renal impairment requiring drug withdrawal. These results suggest that first-line fluconazole therapy is effective and well tolerated in patients with AIDS-associated non meningeal cryptococcosis.

AIDS-Related Opportunistic Infections↗

Pulmonary cryptococcosis due to a capsule-deficient strain confused with metastatic lung cancer.

A patient with hepatocellular cancer developed pulmonary cryptococcosis due to infection with a capsule-deficient Cryptococcus neoformans. Pulmonary lesions initially diagnosed as metastatic cancer by chest x-ray film and CT scan were subsequently found to be fungal granulomas by autopsy. Although morphologic studies of the fungi were insufficient to render a specific mycologic diagnosis because of the absence of encapsulated yeasts, fluorescent antibody studies confirmed the diagnosis of cryptococcosis. The use of various stains and electron microscopy for the pathological differential diagnosis of cryptococcosis caused by capsule-deficient yeasts is discussed.

Carcinoma, Hepatocellular↗

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.

AIDS-Related Opportunistic Infections↗

Pulmonary cryptococcosis: a case report and review of the Asian-Pacific experience.

Pulmonary cryptococcosis is a very rare form of pneumonia, which is seldom seen among immunocompetent patients. We report the case of a 36-year-old man who presented with indolent pneumonia that was subsequently diagnosed to be pulmonary cryptococcosis without other systemic involvement. Contrary to formal belief, there was evidence of residual lung fibrosis 12 months after initial presentation. The features of pulmonary cryptococcosis reported in the Asian Pacific region are also reviewed.

Adult↗

Intracranial granuloma and skull osteolysis: complication of a primary cutaneous cryptococcosis in a kidney transplant recipient.

Cryptococcosis is the third most common invasive fungal infection in organ transplant recipients after candidiasis and aspergillosis. It occurs almost exclusively in the late posttransplantation period (>6 months after the initiation of immunosuppression). Subclinical onset of meningitis is the usual clinical presentation. Despite initiation of therapy, the mortality rate associated with this infection in this patient population remains high. To the best of our knowledge, this report describes one of the first cases of a rare entity: a primary cutaneous cryptococcosis in a renal transplant recipient disclosed by skull osteomyelitis and pseudotumoral intracranial extension. Surgical debridement and azole antifungal therapy were performed. Ten months after the onset of treatment, the patient feels good, clinical examination findings are normal, and no sign of evolutive cryptococcosis is noted.

Abscess↗

Analysis of antibody response to Cryptococcus neoformans in five patients with AIDS and cryptococcosis by immunoblotting.

OBJECTIVES: The serological response of five patients with AIDS and cryptococcosis to non capsular antigens from Cryptococcus neoformans var. neoformans has been investigated. METHODS: Pressates of different isolates of C. neoformans were used as antigenic preparation for immunoblotting of patient samples. RESULTS: Multiple sera and cerebrospinal fluids sequentially collected from five AIDS patients with cryptococcosis showed a wide heterogeneity in antibody response with bands at 48. 43, 38 and 26 kD being present in all clinical samples of all five patients. The variation in banding patterns of the sequential samples from three patients was correlated with a decrease of the antigen titre and with an amelioration of the cryptococcal infection. CONCLUSIONS: We identified antibodies to four immunodominant non-capsular antigens, which might represent major target molecules of the humoral response of patients with cryptococcosis.

AIDS-Related Opportunistic Infections↗

Clinical and radiographic presentations of pulmonary cryptococcosis in immunocompetent patients.

Pulmonary cryptococcosis is often noted in immunocompromized patients, especially in HIV-seropositive patients and post-transplant patients. Only a few case reports and small-scale studies on pulmonary cryptococcosis in immunocompetent patients have been published in the English literature. However, there are several areas of uncertainty in this group of patients including image presentations and management strategy. This retrospective study including 17 patients is designed to share our 7 y of experience in clarifying the characteristics of pulmonary cryptococcosis in immunocompetent patients, including initial symptoms, diagnostic criteria, pulmonary imaging, treatment and outcome in a tertiary teaching hospital in Taiwan.

Adult↗

Cryptococcosis in India: the awakening of a giant?

The menace of cryptococcosis has assumed global proportions over the years. The tropical climate of the Indian subcontinent offers a suitable environment for Cryptococcus neoformans, and the onslaught of the acquired immune deficiency syndrome (AIDS) pandemic since the early 1990s has substantially influenced the situation. Coupled with that are the advances in laboratory diagnostic techniques that have made accurate diagnosis increasingly available. These factors together have led to a sharp increase in the number of reported cases of cryptococcosis. This review attempts to present an overview of the status of cryptococcosis in India from its first description to the most recent times. The disease has been reported from almost all parts of the country. C. neoformans var. neoformans is predominantly found in clinical samples, while C. n. var. gattii infection has also been reported. An organ commonly involved is the central nervous system, among others. Both immunocompromised and apparently immunocompetent patients have been affected. Laboratory diagnosis is mostly by conventional methods, while effective therapeutic options are limited. Early diagnosis followed by institution of specific therapy, where possible, has effectively reduced mortality. Awareness of the disease and maintenance of a high index of clinical suspicion is required. An integrated approach to patient management with active interaction between the clinicians and the laboratory personnel would be highly beneficial. The wide variety of presentations of the disease seen in India suggests the possibility of occurrence of strain variation which needs to be investigated fully. Introduction of routine testing of antifungal susceptibility of clinical isolates is also important in order to obtain baseline data on susceptibility patterns and to predict in advance any shift in those patterns in the population. To maintain a high standard in all such endeavours, the establishment of an external quality control system is desirable.

AIDS-Related Opportunistic Infections↗

Levels of L-selectin (CD62L) on human leukocytes in disseminated cryptococcosis with and without associated HIV-1 infection.

Patients with disseminated cryptococcosis typically have measurable levels of cryptococcal polysaccharide in serum samples but minimal leukocyte infiltration into infected tissues. In vitro data have shown that cryptococcal polysaccharide induces L-selectin (CD62L) shedding from leukocytes. To assess shedding in vivo, we compared leukocyte L-selectin levels in human immunodeficiency virus (HIV) type 1-negative and -positive subjects with and without circulating cryptococcal polysaccharide. Results showed that subjects with cryptococcal polysaccharide in serum samples have significantly lower percentages of neutrophils, monocytes, and CD3+ T cells with L-selectin on their surfaces than do healthy subjects, regardless of HIV status. There was significantly more soluble L-selectin in serum samples from subjects with cryptococcosis than in those from uninfected subjects. Reduced L-selectin levels on leukocytes in subjects with circulating cryptococcal polysaccharide and increased serum levels of soluble L-selectin indicates that surface L-selectin shedding is a mechanism that likely explains reduced leukocyte extravasation into infected tissues of patients with disseminated cryptococcosis.

Adult↗

Cryptococcosis in children with AIDS.

We compiled the clinical and immunologic features of Cryptococcus neoformans infections in human immunodeficiency virus (HIV)-infected children from 1985 to 1996 in a retrospective case series. Thirty cases of cryptococcosis were identified. These children had a median age of 9.8 years, a median CD4+ cell count of 54/microL at the time of diagnosis, and either a culture positive for C. neoformans or cryptococcal antigen in serum or cerebrospinal fluid. Sixty-three percent of the cases occurred in children vertically infected with HIV and in children between 6 and 12 years of age. The clinical and laboratory characteristics of this pediatric cohort were similar to those of adults with AIDS and cryptococcosis. On the basis of a subset of the cases, a 10-year point prevalence of cryptococcosis among children with AIDS of approximately 1% was estimated.

AIDS-Related Opportunistic Infections↗

The ecology of Cryptococcus neoformans and the epidemiology of cryptococcosis.

The ecology of Cryptococcus neoformans and the epidemiology of cryptococcosis are reviewed. Two varieties of C. neoformans have been recognized. C. neoformans variety neoformans has been found in nature worldwide, primarily in association with bird droppings, although nonavian sources have also been found. Most cases of human cryptococcosis are caused by this variety. C. neoformans var. gattii has recently been isolated in nature in association with Eucalyptus trees. Infections caused by this variety occur mainly in tropical and subtropical regions. Because exposure to C. neoformans is probably common and clinically apparent cases of cryptococcosis in healthy hosts are rare, it is presumed that most people can mount adequate host defenses upon exposure to the organism. At least 5%-10% of patients with AIDS become infected with Cryptococcus; the epidemiology of this infection is different in many respects from that seen in patients without AIDS.

Acquired Immunodeficiency Syndrome↗

Clinical epidemiological study of 171 cases of cryptococcosis.

We retrospectively studied 171 patients with cryptococcosis who were divided into three groups according to their associated predisposing conditions (if any): group 1 comprised nonimmunosuppressed patients, group 2 comprised patients with AIDS, and group 3 comprised those patients with other conditions and/or who were users of immunosuppressive drugs. Analysis and correlation of the behavior of the mycosis among the three groups showed differences in the demographic data, clinical forms and manifestations of cryptococcosis, laboratory results, morbidity and mortality rates, and histopathologic aspects. Study of the clinical isolates of Cryptococcus neoformans from 83 patients with cryptococcosis showed that 75 were characterized as C. neoformans variety neoformans and eight as C. neoformans var. gatti. Comparison of the distribution of the gattii and neoformans varieties between the nonimmunosuppressed (group 1) and immunosuppressed (groups 2 and 3) patients showed a significant statistical difference (P < .01).

AIDS-Related Opportunistic Infections↗