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Cutaneous cryptococcosis as the first symptom of a disseminated cryptococcosis in a patient with lymphogranulomatosis X.

A 63-year-old patient, known to have suffered from lymphogranulomatosis X for 4 years is reported, in whom a cutaneous cryptococcosis appeared as first sign of a disseminated cryptococcosis. Despite systemic therapy with amphotericin B, the patient died after a period of 2 months. Differential diagnosis of skin tumours of immunosuppressed patients includes rare skin mycoses, and both histological and mycological examinations should be performed.

Cryptococcosis

Immunosuppression in experimental cryptococcosis in rats: modification of macrophage functions by T suppressor cells. Macrophages functions in cryptococcosis.

The influence of lymphocytes on the modulation of macrophage functions in altered immune states induced by Cryptococcus neoformans infection in rats has been investigated. In this report we observed a decrease of 'in vitro' phagocytic activity by peritoneal cells (PC) from rats that received T suppressor cells induced by cryptococcal infection, against both the same microorganism that stimulated this suppressor population (p less than 0.05) and another non-pathogenic primary yeast (Candida tropicalis), (p less than 0.02). The microbicide function of the PC from these animals present a significant decrease in challenge by C. tropicalis (p less than 0.002) when compared with PC from animals transferred with T normal cells. The transference of T suppressor cells induced by cryptococcal infection in animals immunized with human serum albumin-complete Freund's adjuvant (HSA-CFA) produces a significant alteration of the phagocytosis to HSA-human red cells (HSA-HRC) when compared with the phagocytosis observed in animals that received T normal cells or the phagocytosis of normal animals (p less than 0.001). We could also observe that the DTH to HSA studied during 30 days was negative in rats transferred with PC sensitizated with HSA and treated with suppressor T cells, when compared with the DTH response of animals transferred with PC-HSA cocultured with normal cells (p less than 0.05 21st day). The data presented in this paper illustrated that following infection of rats with C. neoformans there is a change in some population of accessory cells behavior reflected by the modification of several functions, such as phagocytosis, lytic activity and antigen presentation.

Animals

Itraconazole therapy for cryptococcal meningitis and cryptococcosis.

We studied the efficacy of itraconazole, a new oral triazole, in 33 patients (32 were immunocompromised) with cryptococcosis. Diagnoses included cryptococcal meningitis (24 patients), cryptococcemia (19 patients), cryptococcuria (4 patients), osteomyelitis (1 patient), pulmonary cryptococcosis (1 patient), and soft-tissue cryptococcosis (2 patients). Twenty-six patients had the acquired immunodeficiency syndrome, and 4 were transplant recipients. Therapy (200 mg two times per day) was monitored by clinical response, culture, and cryptococcal antigen testing. Cryptococcemia was abolished in 10 (100%) of 10 assessable patients; clinical abnormalities also cleared. Thirteen (65%) of 20 assessable patients with cryptococcal meningitis had complete responses (clinical resolution and negative cultures), 5 (25%) had partial responses, and therapy failed in 2 (10%). Ten (71%) of 14 patients with the acquired immunodeficiency syndrome who had meningitis and were treated with itraconazole as their sole therapy had complete responses, 3 (21%) had partial responses, and therapy failed in 1 (7%). Partial responses or failures were all associated with the failure of previous therapy, severe disease, low serum itraconazole concentrations, or a resistant organism. Noncompliance was associated with relapse (4 patients). Meningitis recrudesced in 3 (20%) of 15 patients who responded to therapy. All 4 patients with pulmonary cryptococcosis, soft-tissue cryptococcosis, or osteomyelitis responded to therapy (100%). Cryptococcuria was abolished in 3 (60%) of 5 assessable patients. The median survival of the 20 patients with the acquired immunodeficiency syndrome who had meningitis exceeded 10.5 months at this writing. Overall results compare favorably with amphotericin B therapy with or without flucytosine. Forty of 44 isolates of Cryptococcus neoformans were susceptible in vitro to itraconazole (minimum inhibitory concentration less than or equal to 3.13 mg/L), 3 were borderline (minimum inhibitory concentration, 6.25 mg/L), and 1 was resistant (minimum inhibitory concentration, 12.5 mg/L). As itraconazole does not penetrate cerebrospinal fluid, the meningitis results are noteworthy and suggest that meningeal and parenchymal penetration is critical. Itraconazole is promising for the treatment of cryptococcosis in patients with and without the acquired immunodeficiency syndrome.

Acquired Immunodeficiency Syndrome

CSF in 85 patients with AIDS and CNS cryptococcosis.

In an eight years time period (July 1984-June 1992) CSF samples of 40718 patients were studied, and 610 were from patients with AIDS clinically diagnosed and immunologically confirmed through HIV antibodies detection. Among opportunistic infections detected in them 85 were CNS cryptococcosis. For the purpose of this study the CSF of these 85 patients are the AIDS group of CNS cryptococcosis. For comparison, CSF data from 50 patients with CNS cryptococcosis but without AIDS were taken (non-AIDS group); in this group, 22 patients were immunosuppressed after renal transplant. In AIDS group, the more frequent CSF findings were: yeast presence at direct exam (Fuchs-Rosenthal cell counting chamber), growing of the yeast in cultures, and gamma globulins increase. In non-AIDS group were more frequent: hypercytosis, neutrophil cells presence, and total protein increase. Differences between the two groups are discussed taking into account CNS/CSF immune changes induced by HIV infection. It is concluded that in CNS cryptococcosis of patients with AIDS the CSF evidenced more extensive signs of the fungal opportunistic infection than signs of inflammatory response to the infection. The latter were more prominent among patients of the non-AIDS group of CNS cryptococcosis.

Acquired Immunodeficiency Syndrome

Prevalence of HTLV-I antibody in pulmonary cryptococcosis.

A retrospective study was done to determine the prevalence of anti-HTLV-I antibodies in patients with pulmonary cryptococcosis. None of the 19 patients with pulmonary cryptococcosis had underlying immunodeficiency. Anti-HTLV-I antibody was present in 6 (32%) of 19 patients with pulmonary cryptococcosis, a significantly higher prevalence than found in patients with bronchial asthma (4 (7%) of 58) (p less than 0.01, chi-square test). No statistical difference was noted when anti-HTLV-I antibody seropositivity was compared to that of patients with pulmonary tuberculosis (16% (17/105)), lung cancer (17% (22/129)) and pneumonia (9% (6/64)). A reduced cellular immunity as shown by lymphopenia, the CD4/CD8 ratio, and purified protein derivative skin test was found in only 1 (5%) of 19, 2 (12%) of 17, and 6 (33%) of 18 patients, respectively. These results do not explain the susceptibility to pulmonary cryptococcosis in HTLV-I carriers. This is the first report of high prevalence of pulmonary cryptococcosis in HTLV-I carriers and it raises the question whether HTLV-I carriers are more susceptible to opportunistic infections and other malignancies probably due to subtle immunological abnormalities.

Adolescent

Current concepts in cryptococcosis.

Cryptococcus neoformans has become an increasingly important pathogen. Cryptococcosis is an important cause of morbidity and mortality in immunocompromised hosts and is the second most common fungal infection complicating AIDS. In recent years, research has focused on the host defenses against Cryptococcus and has led to an improved understanding of the capsular virulence of the organism, the mechanisms of T-cell defenses, and the role of phagocytic cells in the fungistasis and killing of cryptocci. Amphotericin B with or without flucytosine has clearly improved treatment of cryptococcosis, but therapy is associated with significant toxicity. Current investigation is focused on the triazoles, which may offer improved therapy for cryptococcosis. In this report, we review recent developments in the understanding of the host defenses against Cryptococcocus and discuss current recommendations for the management of cryptococcosis.

Acquired Immunodeficiency Syndrome

Oral fluconazole as suppressive therapy of disseminated cryptococcosis in patients with acquired immunodeficiency syndrome.

PURPOSE: Because of the increasing numbers of patients with acquired immunodeficiency syndrome (AIDS) who will require treatment for cryptococcosis and because of the problems associated with long-term administration of intravenous amphotericin B, an alternative therapeutic approach in the form of an efficacious and easily administered oral antifungal drug would be of great benefit. Fluconazole, a new triazole antifungal agent, represents such an alternative. We therefore conducted an open, non-randomized trial of oral fluconazole as maintenance suppressive therapy of disseminated cryptococcosis in patients with AIDS. PATIENTS AND METHODS: Twenty patients with AIDS, 19 of whom had cryptococcal meningitis, were studied. Patients were followed for up to 21 months. All patients received amphotericin B as primary therapy, from 20 to 257 days prior to entry (500 to 5,080 mg total dose). Eight also received flucytosine. After administration of amphotericin B for acute disseminated cryptococcosis, and prior to initiation of fluconazole therapy, Cryptococcus neoformans was isolated from the cerebrospinal fluid (CSF) in two patients and from the blood in one patient. Fluconazole was given once daily, in doses of 50 to 200 mg/day. RESULTS: Following initiation of fluconazole, results of CSF and blood cultures continued to be negative, except for the CSF culture in one patient who had a relapse in the 32nd week of therapy. Fluconazole therapy has been successfully continued in nine patients, for a median of 11 months (nine to 21 months). Seven patients died; five had no evidence of active cryptococcosis at the time of death. Two patients had a relapse, although the CSF culture showed growth of the fungus in only one patient. One patient was lost to follow-up after five months of therapy and one was unevaluable. Fluconazole had to be discontinued in only one patient in whom thrombocytopenia developed, and then resolved when the drug was stopped. CONCLUSION: We conclude that oral fluconazole represents a significant advance in the management of cryptococcal meningitis and should be useful in the long-term suppressive therapy of this opportunistic infection in patients with AIDS.

Acquired Immunodeficiency Syndrome

Cryptococcosis in seven horses.

The clinical, radiographic and post-mortem findings in 6 horses with cryptococcal pneumonia and one horse with an abdominal cryptococcal granuloma are described. In pulmonary cryptococcosis, the lesions were either diffuse and multiple, with bilateral lung involvement, or localised mainly to the dorsocaudal region of one lung. The cases of diffuse multiple cryptococcosis were thought to be associated with haematogenous spread of the fungus after gastrointestinal infection and dissemination from regional lymph nodes. The localised form of the disease was thought to have been associated with inhalation of cryptococci. In all cases of pulmonary cryptococcosis, encapsulated yeast-like organisms were demonstrated in Wright's-stained sediment of tracheal washes. In the horse with the abdominal granuloma, cryptococci were present in a fine needle aspirate sample. Isolates of Cryptococcus neoformans var gattii were recovered from 2 of the 5 horses in which cultures were attempted. In addition to a history of previous illness that may have predisposed to infection, most horses in this report had been in areas in which Eucalyptus camaldulensis, or the closely related E rudis, were growing. In humans, an epidemiological relationship between E camaldulensis and infection with C neoformans var gattii has been suggested. Cases of equine cryptococcosis carry a poor prognosis and treatment was not attempted in any of these cases.

Abdomen

Improvement of amphotericin B activity during experimental cryptococcosis by incorporation into specific immunoliposomes.

Cryptococcosis is an opportunistic infection that is responsible for increased morbidity and mortality in patients with the acquired immunodeficiency syndrome. The high toxicity of the antifungal agent that is mainly used against cryptococcosis, amphotericin B (AMB), accounts for the need for new treatments, especially in patients with the acquired immunodeficiency syndrome because of the high relapse rate of cryptococcosis. Drug targeting may be one of these alternate treatments. Since we have demonstrated that an immunoglobulin G1 (IgG1) anti-Cryptococcus neoformans serotype A monoclonal antibody (E1) was protective during experimental cryptococcosis in mice, we investigated whether specific targeting of AMB with liposomes that bear E1 would improve the therapeutic index of the drug. For that purpose, in vitro and in vivo experiments were designed to compare the specificities and activities of these liposomes with those of control immunoliposomes bearing a nonrelated IgG1 monoclonal antibody (CY34). The immunoliposomes were prepared by covalently linking E1 or CY34 and small unilamellar vesicles. When immunoliposomes were incubated with yeast cells, only E1-bearing liposomes recognized C. neoformans. In vivo, mice that were treated 24 h after infection with one injection of AMB (0.12 mg/kg of body weight) intercalated into E1-bearing liposomes survived significantly longer than did those given the same dose of AMB alone or AMB intercalated into nontargeted liposomes or control immunoliposomes. None of the mice that were given control treatments did statistically better than those that were given AMB. Keeping in mind that this kind of therapy requires knowledge of the antigenic type of the infecting organism, the results suggest that specific targeting of small doses of AMB improve the efficacy of AMB and might be an alternative to the use of larger doses of AMB.

Amphotericin B

Cutaneous manifestations of disseminated cryptococcosis.

Five patients with disseminated cryptococcosis had lesions on the extremities resembling cellulitis, which evolved into areas of blistering and ulceration in three patients. All had underlying disease and were medically immunosuppressed. Disseminated cryptococcosis appears to present with cellulitis or herpes-like vesiculation more commonly than is currently appreciated. India ink preparations of aspirates from areas of cellulitis or Tzanck preparations from blisters may show characteristic organisms, and make possible an immediate diagnosis of cutaneous cryptococcosis. If cutaneous infection is confirmed by performing biopsies and growing cultures, dissemination must be presumed and the patient treated with a full course of systemic antifungal therapy. With increasing awareness of cutaneous involvement, some cases of disseminated cryptococcosis will be diagnosed sooner, leading to earlier therapy and improved prognosis.

Adolescent

[Cryptococcosis: presentation of 26 cases].

BACKGROUND: Cryptococcosis is more frequently observed since the appearance of the acquired immunodeficiency syndrome (AIDS). AIDS has modified the clinical and evolutive forms of the disease. This study reviews the changes produced in the infection from the context of AIDS. METHODS: The present is a retrospective study (1985-1990) including patients presenting: 1) a positive latex agglutination test (serum or spinal fluid) or 2) a Sabouraud culture positive for cryptococcus. Clinical histories were revised collecting clinical, radiologic, analytic, therapeutic and evolutive data. RESULTS: Twenty-six patients (21 males) were included in the study. Twenty patients had the human immunodeficiency virus. The clinical picture was: 22 cases with cryptococcal meningitis (13 with hematogenous participation), 3 with pulmonary cryptococcosis and one with disseminated cryptococcosis without meningeal involvement. The patients with AIDS had: greater frequency of positive hemocultures, higher serologic titers and fewer with the meningeal syndrome. The number of T4 lymphocytes was lower than 150 elements/ml in AIDS patients. In 17 patients treatment with amphotericin B and 5-fluorocytosine was administered, 5 received amphotericin B and two fluconazole and two did not receive the above since they had not been diagnosed alive. There were 6 deaths and 10 relapses in 6 AIDS patients and none in the remaining patients. CONCLUSIONS: The incidence of cryptococcosis has increased as a consequence of AIDS. In these patients the disease occurs in advanced stages of immunodeficiency and frequently in disseminated, severe and paucisymptomatic forms. Treatment is usually effective although a maintenance therapy is required to avoid relapse.

Acquired Immunodeficiency Syndrome

[Cryptococcosis of the central nervous system. Clinical and diagnostic characteristics].

BACKGROUND: Evaluation of the clinical features and diagnostic methods in the cryptococcosis of central nervous system (CNS), so as to facilitate a rapid recognition which may result in earlier diagnosis in view of the rapid increase in frequency shown in that condition. METHODS: A retrospective study of 13 patients with CNS cryptococcosis seen during the last 4 years. The isolation of C. neoformans in CSF, cerebral biopsy or other appropriate tissue was required for inclusion. The following were evaluated: 1) Age, sex, and underlying disease; 2) Clinical features; 3) Yield of biochemical, microbiological, pathological and imaging diagnostic procedures; 4) Treatment and evolution. RESULTS: Age (X +/- SD): 37 +/- 20 years (range: 15-81). Sex: 77% males. Underlying disease was identified in 10 cases (77%): HIV infection in 7 (54%), diabetes mellitus in 2, alcohol abuse in 2, systemic erythematous lupus on corticoid and immunosuppressant therapy in 1 and chronic liver disease in 1. Clinical features on admission: abnormal behaviour in 10 (77%), headache in 10, low/high grade fever in 9 (69%), abnormal consciousness in 7, respiratory features in 5 (38%); motor deficit, cranial nerve involvement and visual abnormalities in 4 (31%) each; and meningeal signs in 3. Investigation of CSF was carried out in 12 cases. The biochemical studies were normal in 5 (42%). China ink stain was positive in 55% of cases, and latex agglutination in 80%. CSF culture was diagnostic in 92% of cases and the culture for C. neoformans was positive in 2 cerebral and one pulmonary biopsies and in two urine cultures. All patients were treated with amphotericin B and flucytosine was associated in 9. Two patients were subsequently treated with fluconazole. The outcome was good in 8 patients, and 4 had sequelae. One case relapsed. CONCLUSIONS: 1) HIV infection is the most common underlying disease. 2) There is a high rate of CNS cryptococcosis with normal CSF or with mild biochemical abnormalities. 3) The yield of the microbiological studies of CSF is high, with diagnostic confirmation in 92% of cases. 4) Differences in CNS cryptococcosis were not found between cases with HIV infection and those with other underlying diseases.

Adolescent

Evaluation of ketoconazole and itraconazole for treatment of disseminated cryptococcosis in cats.

During the first part of a study, cats were inoculated with Cryptococcus neoformans via the following routes: intradermal, intranasal, IV, and intracisternal. Only use of the IV route of inoculation consistently induced disseminated cryptococcosis. In the second part of the study, disseminated cryptococcosis was experimentally induced in cats via IV inoculation of C neoformans. One month after inoculation, 3 cats were treated with ketoconazole (10 mg/kg of body weight/d) and 3 cats were treated with itraconazole (10 mg/kg/d) for 3 months. One of the ketoconazole-treated and 2 of the itraconazole-treated cats also had cryptococcosis of the CNS when treatment was begun. During treatment, serum cryptococcal antigen titer progressively decreased in all cats. Abnormalities in CBC values or the serum biochemical profile were not found in any cat during treatment. However, all ketoconazole-treated cats became anorectic and lost weight. Side effects were not seen in itraconazole-treated cats. During the 3-month posttreatment observation period, all cats remained healthy. At necropsy, histologic evidence of cryptococcosis was not found in the 3 ketoconazole-treated cats or in 2 of the itraconazole-treated cats. In the third itraconazole-treated cat, cryptococcal organisms were found in the kidneys.

Animals

Clinical evaluation of a cryptococcal antigen latex agglutination test for diagnosis of cryptococcosis in cats.

A commercial cryptococcal antigen latex agglutination test was used to evaluate sera from 20 cats with cryptococcosis and 184 cats without cryptococcosis. Cryptococcal antigen was detected in the sera from 19 of 20 cats with cryptococcosis. Antigen was not detected in sera from any of the cats without cryptococcosis. The test had sensitivity of 95% and specificity of 100%.

Animals

[The clinical study of fluconazole against pulmonary mycosis. Effects of fluconazole on pulmonary cryptococcosis and aspergillosis, and its pharmacokinetics in patients].

Effects on pulmonary cryptococcosis and aspergillosis and the pharmacokinetics of the new antimycotic agent, fluconazole, were examined. 1. Cases Pulmonary cryptococcosis: Two cases, 30 and 29 year-old men who were suspected of pulmonary tuberculosis by routine health examinations. Pulmonary aspergillosis: A 65 year-old man with collagen disease and a 62 year-old man with bacilli free cavities of tuberculosis. 2. Method Fluconazole was administered at a dose level of 400 mg/day per os for 2 to 4 weeks. One exception was the 65 year-old aspergillosis patient who was administered with fluconazole 50 mg/day for 4 weeks, 100 mg/day for 6 weeks then 400 mg/day for 4 weeks. Sera of the cases 1, 2 and 4 were harvested before, and 1/2, 1, 2, 4, 8 and 24 hours after administration of fluconazole on the 1st and the 7th day, and in every morning until the 9th day before administration and stored in a freezer. Serum fluconazole concentrations were determined at Pfizer Taito Laboratory. As pharmacodynamic parameters, T1/2, Tmax and Cmax were calculated. 3. Result Effects of fluconazole on 2 of the 2 cases with cryptococcosis were excellent. On the other hand, the effects on the aspergillosis were poor. The average Tmax was 2-4 hours. The average C maxs were 10.3 micrograms/ml on the 1st day and 30.6 micrograms/ml on the 7th day. Serum concentrations reached the plateau on the 5th-7th day, and the average C min (concentration before administration) was 21-23 micrograms/ml. Average T1/2s were 34.4 hours on the 1st day and 37.2 hours on the last (32th) day. 4. Conclusion Fluconazole may be regarded as the promising remedy for pulmonary cryptococcosis but not for pulmonary aspergillosis.

Adult

Large mass-like pulmonary cryptococcosis: report of 2 cases.

Pulmonary cryptococcosis, a less common fungal infection, frequently reveals nodular lesions (single or multiple) and patchy infiltrations (alveolar or interstitial) on chest X rays. A large mass-like pattern is less common. Here we report 2 cases of pulmonary cryptococcosis with negative bronchoscopic findings. One patient received a right lower lobectomy under the impression of malignancy; the other received a transthoracic needle aspiration, and numerous cryptococci were found by India ink preparation. Thus, pulmonary cryptococcosis should be included in the differential diagnosis of a mass lesion. A brief review of the literature is also included about diagnostic approach and management of pulmonary cryptococcosis.

Cryptococcosis

Cryptococcosis in a cancer hospital: clinical and pathological correlates in forty-six patients.

The clinical and pathological findings in 46 patients with cryptococcosis at Memorial Sloan-Kettering Cancer Center from 1956 to 1972 are reported. The striking predilection for cryptococcal infection in patients with leukemias and lymphomas is again confirmed. Of 41 patients with neoplastic disease, those with chronic lymphatic leukemia (CLL), Hodgkin's Disease, chronic myelogenous leukemia (CML), myeloma and lymphosarcoma had the highest incidence of cryptococcosis. In all cases, neoplastic disease was widespread when infection occurred. All of these patients had leukopenia and absolute lymphopenia at the time of infection. Thirty-nine were on steroids. Thirty-one patients with neoplastic disease had disseminated infection. Review of pathology revealed a spectrum of inflammatory lesions. Histiocytic-lymphocytic infiltrates occurred in the central nervous system in 10 patients. In six cases, reaction was granulomatous. There were single instances of suppurative and fibrotic reactions. Mortality from infection was high in patients with neoplastic disease. Twenty-four of 28 deaths occurred within 60 days as a result of infection. Within one year, 10 more patients died, nine of cryptococcosis. Only three survived more than one year, and all patients died within 600 days. Twenty-nine patients with neoplastic disease received amphotericin B. Only nine survived more than 60 days.

Amphotericin B