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Disseminated African histoplasmosis in a Congolese patient with AIDS.

We report the first Congolese case of African histoplasmosis in a patient with AIDS which represents the third case to be described in the literature. This contrasts with the now frequent occurrence of Histoplasma capsulatum histoplasmosis in HIV-infected subjects in North America; the difference is likely to be due to differences in exposure to the fungus rather than to differences in behaviour of the fungus or in the epidemiology of HIV.

Acquired Immunodeficiency Syndrome↗

Effects of CD4 and CD8 T lymphocyte depletion on the course of histoplasmosis following pulmonary challenge.

Use of a pulmonary model of histoplasmosis in CD4/CD8 lymphocyte depleted animals offers an opportunity to study pathogenesis in a setting resembling AIDS. Flow cytometric analysis demonstrated that administration of anti-CD4 and anti-CD8 antibodies reduced CD4 and CD8 T cell subsets in the lungs, lymph nodes and spleen. Depletion of these cells transformed the infection from a self-limited course in normal mice to a progressive, fatal course in CD4/CD8 depleted mice. CD4 depletion alone had a lesser effect on survival, but increased fungal burden, while CD4/CD8 depletion had the greatest effect. Histopathologic studies showed marked differences in the inflammatory response between the dually depleted animals and the non-depleted controls. In conclusion, the course of histoplasmosis in CD4/CD8 depleted animals is progressive and fatal, resembling that observed in immunosuppressed patients. This model appears suitable for investigation of immunity to H. capsulatum, and should be useful for evaluation of treatment in the immunocompromised host.

Animals↗

Effect of CD40 ligand on the course of murine histoplasmosis.

CD40 ligand-CD40 ligation is important in the development of T-cell-mediated immune responses. The purpose of this study was to examine the role of CD40L in recovery from histoplasmosis using a murine model of intratracheally induced infection. B6C3F1 mice were infected intratracheally with Histoplasma capsulatum yeast and monitored for clearance of the organism from the lungs and spleen. CD40L treatment was begun on either day -2 or +2 post inoculation and continued until day 14 in CD4-depleted animals and from day -2 to day +4 in non-immunosuppressed animals. Amphotericin B treatment was begun four days following inoculation and given every other day for 10 days. CD40L reduced fungal burden by less than one log when started two days before infection but did not act synergistically with low-dosage amphotericin B (0.2 mg kg(-1) qod) in CD4 depleted mice. Low-dose amphotericin B, CD40L, and the combination of the two failed to lower the fungal burden in a second experiment using a more virulent isolate of the same strain of H. capsulatum in CD4-depleted mice. Furthermore, CD40L did not increase the concentrations of IFN-gamma, IL-12 or IL-10 in the lungs or spleens of infected animals. In summary, CD40L had minimal or no effect on the course of infection in this murine model of histoplasmosis.

Animals↗

Factors associated with severe manifestations of histoplasmosis in AIDS.

We report factors associated with severe manifestations of histoplasmosis (such as shock, respiratory failure, and death) in patients with AIDS during an outbreak. Severe disease was present in 28 of 155 patients (17.9%). The following factors were associated with severe disease: black race (odds ratio [OR], 2.8; 95% confidence interval [CI], 1.2-6.2); hemoglobin level <9.5 g/dL (OR, 2.7; 95% CI, 1.2-6.4), partial thromboplastin time >45 s (OR, 3.1; 95% CI, 1.1-9.3); alkaline phosphatase level >2.5 times normal (OR, 3.4; 95% CI, 1.3-8.7); aspartate aminotransferase level >2.5 times normal (OR, 4.2; 95% CI, 1.7-10.0); bilirubin level concentration >1.5 mg/dL (OR, 9.2; 95% CI, 2.5-34.3); creatinine concentration >2.1 mg/dL (OR, 8.3; 95% CI, 2.2-31.9); and albumin concentration <3.5 g/dL (OR, 4.6; 95% CI, 1.3-16.4). Zidovudine use was associated with decreased risk of severe disease (OR, 0.3; 95% CI, 0.1-0.7). Multivariate analysis showed that a creatinine value >2.1 mg/dL (OR, 9.5; 95% CI, 1.7-52) and an albumin value <3.5 g/dL (OR, 4.8; 95% CI, 1.0-22) were associated with an increased risk of severe disease, and zidovudine therapy remained associated with a decreased risk (OR, 0.2; 95% CI, 0.1-0.6). Findings associated with severe histoplasmosis should be recognized early and the cases managed aggressively.

AIDS-Related Opportunistic Infections↗

Chronic infection and reactivation in a pulmonary challenge model of histoplasmosis.

Reactivation may be a mechanism for the development of histoplasmosis in AIDS. In this study, histoplasmosis was reactivated by the depletion of CD4 and CD8 lymphocytes in mice. CD4 and/or CD8 depletion beginning 1 month after intratracheal infection and continuing for 2 months caused reactivation with a 2.1 log/g increase in the lungs and a 1.5 log increase in the spleen of B6C3F1 mice. Because control animals showed persistent infection, a subsequent experiment sought to determine the long-term outcome in competent mice. Twelve of 32 immunocompetent mice died at weeks 26-52 of infection, and 4 survivors appeared to be clinically ill; all ill mice had high fungus burdens, whereas cultures were sterile in the healthy mice. Eight of the surviving healthy-appearing mice underwent autopsy 2 years after infection, and cultures were sterile. Thus, 16 of 32 immunocompetent mice exhibited progressive infection. CD4 and/or CD8 depletion exacerbated infection, but a chronic progressive and ultimately fatal infection occurred in half the immunocompetent mice.

Analysis of Variance↗

Diagnosis and management of central nervous system histoplasmosis.

Two cases of Histoplasma meningitis are presented, illustrating the difficulty in diagnosis and treatment. The first case occurred in a patient with acquired immunodeficiency syndrome as a relapse of disseminated histoplasmosis and resolved after prolonged treatment and ongoing antiretroviral therapy. The second case occurred in a cardiac allograft recipient as meningitis and focal brain lesions that responded to liposomal amphotericin B, but the patient died shortly after therapy was completed. Unfortunately, there are no prospective studies addressing the diagnosis and management of patients with histoplasmosis of the central nervous system from which to provide evidence-based guidelines for care. In the absence of such data, an approach will be presented on the basis of our experience and opinions.

Acquired Immunodeficiency Syndrome↗

Disseminated histoplasmosis in patients with AIDS in Panama: a review of 104 cases.

We identified the incidence and primary clinical characteristics of histoplasmosis in patients with acquired immunodeficiency syndrome (AIDS) in our hospital. Disseminated histoplasmosis is a common and severe disease among patients with AIDS in Panama and should be suspected for patients with a CD4 cell count of <100 cells/ microL, fever, respiratory symptoms, weight loss, and diarrhea.

Acquired Immunodeficiency Syndrome↗

Interleukin-1 and host control of pulmonary histoplasmosis.

We found that interleukin (IL)-1beta levels were elevated in the lungs of mice infected with Histoplasma capsulatum. Hence, we examined the influence that IL-1beta and IL-1 signaling has on host defenses against pulmonary histoplasmosis. In IL-1 receptor 1 knockout (IL-1R(-/-)) mice challenged intratracheally, fungal recovery on day 7 after infection exceeded that in wild-type (WT) mice. Antibody neutralization of IL-1beta also exacerbated infection. For both groups of mice, the absence of bioactive cytokine led to a failure to control infection in a high proportion of mice. The absence of signaling had a modest effect on host resistance in mice with secondary histoplasmosis. Several perturbations in host defense mechanisms were detected in the lungs of IL-1R(-/-) mice. The number of CD4+ cells was decreased, and transcription of the gene for inducible nitric oxide synthase was depressed transiently. IL-4 and IL-10 levels were elevated in the lungs of IL-1R(-/-) mice, compared with those in the lungs of WT mice. Conversely, interferon- gamma levels were decreased. Thus, IL-1 contributes to host resistance to infection with H. capsulatum.

Animals↗

Histoplasmosis in patients with acquired immunodeficiency syndrome. Hematologic and bone marrow manifestations.

In areas where Histoplasma capsulatum infections are endemic in the United States, there is an increasing frequency of progressive disseminated histoplasmosis (PDH) as an opportunistic infection in patients with acquired immune deficiency syndrome (AIDS). The bone marrow and peripheral blood (PB) specimens in 13 patients with AIDS and PDH were reviewed. Anemia, leukopenia, and thrombocytopenia were found in 12, 10, and 7 patients, respectively. Circulating organisms were detected in the blood smears or buffy coat preparations from five patients and were associated with PB nRBCs and severe absolute monocytopenia. Morphologically, the marrow specimens showed one of four patterns: (1) no morphologic evidence of infection (two patients, one with a positive marrow culture); (2) discrete granulomas (two patients, both with positive marrow cultures); (3) lymphohistiocytic aggregates (six patients, four with positive marrow cultures); and (4) diffuse macrophage infiltrates (three patients, all with positive marrow cultures). Morphologic examination of the bone marrow combined with cultures is useful in diagnosing disseminated histoplasmosis in patients with AIDS. However, the morphologic findings in the bone marrow may be different in patients with AIDS compared with non-AIDS patients, and seemingly nondiagnostic morphologic features must be approached with a high degree of suspicion in diagnosing infections with H. capsulatum in this population.

Acquired Immunodeficiency Syndrome↗

Transmission of disseminated histoplasmosis via cadaveric renal transplantation: case report.

A 30-year-old woman received a cadaveric renal allograft from a donor who was subsequently found to have renal infection due to Histoplasma capsulatum. The recipient had funguria in the early postoperative period and later developed cutaneous manifestations of disseminated histoplasmosis. We report a case of histoplasmosis transmitted via renal transplantation and describe the subsequent 20-year clinical course.

Adult↗

Disseminated histoplasmosis in patients infected with human immunodeficiency virus.

Progressive disseminated histoplasmosis (PDH) is a common opportunistic infection complicating the course of infection with human immunodeficiency virus (HIV). PDH has been noted in areas nonendemic for histoplasmosis and occurs more frequently in areas heavily endemic for the fungus. PDH is frequently the AIDS-defining illness and presents as a febrile and wasting disease. The respiratory component may be overshadowed by the severity of the systemic illness. Chest roentgenograms show diffuse reticulonodular infiltrates. Frequently, the initial chest roentgenogram may show no abnormalities. Timely diagnosis requires a high index of diagnostic suspicion. Blood cultures, with use of the lysis-centrifugation system, are highly useful, as is the examination of the bone marrow, the peripheral blood smear, and the respiratory secretions. An experimental serological test that detects histoplasma polysaccharide antigen appears to be the simplest diagnostic test. Amphotericin B is the drug of choice for initial therapy, followed by further administration of amphotericin B for suppression. Early results with itraconazole are encouraging for long-term suppression.

HIV Infections↗

Ketoconazole in the treatment of paracoccidioidomycosis and histoplasmosis.

Ketoconazole was given orally to 33 patients with paracoccidioidomycosis and 23 with histoplasmosis. There were 55 men and one woman, and ages ranged from 28 to 67 years. Each patient had either the chronic disseminated or the chronic pulmonary form of disease. The diagnosis was established in 54 patients by culture of Paracoccidioides brasiliensis or Histoplasma capsulatum from lesions and in two patients by the clinical picture and results of serologic tests for histoplasmosis. The initial dosage was 400 mg per day. The dosage was reduced to 200 mg when a cure was achieved. The duration of treatment ranged from two to 18 months. Results of treatment were classified as very good (clinical and serologic cure) in 23 (41%) of the patients; good (clinical cure only) in 28 (50%); fair (partial improvement) in one (2%); and poor (no improvement) in three (5%). The results were not assessable in one patient who did not complete therapy. The three patients who did not respond to treatment had less than or equal to 0.19 microgram of ketoconazole/ml in their blood. The drug was well tolerated, and no side effects were reported.

Administration, Oral↗

Reactive hemophagocytic syndrome: a new presentation of disseminated histoplasmosis in patients with AIDS.

We report the cases of six patients with AIDS in whom reactive hemophagocytic syndrome (RHPS) secondary to disseminated histoplasmosis was diagnosed. RHPS was diagnosed by established criteria, including fever (duration of > or = 7 days, with peak temperatures of > 38.5 degrees C), unexplained thrombocytopenia with anemia and/or neutropenia, and bone marrow biopsy findings of hemophagocytic histiocytosis. Disseminated Histoplasma capsulatum infection was diagnosed on the basis of the results of cultures of the bone marrow sample. The serum lactate dehydrogenase (LDH) level was elevated (> 1,000 IU/L) in all patients, and five of six patients had hyperferritinemia (range of ferritin level, 15,848-425,984 ng/mL). Five patients had features resembling severe sepsis with multiorgan dysfunction. Three patients recovered, and the findings of RHPS resolved following therapy with amphotericin B. In patients with AIDS, the combination of fever, cytopenia, elevated serum LDH level (> 1,000 IU/L), and/or hyperferritinemia (ferritin level of > 10,000 ng/mL) is a clue to the diagnosis of RHPS and disseminated histoplasmosis; bone marrow biopsy is valuable in establishing the diagnosis.

AIDS-Related Opportunistic Infections↗

Oral treatment of paracoccidioidomycosis and histoplasmosis with itraconazole in humans.

Twenty-five patients with paracoccidioidomycosis and 17 patients with histoplasmosis were treated with itraconazole. All patients were adults. Those with paracoccidioidomycosis exhibited the chronic disseminated form of the disease; 21 of these patients had lesions in two or more locations, and four had lesions only on the larynx or mouth. Itraconazole was administered at a daily dosage of 50 mg for six months in the majority of these cases. All infections were clinically cured or showed striking improvement. Patients with histoplasmosis had the chronic pulmonary or chronic disseminated form of the disease. A daily dose of 100 mg was administered until clinical cure was established; the dose was then changed to 50 mg until the completion of six months of treatment. Twelve infections were clinically cured; four were strikingly alleviated. The remaining patient, who discontinued treatment with itraconazole after two months, had a severe relapse and died of respiratory failure.

Administration, Oral↗

Functional T cells in primary immune response to histoplasmosis.

Functional T cells are critical to host defense against infection. It has been reported that functional T cells as determined by their cytokine production represent antigen-specific T cells in infectious disease models. In this study, we enumerated Histoplasma-specific interferon gamma-producing cells in bulk splenocyte culture and showed that infection with Histoplasma capsulatum, an intracellular pathogen of the macrophage, activated both CD4 and CD8 T cells. The magnitude of CD8 T cell response was lower than CD4 T cell, but the expansion and contraction of both cell types followed the same kinetics. Over 90% of interferon gamma-producing CD4 T cells and >85% of CD8 T cells expressed CD44(hi) phenotype. The strong correlation between interferon gamma production and CD44(hi) expression was observed not only at the peak of response but also throughout the course of infection. Moreover, a broad spectrum of Vbeta populations responded to systemic as well as pulmonary infections, suggesting no obvious T cell receptor bias in primary immune response to histoplasmosis. While each Vbeta population contributed to interferon gamma production, several specific Vbeta populations made up higher percentages of interferon gamma-producing cells. Our study laid the groundwork for further investigations in immune response to histoplasmosis.

Animals↗

Histoplasmosis in South Carolina: support for the microfocus concept.

An outbreak of anthropurgic histoplasmosis occurred in rural South Carolina when a canebrake which served as a blackbird roost was cleared with a bulldozer. Seven days later the index patient became ill with histoplasmosis. Nine other patients contracted the disease, but only the index case was fatal. Serologic studies on the 10 patients demonstrated high titers in the histoplasmin latex agglutination test within two to three weeks after exposure. Serologic titers to the yeast-form Histoplasma capsulatum antigen in the complement fixation test appeared most frequently, but these antibodies were not diagnostic because complement-fixing antibodies to Blastomyces dermatitidis appeared at the same time. Soil studies demonstrated that viable particles of H. capsulatum persisted at declining levels over a nine-year period. A skin test survey showed that 27.3% of eighth grade students who resided within a 20 km radius of the contaminated site and who were lifelong residents of the same dwelling had a positive histoplasmin skin test.

Adolescent↗

Pulmonary histoplasmosis associated with exploration of a bat cave.

Approximately 14 days after exploring a limestone cave in northcentral Florida in February 1973, an 18-year-old female developed a respiratory illness with pronounced shortness of breath and cyanosis. The following day, an 18-year-old male presented to the hospital with similar complaints. The association of illness with their recent caving experience prompted further epidemiologic investigation. Twenty-nine members of a church-sponsored youth group explored the implicated cave. Twenty-three of them later became ill with complaints of cough, afternoon fever and sweats, chest discomfort, and dyspnea on exertion. Histoplasmin skin tests were positive in 18 of 24 individuals tested. Serum for complement fixation (CF) was positive in 12 of 26. Testing of area residents revealed a low incidence of skin test and CF positivity (7% and 0%, respectively). That spelunkers are at risk of acquiring pulmonary histoplasmosis has been noted previously; in Florida this has been related to the exploration of caves infested with bats. This is the largest reported outbreak of acute pulmonary histoplasmosis that has been associated with spelunking and further points out that only those individuals who enter the cave are at risk of acquiring the disease, and not those who reside in the surrounding area.

Adolescent↗