Histoplasmosis. Experience during outbreaks in Indianapolis and review of the literature

Histoplasmosis remains a common infection in endemic regions of North America and Latin America, causing a broad spectrum of clinical findings. Experience during recurrent outbreaks in Indianapolis has shown the importance of immunosuppressive conditions including the acquired immunodeficiency syndrome (AIDS) as a risk factor for disseminated disease and expanded our knowledge of the common clinical manifestations. Pericarditis, rheumatologic manifestations, esophageal compression, and sarcoidlike manifestations were found to be relatively common findings in histoplasmosis. These studies have established the useful role of serologic testing and have led to the discovery of antigen testing for diagnosis of histoplasmosis. This experience also has offered the opportunity to examine the outcome of treatment in persons with AIDS, contributing to studies that have found itraconazole to be an excellent alternative to amphotericin B in persons with mild or moderately severe infection.     

Acute pulmonary histoplasmosis as an imported disease

A previously healthy 44-year-old male traveller presented with a dry cough, fever and an abnormal chest X-ray after a stay in Guatemala, where he had explored bat caves. Acute pulmonary histoplasmosis was diagnosed after culture of Histoplasma capsulatum from bronchial washings. A favourable response was seen upon treatment with itraconazole for six weeks. Acute pulmonary histoplasmosis should be considered in a healthy traveller returning with fever from the USA or subtropical areas.     

Relationship between feed withdrawal and viscera condition of broilers

An AIDS patient with disseminated histoplasmosis who improved during treatment with fluconazole but remained fungemic and subsequently relapsed is described. Isolates obtained from blood during therapy showed a progressive increase in fluconazole MIC from 0.625 to 20 micrograms/ml. The pretreatment, or parent, isolate and the posttreatment, or relapse, isolate demonstrated identical genetic patterns by PCR fingerprinting with three different primers. Fluconazole was less potent inhibitor of the growth of the relapse isolate than of the pretreatment isolate (50% inhibitory concentration [IC50] = 11.7 microM), while itraconazole was more potent (relapse isolate IC50 = 0.0011 microM versus pretreatment isolate IC50 = 0.0064 microM). Neither the increased sensitivity to itraconazole nor the decreased activity of fluconazole on the growth of the relapse isolate results from changes in the intracellular content of these agents. To reach 50% inhibition of ergosterol synthesis in both the parent and relapse isolates, about 2 nM itraconazole was needed; with fluconazole, 50% inhibition was achieved at 20.9 microM and 55.5 microM, respectively. Resistance to fluconazole may develop during treatment and results from decreased sensitivity of ergosterol synthesis.     

Incidence of autoantibodies in the infertile population

The diagnosis of histoplasmosis was made by isolation of Histoplasma capsulatum from cerebrospinal fluid (CSF), blood and bone marrow or by histopathologic (biopsy or post mortem) examination. The mean age of the patients was 35.8 years; 13 patients were male (72.2%). The disease was disseminated, with the following distribution:skin (38.8%), bone marrow (27.7%), nasopharyngeal mucosa (22.2%), lungs (22.2%), colon (11.1%), central nervous system (5.5%) and esophagus (5.5%). Adenomegaly (50%), hepatomegaly (77.7%) and splenomegaly (61.1%) were frequently seen. The most common hematologic abnormality was pancytopenia (33.3%) of the patients. Eleven patients were treated, 9 with amphotericin B and 2 with itraconazole. Eight had good clinical improvement and all of them were given amphotericin B or a triazolic as maintenance therapy. This study emphasize the importance of this mycosis in immunodepressed patients, specially AIDS patients, in whom the infection tends to invade the macrophagic-lymphoid system and preferentially the cutaneous tegument.     

Comparison of a new triazole antifungal agent, Schering 56592, with itraconazole and amphotericin B for treatment of histoplasmosis in immunocompetent mice

A murine model of intratracheally induced histoplasmosis was used to evaluate a new triazole antifungal agent, Schering (SCH) 56592, for treatment of histoplasmosis. MICs were determined for SCH 56592, amphotericin B, and itraconazole by testing yeast-phase isolates from 20 patients by a macrobroth dilution method. The MICs at which 90% of the isolates are inhibited were for 0.019 microgram/ml for SCH 56592, 0.5 microgram/ml for amphotericin B, and < or = 0.019 microgram/ml for itraconazole. Survival studies were done on groups of 10 B6C3F1 mice with a lethal inoculum of 10(5). All mice receiving 5, 1, or 0.25 mg of SCH 56592 per kg of body weight per day, 2.5 mg of amphotericin B per kg every other day (qod), or 75 mg of itraconazole per kg per day survived to day 29. Only 44% of mice receiving 5 mg of itraconazole/kg/day survived to day 29. Fungal burden studies done in similar groups of mice with a sublethal inoculum of 10(4) showed a reduction in CFUs and Histoplasma antigen levels in lung and spleen tissue in animals treated with 2 mg of amphotericin B/kg qod, 1 mg of SCH 56592/kg/day, and 75 mg of itraconazole/kg/day, but not in those treated with lower doses of the study drugs (0.2 mg of amphotericin B/kg qod, 0.1 mg of SCH 56592/kg/day, or 10 mg of itraconazole/kg/day). Serum drug concentrations were measured 3 and 24 h after the last dose in mice (groups of five to seven mice), each treated for 7 days with SCH 56592 (10 and 1 mg/kg/day) and itraconazole (75 and 10 mg/kg/day). Mean levels measured by bioassay were as follows: SCH 56592, 10 mg/kg/day (2.15 micrograms/ml at 3 h and 0.35 microgram/ml at 24 h); SCH 56592, 1 mg/kg/day (0.54 microgram/ml at 3 h and none detected at 24 h); itraconazole, 75 mg/kg/day (22.53 micrograms/ml at 3 h and none detected at 24 h); itraconazole, 10 mg/kg/day (1.33 micrograms/ml at 3 h and none detected at 24 h). Confirmatory results were obtained by high-pressure liquid chromatography assay. These studies show SCH 56592 to be a promising candidate for studies of treatment of histoplasmosis in humans.     

Fluconazole versus itraconazole for candida esophagitis in acquired immunodeficiency syndrome. Candida Esophagitis

BACKGROUNDS & AIMS: Contrasting opinions exist about the pharmacological treatment of esophageal candidiasis in patients with acquired immunodeficiency syndrome (AIDS). The aim of this study was to assess the long-term efficacy of fluconazole and itraconazole treatment. METHODS: This study evaluated 2213 human immunodeficiency virus-positive patients at first episode of esophageal candidiasis diagnosed by endoscopy; 1105 received fluconazole and 1108 received itraconazole. The endoscopic and clinical response to treatment was assessed periodically until the end of the follow-up period (1 year). RESULTS: At week 2, endoscopic cure occurred in 81.2% of patients treated with fluconazole and in 65.6% of patients treated with itraconazole (P < 0.001). Clinical cure was observed in 81.5% of patients treated with fluconazole and in 75.2% of patients treated with itraconazole (P < 0.001). At the end of the follow-up period, endoscopic and clinical cure were observed in 96% of patients treated with fluconazole and in 95.6% of patients treated with itraconazole (P = 0.788), with similar differences by intention-to-treat analysis (93.6% vs. 93.3%; P = 0.853). Treatment failure was observed in 22.3% of fluconazole-treated patients and in 26.6% of itraconazole-treated patients (P = 0.022). CONCLUSIONS: Fluconazole and itraconazole are provided with good long-term therapeutic efficacy in the treatment of Candida esophagitis in patients with AIDS. Fluconazole is associated with a higher rate of cure than itraconazole in short-term treatment.     

Value of direct and indirect diagnostic methods in systemic mycoses associated with AIDS

One hundred and seventeen patients suffering systemic mycosis and AIDS were studied during 5 years in the Mu?iz Hospital of Buenos Aires City. Seventy four of them presented cryptococcosis, 39 histoplasmosis and 4 both mycoses. The following specimens were studied for the diagnosis: skin and mucous membrane scrapings, bone marrow aspirations, bronchial secretions, biopsies of different organs, cerebral spinal fluid and blood cultures. Sera were also collected for serologic tests. A total of 203 samples from patients with histoplasmosis were studied, 46.3% of them showed H. capsulatum in microscopic examinations or in cultures, skin scraping was the most sensitive diagnostic method (94.7% of positive results), followed by biopsies (80%) and bone marrow cultures (42.1%). Specific antibodies were detected in 45.4% of the patients with histoplasmosis, using 2 different antigens and 3 types of serologic reactions (complement fixation test, immunodiffusion and counterimmunoelectrophoresis). A total of 413 samples from patients with cryptococcosis were examined, 69% of them confirmed the diagnosis. The mycologic study of CSF was the most sensitive method of study, since it registered positive results in 89.5%, followed by blood cultures (61.2%), skin scrapings (42.9%), and urine cultures (41.7%). Polysaccharyde antigens from C. neoformans in organic fluids were detected in almost all the cases. The aim of this study is to compare all the suitable diagnostic methods which can be used in systemic mycosis associated with AIDS in order to find the most rapid way of diagnosis.     

Disseminated histoplasmosis in AIDS patients. A study of 2 cases and review of the Spanish literature

The characteristics of two cases of histoplasmosis in AIDS patients in our institution are presented together with a review of the 11 cases published in Spain since 1988 in addition to the current knowledge on histoplasmosis in patients with human immunodeficiency virus infection (HIV). In all except 2 of the 13 patients there was epidemiologic history of a stay in a country in which histoplasmosis is endemic. The 12 cases described in which this information is available had CD4 counts under 100/microL. The clinical manifestations of presentation were fever (92.3%) associated or not with other unspecific symptoms (asthenia, anorexia, cough, diarrhea) with a subacute course of two or three months. Physical examination demonstrated hepatosplenomegaly in 76.9% of the cases and 61.5% of the patients presented cutaneous lesions. Thoracic radiography was abnormal in 55% (61.5% had respiratory symptoms). Diagnosis was achieved by isolation of the fungus in the cutaneous biopsies in all the patients with dermatologic involvement and in 7 cases identification was performed in the bone marrow. In all the cases induction treatment was with anphotericin B and in those who reached the maintenance phase itraconazol was used in 7 cases and ketoconazol in one case. None of the patients treated with itraconazol, including the two in our center, presented recurrence at the time of completion of follow up. In conclusion, histoplasmosis is frequently presented as a prolonged febrile syndrome with unspecific characteristics, thus emphasizing the importance of including travel history to other countries in the anamnesis. The increase in journeys to endemic countries and immigration from these areas had led to an increase in the number of cases of histoplasmosis in patients with HIV infection in Spain.     

Lignocaine spray applicators are a potential source of cross-infection in the anaesthetic room

A 27 year old female with AIDS and disseminated histoplasmosis is presented. The clinical features include fever, weight loss, productive cough, splenomegaly and moderate pallor. The initial working diagnosis was pulmonary tuberculosis. The diagnosis of disseminated histoplasmosis was made terminally from bone marrow aspirate examination. Disseminated histoplasmosis with its varied clinical picture is likely to be missed in a patient with AIDS, and therefore a high index of suspicion is necessary for diagnosis.     

Increase of antimicrobial resistance of faecal aerobic gram-negative bacteria in a geriatric hospital

Apart from cryptococcosis and histoplasmosis, which are mycoses contained by T cell-mediated mechanisms of host defense, fungemia is rarely found in AIDS patients. The frequency of fungemia due to Candida spp. has been reported to be as low as 1%. We report a non-neutropenic AIDS patient who presented a candidemia which probably arose from her gastrointestinal tract.     

Disseminated histoplasmosis: 2 cases in patients with human immunodeficiency virus infection in French Guiana

The authors report two cases of disseminated histoplasmosis occurring in HIV-infected patients living in French Guiana. The first case was an acute disseminated histoplasmosis with a rapid fatal evolution. The second case was diagnosed on a mucosal localisation, and improved under itraconazole therapy. These two cases show the diversity of the clinical course of this opportunistic infection. The authors focus on the difficulty of the diagnosis and the need for direct microscopic examination to identify histoplasma and to enable a swift therapeutic intervention.     

Fluconazole. An update of its pharmacodynamic and pharmacokinetic properties and therapeutic use in major superficial and systemic mycoses in immunocompromised patients

Fluconazole is a triazole antifungal agent which is now an established part of therapy in patients with immune deficiencies. It is effective against oropharyngeal/oesophageal candidiasis (candidosis) when used orally once daily either as treatment or secondary prophylaxis in patients with AIDS or as treatment or primary prophylaxis in neutropenia associated with cancer therapy. Fluconazole also resolves symptoms in up to 60% of patients with cryptococcal meningitis and AIDS. However, in this infection its efficacy as treatment relative to that of amphotericin B is equivocal, and its major role is as the drug of choice for maintenance therapy following amphotericin B induction. In this regard, fluconazole has been proven superior to amphotericin B and to itraconazole 200 mg/day. Comparisons with other drugs used for the treatment of mucosal candidiasis in patients with AIDS show fluconazole to be superior to nystatin, similar to itraconazole and at least as effective as clotrimazole and ketoconazole; it was more so than the latter azole in 1 study. In patients undergoing chemotherapy or bone marrow transplantation, fluconazole as primary prophylaxis has produced greater clinical benefit than a clotrimazole regimen. The incidence of adverse events appears to be somewhat higher in patients with AIDS compared with HIV-negative cohorts, but the qualitative pattern of events is similar. The most frequent events are gastrointestinal complaints, headache and skin rash: rare exfoliative skin reactions and isolated instances of clinically overt hepatic dysfunction have occurred in patients with AIDS. Issues yet to be clarified include: the use of fluconazole in children with AIDS, in whom results have been promising; its efficacy against other fungal infections encountered in immunocompromised patients; whether the drug influences mortality, as has been suggested by one placebo-controlled trial in patients undergoing bone marrow transplant; and the appropriateness of its potential for use as primary prophylaxis against cryptococcal meningitis in patients with AIDS, where it shows efficacy but there is concern over increasing risk of development of secondary resistance. Notwithstanding these undefined aspects of its clinical profile, fluconazole is now confirmed as an important antifungal drug in the management of fungal infections in patients with immune deficiencies. In patients with AIDS it is the present drug of choice as maintenance therapy against cryptococcal meningitis and is a preferred agent for secondary prophylaxis against candidal infections; it is also a favoured agent for primary prophylaxis in patients at risk because of neutropenia associated with chemotherapy or bone marrow transplantation .     

African histoplasmosis in a patient with HIV-2 infection

9 months after immigration into Switzerland, a 38-year-old male patient from Liberia/West Africa developed granulomatous and subsequently ulcerative nodules in the face. The heterosexual patient, with no history of i.v. drug abuse, tested positive for HIV-2. Histology of a skin biopsy revealed superficial colonization by numerous fungal elements described as spores and hyphae that were compatible with the initial isolation of Candida parapsilosis. The definite diagnosis of African histoplasmosis was established 3 weeks later after review of the PAS-stained direct smear and after cultures had grown a cream-colored mold subsequently identified as Histoplasma capsulatum var. duboisii. There were no signs of disseminated disease. The lesions cleared under therapy with itraconazole (200 mg q 24h for 2 weeks, subsequently 100 mg q 24h) as well as ketoconazole and Aqua Dalibour (A. zinco-cuprica) locally for 2 months. Follow-up was not possible. Despite alarmingly increasing numbers of HIV-positive patients in Africa, the general incidence of African histoplasmosis seems to be stable with only a few cases per year. To our knowledge only four cases of disseminated African histoplasmosis have been reported in HIV-positive patients; localized cutaneous infection as in our patient, seems to be the exception. The low incidence of this infection is in contrast to the substantial number of HIV-positive patients with disseminated histoplasmosis by H. capsulatum var. capsulatum in the United States.     

AIDS-associated renal tuberculosis

In order to study the prevalence and the clinical features of renal tuberculosis associated with AIDS, we studied the renal tissue of the necropsies made in 46 AIDS patients under light microscopy. We found renal tuberculous granuloma in 11 (23%) patients (in 3 without previous diagnosis of renal or extrarenal tuberculosis) and only 4 of them presented moderate hematuria or pyuria sterile. As subclinical renal tuberculosis was frequent in this group of AIDS patients, the urine culture for Mycobacterium tuberculosis may be useful for diagnosing tuberculosis in AIDS patients.     

Isolated cervical tuberculosis in patients with HIV infection

OBJECTIVE: Tuberculosis isolated to the head and neck region is common in patients with HIV infection. However, the management of isolated head and neck tuberculosis has not been reported in the literature. This study was done to describe the characteristics of tuberculosis isolated to the head and neck region in patients infected with HIV and to detect differences in presentation and diagnostic management based on the status of HIV infection at presentation. METHODS: A retrospective study was performed including 38 patients infected with HIV who were seen with tuberculosis isolated to the head and neck region at two tertiary care centers during a 10-year period. These patients were divided into two groups on the basis of the HIV status at presentation, which indirectly reflects the level of immunosuppression. Group 1 included 11 patients (29%) with AIDS at presentation. Group 2 included 27 patients (71%) with HIV infection but not AIDS. RESULTS: The cervical lymphatics were the most common site for isolated head and neck tuberculosis (89%), with the supraclavicular nodes most often involved (53%). Extralymphatic involvement was less common (11%), but involved a variety of anatomic locations (skin, spinal cord, larynx, parotid). The presenting history and physical examination had a low sensitivity for tuberculosis in patients with HIV infection, mainly because of the presence of multiple confounding factors. Purified protein derivative testing was highly sensitive for tuberculosis in patients with HIV infection alone (61 %); however, its usefulness was diminished in patients with AIDS (14%; p=0.03). Fine-needle aspiration biopsy was 94% sensitive for diagnosing tuberculosis and was not affected by the status of HIV infection. Surgical biopsy was the gold standard for diagnosing tuberculosis but was associated with chronically draining fistulas in a significant number of cases (14%). CONCLUSIONS: These data suggest that tuberculosis should be considered in the differential diagnosis of all head and neck lesions in patients infected with HIV, even in the absence of pulmonary involvement. Purified protein derivative testing should be done liberally in these patients, with realization that the sensitivity of purified protein derivative testing is reduced in patients with AIDS. Fine-needle aspiration biopsy should be the key diagnostic test in this patient population, with open surgical biopsy reserved for highly suspicious cases in which other measures were not diagnostic.     

Echinococcus granulosus: cloning of a thioredoxin peroxidase

Disseminated histoplasmosis has been recognized as a serious opportunistic infection in patients with acquired immunodeficiency syndrome (AIDS). However, cases reported in the literature have been predominantly in adult patients. Here we report an infant with AIDS who presented with fever, cough, rhinorrhea, hepatosplenomegaly, pancytopenia and coagulopathy, and died of respiratory failure. Autopsy revealed disseminated histoplasmosis involving multiple organs including lungs, intestines, liver, spleen, bone marrow, lymph nodes, kidneys, and meninges. The diagnosis was established based on histomorphology and confirmed by blood culture.     

Cryptococcal meningitis: the place of itraconazole

Itraconazole, an orally active broad-spectrum triazole antimycotic, has demonstrated anti-Cryptococcus activity in vitro and in animal models of cryptococcal meningitis. The drug has been used by a number of clinical groups for the treatment of cryptococcal meningitis, predominantly in AIDS patients. A problem that has been found with ketoconazole is the relatively low absorption of the drug in AIDS patients. This has resulted in ketoconazole plasma levels below the MIC90 (1-5 micrograms ml-1) needed to eliminate Cryptococcus neoformans. In addition, tissue levels of ketoconazole are lower than plasma levels. For itraconazole, the required MIC90 for Cr. neoformans is 0.1 microgram ml-1, and the plasma levels in AIDS patients receiving 200-400 mg daily, even in the case of reduced absorption, are well above this MIC90. The itraconazole levels in the brain and in the meninges are higher than the plasma levels. Consequently, itraconazole has been considered a valid candidate for studies in patients with cryptococcal meningitis. Various treatment modalities have been used: primary oral therapy alone or in combination with amphotericin B or 5-fluorocytosine (5-FC); maintenance oral therapy after initial treatment with amphotericin B (with or without 5-FC); and first-line intravenous treatment in severely ill patients. The results were evaluated in four different groups. When the drug was given as primary oral therapy without combination with amphotericin B or 5-FC, the results depended greatly on the dose administered and on the life expectancy of the patient at inclusion. In general, daily doses of 400 mg were better than 200-mg doses.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Percent 131I uptake and post-therapy 131I scans: their role in the management of thyroid cancer

Renal disease in patients infected with human immunodeficiency virus (HIV) often presents with significant proteinuria and progressive renal failure; focal glomerulosclerosis is the most common renal pathology identified. To our knowledge, we report the first case of nephrotic-range proteinuria and preserved renal function in an HIV-infected patient in association with disseminated histoplasmosis. The initial level of proteinuria was 12.5 g/24 h. The patient developed a concomitant lesion on his neck, which was biopsied and identified as Histoplasma capsulatum by fungal stains and culture. The serum CF titer of antibody against yeast antigens of H. capsulatum was 1:8. The level of serum albumin decreased to 2.0 g/dL, and the level of serum cholesterol increased to 284 mg/dL. Immunohistochemical staining of renal biopsy tissue demonstrated immune complexes within the mesangium; H. capsulatum antigen was also demonstrated in the mesangium. Therapy with oral itraconazole resulted in marked clinical improvement. The findings in this case emphasize the need to rule out treatable causes of the nephrotic syndrome in AIDS, especially in cases of immune-complex glomerulonephritis.     

Detection of anti-Histoplasma capsulatum antibodies by the ELISA technique. Preliminary study

An indirect micro-ELISA system is presented for diagnosing histoplasmosis. The diagnostic criteria are defined by using sera from 12 patients who are histoplasmosis carriers. For this group, the optical density values were superior to 1,000; use was made of 43 sera from blood bank donors and 9 sera from children without a history of exposure. The optical density values in these cases were inferior to 0,200. The significant difference found led to the diagnostic criterion for confirming 3 histoplasmosis carriers who showed clinical manifestations but had been negative to double immunodiffusion. Thus, the usefulness of the proposed micro-ELISA system for early diagnosis was proved.