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ABSTRACT: Antigen detection, which has proven useful in diagnosis of disseminated histoplasmosis, has not been studied in acute pulmonary histoplasmosis (APH). Because treatment is indicated in most patients with moderately severe or severe APH, antigen detection for rapid diagnosis could be helpful.
Histoplasma antigen detection was evaluated in 130 patients with APH.
Antigenuria was detected in 64.6%, antigenemia in 68.6%, and antibody in 64.3%. If both urine and serum specimens were tested, antigen was detected in 82.8%, of which 45.8% had antigenemia only; and if both antigen and antibody were measured, results were positive in 93.3%, of which antigen only was positive in 35.7%.
Testing for antigenemia, antigenuria, and antibodies using the complement fixation test offers a sensitive, noninvasive method for diagnosis of APH.
Clinical Infectious Diseases 11/2009; 49(12):1878-82. · 9.15 Impact Factor
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ABSTRACT: The sensitivity for detection of Histoplasma antigen is lower in serum than in urine. In other antigen assays, treatment of serum at 104 degrees C in the presence of EDTA was required for detection of antigenemia. Sensitivity and specificity for detection of Histoplasma antigenemia were examined with or without EDTA heat treatment of the serum using the MVista Histoplasma antigen enzyme immunoassay. A total of 94.6% of serum specimens from patients with AIDS and histoplasmosis that were negative untreated were positive after EDTA-heat treatment. Two-thirds of the negative serum specimens from patients with probable histoplasmosis, based upon clinical suspicion and Histoplasma antigenuria, were positive after heat treatment. Specificity was 99.0% in controls, including healthy subjects and patients in whom histoplasmosis or blastomycosis, were excluded. Precision and reproducibility were good and excellent, respectively. These findings demonstrate improvement in sensitivity without reduction in specificity, precision, or reproducibility after heat-EDTA treatment.
Clinical and vaccine immunology: CVI 02/2009; 16(3):320-2. · 2.37 Impact Factor
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S Husain,
C J Clancy,
M H Nguyen,
S Swartzentruber,
H Leather,
A M LeMonte,
M M Durkin,
K S Knox,
C A Hage,
C Bentsen,
N Singh,
J R Wingard, L J Wheat
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ABSTRACT: We have evaluated the Platelia Aspergillus enzyme immunoassay for detection of galactomannan in bronchoalveolar lavage (BAL) specimens in solid organ transplant patients with aspergillosis. The precision and reproducibility in serum or BAL to which galactomannan was added were similar. Sensitivity was 81.8% in patients with aspergillosis, and specificity was 95.8% in lung transplant patients who underwent BAL for surveillance for infection or rejection. Among transplant controls, positive results were more common in patients (i) who underwent diagnostic BAL performed for evaluation of symptoms or chest computed tomographic abnormalities, (ii) who had undergone lung transplantation, or (iii) who were colonized with Aspergillus. Galactomannan testing in BAL is useful for diagnosis of aspergillosis in transplant patients. The significance of positive results in patients without confirmed aspergillosis requires further evaluation.
Clinical and vaccine immunology: CVI 11/2008; 15(12):1760-3. · 2.37 Impact Factor
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ABSTRACT: False-positive Histoplasma antigenemia was reported in solid organ allograft recipients who had received rabbit anti-thymocyte globulin (RATG, RATG) caused by human anti-rabbit antibodies (HARA). A second-generation Histoplasma antigen detection assay was developed to overcome false positivity caused by HARA. With the second-generation assay, false-positive results were eliminated in 18 of 19 cases without reduction in the sensitivity in patients with histoplasmosis. In fact, sensitivity for detection of antigenuria in patients with acquired immunodeficiency syndrome and disseminated histoplasmosis was higher in the second-generation assay. Physicians should be aware of the potential for false-positive results in sandwich immunoassays in specimens from patients who have received RATG.
Transplant Infectious Disease 01/2007; 8(4):219-21. · 2.22 Impact Factor
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ABSTRACT: False-positive Histoplasma antigenemia was reported in solid organ allograft recipients who had received rabbit anti-thymocyte globulin (RATG, RATG®) caused by human anti-rabbit antibodies (HARA). A second-generation Histoplasma antigen detection assay was developed to overcome false positivity caused by HARA. With the second-generation assay, false-positive results were eliminated in 18 of 19 cases without reduction in the sensitivity in patients with histoplasmosis. In fact, sensitivity for detection of antigenuria in patients with acquired immunodeficiency syndrome and disseminated histoplasmosis was higher in the second-generation assay. Physicians should be aware of the potential for false-positive results in sandwich immunoassays in specimens from patients who have received RATG.
Transplant Infectious Disease 11/2006; 8(4):219 - 221. · 2.22 Impact Factor
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ABSTRACT: False-positive Histoplasma antigen results were identified in two patients who received rabbit antithymocyte globulin (ATG, Thymoglobulin(R)) to prevent allograft rejection. To determine the prevalence of false-positive results following the administration of Thymoglobulin, sequential specimens were tested from a cohort of transplant recipients. Of 107 such patients, 17 (15.9%) demonstrated false-positive tests for Histoplasma antigenemia. False antigenemia peaked at 2-4 weeks after ATG administration and cleared over the next few months. Physicians should be aware of the potential for false-positive results in specimens from patients who have received ATG.
Transplant Infectious Disease 04/2004; 6(1):23-7. · 2.22 Impact Factor
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ABSTRACT: 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.
Medical Mycology 07/2003; 41(3):189-97. · 2.46 Impact Factor
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ABSTRACT: We report a case of relapse of coccidioidomycosis in an HIV-infected person who discontinued maintenance azole therapy following a response to antiretroviral therapy. This experience raises concern about the safety of withholding secondary prophylaxis for coccidioidomycosis in persons with HIV infection who have achieved immunological responses to antiretroviral therapy.
Mycoses 03/2003; 46(1-2):42-4. · 2.25 Impact Factor
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ABSTRACT: 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.
Medical Mycology 11/2002; 40(5):501-5. · 2.46 Impact Factor
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ABSTRACT: Questions have arisen regarding the risk of developing symptomatic Histoplasma capsulatum infection among patients who undergo transplant-related immunosuppression in areas endemic for histoplasmosis. Our medical center is located in a hyperendemic area for histoplasmosis, where three large outbreaks occurred since 1978. We undertook a retrospective chart review of 137 patients who received allogeneic bone marrow transplant and of 449 patients who received solid organ transplant from January 1994 to December 1996 in order to assess the incidence of active histoplasmosis. Charts were reviewed before and after transplantation for clinical outcomes, H. capsulatum serologies and antigen results, and microbiological and radiological results. After a mean follow-up duration exceeding 16 months, no patient was diagnosed with histoplasmosis. In the absence of an outbreak, histoplasmosis is a rare infection following the immunosuppression of allogeneic bone marrow or solid organ transplantation even in a hyperendemic area. Pre-transplant serologies or chest radiographs consistent with prior infection were not associated with post-transplant histoplasmosis.
Transplant Infectious Disease 10/2002; 4(3):148-51. · 2.22 Impact Factor
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ABSTRACT: Advances in the management of fungal infections in AIDS justify this review. First, their incidence has fallen with the introduction of potent antiretroviral therapy. Now, most cases occur in patients with advanced HIV disease who have failed multiple antiretroviral regimens, are nonadherent to therapy, or treatment na ve. Immune reconstitution has reduced the incidence of these infections and permitted discontinuation of maintenance therapy. However, the immune response to antiretroviral therapy has resulted in paradoxical worsening in some cases, "so-called immune reconstitution inflammatory syndromes". Finally, new antifungal agents expand our treatment choices. This review updates management of fungal infections in AIDS.
European journal of medical research 06/2002; 7(5):236-41. · 1.13 Impact Factor
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ABSTRACT: Presumed ocular histoplasmosis involves the classic triad of discrete atrophic choroidal scars in the macula or midperiphery known as histo spots, peripapillary atrophy, and choroidal neovascularization, which leads to severe loss of central vision. The histo spots from which the choroidal neovascularization develop do not show active inflammation but do represent focal defects in Bruch membrane that could facilitate development of choroidal neovascularization. The macular photocoagulation studies unequivocally show the benefit of photocoagulation compared with observation in reducing the risk of vision loss in patients with presumed ocular histoplasmosis, well defined extrafoveal or juxtafoveal choroidal neovascularization, and choroidal neovascularization in the peripapillary area. However, laser treatment itself causes an absolute scotoma correlating with the site of the laser photocoagulation scar, and subfoveal choroidal neovascularization is not amenable to laser photocoagulation because this would cause a blinding central scotoma. Consequently, other treatments have been sought. The Verteporfin in Ocular Histoplasmosis study evaluated photodynamic therapy for subfoveal choroidal neovascularization caused by presumed ocular histoplasmosis and demonstrated stabilization of the choroidal neovascularization and visual acuity benefit. In addition to photodynamic therapy, antiangiogenic compounds are being developed for choroidal neovascularization caused by age-related macular degeneration, and these agents will likely be of benefit in presumed ocular histoplasmosis associated choroidal neovascularization. Finally, submacular surgery for the removal of subfoveal choroidal neovascularization has promising results. The results of these research efforts will produce more effective therapeutic approaches in the future.
Current Opinion in Ophthalmology 01/2002; 12(6):442-9. · 2.65 Impact Factor
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ABSTRACT: In sequential clinical trials of treatment for histoplasmosis in patients with acquired immunodeficiency syndrome, therapy with fluconazole failed in a higher proportion of patients than did therapy with itraconazole. To determine the cause for failure with fluconazole, antifungal susceptibility testing that used modified National Committee on Clinical Laboratory Standards procedures was performed on all baseline and failure isolates. Failure occurred more frequently in patients with baseline isolates with fluconazole minimum inhibitory concentrations (MICs) > or =5 microg/mL versus lower MICs; 29% versus 3%, respectively. There was at least a 4-fold increase in fluconazole MIC in the isolates from 10 (59%) of 17 patients for whom paired pretreatment and failure or relapse isolates were available. Cross-resistance to itraconazole was not seen. In conclusion, fluconazole is less active than itraconazole for Histoplasma capsulatum and induces resistance during therapy, which accounted for treatment failure in some patients.
Clinical Infectious Diseases 12/2001; 33(11):1910-3. · 9.15 Impact Factor
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ABSTRACT: Animal studies have shown that fungal burden correlates with survival during treatment with new antifungal therapies for histoplasmosis. The purpose of this report is to compare the clearance of fungal burden in patients with histoplasmosis treated with liposomal amphotericin B versus itraconazole. In two separate closed clinical trials that evaluated the efficacy of liposomal amphotericin B and itraconazole treatment of disseminated histoplasmosis in patients with AIDS, blood was cultured for fungus and blood and urine were tested for Histoplasma antigen. The clinical response rates were similar; 86% with liposomal amphotericin B (n = 51) versus 85% with itraconazole (n = 59). Of the patients with positive blood cultures at enrollment, after 2 weeks of therapy cultures were negative in over 85% of the liposomal amphotericin B group versus 53% of the itraconazole group (P = 0.0008). Furthermore, after 2 weeks, median antigen levels in serum fell by 1.6 U in the liposomal amphotericin B group versus 0.1 U in the itraconazole group (P = 0.02), and those in urine fell by 2.1 U in the liposomal amphotericin B group and 0.2 U in the itraconazole group (P = 0.0005). The more rapid clearance of fungemia supports the use of liposomal amphotericin B rather than itraconazole for initial treatment of moderately severe or severe histoplasmosis.
Antimicrobial Agents and Chemotherapy 09/2001; 45(8):2354-7. · 4.84 Impact Factor
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ABSTRACT: 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.
The Journal of Infectious Diseases 07/2001; 183(12):1822-4. · 6.41 Impact Factor
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L J Wheat
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ABSTRACT: Histoplasmosis is a common infection in endemic regions of North and Latin America, causing a broad spectrum of clinical findings. Although acute pulmonary infection, chronic pulmonary, and progressive disseminated histoplasmosis are the most commonly recognized clinical manifestations, pericarditis, rheumatologic syndromes, esophageal compression, and sarcoid-like manifestations are well-recognized complications of histoplasmosis. Although excellent laboratory methods for diagnosis are available, diagnosis in many cases is missed or delayed because histoplasmosis is not considered in the differential. Physicians must be aware of the clinical syndromes and take advantage of epidemiologic clues. Furthermore, clinicians must be familiar with the uses and limitations of a battery of serologic and mycologic tests. Cultures, fungal stains, antigen detection, and serologic tests for antibodies are useful for diagnosis of histoplasmosis. All are reasonably specific and can serve as the basis for diagnosis in patients with compatible clinical findings. Each has certain limitations that must be recognized if they are to be used correctly. The approach to diagnosis of histoplasmosis will be reviewed.
Seminars in Respiratory Infections 07/2001; 16(2):131-40.
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ABSTRACT: Histoplasmosis is an endemic mycosis, which is most prevalent in the Ohio and Mississippi valleys of North America. The causative organism is a dimorphic fungus, Histoplasma capsulatum. Histoplasmosis can present as a self-limited disease or cause life-threatening diseases resulting in considerable morbidity and mortality. Treatment is appropriate in patients with diffuse acute pulmonary infection, chronic pulmonary infection, mediastinal granuloma causing obstruction of important structures, or disseminated infection. Other chronic forms of disease such as fibrosing mediastinitis and broncholithiasis are unresponsive to pharmacologic treatment. Options for therapy include amphotericin B or one of its lipid formulations, and ketoconazole, itraconazole, or fluconazole. Recently, newer antifungal agents have been evaluated in animals models of histoplasmosis. Of these, a new triazole, posaconazole (SCH56592) appears most promising. Generally, amphotericin B or one of the lipid formulations is recommended as initial treatment in patients with more extensive diseases, felt to be ill enough to require hospitalization, and itraconazole for those who have milder illness, or to complete treatment after patients respond to amphotericin B. The role of intravenous formulation of itraconazole for severe histoplasmosis is unknown because studies comparing it with amphotericin B have not been conducted.
Seminars in Respiratory Infections 07/2001; 16(2):141-8.
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ABSTRACT: During a randomized double-blind placebo-controlled study testing the efficacy of itraconazole for prophylaxis of systemic and mucosal fungal infections in patients with acquired immune deficiency syndrome, 298 patients were enrolled with 295 evaluable. Of those, 46 patients were considered prophylaxis failures because of recurrent oral or esophageal candidiasis. Oropharyngeal fungal cultures were taken at the time of suspected thrush or Candida esophagitis, but not at baseline. All of the Candida spp. isolates were cultured on CHROMagar Candida medium then identified using API 20 AUX strips. Antifungal susceptibility testing was performed following the National Committee for Clinical Laboratory Standards M-27A guidelines. Sequential isolates were genotyped using randomly amplified polymorphic DNA. Polymerase chain reaction fingerprints were generated using two repetitive sequence primers, (GGA)7 and (GACA)4. The study group consisted of 23 patients, nine from the itraconazole arm and 14 from the placebo arm, who were prophylaxis failures and had more than two C. albicans isolates. Five of 23 had isolates showing a > or =4-fold reduction in susceptibility; four of these patients were in the itraconazole prophylaxis arm and one was in the placebo arm. Three of the five had yeast isolations showing changes in banding patterns over time. Such changes may indicate genetic changes in the same strain that could be linked to acquired resistance to itraconazole, or acquisition of a new strain, or emergence of a previously minor component of the original population.
Medical Mycology 04/2001; 39(2):207-13. · 2.46 Impact Factor
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R A Hajjeh,
P G Pappas,
H Henderson,
D Lancaster,
D M Bamberger,
K J Skahan,
M A Phelan,
G Cloud,
M Holloway,
C A Kauffman, L J Wheat
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ABSTRACT: We conducted a multicenter case-control study to identify risk factors for histoplasmosis among persons with acquired immunodeficiency syndrome (AIDS) and to evaluate predictors of a poor outcome (defined as death or admission to the intensive care unit). Patients with histoplasmosis were each matched by age, sex, and CD4 lymphocyte count to 3 controls. From 1996 through 1999, 92 case patients and 252 controls were enrolled. Of the case patients, 81 (89%) were men, 50 (55%) were black, 78 (85%) had a CD4 lymphocyte count of <100 cells/microL, 80 (87%) were hospitalized, and 11 (12%) died. Multivariable analysis found that receipt of antiretroviral therapy and of triazole drugs were independently associated with a decreased risk of histoplasmosis. Chronic medical conditions and a history of infections with herpes simplex virus were associated with poor outcome. Triazoles should be considered for chemoprophylaxis for persons with AIDS, especially those who take part in high-risk activities that involve frequent exposure to soil, who have CD4 lymphocyte counts of <100 cells/microL, and who live in areas where histoplasmosis is endemic.
Clinical Infectious Diseases 04/2001; 32(8):1215-20. · 9.15 Impact Factor
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New England Journal of Medicine 11/2000; 343(16):1163-6. · 53.30 Impact Factor
