Clearance of Fungal Burden during Treatment of Disseminated Histoplasmosis with Liposomal Amphotericin B versus Itraconazole

Wheat, L. Joseph; Cloud, Gretchen A.; Johnson, Philip C.; Connolly, Patricia; Goldman, Mitchell; Monte, A Le; Fuller, D.; Davis, Thomas E.; Hafner, Richard

doi:10.1128/aac.45.8.2354-2357.2001

Cited by 90 publications

(52 citation statements)

References 6 publications

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“…Until now, antigen results have been expressed semiquantitatively as antigen units (calculated as enzyme immunoassay [EIA] units [EU]) based upon comparison to a negative control. Antigen levels decline with effective therapy (9,12) and increase with relapse (13), providing a useful method for monitoring treatment. Based upon analysis of the course of antigen clearance during treatment of histoplasmosis in patients with AIDS (4, 6, 7), a Ն4-EU increase in antigen was chosen as evidence suggesting a relapse of histoplasmosis.…”

mentioning

confidence: 99%

Detection of Histoplasma Antigen by a Quantitative Enzyme Immunoassay

Connolly¹,

Durkin²,

LeMonte³

et al. 2007

Clin Vaccine Immunol

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181

171

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The second-generation Histoplasma antigen immunoassay is semiquantitative, expressing results as a comparison to a negative control, which requires repeat testing of the prior specimen with the current specimen to accurately determine a change in antigen. Reporting results in this manner often is confusing to the ordering physician and laboratory. Development of a quantitative assay could improve accuracy, reduce interassay variability, and eliminate the need to test the prior sample with the current sample in the same assay. Calibrators with known concentrations of Histoplasma antigen were used to quantitate antigen in specimens from patients with histoplasmosis and from controls. Samples from cases of disseminated histoplasmosis or other mycoses and controls were tested to evaluate the performance characteristics of the quantitative assay. Paired specimens were evaluated to determine if quantitation eliminated the need to test the current and prior specimens in the same assay to assess a change in antigen. The sensitivity in samples from patients with AIDS and disseminated histoplasmosis was 100% in urine and 92.3% in serum. Cross-reactions occurred in 70% of other endemic mycoses, but not in aspergillosis. Specificity was 99% in controls with community-acquired pneumonia, medical conditions in which histoplasmosis was excluded, or healthy subjects. A change in antigen level categorized as an increase, no change, or decrease based on antigen units determined in the same assay agreed closely with the category of change in nanograms/milliliter determined from testing current and prior specimens in different assays. Sensitivity, specificity, and interassay precision are excellent in the new third-generation quantitative Histoplasma antigen immunoassay.Antigen detection is a useful method for the diagnosis of histoplasmosis (8). Until now, antigen results have been expressed semiquantitatively as antigen units (calculated as enzyme immunoassay [EIA] units [EU]) based upon comparison to a negative control. Antigen levels decline with effective therapy (9, 12) and increase with relapse (13), providing a useful method for monitoring treatment. Based upon analysis of the course of antigen clearance during treatment of histoplasmosis in patients with AIDS (4, 6, 7), a Ն4-EU increase in antigen was chosen as evidence suggesting a relapse of histoplasmosis. In that evaluation, the change in antigen units between current and prior specimens tested concurrently rarely exceeded 4 EU in patients who did not relapse clinically (unpublished observation).Due to interassay variability, prior specimens have been tested simultaneously with current specimens to accurately assess changes in antigen levels. Test reports including current and prior results often are confusing, however, and do not always reach the ordering physician. In this report, a method for quantitation of Histoplasma capsulatum antigen is described, and its performance characteristics, including accuracy, specificity, sensitivity in patients with AIDS and dissemi...

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mentioning

confidence: 99%

Detection of Histoplasma Antigen by a Quantitative Enzyme Immunoassay

Connolly¹,

Durkin²,

LeMonte³

et al. 2007

Clin Vaccine Immunol

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181

171

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“…Antigen levels decline with effective therapy (9,11) and increase with relapse (10). The Infectious Diseases Society of America (IDSA) guidelines for treatment of patients with progressive disseminated histoplasmosis (PDH) recommend monitoring antigen levels during and after completion of treatment (13).…”

mentioning

confidence: 99%

“…The Infectious Diseases Society of America (IDSA) guidelines for treatment of patients with progressive disseminated histoplasmosis (PDH) recommend monitoring antigen levels during and after completion of treatment (13). Prior studies of antigen clearance in PDH used the original Histoplasma antigen radioimmunoassay (11) and enzyme immunoassay (EIA) (2,9). Subsequently, the assay was modified to reduce false-positive results caused by interfering substances (14) and to provide quantification (1).…”

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confidence: 99%

Histoplasma Antigen Clearance during Treatment of Histoplasmosis in Patients with AIDS Determined by a Quantitative Antigen Enzyme Immunoassay

Hage

Kirsch

Stump

et al. 2011

Clin. Vaccine Immunol.

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Clearance of Histoplasma antigen has been used as a marker for response to treatment of progressive disseminated histoplasmosis (PDH) in patients with AIDS. Advancements in Histoplasma antigen detection permit accurate quantification of antigen concentration. We compared the clearance of antigenemia and antigenuria during effective treatment of PDH. Urine and serum specimens were serially collected from patients with AIDS who were successfully treated for PDH as part of two prospective clinical trials. Samples were stored frozen until they were tested in the quantitative Histoplasma antigen enzyme immunoassay. The kinetics of antigen clearance during the first 12 weeks of therapy were assessed in urine and serum during treatment with liposomal or deoxycholate amphotericin B followed by itraconazole and, in a separate analysis, in patients receiving only itraconazole. Latent class growth analysis was performed to define patterns of antigen clearance over time. In patients receiving amphotericin B, antigen levels declined the most during the first 2 weeks of treatment and antigenemia decreased more rapidly than antigenuria (5.90 ng/ml per week versus 4.21 ng/ml per week, respectively; P ‫؍‬ 0.09). Mean reductions of antigen levels from baseline at weeks 2 and 12 were greater in sera than in urine: 11.26 ng/ml versus 7.65 ng/ml (P ‫؍‬ 0.0948) and 18.52 ng/ml versus 14.64 ng/ml (P ‫؍‬ 0.0440), respectively. In patients who received itraconazole alone, most of the decline in antigenuria occurred later during treatment and was overall slower than that seen with amphotericin B (P < 0.0001). Results of latent class growth modeling showed two distinct trajectories for each parameter. With effective therapy, Histoplasma antigenemia decreases more rapidly than antigenuria, providing a more sensitive early laboratory marker for response to treatment. Antigenuria declines earlier with amphotericin B than with itraconazole.

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“…However, development of antibodies by the host requires time and an efficient immune response, both of which histoplasmosis patients may lack. Antigen, rather than antibody, detection is one way to avoid reliance on B-cell responses, and the level of antigenemia often correlates with the fungal burden in active disease (42,(44)(45)(46)(47). As an abundantly secreted protein, Cfp4 could potentially be a target for antigen detection-based diagnostics, but further studies to establish its utility as a biomarker will be required.…”

Section: Discussionmentioning

confidence: 99%

Glycosylation and Immunoreactivity of the Histoplasma capsulatum Cfp4 Yeast-Phase Exoantigen

Holbrook

Kemski

Richer³

et al. 2014

Infect Immun

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The yeast phase of Histoplasma capsulatum is the virulent form of this thermally dimorphic fungal pathogen. Among the secreted proteome of Histoplasma, culture filtrate protein 4 (Cfp4) is a heavily glycosylated factor produced abundantly and specifically by Histoplasma yeast cells, suggesting its role in pathogenesis. We have generated three monoclonal antibodies as tools for characterization and detection of Cfp4 and determined the epitope each recognizes. Through site-directed mutagenesis of Cfp4, we identified three asparagines that function as the principal sites of N-linked glycan modification. To test the function of Cfp4 in Histoplasma pathogenesis, we generated Cfp4-deficient strains by insertional mutagenesis and by RNA interference. Cfp4-deficient strains are not attenuated in virulence in human macrophages or during lung infection in a murine model of histoplasmosis. Coinfection of differentially marked Cfp4-producing and Cfp4-deficient strains demonstrates that production of Cfp4 does not confer a fitness advantage to Histoplasma yeasts during murine lung infection. Despite no apparent role in acute virulence in mice, secretion of the Cfp4 glycoprotein by yeast cells is consistent across clinical and laboratory isolates of the North American type 1 and type 2 phylogenetic groups as well as a strain from Panama. In addition, human immune sera recognize the Histoplasma Cfp4 protein, confirming Cfp4 production during infection of human hosts. These results suggest the potential utility of Cfp4 as a diagnostic exoantigen for histoplasmosis.

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Clearance of Fungal Burden during Treatment of Disseminated Histoplasmosis with Liposomal Amphotericin B versus Itraconazole

Cited by 90 publications

References 6 publications

Detection of Histoplasma Antigen by a Quantitative Enzyme Immunoassay

Detection of Histoplasma Antigen by a Quantitative Enzyme Immunoassay

Histoplasma Antigen Clearance during Treatment of Histoplasmosis in Patients with AIDS Determined by a Quantitative Antigen Enzyme Immunoassay

Glycosylation and Immunoreactivity of the Histoplasma capsulatum Cfp4 Yeast-Phase Exoantigen

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