Diagnostic accuracy of antigen detection in urine and molecular assays testing in different clinical samples for the diagnosis of progressive disseminated histoplasmosis in patients living with HIV/AIDS: A prospective multicenter study in Mexico

Abstract

Background

The progressive disseminated histoplasmosis (PDH) has been associated with severe disease and high risk of death among people living with HIV (PLWHIV). Therefore, the purpose of this multicenter, prospective, double-blinded study done in ten Mexican hospitals was to determine the diagnostic accuracy of detecting Histoplasma capsulatum antigen in urine using the IMMY ALPHA Histoplasma EIA kit (IAHE), clarus Histoplasma GM Enzyme Immunoassay (cHGEI IMMY) and MiraVista Histoplasma Urine Antigen LFA (MVHUALFA); as well as the Hcp100 and 1281-1283 ₂₂₀SCAR nested PCRs in blood, bone-marrow, tissue biopsies and urine.

Methodology/Principal findings

We included 415 PLWHIV older than 18 years of age with suspicion of PDH. Using as diagnostic standard recovery of H. capsulatum in blood, bone marrow or tissue cultures, or histopathological exam compatible, detected 108 patients (26%, [95%CI, 21.78–30.22]) with proven-PDH. We analyzed 391 urine samples by the IAHE, cHGEI IMMY and MVHUALFA; the sensitivity/specificity values obtained were 67.3% (95% CI, 57.4–76.2) / 96.2% (95% CI, 93.2–98.0) for IAHE, 91.3% (95% CI, 84.2–96.0) / 90.9% (95% CI, 87.0–94.0) for cHGEI IMMY and 90.4% (95% CI, 83.0–95.3) / 92.3% (95% CI, 88.6–95.1) for MVHUALFA.

The Hcp100 nested PCR was performed on 393, 343, 75 and 297, blood, bone marrow, tissue and urine samples respectively; the sensitivity/specificity values obtained were 62.9% (95%CI, 53.3–72.5)/ 89.5% (95%CI, 86.0–93.0), 65.9% (95%CI, 56.0–75.8)/ 89.0% (95%CI, 85.2–92.9), 62.1% (95%CI, 44.4–79.7)/ 82.6% (95%CI, 71.7–93.6) and 34.9% (95%CI, 24.8–46.2)/ 67.3% (95%CI, 60.6–73.5) respectively; and 1281-1283 ₂₂₀SCAR nested PCR was performed on 392, 344, 75 and 291, respectively; the sensitivity/specificity values obtained were 65.3% (95% CI, 55.9–74.7)/ 58.8% (95%CI, 53.2–64.5), 70.8% (95%CI, 61.3–80.2)/ 52.9% (95%CI, 46.8–59.1), 71.4% (95%CI, 54.7–88.2)/ 40.4% (95%CI, 26.4–54.5) and 18.1% (95%CI, 10.5–28.1)/ 90.4% (95%CI, 85.5–94.0), respectively.

Conclusions/Significance

The cHGEI IMMY and MVHUALFA tests showed excellent performance for the diagnosis of PDH in PLWHIV. The integration of these tests in clinical laboratories will certainly impact on early diagnosis and treatment.

Author summary

Histoplasmosis, an infection caused by Histoplasma capsulatum, is prevalent in the Americas, it is a common cause of pulmonary acute disease in cave explorers, speleologists, boy scouts and some other people in circumstantial risk, in most of these people the infection is commonly self-limited. However, in people living with HIV (PLWHIV) this infection might be acquired without specific exposition and it behaves like a severe disease with high fever, consumption, septic shock and death. Thus, there is a need for rapid and accurate methods for diagnosis in this population at risk. We tested five different methods for rapid diagnosis (three based on antigen detection in urine and two molecular assays based on PCR amplification, widely used) of disseminated histoplasmosis and we were able to demonstrate that two urine antigen detection tests (clarus Histoplasma GM Enzyme Immunoassay kit and MiraVista Histoplasma Urine Antigen LFA) showed excellent performance to diagnose of disseminated histoplasmosis in PLWHIV. The antigen detection tests have advantages over the PCR tests, their performance is higher, they are commercial standardized tests, easy to perform, and provide results in hours, therefore the integration of these tests in clinical laboratories will certainly impact on early diagnosis/treatment and consequently on the outcome of patients.