ABSTRACT
A patient with progressive disseminated histoplasmosis was noted to have an increase in urine Histoplasma antigen level during monitoring of her disease. The patient revealed she had inadequately hydrated, and her urine volume was low and subjectively concentrated. Following hydration, urine antigen was retested and became undetectable.
KEYWORDS: Histoplasmosis, urine histoplasma antigen, volume status
1. Case report
A 42-year-old woman with ulcerative colitis on high-dose infliximab was diagnosed with progressive disseminated histoplasmosis at two weeks postpartum. Her unusual case involved vertical transmission of histoplasmosis to her child and has been previously reported [1]. Given fever and systemic symptoms with nodular infiltrate on chest imaging and laboratory evidence of anemia and hepatitis, she was treated with intravenous Amphotericin B for two weeks and then transitioned to itraconazole capsules. Initial urine histoplasma antigen (UHAg) was >19 ng/ml, which is above the limit of quantification (LoQ) for the MiraVista assay used (scale of results: Negative; Positive – below the LoQ <0.4 ng/ml; Positive – 0.4–19 ng/ml; Positive – above the LoQ >19 ng/ml; Histoplasma Quantitative Enzyme Immunoassay). Her itraconazole levels were monitored every 3–4 months and were in therapeutic range throughout her treatment, and she clinically improved [Figure 1].
Figure 1.
UHAg and itraconazole levels over time.
At her 12-month follow-up visit, UHAg was measured at 1.81 ng/ml. Itraconazole was continued due to her significant immunosuppression at diagnosis, high antigen levels at diagnosis, and persistently positive UHAg. UHAg subsequently increased at month fifteen to 3.07 ng/ml. During the discussion of results, the patient noted that she was subjectively volume depleted, resulting in a low-volume, concentrated-appearing urine specimen. She increased water intake and provided a repeat sample seven days later that showed a ‘Negative’ UHAg result [Figure 1].
Histoplasmosis is a common fungal infection in the Ohio and Mississippi River Valley regions caused by inhalation of Histoplasma capsulatum with a wide range of clinical manifestations [2]. Immunosuppressed patients are at higher risk for the development of progressive disseminated histoplasmosis [2]. While culture remains the gold standard for diagnosis, its sensitivity is limited. Thus, antigen detection assays utilizing serum, urine, bronchoalveolar lavage, and cerebrospinal fluid have emerged as an effective tool for the diagnosis of active infection [3].
While UHAg testing has a high sensitivity of 91–95%, unexpected variability of UHAg during monitoring of disease has been reported [4,5,6]. Fluctuating urine concentrations have been hypothesized as a cause of this variability; however, no study has directly evaluated the physiologic concentration of urine and effects on antigenuria [5,6]. One study, conducted to evaluate if ultrafiltration of false-negative UHAg samples improved detection rates, concluded that ultrafiltration increases antigen detection in previously false-negative samples [7]. This research supports the theory that dilution of urine may result in reduced sensitivity of antigen detection. Given the effects of urinary concentration on antigen detection, we hypothesize that the variability of this patient’s UHAg may be related to her volume status and urine concentration. Alternatively, it is possible that this variability may have been a laboratory error.
If levels of urine antigen do vary based on concentration as has been suggested in this case report and in the ultrafiltration study, volume status should be considered when interpreting UHAg testing, which can be of considerable importance in both inpatient and outpatient populations [7]. Urine dilution may lead to more false-negative results than previously appreciated, and conversely, increased urinary concentration may lead to spuriously elevated results, complicating interpretation of treatment response. Determining whether urine dilution affects antigenuria to a clinically significant degree is especially important since many patients with progressive disseminated histoplasmosis are volume resuscitated when initial testing occurs. Further study is warranted to determine if urine concentration affects urine antigen levels and its subsequent clinical significance.
Funding Statement
This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.
Acknowledgments
The authors would like to acknowledge the astute patient involved in this case report. She noticed her urine concentration differences and formulated the hypothesis that her unexpected UHAg levels may be related to volume status. Written informed consent was obtained from the patient for publication of this case report.
Disclosure statement
No potential conflict of interest was reported by the authors.
Correction Statement
This article has been republished with minor changes. These changes do not impact the academic content of the article.
References
- [1].Carlucci JG, Halasa N, Creech CB, et al. Vertical transmission of histoplasmosis associated with anti-tumor necrosis factor therapy. J Pediatric Infect Dis Soc. 2016. June;5(2):9–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [2].Azar MM, Hage CA.. Laboratory diagnostics for histoplasmosis. J Clin Microbiol. 2017. June;55(6):1612–1620. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [3].Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the infectious diseases society of America. Clin Infect Dis. 2007. October 1;45(7):807–825. [DOI] [PubMed] [Google Scholar]
- [4].Wheat LJ. Improvements in diagnosis of histoplasmosis. Expert Opin Biol Ther. 2006;6(11):1207–1220. [DOI] [PubMed] [Google Scholar]
- [5].Hage CA, Kirsch EJ, Stump TE, et al. Histoplasma antigen clearance during treatment of histoplasmosis in patients with AIDS determined by a quantitative antigen enzyme assay. Clin Vaccine Immunol. 2011. April;18(4):661–666. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [6].Wheat LJ, Connolly-Stringfield P, Blair R, et al. Effect of successful treatment with amphotericin B on Histoplasma capsulatum variety capsulatum polysaccharide antigen levels in patients with AIDS and histoplasmosis. Am J Med. 1992. February;92(2):153–160. [DOI] [PubMed] [Google Scholar]
- [7].Egan L, Connolly PA, Fuller D, et al. Detection of Histoplasma capsulatum antigenuria by ultrafiltration of samples with false-negative results. Clin Vaccine Immunol. 2008. April;15(4):726–728. [DOI] [PMC free article] [PubMed] [Google Scholar]