Indication - HIV infection
Histoplasma capsulatum antigen
First added in 2019
Changed in 2020
Aid to diagnosis
To aid in the diagnosis of disseminated histoplasmosis
WHO prequalified or recommended products
WHO supporting documents
ICD11 code: 1C62.Z
Summary of evidence evaluation
The evidence for the accuracy of the test is poorly presented in the systematic review. A few reasonable studies may exist, and some show good diagnostic accuracy, but there appears to be unexplained variation in the accuracy of the test. Further detailed analysis of the evidence is needed to evaluate the quality of the studies and their findings.
Summary of SAGE IVD deliberations
Histoplasma antigen has been detected in the urine of 95–100% and in the serum of 80% of patients with disseminated AIDS. The availability of a simple, rapid method to detect H. capsulatum infection in LMICs would dramatically decrease the time to diagnosis and treatment and the number of deaths among patients with AIDS-related disseminated histoplasmosis. In immunocompromised people, tests for detecting histoplasma polysaccharide antigen in urine, serum, bronchoalveolar lavage and cerebrospinal fluid samples allow rapid diagnosis of disseminated histoplasmosis before positive cultures can be identified. The concentration of antigen is highest in urine, which can be used to monitor the response to antifungal therapy and to identify relapses. Lack of availability of the test is a major contributor to deaths from AIDS in endemic areas.
SAGE IVD recommendation
SAGE IVD recommended conditional inclusion in the EDL of the histoplasma antigen EIA, pending submission within 1 year of more evidence on the performance of the test. The Group requested the WHO technical department on HIV infection to include advice on use of the test in their guidelines. 3rd EDL Edition: Additional evidence to support this listing was provided and reviewed by SAGE IVD. During their third annual meeting (held as a series of remote sessions from June to July 2020), SAGE IVD recommended reversing the conditional listing.
Details of submission from 2020
Disease condition and impact on patients: Progressive disseminated histoplasmosis is an increasingly common recognized cause of infection in patients with advanced HIV infection in areas endemic for histoplasmosis (1, 2). Histoplasmosis is the most common endemic human mycosis (3). It is caused by the thermally dimorphic fungus Histoplasma capsulatum, which has worldwide distribution, and Histoplasma duboisii, which is endemic in Africa. Histoplasma is transmitted through the respiratory tract, but, once inhaled into the alveoli, the organism readily spreads throughout the body, causing a wide spectrum of manifestations that range from subclinical infections to progressive disseminated disease, affecting both immunocompetent and immunosuppressed individuals (4). Bat guano is the primary ecological niche of histoplasma, and the number of cases shows substantial seasonal variation. The clinical presentation of disseminated histoplasmosis in patients with AIDS is subtly different from that of TB, with more gastrointestinal and fewer respiratory features, pyrexia and usually some degree of pancytopenia. Most patients with disseminated histoplasmosis and AIDS are in their 30s, and in the absence of treatment, death usually occurs within 10–14 days. The fungus typically takes 2 weeks to grow on mycological media and does not grow on media for bacterial culture. Does this test meet a medical need? Histoplasma antigen has been detected in the urine of 95–100% and in the serum of 80% of patients with disseminated AIDS (5–7). The availability of a simple, rapid method to detect H. capsulatum infection in LMICs would dramatically decrease the time to diagnosis and treatment and the number of deaths among patients with AIDS-related disseminated histoplasmosis. Skin test reactivity in immunocompetent people indicates previous exposure and contributes to assessment of local risk of exposure; it could be used to focus diagnostic testing. In immunocompromised people, tests for detecting histoplasma polysaccharide antigen in urine, serum, bronchoalveolar lavage and cerebrospinal fluid samples allow rapid diagnosis of disseminated histoplasmosis before positive cultures can be identified (8). The concentration of antigen is highest in urine and can be used to monitor the response to antifungal therapy and to identify relapses (9). How the test is used: Histoplasma antigen testing is used in patients with advanced HIV infection, similar to testing for cryptococcal antigen or lipoarabinomannan.
Public health relevance
Prevalence: The number of cases of disseminated histoplasmosis in people with AIDS has been estimated to be 100 000–300 000 (10, 11). Very high rates are confined to certain countries and localities. For example, in Fortaleza, Brazil, 164 (43%) of 378 consecutively hospitalized HIV-positive patients had disseminated histoplasmosis (12), and, in Venezuela, autopsies of 66 patients with AIDS revealed histoplasmosis in 44% (13). In a series in Brazil, overall mortality was 71% in 275 patients (14). Disseminated histoplasmosis also occurs in Africa (15), on the Indian subcontinent and in southern China and South East Asia. The estimated global burden in people with AIDS is 100 000 cases, with about 80 000 deaths, as most cases are not diagnosed (16). The estimates in AIDS patients in countries with suboptimal diagnostic methods were 300 cases in Indonesia, 175 cases in Malaysia, 158 cases in Mozambique, 32 cases in Thailand and 135 cases in the United Republic of Tanzania, which are probably significant underestimates. Large and small outbreaks have been attributed to histoplasmosis, but most infections are sporadic (3), and localized hot spots have been well described but poorly mapped. Focal hotspots confound global estimates of the burden of disease. Socioeconomic impact: Not provided
WHO or other clinical guidelines relevant to the test
The test is recommended in the WHO guidelines for advanced HIV infection (17).
Evidence for clinical usefulness and impact
The impact of accurate, fast diagnosis with antigen testing of disseminated histoplasmosis in people with AIDS has been modelled (16).
Evidence for economic impact and/or cost–effectiveness
The test has a small effect on budgets overall; however, it should be focused on areas of moderate and high prevalence.
Ethical issues, equity and human rights issues
Consent is required to obtain a urine sample. Lack of availability of the test is a major contributor to deaths from AIDS in endemic areas, especially in Brazil and French Guiana. Death from histoplasmosis in people with AIDS typically occurs in the prime of life, around 35 years. A reduction in the number of such deaths would be beneficial for the affected individuals, families and communities.
1. Johnson PC, Sarosi GA, Septimus EJ, Satterwhite TK. Progressive disseminated histoplasmosis in patients with acquired immune deficiency syndrome: a report of 12 cases and a literature review. Semin Resp Infect. 1986;1(1):1–8. 2. Adenis AA, Valdes A, Cropet C, McCotter OZ, Derado G, Couppie P, et al. Burden of HIV-associated histoplasmosis compared with tuberculosis in Latin America: a modelling study. Lancet Infect Dis. 2018;18(10):1150–9. 3. Kauffman CA. Histoplasmosis. Clin Chest Med. 2009;30(2):217. 4. Wheat LJ. Histoplasmosis: a review for clinicians from non-endemic areas. Mycoses. 2006;49(4): 274–82. 5. Wheat LJ, Azar MM, Bahr NC, Spec A, Relich RF, Hage C. Histoplasmosis. Infect Dis Clin North Am. 2016;30(1):207–27. 6. Scheel CM, Samayoa B, Herrera A, Lindsley MD, Benjamin L, Reed Y, et al. Development and evaluation of an enzyme-linked immunosorbent assay to detect Histoplasma capsulatum antigenuria in immunocompromised patients. Clin Vaccine Immunol. 2009;16(6):852–8. 7. Cáceres DH, Samayoa BE, Medina NG, Tobón AE, Guzmán BJ, Mercado D, et al. Multicenter validation of commercial antigenuria reagents to diagnose progressive disseminated histoplasmosis in people living with HIV/AIDS in two Latin American countries. J Clin Microbiol. 2018;56:e01959-17. 8. Hage CA, Ribes JA, Wengenack NL, Baddour LM, Assi M, McKinsey DS, et al. A multicenter evaluation of tests for diagnosis of histoplasmosis. Clin Infect Dis. 2011;53(5):448–54. 9. Richardson MD, Warnock DW. Fungal infection: diagnosis and management, 4th edition. New York City (NY): Wiley; 2012. 10. Armstrong-James D, Meintjes G, Brown GD. A neglected epidemic: fungal infections in HIV/AIDS. Trends Microbiol. 2014 ;22(3):120–7. 11. Global fungal infection forum III. Essential diagnostics for advanced HIV disease and serious fungal infections. Kampala, Uganda, 10–12 April 2018. Geneva: Global Action Fund for Fungal Infections; 2018 (https://www.who.int/medical_devices/diagnostics/selection_in-vitro/selection_in-vitro- meetings/00005_12_GFIF3Report_email.pdf?ua=1). 12. Daher EF, Silva GB Jr, Barros FA, Takeda CF, Mota RM, Ferreira MT, et al. Clinical and laboratory features of disseminated histoplasmosis in HIV patients from Brazil. Trop Med Int Health. 2007;12(9):1108–15. 13. Murillo J, Castro KG. HIV infection and AIDS in Latin America. Epidemiologic features and clinical manifestations. Infect Dis Clin North Am. 1994 ;8(1):1–11. 14. Silva TC, Treméa CM, Zara ALSA, Mendonça AF, Godoy CSM, Costa CR, et al. Prevalence and lethality among patients with histoplasmosis and AIDS in the midwest region of Brazil. Mycoses. 2017;60(1):59–65. 15. Oladele RO, Ayanlowo OO, Richardson MD, Denning DW. Histoplasmosis in Africa: an emerging or a neglected disease? PLoS Negl Trop Dis. 2018;12(1):e0006046. 16. Denning DW. Minimizing fungal disease deaths will allow the UNAIDS target of reducing annual AIDS deaths below 500 000 by 2020 to be realized. Phil Trans R Soc B. 2016;371:20150468 17. Guidelines for managing advanced HIV disease and rapid initiation of antiretroviral therapy. Geneva: World Health Organization; 2017 (http://www.who.int/hiv/pub/guidelines/advanced- HIV-disease/en/).