The “Histoplasmosis Porto Alegre manifesto”—addressing disseminated histoplasmosis in AIDS

Publication summary

Histoplasmosis is a fungal infection that primarily affects immunocompromised people, such as people living with HIV and people taking immunosuppressive medications, in endemic or hyperendemic areas. In Latin America, Histoplasma is the most prevalent endemic mycosis that can cause systemic disease, such as disseminated histoplasmosis, which is often fatal if left undiagnosed and untreated. Even in endemic areas, access to appropriate diagnosis and treatment may be difficult, and for years, researchers and clinicians who work with the disease and with immunocompromised people have called for changes in how the disease is approached, especially in low-resource areas of the Americas. In this summary of the Histoplasmosis Porto Alegre Manifesto, following the May 2022 Brazilian Histoplasmosis Meeting, the authors call for urgent improvements to the availability of Histoplasma antigen testing and liposomal amphotericin B antifungal treatment.

Who this is for

• Clinicians and microbiologists working in areas where Histoplasma is endemic
• Diagnostics and pharmaceutical manufacturers
• Health policymakers
• Advocates for immunocompromised patients, particularly people living with HIV

Key findings

Histoplasmosis incidence

Because diagnostic testing, especially the relatively quick method of Histoplasma antigen testing, is not widely available, the incidence of histoplasmosis across Latin American countries is difficult to estimate. Histoplasmosis is usually not reportable at the national level, even though it is associated with a high death rate in people living with HIV. For instance, in endemic regions of Brazil, the death rate from disseminated histoplasmosis was 42% to 53%, and more than 40% of hospitalized people with HIV also had Histoplasma infections. Like other fungal infections that can cause pulmonary disease, histoplasmosis is often misdiagnosed as tuberculosis (TB) and may also occur as a co-infection with TB.

Availability of diagnostic testing

Microscopy. Microscopy with staining is often how histoplasmosis is diagnosed, but the sensitivity of microscopy depends on the microbiologist’s training in recognizing Histoplasma and the quality of the sample. Microscopy is more sensitive when a greater fungal burden is present in the sample, which also means it has a higher chance of correctly diagnosing an infection that has progressed to advanced and disseminated disease.

Culture. Fungal culture may take 4 to 6 weeks to grow and has varying sensitivity, identifying 50% to 80% of positive cases and typically being dependent on the source of the sample, with cultures of bone marrow aspirate, skin, and lymph node biopsy having a greater sensitivity. Because of the long culture time, proper treatment requires a clinician who is skilled in suspecting histoplasmosis and can start empirical antifungal therapy. Histoplasma culture also requires a Biosafety Level 3 laboratory, and microbiologists working with samples are placed at risk of infection when this level of biosecurity is not available at their institution.

Histopathology. Histopathology may be able to diagnose disseminated disease in several days from the time a sample is taken, but it requires a tissue biopsy and clinicians and microbiologists who are skilled in taking and reading a sample for a suspected histoplasmosis diagnosis.

Polymerase chain reaction (PCR). Real-time quantitative PCR assays are not commercially available for Histoplasma, though they have shown promise in detecting fungal DNA in blood samples from patients with disseminated disease and in detecting DNA from localized infection.

Antibody detection. Antibody detection tests for Histoplasma are not commercially available and have low sensitivity in identifying infections in immunocompromised patients.

Antigen testing. Antigen tests have demonstrated a sensitivity and specificity greater than 90%, return results quickly, and use samples obtained from urine, blood, or serum. They require less training than traditional microscopy or histopathology methods, are commercially available, and can be validated easily. Most importantly, the use of comparatively rapid antigen tests with a high sensitivity has had demonstrated effects on survival in patients with disseminated histoplasmosis. A Brazilian study found reductions in mortality from 26.9% to 14.3% when an antigen test was the first diagnostic used to detect positive Histoplasma infections.

Antifungal access. Histoplasmosis is typically treated with the antifungal medications itraconazole and amphotericin B. However, availability of the liposomal form of amphotericin B, which is associated with a significantly lower likelihood of experiencing toxicity and adverse side effects in comparison with the deoxycholate form, varies across Latin America.

Recommendations

Testing. The group affirms that access to antigen testing is critical to reducing deaths from disseminated histoplasmosis and to understanding the true burden of the disease. They recommend that antigen tests be widely available across public and private hospitals in Brazil and that antigen screening be accessible to people at high risk of Histoplasma infection and disseminated disease.

Treatment. The group asserts that liposomal amphotericin B should be available to all patients who require histoplasmosis treatment.

Further research. Areas for further research and discussion include: investigation into individualized durations of therapy, particularly in people living with HIV, to reduce hospital stays, antifungal treatment side effects, and costs; the burden of Histoplasma and TB co-infection; the role of preventative therapies; and ways to reduce the risk of side effects and drug interactions in people with comorbidities and in people receiving antiretroviral therapies.