Opinion: Everyone needs access to fungal disease diagnostics

While acute fungal infections are less common than bacterial and viral infections, they carry a higher death rate. In fact for many with AIDS, patients in intensive care, or with leukemia, fungal disease is not survivable without both correct diagnosis and therapy. This is why rapid diagnostics for these infections are so important. Diagnosis of fungal disease can be done using culture or non-culture tests. Fungal culture requires a moderately sophisticated laboratory, and considerable skill and training to identify positives, unlike the non-culture tests which are simpler to do and straightforward to interpret. Over 50% of fungal diseases are (or should be) diagnosed without culture, including cryptococcal meningitis, disseminated histoplasmosis and Pneumocystis pneumonia in HIV/AIDS, invasive and chronic pulmonary aspergillosis, coccidioidomycosis and coccidioidal meningitis, and many others. Although diagnosis using culture of fungi is important, it is insufficient, often falsely negative, and slow. Misdiagnosis for HIV/AIDS patients At Global Action For Fungal Infections we have run a diagnostic program in Guatemala where over half of new HIV diagnoses had advanced HIV or AIDS, especially in the Indigenous Mayan population. By implementing rapid diagnosis for tuberculosis, histoplasmosis, and cryptococcal meningitis in 13 of 16 HIV units in Guatemala (covering 60% of the nation’s HIV patients), mortality from AIDS decreased by 26% over the first year of the program. The key elements of this program were rapid tests and a courier system to get samples to the Diagnostic Laboratory Hub in Guatemala City, online ordering, and results delivery to each center. It also included extensive and ongoing in-person and online training for clinicians and laboratory staff. Patients were systematically screened for these infections rather than relying on the treating physicians to select specific tests. Among the over 2,000 newly diagnosed HIV patients assessed from 2017 to 2019, the number of TB diagnoses decreased and TB mortality also fell by 87%, indicative of misdiagnosis of TB early in the program. In parallel, histoplasmosis diagnoses rose nearly 8 fold and histoplasmosis mortality fell by 55%. Across the world, histoplasmosis is commonly confused with TB. The key test for histoplasmosis in AIDS is a non-culture test using a urine antigen test, which can be done rapidly on site. Ensuring this type of diagnostics is available to health care centers would avoid misdiagnosis and lower TB mortality among people living with HIV/AIDS. Fungi vs. pulmonary TB Another specific area of concern is the misdiagnosis of pulmonary TB, especially in those without HIV. Several fungal infections can mimic pulmonary TB, notably aspergillosis (known as CPA), other fungi (including histoplasma). Just under 50% of all pulmonary TB diagnoses are unconfirmed in the laboratory (negative or missing samples, or no laboratory service). In many settings, those without a confirmed TB diagnosis but who receive a course of TB treatment have a worse outcome than those with confirmed disease, suggestive of misdiagnosis and unnecessary anti-TB therapy. Very few African countries test for Aspergillus antigen or antibody, both very important to diagnose CPA. These fungi can cause lung disease years later, especially if there is damage after TB therapy, notably a cavity remaining in the lung. Studies from India, Vietnam and Ghana show over 50% of cured TB patients coming back to clinic with symptoms have CPA. The state of essential diagnostics Since 2019, the World Health Organization has identified critically important tests for all diseases, called Essential Diagnostics. In 2022, GAFFI conducted an in-depth survey of the state of fungal diagnostics in 48 countries in Africa, covering 99.6% of the African population. The focus was WHO-listed Essential Diagnostics, along with some sample collection techniques and imaging. These Essential Diagnostics include the rapid, simple, sensitive, and inexpensive non-culture tests for several different serious fungal infections. Some fungal diagnostics are well distributed in Africa, including direct microscopy and fungal culture, although not everywhere or in smaller hospitals. Yet antigen testing for histoplasmosis is almost absent from the continent. Given the results we saw in Guatemala, making these readily available would have a positive impact on HIV/AIDS mortality. Availability of other tests for diagnosing life-threatening infections in AIDS varied a lot — partial coverage was seen for fungal meningitis and fungal pneumonia. Clearly this needs to change. Histoplasma antigen is barely available in Asia either and is poorly distributed in many countries in Latin America. Aspergillus antibody testing costs under $10 and should be made widely available in TB and chest clinics. Doctors specializing in lung disease need to be armed with these laboratory diagnostics, along with chest X-ray and preferably CT scans. Many centers treating TB don’t yet offer Aspergillus antibody testing. This also needs to change. Ensuring fungi diagnostics across health care systems globally can reduce mortality associated with better known diseases such as HIV/AIDS, leukemia, and TB, while also reducing microbial resistance — this is a sensible, cost-effective way of saving lives.