The rapid and accurate diagnosis of fungal infections is crucial to effective treatment and ultimately saves lives. Diagnostics are often not widely available in low income countries leading to inappropriate and delayed treatments. This is the case for a serious fungal infection called chronic pulmonary aspergillosis (CPA), and often for other fungal infections associated with HIV patients. In this blog, Professor David Denning explores the issues surrounding diagnosis of fungal infections and argues that improved access to fungal diagnostics could save lives.

• More than 50% of CPA patients in India, Vietnam, and Ghana were misdiagnosed with tuberculosis.
• Rapid diagnostics are required for the timely diagnosis of fungal disease in patients with advanced HIV and AIDS.
• Promoting access to such diagnostics and integrating them into tuberculosis and HIV care guidelines could improve outcomes to serious fungal disease infections worldwide.

Accurate and timely diagnosis of fungal infections allows treatment to occur quickly, using the appropriate regimen. However, in low income countries diagnosis often never occurs. Of the two million people who die each year from fungal infections, most will never be diagnosed, highlighting the vital importance of effective fungal diagnostics.

Problems with diagnosing fungal diseases

In the absence of formal diagnosis, fungal infections can be misdiagnosed for other diseases, as is often the case with a respiratory fungal disease termed chronic pulmonary aspergillosis (CPA). CPA is often mistaken for tuberculosis (TB) due to the similar symptoms these diseases share. They can be distinguished with appropriate diagnostics, which are not always available in low resource settings.

Strikingly, recent research from India, Vietnam and Ghana show that 54-57% of patients who had completed their 6-month treatment course for TB – but then had new symptoms and a suspected relapse of TB – actually had CPA. This illustrates the extent to which CPA is underdiagnosed, but also the impact misdiagnosis of CPA has on the statistics of TB prevalence. Currently, the mortality of people with unconfirmed TB – but treated as if they have TB – is higher than in confirmed TB cases; this anomaly is most likely the result of an incorrect diagnosis. Misdiagnosis of CPA has a high impact on patients as well as on TB control strategies: CPA fatalities are currently included in TB mortality statistics.

In addition, anti-TB treatment is not harmless. Liver toxicity attributable to anti-TB drugs has been reported in 5%–28% of patients, with 1-3% being severe and some leading to death. Thus, CPA and TB-like fungal disease misdiagnosis leads to excessive anti-TB therapy, cost, patient toxicity, and death. International concern about antimicrobial resistance mandates the use of appropriate therapy only in people who actually have TB. Incorrect therapy leads to a lack of confidence in medical professionals, and healthcare services.

Another area where diagnosis of fungal infections has an enormous impact on patient health is during HIV infection and AIDS. HIV and AIDS patients have compromised immune systems and are at greater risk of serious fungal infections. AIDS itself is not the cause of death, but leaves patients vulnerable to infections which are life-threatening. In fact, fungal infections cause more AIDS deaths than TB, but over half of these fungal disease deaths are avoidable. As HIV leaves the immune system compromised, it is important to measure the extent to which the patient is immunocompromised to predict how susceptible they are to infections.

Counting the number of a specific type of T cell, critical to the proper functioning of the immune system, can help determine the extent the patient is immunocompromised. If their T cell count falls below a threshold, then tests to search for life-threatening infections, including fungal infections, can be done to ensure rapid treatment if such infections are detected. Diagnosis of fungal infections must be rapid in these immunocompromised patients. Currently, counting the number of T cells can take one or two days, in which time an infection may already be taking place.

How to address issues with diagnosis?

The impact that fungal disease misdiagnosis, and often lack of diagnosis at all, has on patient health needs to be tackled. Researchers at The University of Manchester have been working closely with Global Action For Fungal Infections  (GAFFI), which aims to promote access to fungal diagnostics particularly in low income countries, and has set out these recommendations to policymakers.

To tackle the misdiagnosis of CPA for TB and to treat CPA effectively, GAFFI recommends

• Testing for Aspergillus antibodies, which appear in response to CPA infection, and fungal cultures in TB diagnostic guidelines, to ensure that CPA is not misdiagnosed for TB.
• Unconfirmed TB cases and those who return with new symptoms after completion of anti-TB therapy, should be tested for fungal lung disease.
• Access to imaging, preferably CT scans, as a means to distinguish fungal lung disease from TB.
• Access to antifungal agents listed on the WHO Essential Medicines List to a wider number of patients.

To reduce the number of fungal disease deaths for advanced HIV and AIDS patients, GAFFI recommends that access to fungal disease diagnostics be as close as possible to the patient: in clinics, local laboratories or diagnostic hubs, to ensure that results are provided rapidly. Similarly, to reduce the time for diagnosing serious fungal infections in these patients, T cell counts are necessary to identify those patients that are more immunocompromised and at greatest risk of the most serious infections.

To ensure that common fungal diseases affecting HIV and AIDS patients are effectively diagnosed, access to the appropriate testing is required. Cryptococcal testing should be made available to every clinical setting caring for patients with HIV. Additionally, Pneumocystis testing is needed to rapidly diagnose pneumonia. Access to Histoplasma and talarmycosis testing is required in those areas where they are endemic. Once diagnosed treatment of such fungal diseases in AIDS patients requires access to all antifungals listed in the WHO Essential Medicines List and used for their approved indications. Updating country guidelines to reflect the current WHO global guidelines is required and should be done within a few months of WHO publication. Finally, countries should place as much emphasis on reducing deaths associated with AIDS as on antiretroviral therapy.

Fungal diagnostics- a global perspective

Some progress has been made in recent years to ensure that diagnostics for life threatening fungal diseases are accessible across the world. Last year, the WHO added several fungal disease tests to the Essential Diagnostics list, following an application by GAFFI for these tests to be admitted. Countries can utilise this list as a policy tool to implement recommended diagnostics essential to improving disease outcomes.

However, it is not enough that these accurate and rapid diagnostic tests exist; they must be accessible to the healthcare systems where they are desperately needed. The recommendations set out here must be enacted and built upon by policymakers in the UK and globally, if serious fungal diseases are to be effectively diagnosed, monitored and treated.

A full policy briefing from GAFFI, on “Minimising fungal disease deaths in advanced HIV disease and AIDS”, can be read here, and a policy brief on “Chronic pulmonary aspergillosis: global misdiagnosis of TB-like fungal lung disease”, can be read here (you can also listen to a podcast on this topic with Professor Denning). These policy briefs were supported by Policy@Manchester.