Fungal diseases: Health burden, neglectedness, and potential interventions

By Rethink Priorities, jenny_kudymowa, JamesHu, Tom Hird @ 2024-09-03T19:24 (+54)

This is a linkpost to https://rethinkpriorities.org/publications/fungal-diseases

Editorial note

This report is a “shallow” investigation, as described here, and was commissioned by Open Philanthropy and produced by Rethink Priorities from January to February 2023. We revised the report for publication. Open Philanthropy does not necessarily endorse our conclusions, nor do the organizations represented by those who were interviewed.

Our report focuses on exploring fungal diseases as a potential new cause area for Open Philanthropy. We assessed the current and future health burden of fungal diseases, provided an overview of current interventions and the main gaps and barriers to address the burden, and discussed some plausible options for philanthropic spending. We reviewed the scientific and gray literature and spoke with five experts.

While revising the report for publication, we learned of a new global burden study (Denning et al., 2024) whose results show an annual incidence of 6.5 million invasive fungal infections, and 3.8 million total deaths from fungal diseases (2.5 million of which are “directly attributable” to fungal diseases). The study’s results align with this report’s estimate of annual 1.5 million to 4.6 million deaths (80% confidence) but were not considered in this report.

We don’t intend this report to be Rethink Priorities’ final word on fungal diseases. We have tried to flag major sources of uncertainty in the report and are open to revising our views based on new information or further research.

Executive summary

While fungal diseases are very common and mostly mild, some forms are life-threatening and predominantly affect low- and middle-income countries (LMICs). The evidence base on the global fungal disease burden is poor, and estimates are mostly based on extrapolations from the few available studies. Yet, all experts we talked to agree that current burden estimates (usually stated as >1.7M deaths/year) likely underestimate the true burden. Overall, we think the annual death burden could be 1.5M - 4.6M (80% CI), which would exceed malaria and HIV/AIDS deaths combined.[1] Moreover, our best guess is that fungal diseases cause 8M - 49M DALYs (80% CI) per year, but this is based on our own back-of-the-envelope calculation of high-uncertainty inputs.

Every expert we spoke with expects the burden to increase substantially in the future, though no formal estimates exist. We project that deaths and DALYs could grow to approximately 2-3 times the current burden until 2040, though this is highly uncertain. This will likely be partly due to a rise in antifungal resistance, which is especially problematic as few treatment classes exist and many fungal diseases are highly lethal without treatment. 

We estimate that only two diseases (chronic pulmonary aspergillosis [CPA] and candidemia/invasive candidiasis [IC/C]) account for ~39%-45% of the total death and DALY burden. Moreover, a single fungal pathogen (Aspergillus fumigatus) accounts for ~50% of the burden. Thus, much of the burden can be reduced by focusing on only a few of the fungal diseases or on a few pathogens. Available estimates suggest the top fungal diseases have highest burdens in Asia and LMICs, and that they most affect immunocompromised individuals. 

Fungal diseases seem very neglected in all areas we considered (research/R&D, advocacy/lobbying, philanthropic spending, and policy interventions) and receive little attention even in comparison to other diseases which predominantly affect LMICs. For example, we estimate the research funding/death ratio for malaria to be roughly 20 times higher than for fungal diseases. Moreover, fewer than 10 countries have national surveillance systems for fungal infections, and the WHO has no fungal disease program yet. Some fungal diseases are limited to certain geographical areas and are thus not considered a global priority by the WHO, yet they have a significant national burden (e.g., paracoccidioidomycosis is endemic in Brazil and has an incidence of 40 cases per 100k inhabitants in some areas).

Major barriers exist at every stage of the care cascade. In our (low-confidence) view, the top three obstacles to tractability are: 

  1. A limited availability (due to both lack of deployment and development) of accurate diagnostics that are inexpensive and easy to use hampers diagnosis, surveillance, and treatment efforts. 
  2. R&D costs for the development of vaccines and treatments are high (e.g., as antifungal treatments are commonly toxic for humans, finding both effective and non-toxic candidates is harder and more costly) and market incentives are insufficient.
  3. The dual use of antifungals in clinical and agricultural contexts is unregulated and might be a key driver of antifungal resistance.

Several experts pointed out potentially promising interventions, such as:

We have not investigated these interventions in detail and have a very limited sense of how promising and tractable they are, whether they are suited for philanthropic funding, and how they could be supported more concretely.

We estimated the social return-on-investment of directly providing treatment for the top two fungal diseases in terms of health burden in LMICs and came away rather pessimistic. We found the barriers to treatment to be high for both CPA and IC/C (e.g., high side effects, long treatment duration, difficult diagnosis, high cost of treatment). Our best guess is that a life could be saved for at least $630 for CPA and at least $2.6k for IC/C in our most optimistic scenario, but this doesn’t take into account costs for diagnosis and hospitalization. 

Read more

Acknowledgments

Jenny Kudymowa and James Hu jointly researched and wrote this report. Jenny also served as the project lead. Tom Hird supervised the report. Special thanks to Melanie Basnak, Aisling Leow, and Sam Donald (Open Philanthropy) for helpful comments on drafts. Thanks also to Adam Papineau for copy-editing and Rachel Norman for assistance with publishing the report online.

Further thanks to Arturo Casadevall (Johns Hopkins Bloomberg School for Public Health), Tom Chiller (Centers for Disease Control and Prevention), David Denning (Global Action for Fungal Infections [GAFFI]), Matthew Fisher (Imperial College London), Marcio Rodrigues (Fiocruz), and Juan Luis Rodríguez Tudela (GAFFI) for taking the time to speak with us. 

Open Philanthropy provided funding for this report, but it does not necessarily endorse our conclusions.

We invite you to explore more RP research via our database and stay updated on new work by subscribing to our newsletter. 

  1. ^

     According to WHO estimates, there are ~620k malaria deaths and ~650k HIV/AIDS deaths worldwide each year.

NickLaing @ 2024-09-05T12:43 (+4)

Great job! A few comments

1. Like you said, close to half the burden of these fungal diseases comes from infecting immunocomprimised individuals - and much of that from HIV. As with many situations, controlling the HIV underlying cause rather than targeting the fungus itself may often be more cost effective to manage this than controlling the diseases themselves

2. Like you say understanding and diagnosis fungal infections and of antifungals is surprisingly loose in LMICs. At OneDay Health we put a bit of effort in teach our nurses to differentiate fungal skin and other yeast infections from others which is often half the battle won. You can't treat something with fancy drugs if you haven't diagnosed it.

3. I wouldn't have picked that invasive candidiasis kills that many, I'll look into it more - interesting one!

4. You might (speculative) be underrating a little the possibility of a "miracle" drug for fungal infections. A lot of current antifungals have activity across different organisms, and there are a number of single dose treatments that are surprisingly effective. The pipedream exists of a tablet which you could take once and it would wipe most fungal infections.

 Obviously drug companies are already spending huge amounts on this as fungal infections affect high income countries a lot too.

tobycrisford 🔸 @ 2024-10-21T06:36 (+1)

This is a fascinating summary!

I have a bit of a nitpicky question on the use of the phrase 'confidence intervals' throughout the report. Are these really supposed to be interpreted as confidence intervals? Rather than the Bayesian alternative, 'credible intervals'..?

My understanding was that the phrase 'confidence interval' has a very particular and subtle definition, coming from frequentist statistics:

From my reading of the estimation procedure, it sounds a lot more like these CIs are supposed to be interpreted as the latter rather than the former? Or is that wrong?

Appreciate this is a bit of a pedantic question, that the same terms can have different definitions in different fields, and that discussions about the definitions of terms aren't the most interesting discussions to have anyway. But the term jumped out at me when reading and so thought I would ask the question!

jenny_kudymowa @ 2024-10-30T11:05 (+1)

Yes, indeed, what we call 'confidence interval' in our report is better described by the term 'credible interval'. 

We chose to use with the term 'confidence interval' because my impression is that this is the more commonly used and understood terminology within EA specifically, but also global health in general - even though it is not technically entirely accurate.

tobycrisford 🔸 @ 2024-10-31T17:49 (+1)

Makes sense, thank you for the reply and clarification!

PeterMcCluskey @ 2024-09-08T18:42 (+1)

I want to emphasize that this just sets a lower bound on the importance.

E.g. there's a theory that fungal infections are the primary cause of cancer.

How much of chronic fatigue is due to undiagnosed fungal infections? Nobody knows. I know someone with chronic fatigue who can't tell whether it's due in part to a fungal infection. He's got elevated mycotoxins in his urine, but that might be due to past exposure to a moldy environment. He's trying antifungals, but so far the side effects have prevented him from taking more than a few doses of the two that he has tried.

It feels like we need something more novel than slightly better versions of existing approaches to fungal infections. Maybe something as radical as nanomedicine, but that's not very tractable yet.

Mo Putera @ 2024-10-30T13:41 (+1)

Agree with the lower bound on fungal burden. For the post you linked I'd signal-boost J Bostock's 7 criticisms too.

jenny_kudymowa @ 2024-10-30T11:07 (+1)

I agree this is most likely a lower bound - we tried to emphasize this in the report. 

I was not aware of the theory that fungal infections are the primary cause of cancer - many thanks for sharing!