A Primer on Histoplasmosis: Epidemiology, Symptoms, Diagnosis, Treatment, and Prevention
Terri Wilder: Thanks so much for talking with me. I want to start with some basics. What is histoplasmosis?
Joseph Cherabie: Histoplasmosis is what we in the infectious disease realm call a dimorphic fungus that exists in the soil. When we say dimorphic, it means that this fungus takes on two different forms, depending on whether it’s inside the body or, when it’s outside, depending on the temperature. It can exist as yeast or mold, which are the two different typical forms of fungus.
Most commonly you will hear that it exists in the Missouri and the Ohio River Valleys, mainly because of the environments that exist in these soils. But also, it is quite common in any area or any soil that is exposed to bat droppings or bird droppings. So you can imagine that it’s pretty commonly found all over. It isn’t until it is inhaled that it can actually infect human beings. It also exists worldwide and is found in Central and South America, Africa, and in parts of Asia.
Recent studies that we’re performing at Washington University—and other colleagues of ours, in various different fields of mycology—have looked at the spread of histoplasmosis moving beyond the Missouri and the Ohio River Valleys, where we would more commonly see these things, mainly due to things like climate change and the warming climates.
Wilder: Specifically, how is a person exposed to it? And who gets it?
Cherabie: Anybody can get it. Actually, some estimates are that 60 to 90 percent of individuals have been exposed to histoplasma at least during their lifetime.
The major way that we get it is through disruptions of the soil. So, whenever there is construction nearby or any kind of project in which soil is being moved in a large amount, it disrupts the soil. It causes these microconidia to basically go into the air. And when you inhale it, you become exposed to histoplasmosis.
Now, just because you inhale it doesn’t mean that you’ll necessarily be infected with it, or that you’ll suffer from long-term complications of it. In fact, the majority of the people who are, quote-unquote, infected with histoplasmosis are completely asymptomatic and won’t even notice it.
Some people do develop symptoms. However, oftentimes it’s very mild and might be mistaken for a sinus infection or a common cold. One of my colleagues has said: If you’ve ever experienced a kind of sinus infection or cold that just kind of lingers—in this part of the world, meaning St. Louis—then most likely it could be histoplasmosis that you were experiencing, but you just didn’t know it.
Wilder: What are some of the symptoms?
Cherabie: If you do develop symptoms, the mild acute pulmonary disease would be cough, nasal congestion, shortness of breath; your basic respiratory symptoms. However, if people are immunocompromised or immunosuppressed, such as people who have bone marrow transplants or people who have HIV that is uncontrolled, then they might go on to develop more long-term effects. And it could disseminate in a variety of different ways.
Histoplasmosis can do a variety of different things. Some people present with skin lesions, for example. Other people can present if it gets into their central nervous system. Some people develop meningitis. Fungus—and especially histoplasmosis—can do just about anything in the body.
It’s a very humbling disease because it always surprises us. And it’s always in our differential—especially in these really immunocompromised patients, where we don’t know exactly what’s going on and our basic tests have already not proven anything—we will always broaden our differential to look for histoplasmosis and other endemic fungi that live in this region, because we just want to make sure that we’re not missing it. It can manifest in a variety of different ways.
Wilder: How does a person get diagnosed with histoplasmosis?
Cherabie: The most common way of diagnosis is to look for histoplasma antigen, be it in the urine or in blood. You can also do an antibody test.
The issue is that it’s very difficult to sometimes find and diagnose. The sensitivity of these tests are sometimes not as great as we would like them to be.
Oddly enough, one of the tests for another endemic mycosis, which is blastomycosis, is oftentimes positive as well if you have a histoplasmosis infection. Oftentimes we’ll order a test for a completely different fungus because it cross-reacts with the histoplasmosis antigen. These are the most common tests that we do.
The other thing that we do is, if we get a tissue sample, we can culture it and see if it grows on a fungal culture, which can be viewed under the microscope and help us diagnose things as histoplasmosis.
There are people who are looking into newer technology, such as PCRs, which can diagnose these infections on things like blood samples. And there is next-generation sequencing that has been done and has diagnosed histoplasmosis, as well. However, for the majority of infections, we are using the antigen methods, antibodies, and cultures.
Wilder: And is there a treatment for it?
Cherabie: Yes. It’s a long treatment, unfortunately. Usually once we diagnose someone with histoplasmosis, we would give them, depending on the severity of the disease—and depending on whether it is primarily only in the lungs or if it has disseminated elsewhere—amphotericin B, and then usually a longer course as an induction therapy, starting with the amphotericin B and then a long course of itraconazole. There are other azoles that you can use as well.
Usually I would recommend, with any person who is diagnosed with histoplasmosis, if you have a fungal expert within your respective institutions, you should probably involve them in the care of these patients, because oftentimes they’ll require long-term follow-ups, with courses going from six weeks to 12 weeks, up to a year. These medications require a lot of monitoring of levels as well. So it’s really important that you use all the resources that are available to you, to make sure that you get control of these infections, and that you adequately treat according to how disseminated the disease is.
Wilder: What might happen if histoplasmosis is left untreated?
Cherabie: That honestly depends on the person and how immunocompromised they are. We know that people who are more immunocompromised carry a higher mortality. We actually did a study on this cohort that I used for this study. In a key sense, histoplasmosis carries a high mortality of around 16%, per our preliminary results. However, if you’re immunocompromised, it goes up to 24%.
Now, again, the majority of people who are exposed to histoplasma—and that’s a lot of people—are completely asymptomatic. Some people go on to develop pulmonary disease, which causes the respiratory symptoms that we described earlier. Other people go on to have disseminated disease that can spread to a variety of different parts of the body. If you have disseminated disease, then this would carry a higher mortality [risk] and possibly cause further complications.
Some subacute manifestations of histoplasmosis include things like lung nodules that we commonly find on imaging. We have patients that show up to our clinic, very often, who were told that they have things like sarcoidosis or lung cancer, and then upon further studying and biopsies and cultures, we found out actually they had histo.
It’s a very smart disease, but it’s also very crafty. It can do a variety of different things, which is why it always surprises us. It’s often a common feature in our weekly grand rounds, where we’re discussing the most interesting cases of the week in our department.
Wilder: Is there a way to prevent a person from contracting it?
Cherabie: Not really. With our very immunocompromised patients, a lot of these patients will be on some kind of form of antifungal prophylaxis for a variety of different diseases, including candida, less likely to prevent histo.
The thing is, with these immunocompromised patients, we just have to always have that possibly on our differential, that this might be causing a disease, if you are in an endemic area. It should always be on your differential, and just kind of in the back of your mind. But there’s no real ways to prevent it, like we would many other of the opportunistic infections.
The biggest issue with most histo studies is that it’s not a notifiable disease. So oftentimes you have to rely on these internal cohorts in places where histoplasmosis is really endemic in order for us to perform studies on it. It’s hard for us to tell when people have acute diseases, because it’s often asymptomatic. It often causes a mild disease. It’s often not recordable. Unless people have fulminant disseminated disease or really bad pulmonary disease, it can often go missed.
Wilder: Do you have an idea of how many people with HIV are diagnosed with histoplasmosis annually?
Cherabie: Any study that you look at that has looked at histoplasmosis amongst people living with HIV, they will all come with the subtext that says, “Of course, there is massive underreporting because this isn’t a notifiable disease.” But we do have cohorts that have been followed for years, in places like French Guinea, and also, in parts of Central and South America.
There have been places looking at how histoplasmosis affects people in this variety of different areas. But I would caution against generalizing those results, because we have to remember it’s not necessarily that those people have the same access to antifungal treatments or have the same access to antiretroviral therapy that we have here in the United States. Which is why, specifically in our study, we’ve looked at the effect of having modern antiretroviral therapy, and if that affected people dying from histoplasmosis.
We have some estimates of how many people will develop histoplasmosis with HIV. But, luckily for us, nowadays people are getting treated much more rapidly and getting started on antiretroviral therapy a lot earlier, which means that they might not get to the point where they are so immunosuppressed that they might develop histoplasmosis.
New Research on Histoplasmosis Mortality Among People Living With HIV in the U.S.: Background and Patient Demographics
Wilder: Talk to me about the research you and your colleagues conducted.
Cherabie: Here in St. Louis, we see a lot of histoplasmosis. My mentor, Andrej Spec, started this cohort years ago, looking at histoplasmosis in any patient who showed up either in the hospital or in our clinic, trying to follow the outcomes of histoplasmosis on the long term. Of course, a cohort study is kind of the best way to look at that.
We took a look at this cohort, and then we sub-selected people living with HIV and tried to see what the long-term mortality effects were on these people. How many people died within 90 days? How many people died after 90 days? And then what factors were associated with mortality? To see if we could act in any way to improve mortality on these very vulnerable populations.
There is no other study that has been done so far that has looked at long-term mortality with the same factors that we were looking at: the HIV-associated characteristics, as well as the social characteristics, such as insurance status, history of psychiatric disease, history of substance use. It was really interesting to take a look at all of these various factors and try to figure out what makes things better for these patients and how we can affect mortality in this really vulnerable population group.
Wilder: What were the patient demographics in the study?
Cherabie: We were able to find 54 patients—so, the numbers are not huge. But this means that there are areas for future research, which is really exciting.
Overall, the majority were male. The age distribution didn’t differ really amongst any of our groups. But one of the things that is different about the population here in St. Louis is that we do have a large representation of the Black community. And so, a majority of our patients were Black. The minority were non-African American.
With regards to how they presented, the majority of our patients did present with the typical symptoms of cough, weight loss, and [gastrointestinal] symptoms. The majority also had disseminated disease. The majority were also starting to have pulmonary disease.
Wilder: Were the participants newly diagnosed with HIV, long-term survivors, or somewhere in the middle?
Cherabie: We did look at how many of these individuals had antiretroviral therapy experience, and it was somewhere around 50%. It was 41% in the survivors and 58% in the individuals with late mortality. So, hovering right around 50% were experienced on antiretroviral therapy.
Less than 50% had new HIV diagnoses. But seeing as histoplasmosis affects people who are more [immune] compromised, it would be expected that these people, even if they did have experience with antiretroviral therapy, were more likely to not be taking their antiretroviral therapy—and/or if they were new diagnoses, they would be expected to have lower CD4 counts and, therefore, have a more immunocompromised state.
Within our study, we didn’t really capture how long people had been on antiretroviral therapy. That wasn’t one of the factors that we had necessarily measured.
Wilder: And what about a history of opportunistic infections?
Cherabie: We did find that there were a large amount of people who did have a history of previous opportunistic infections. The most common opportunistic infections that we saw were candidiasis, as well as CMV and Pneumocystis pneumonia.
If you look at other studies that have looked at long-term effects of histoplasmosis in people living with HIV, opportunistic infections are quite common in those cohorts, as well. The difference is that our study found different opportunistic infections compared to the other studies in terms of what was more common. These often differ based on geographical area.
Histoplasmosis Mortality Among People Living With HIV in the U.S.: Study Findings
Wilder: Tell me about the results of the study. What were your findings?
Cherabie: Overall mortality for our cohort was actually quite high; it was at 37%. And then 14.8% of our participants had what was deemed early mortality, within 90 days of the histoplasmosis diagnosis, with a median length of survival of 13.5 days; 22% had late mortality after 90 days, with a median length of survival of 338 days.
Then when we looked at factors associated with late mortality, because it is kind of an interesting result that we had, that the majority—actually, two-thirds of the individuals—died after 90 days. More commonly with opportunistic infections, except for save maybe Cryptococcus, people die from early mortality within 90 days, as opposed to later mortality. It is a very interesting effect that histoplasmosis causes more mortality later on. So we wanted to see what was associated with this.
We looked at a variety of different underlying baseline HIV-related characteristics, as well as the baseline characteristics of our patient population. With the baseline characteristics of the patient population, across the board there was no differences between the survivor, early mortality, or late mortality group, with respect to sex, age, race, site of infection, presenting symptoms, or if they had disseminated disease.
As for the comparison of late mortality and the survivor group for baseline HIV characteristics, we did see the only significant factor associated with worse late mortality was median HIV viral load at last observation. Survivors were more likely to have a suppressed HIV viral load, compared to individuals with late mortality.
As you may know, people with suppressed HIV viral loads usually are taking their antiretroviral therapy regularly, so much so that they are able to suppress the virus and improve their CD4 count. That having been said, the median CD4 count was not statistically significant in terms of difference between survivors and the late mortality group.
When we looked at other factors that were close to being associated—that had an effect but didn’t necessarily meet statistical significance—the only other factor was if the patients had private [health] insurance. We compared private insurance versus governmental or no insurance, and actually it mirrored statistical significance. But when we looked at this effect a little bit further, we saw that people who survived were over twice as likely to have private insurance, compared to governmental or no insurance.
That’s actually quite interesting, because it shows that social effects could have an effect on mortality.
Just a quick note on when we looked at viral suppression: Survivors were six times more likely to have viral load suppression. But what was surprising for us is, what we had been suspecting was, when we look at survival amongst people of histoplasmosis in other parts of the world, oftentimes they’ll say, well, the presence of antifungals or the presence of antiretroviral therapy would have an effect. However, over here, when we looked at being diagnosed in the era of modern [antiretroviral therapy]—in other words, after 2008—it didn’t have an effect on survival with histoplasmosis, or long-term mortality with histoplasmosis. Which, for us, was quite a surprising result, as well.
Wilder: Could your study’s results inform clinical practice or even policy change?
Cherabie: I think that it could. What this study shows is that, oftentimes with HIV, we commonly think of the most common opportunistic infections. We look at Cryptococcus; we look at Pneumocystis jirovecii pneumonia; we look at CMV, and candida, and [tuberculosis], and Mycobacterium avium complex. These are the most commonly spoken-about opportunistic infections.
But we have to remember that, in different parts of the world, the most common opportunistic infection oftentimes is histoplasmosis. Within endemic areas like the Mississippi and Ohio River Valleys, it might be overlooked.
What this study can do is inform clinical practice and put the radar on histoplasmosis as being one of the opportunistic infections that we should look at—and that, in fact, can cause a high rate of mortality in our uncontrolled HIV population.
What’s Next for Research on HIV and Histoplasmosis
Wilder: What further research needs to be conducted on histoplasmosis in people with HIV? Do we need treatment trials? Do we need to develop better prophylactics?
Cherabie: One of the biggest limitations of our study was sample size. Unfortunately, that limits a lot of our abilities to perform really in-depth statistical analyses. And so, what would be really interesting is to create a national cohort of histoplasmosis cases across the United States and look at, with a fine-toothed comb, more in-depth analyses of what is associated with mortality in these populations.
Then, afterwards, you can look at trying to change clinical practice. Maybe you will find out that treatment with a particular antifungal had better outcomes compared to the antifungals that we’re currently using, even though there are studies that exist that have looked at that. Looking more specifically at a larger patient population would allow us to inform these clinical decisions a little bit more.
Then, once you have that observational data, you can of course do clinical trials, you can do randomized controlled trials, and you can look into prophylaxis. You can look into these things. But those things have to be informed by a more detailed analysis.
It is my hope that, in the future, we can possibly extend this cohort and create a database that would allow us to do more in-depth fungal research.
Wilder: At the conference, there was actually another poster on this topic entitled “Clinical Presentation Treatment and Outcomes for People with HIV with Histoplasmosis in Memphis, Tennessee.” So, research is happening in Tennessee as well.
Cherabie: It’s happening all over the place. This is one of the things that I find fascinating about academic medicine, and one of the great things about conferences: It’s a great opportunity for you to walk around and network and be able to find out what people have been working on and then say, “Hey, you know what? I’m working on the same thing. Maybe we can collaborate.” Then from that creates new databases and new research opportunities and new trials.
That’s one of the magical things about IDWeek that I love the most, and that I miss the most with it now having to be virtual. Hopefully, a lot of those connections will still be able to be made.
Wilder: Maybe you can give a call to the folks in Memphis.
Cherabie: The fungal community is a very small community. I think everybody knows everybody. One of the things that we had spoken about with my primary investigator was, “Hey, do you think that maybe we can reach out to other people who are working on similar things and possibly create a bigger cohort?”
That’s probably the next step, and seeing what else we can get from this data.
Wilder: If COVID goes away, maybe you can go visit, you know, Elvis Presley’s home.
Cherabie: Oh, definitely on my list. But I think there’s a lot of that stuff on my list once COVID goes away.