PNEUMONIA SYMPTOMS?

WHEN IT’S TIME TO THINK FUNGUS AND GET TESTED

Valley Fever (Cocci or Coccidioidomycosis)

Introduction: My name is Lisa Tushla. I am a Managing Director at MyCARE Foundation. We are very pleased to be joined today by Dr. Andrej Spec. Dr. Spec is a specialist in infectious diseases at Washington University in St. Louis and a member of our MyCARE board. We’re very excited to talk to Dr. Spec today about fungal diagnostic testing for patients with symptoms of walking pneumonia and community-acquired pneumonia. We thank MiraVista Diagnostics for support of this content.

Respiratory Infections: Where Fungi Fit In

Question: Dr. Spec, could you please discuss fungal infections as part of the spectrum of respiratory tract infections? Many patients with symptoms consistent with walking pneumonia will automatically get an antibiotic. Can you tell us more about what the optimal diagnostic process should be for these patients?

Dr. Spec: The most common cause of respiratory infections is viruses. Even for some of the more serious infections that are typically treated with antibiotics, most of the time, those end up being viral. The second most common cause is bacteria. Because we often give antibiotics early for symptomatic patients in the modern era, we probably see a lot fewer bacterial infections than we think we do. Interestingly, what has actually risen over time is respiratory infections caused by fungi. They’re probably not as common at this point as bacterial infections, but they are much more common now than in the past, and they certainly represent a larger share of respiratory infections than they used to. And even with that, historically, we’ve probably also underestimated the number of fungal infections that have existed.

So, if you’re suffering with a respiratory infection, especially one that may be more difficult to get rid of—one that doesn’t go away in less than a week or so—it might be time for your healthcare provider to start looking into additional diagnostics. Those will help determine whether you’re dealing with a bacterial infection, a viral infection, or a fungal infection. Doing that testing will probably be more useful than just trying to cycle through different antibiotics or giving the same antibiotic for a longer course of time. Multiple courses of antibiotics without proving the underlying course is not a good approach.

Patients Advocating For Diagnostics

Question: That’s very helpful. Do you believe that patients are in a position to advocate for these diagnostic tests? Do you think most healthcare providers would listen to them?

Dr. Spec: Oh, absolutely. It’s both the responsibility and the right of every patient to advocate for themselves. There are obviously ways to do it kindly, but it is absolutely appropriate for a patient to have a discussion with their physician. Now, there might be times when the physician disagrees with what the patient is saying, and that should also just be part of the discussion. We don’t live in an era of medicine where “physicians know best,” and we decide everything, and the patient is just supposed to do what we tell them. That’s not the way it should have been practiced in the old days, and it’s not the way we choose to practice now. We practice using what’s usually referred to as a shared decision-making model, meaning that what we decide to do is actually a result of a conversation between the patient and the physician. A patient mentioning ideas of what may be causing the infection should be something that a physician encourages, accepts, and is very happy to see. Personally, if a patient is willing to talk to me more about their illness, that actually makes my job easier. Hopefully, we should all be seeing it that way.

THE DIRT ON ENVIRONMENTAL FUNGI

Question: Today, we are going to focus on three environmental fungal infections that live in the soil—histoplasmosis, blastomycosis, and coccidioidomycosis. What can you tell us about these fungi?

Dr. Spec: All three of these types of fungal infections are called dimorphic fungi, which means they have two shapes. That probably doesn’t matter much to a patient—that’s just the bucket category we mycologists put them in. What’s important to know about these is that they’re what we call environmental pathogens. They exist out in the environment. So, absolutely everybody is at risk of getting these infections.

There are specific locations where these infections occur more commonly. Those are shown in the maps in the visual algorithms. We used to call these organisms endemic mycoses, and the areas where they are found very commonly, the endemic regions. I don’t like the term endemic for many reasons. I prefer to describe those areas where the fungi occur very commonly as hyperendemic. Histoplasmosis has now been found on all continents. It’s actually even been found on Antarctica (in penguin poop). In some areas of the country, you are at much higher risk. For histoplasmosis, that would be all areas east of the Rockies. The areas around the Ohio and the Mississippi River Valley are areas we call hyperendemic—they have very high rates of disease. But we see histoplasmosis in places that are commonly considered not to be part of the “endemic” area, such as New England and Florida and even out in California. For blastomycosis, the hyperendemic area includes the Ohio and Mississippi River Valley regions, but it also includes the St. Lawrence Seaway up into Canada. Our understanding of the spread and localization in Canada is actually pretty weak. I believe these organisms are probably more widespread than we think they are. We believe, as we change our world (by redirecting rivers and building cities) and as our climate changes (i.e., changing rainfall patterns etc), we are going to see these fungi in different places.

Therefore, it is very important for both physicians and patients to keep an open mind about the possibility of these infections in different regions. Traditionally, we’ve thought that west of the Rockies, you’re much more likely to develop coccidioidomycosis. If you’re east of the Rockies, it’s more likely to be histoplasmosis, and to a lesser extent, blastomycosis, because blastomycosis is just a fair bit rarer than histoplasmosis. But these are not cut-and-dry rules—sporadic cases of coccidioidomycosis have shown up east of the Rockies, and histoplasmosis has been seen in California. And so, while we are presenting some general approaches to follow, it’s important to keep an open mind and keep thinking fungus and testing for fungus, because we may pick up cases that reflect the expanding range of these infections.

Question: You’re based in St Louis. Can you tell us about the fungal infections more commonly associated with pneumonia in your area—histoplasmosis and blastomycosis?

Dr. Spec: As mentioned, patients in our area are exposed to these fungi just because they live here. In addition, there are certain things you can do that would increase your risk for blastomycosis or histoplasmosis. These include:

Exposure to bird or bat droppings
Cave exploration
Exposure to a demolition project or a big construction project. If they are building a new skyscraper in your neighborhood, have they dug up the whole foundation?
Planting a garden bed or doing renovation work outside
Connection to an outbreak. You live in the right area, you work in the right place, or you traveled to an area where the outbreak occurred.

Also, people who are immunosuppressed will develop these diseases more commonly and will experience them more seriously. But, in the end, many patients never really know where their risk came from. Because the way you get infected is by breathing. You breathe it in from the air, and you may end up with a pneumonia that is kind of long and hard to heal. It’s important that everybody gets considered for a possible diagnosis.

For histoplasmosis, it takes a patient up to 4 visits to a physician, on average, before they’re diagnosed. And by then, the disease has typically gotten worse and progressed. We hope we can decrease that diagnostic delay.

When and How to Test for Histoplasmosis and Blastomycosis

The best time to use the fungal tests for histoplasmosis and blastomycosis is when you have pneumonia that hasn’t responded well to the first round of antibiotics. But there are some additional clues.

Connection to a known outbreak or certain environmental exposures, as discussed above
Skin problems (for blastomycosis). Do you have new spots on your skin that look crusted and raised?
Certain results on imaging such as a chest X ray. Has your healthcare provider mentioned the words such as nodules and lymphadenopathy (swollen lymph nodes) after looking at your X-ray? These are suspicious for histoplasmosis.

If we turn back to that criterion of not responding well to a round of antibiotics, you may ask what that means. Even if you are in a situation where you say, “Well, I kinda got a little bit better with antibiotics,” but you didn’t get better all the way, fungal testing is worth it. Many people start to feel a little bit better with antibiotics. Even if the antibiotics don’t do anything for the infection, because they decrease the amount of mucus that we get, we just feel better because there’s less mucus. Or there’s also placebo effects. None of us is immune to that. Even if you’re having a little bit of a response to antibiotics. If it hasn’t taken care of it by, like, day 7 or something like that with antibiotics, it’s probably not bacterial.

The tests for histoplasmosis and blastomycosis have quite a bit of overlap. If you’re being tested according to the clinical testing guidance developed by the Centers for Disease Control and Prevention (CDC), you should get a urine antigen test, which is pretty easy to obtain. This test, an enzyme immunoassay (EIA), looks for the presence of fungal content shed into the urine. For histoplasmosis, your doctor will most likely also order a serum antibody test, which tests the blood. This basically will tell us how strongly your body is reacting to the fungus. With the serum antibody test, some of the positive tests may not reflect an active infection, because they can’t distinguish a previous infection, which may have been so mild that you never noticed it. That’s important to consider for patients who have a normal immune system—patients with problems with their immune system may not develop a robust immune response. For blastomycosis, some physicians also order a serum antibody test, but the blastomycosis serum antibody test is not that helpful because it misses a lot of cases and is not recommended initially in the CDC clinical testing guidance.

The other point I want to make is, and the CDC emphasizes this as well, is that if you are negative on the first fungal test, and the suspicion for a fungal cause still remains high (for example, you have a connection to an outbreak or you’re not still responding to antibiotics), it may be worth retesting. That’s because, as the disease progresses, the testing is more likely to become positive. In fact, it’s often times 4 to 6 weeks into these diseases that the antibody levels are high and very likely to be picked up by testing. So if you test earlier, you may not have the antibodies yet, even though you are sick. I want to emphasize that the testing is far from perfect, but it’s a lot better than not testing at all.

Question: Please go over risk factors and testing for Valley Fever.

Risk Factors for Valley Fever

Dr. Spec: Valley Fever is the common name for coccidioidomycosis. As mentioned, it’s generally present on the west side of the Rockies. The fungus that causes Valley Fever, Coccidioides (we’ll call it Cocci because it’s a mouthful), lives in the dry, basic desert soil, such as we see in the desert southwest. That’s very different from the fungi that cause histoplasmosis and blastomycosis, which like moist, acidic soil. The areas where we see a lot of Cocci are places like Arizona, Nevada, West Texas, locations in southern Utah, and California (see the diagram in the algorithm). That’s not to say those are the only places we have. Some of the data that we have and other groups have produced suggest that it’s actually marching up closer to the Canadian border.

The fungus also comes in booms and busts. It often will come after we have a wet season, which is then followed by a dry season. It’s associated with dust storms that are so common in the Southwest. We know that a large proportion of cases of pneumonia in the desert Southwest are caused by Cocci. It might be that a large proportion of walking pneumonia in the Midwest are caused by histoplasmosis; we just don’t have as much information on that. But, with Cocci, we know that it’s responsible for around 20% of the cases of pneumonia in the hyperendemic areas. So, that means that even in the first instance of a pneumonia in those regions, it may be worth testing for Valley Fever.

When and How to Test for Valley Fever

There are 2 clear instances where patients could be considered for Valley Fever testing:

People on the initial presentation of pneumonia or a rash called erythema nodosum following recent respiratory symptoms who:

Have a link to a known outbreak OR
Live in or recently traveled to hyperendemic regions, including the Desert regions of south-Central Arizona or the San Joaquin Valley and Central Coast of California

People with symptoms of pneumonia who:

Live in or recently traveled to areas affected by Valley Fever AND
Have symptoms that do not improve significantly following a round of antibiotics (without testing to establish that the infection is bacterial)

For Valley Fever, most of the commonly used tests boil down to a blood test checking for antibodies. As I mentioned earlier, often the tests for these environmental fungi become most positive about 4 to 6 weeks into the disease. Most of the time, we see these patients well before that period. We may do a test at an imperfect time, but we still pick up a decent proportion of patients on this test.

There are some additional tests that are sometimes used for Cocci. They are discussed in the algorithm. These include antigen testing and tissue-based tests. I don’t use these that often (I am outside the hyperendemic area), but they can have a role.

Question: Are these tests expensive, and are there any issues getting them reimbursed?

Dr. Spec: The testing is not cheap, but it’s not terribly expensive either. But it’s a lot cheaper than missing the disease. I have not had any patients whose tests have been rejected for reimbursement by their insurance company. And I test for them a lot.

Question: Are these tests done most frequently in the primary care setting or the urgent/emergency department settings? And do those providers sometimes have difficulty interpreting those test results?

Dr. Spec: Yes, those are the settings in which the testing should occur, because those are the settings in which most patients present with these symptoms. And yes, sometimes providers do have difficulty interpreting the tests. Also, they may lack the ability to take care of patients appropriately. These are not diseases that are commonly managed by primary care providers. Ideally, there should be infectious diseases (ID) doctors available in most places within driving distance to refer these patients to. However, ID physicians are not as widely available as we would like. For example, there are certainly counties in the United States without ID physicians. So, trying to find one may involve some travel or a telemedicine consult.

Fortunately, there are some resources available to help these providers. Our collaborator’s website, funguseducationhub.org, has a lot of resources directed to primary care providers and emergency medicine/urgent care providers to help them through the identification of these infections. There are educational courses and diagnostic resources, developed by primary care providers in conjunction with ID experts, the Mycoses Study Group Education & Research Consortium (MSGERC), and CDC. The CDC also has a consult line providers can use to contact an expert for guidance. If the provider needs help with interpretation, the CDC will often reach out to someone like me who sees a lot of these patients. I can help them interpret test results or manage the case in a situation where things get a bit more complicated. There are other experts and centers they may connect the providers with. So, your provider can find that information on our companion website for providers, funguseducationhub.org, under the diagnostic hub. Or, they can reach out directly to the CDC Mycotic Diseases Branch.

Concluding Remarks: Thanks, Dr Spec. This has been a helpful overview of these infections and how to get them diagnosed. We hope that, after reviewing this commentary and the infographics, patients will be empowered to “think fungus” and advocate for fungal testing when appropriate for their walking pneumonia symptoms.