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Here, there, but not everywhere

Localized fungi complicate pneumonia diagnosis and treatment

From the April ACP Hospitalist, copyright © 2012 by the American College of Physicians

By Stacey Butterfield

What do a bat with a white nose, rust-colored wheat, and your pneumonia patient who winters in Arizona have in common?

The answer might be fungus.

Design by Lorraine Lostracco and Mike Ripca with i...

Design by Lorraine Lostracco and Mike Ripca with images from Wikimedia Commons and Thinkstock.



In general, fungi are a relatively uncommon cause of illness, compared to bacteria or viruses. “There are about 75,000 species of fungi that have been identified and probably one million more that haven't been identified,” said infectious disease specialist John Baddley, MD. “Most fungi don't cause disease.”

Yet the relative rarity of dangerous fungi, and their tendency to be localized to certain parts of the world, can make them especially difficult to diagnose and treat. The Institute of Medicine (IOM) was concerned enough to gather experts in 2010 to discuss “Fungal Diseases: An Emerging Threat to Human, Animal, and Plant Health.” The workshop and resulting IOM report describe the potential of fungi to cause white noses on bats, inedible wheat and pneumonia.

The last of those is most likely to concern hospitalists. While the ability of certain fungi to cause pneumonia, especially among immunocompromised patients, is well-known and widespread (Pneumocystis for example), other species are only locally famous.

Histoplasmosis and blastomycosis are the fungal scourges of the Midwest, while coccidioidomycosis strikes Southwest residents, and Cryptococcus gattii has become an emerging threat in the Northwest. Greater physician awareness of these health threats is needed both inside and outside the endemic regions of the fungi, according to experts.

“[Physicians in other areas] won't see them very often, but because of that, they do have to be particularly vigilant and aware of signs and symptoms,” said Thomas Patterson, MD, FACP, professor of infectious disease at the University of Texas Health Science Center at San Antonio.

Uneven distribution

A recent survey of Medicare data, published in the September 2011 Emerging Infectious Diseases, assessed prevalence of histo, blasto and cocci (as the fungi are known informally) and found them to be very unevenly distributed.

Between 1999 and 2008, histoplasmosis cases were found in every U.S. region, but they were most common in the Midwest. Indiana, for example, had an incidence rate of 13.0 per 100,000 person-years, compared to less than 1 per 100,000 person-years in western states. Blastomycosis is also Midwestern, but rarer and more endemic to the Mississippi River Valley. States with the highest incidence were Mississippi (6.4 per 100,000 person-years) and Wisconsin (5.7 per 100,000).

“There's something about the soil around the river valleys that the germs like,” said Dr. Baddley, who is an associate professor of medicine at the University of Alabama at Birmingham and lead author of the incidence study.

On the other hand, coccidioidomycosis, which is also known as Valley Fever, likes dry conditions and is most common in Arizona and California. According to the study, incidence in Arizona was 90.5 per 100,000 person-years. The disease is even more concentrated than that statistic might indicate, according to John N. Galgiani, MD, FACP, professor at the University of Arizona College of Medicine in Phoenix and director of the school's Valley Fever Center for Excellence.

“Half of all U.S. infections occur in one county, Maricopa County, surrounding Phoenix,” he said. “If you get pneumonia in Arizona, or at least in the Phoenix/Tucson area, the chance of it being Valley Fever is one in three.”

Cryptococcus gattii is the newest of these localized fungi. It was first noticed in 2004. Between then and mid-2011, 96 infections were reported to the Centers for Disease Control and Prevention (CDC), 83 of which were in people who either lived in or traveled to Oregon or Washington, according to an article in the Dec. 15, 2011 Clinical Infectious Diseases.

The travel component of that statistic is important, and a key reason that hospitalists around the country need to know about distant fungi, the experts said. “If [patients] go home and get pneumonia in the month after visiting our beautiful state, they have exactly the same risk [of it being cocci] as if they lived here,” said Dr. Galgiani.

The risk can extend much longer than a month, according to Carol Kauffman, MD, FACP, a professor of medicine and an infectious disease specialist at University of Michigan Medical School and the Veterans Affairs Medical Center in Ann Arbor.

“In the case of histo, blasto and cocci, but best identified for histo, people can reactivate many years later. A little bit of fungus may have been left after an episode that they didn't even know was histo,” she said. “Years later, people now living elsewhere in the country, get steroids, or maybe anti-TNF [tumor necrosis factor] drugs, or a transplant, and that's when the infection can relapse.”

Risk factors

Although all of the fungi can infect healthy patients, people with abnormal immune systems are in the most danger from them. “These organisms do cause primary infections, but usually in most patients, the disease is self-limited,” said Dr. Patterson. “Infections like coccidioidomycosis and histoplasmosis can lead to much more serious infection in persons with abnormal immune systems.”

More than a third of the fungus-infected patients in Dr. Baddley's study had chronic obstructive pulmonary disease, with diabetes, cancer and rheumatoid arthritis as the next most common concurrent medical conditions. “Any damage to the lungs, you're sort of predisposed to bad pneumonias,” he said. Not surprisingly, AIDS should also be on the list of risk factors, the experts said.

Patients' comorbidities are typically mentioned early in the hospital admission process, but hospitalists might have to do some questioning to elicit a travel history. “You have to always find out where the patient has been, where they spent their time in the service, where they grew up, where they're currently living, as well as what activities they have been involved in, especially those out in the environment,” said Dr. Kauffman.

The trigger for this questioning should be any pneumonia that doesn't get better when expected. “If they're treating a case of pneumonia and it's not responding to standard therapy, they should start thinking of fungal pneumonias like histoplasmosis and blastomycosis,” said Chadi A. Hage, MD, an infectious disease and pulmonary/critical care specialist and assistant professor at Indiana University in Indianapolis.

Crypto gattii, cocci, blasto, histo—they can all look like bacterial pneumonia,” said Julie R. Harris, PhD, MPH, an epidemiologist in the CDC's Mycotic Diseases Branch. “The patients get treated for the bacterial pneumonia and they get worse while they're being treated with anti-bacterials because nobody has tested them for a fungal infection.”

Prompt diagnosis is very important for these already high-risk patients, noted Dr. Baddley. “If you fail to make a diagnosis in time and start medicine later, then you can have some pretty bad outcomes,” he said.

A difficult diagnosis

The problem is that diagnosis can be difficult. “The diagnostic tools are terrible. A lot of these diseases are diagnosed at autopsy because they don't cause syndromes that are easily recognized,” said Arturo Casadevall, MD, PhD, a professor of infectious disease at Albert Einstein College of Medicine in New York. “There are some assays that have been introduced in the past decade that appear to give you some information, but generally, the diagnostics are really underdeveloped.”

Cultures are typically used to make a diagnosis, but should not be relied on too definitively. “They may not be positive in many patients and it may take invasive specimens to get good culture material,” said Dr. Patterson. “Blood cultures for many of these are often negative, even with advanced disease, and serologic tests are generally not all that valuable.”

Antigen tests exist for most of the fungi but require that a physician know which species is the likely culprit, since the tests are specific. In some cases, skin abnormalities can hint at the presence of fungi, and C. gattii has presented as meningitis.

“There are a lot of things that can mimic these diseases,” added Dr. Patterson. The differential list could include a drug-resistant bacterial infection or tuberculosis (TB). “TB is probably more common in most patient groups than these fungal infections and malignancy would also be an important occurrence,” he said. “The differential diagnosis is often pretty broad.”

Infectious disease (ID) specialists may be of help in making these diagnoses. “If you see a patient with Cryptococcus gattii, or you suspect that they have cryptococcal infection, it's really urgent that they get referred to an ID doctor,” said Dr. Harris.

Treatment

For patients who turn out to have C. gattii, diagnosis will be only the first, small step. “It usually ends up being quite a long course of treatment. Sometimes these patients have to have shunts to drain off cerebrospinal fluid when they have an increase in pressure. Some of them have to have resection of parts of their lungs,” said Dr. Harris. The fatality rate from C. gattii is currently 25% to 30%, she noted.

The Midwestern fungi are somewhat easier to treat. “We use amphotericin B first in very ill patients,” said Dr. Kauffman. “Histo is exquisitely susceptible and blasto usually responds quickly.” Patients are then stepped down to an oral azole antifungal, usually itraconazole, she added.

The search for the ideal treatment for cocci is currently under way at the Valley Fever Center for Excellence. “We have taken on a drug development program. There is no company willing to do that,” said Dr. Galgiani. Although cocci is a major issue in Arizona (costing $86 million in 2007 hospital costs alone), on a national level it's an orphan disease that attracts little interest from pharmaceutical developers.

The Center also conducts outreach to raise physician and public awareness. A recent survey by the Arizona Department of Health Services found that even local Arizona physicians had limited knowledge of cocci. “Half the doctors didn't know how to diagnose it, and another half didn't know how to manage it if it was diagnosed,” said Dr. Galgiani. Histo and blasto are also often missed, even in the Midwest, said Dr. Hage. And C. gattii is new enough that awareness of it is still low.

A growing problem

Physicians may come to know more about these diseases if current trends continue. Blasto has been on the rise in Indiana, according to Dr. Hage. “We used to get one or two cases a year. In the last few years, we've been getting seven, eight cases a year, sometimes 10 or 12,” he said. The local increase was attributed to highway construction stirring up dust, but he's also heard reports of increases in other Midwestern states and Canada. “The thought is it could be related to weather changes,” he said.

A recent uptick in cocci cases (for example, 12,000 reported in Arizona in 2010 and over 16,000 in 2011) is fairly certainly related to the weather. “It was quite dry and so more spores get out of the dry earth than they do out of the wet earth,” said Dr. Galgiani. He noted that reporting of the infection has also improved, potentially confounding statistics.

C. gattii surveillance has certainly gotten better, but it's also clear that the disease wasn't infecting people at the same rate before 2004. There are several possible explanations, according to Dr. Harris.

“One popular one is climate change. The Pacific Northwest climate has been changing at a more rapid pace than the rest of the United States. Some people have suggested that C. gattii has been there for a long time but that the changing climate has made a more habitable environment. Other people say increasing globalization has essentially introduced these strains from other areas of the world,” she said.

Global travel is certainly increasing the number of people exposed to these fungi. Advances in medical care that suppresses the immune system, or keeps those with weakened immune systems alive, are also increasing the ranks of patients most likely to become ill after exposure. “Our society continues to generate more and more immunocompromised hosts,” said Dr. Casadevall. “You have more and more populations at risk.”

More people living and traveling in old age could also increase incidence. “As people get older, you have more trouble with your immune system. So we expect these infections to get worse or get more popular, if you will, over time,” said Dr. Baddley.

The potential for all of these factors to increase infection rates means that hospitalists, both in and out of the endemic areas, will want to keep an eye out for the fungi when treating pneumonia. “They say look for horses and not zebras. Consider sometimes that it could be the zebra,” said Dr. Harris.

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For more information

The Centers for Disease Control and Prevention has websites about histoplasmosis, blastomycosis, coccidioidomycosis and cryptococcosis.

The Infectious Diseases Society of America offers guidelines for treatment of all four fungal infections.

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