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Team explores fungal infection quandary in lung cancer screenings

Apr. 18, 2019, 8:13 AM

The Vanderbilt team studying histoplasmosis includes (front row, from left, Heidi Chen, PhD, Melinda Aldrich, PhD, MPH, (back row, from left) Stephen Deppen, PhD, Eric Grogan, MD, MPH, and Jeffrey Blume, PhD.
The Vanderbilt team studying histoplasmosis includes (front row, from left, Heidi Chen, PhD, Melinda Aldrich, PhD, MPH, (back row, from left) Stephen Deppen, PhD, Eric Grogan, MD, MPH, and Jeffrey Blume, PhD. (photo by Steve Green)

by Tom Wilemon

Serving a region that lies within the tobacco belt, clinicians at Vanderbilt Health face challenges distinguishing lung cancer from histoplasmosis, a fungal infection that creates cancer-mimicking lesions in the lungs.

Their work, published October 2018 in Emerging Infectious Diseases, revealed that histoplasmosis is prevalent beyond previously identified regions of the United States and led to the U.S. Centers for Disease Control and Prevention (CDC) updating its maps in December.

A collaboration from across Vanderbilt, and with contributions from researchers at the University of Alabama at Birmingham, their model expanded likely histoplasmosis exposure areas beyond the Ohio and lower Mississippi River basins to include the upper Missouri River basin.

Other research by the team, in partnership with MiraVista and Vanderbilt-Ingram Cancer Center, published in February in Cancer Epidemiology Biomarkers & Prevention, indicates that a new blood test for histoplasmosis antibodies shows promise as a diagnostic tool for distinguishing cancer tumors from benign nodules caused by the fungal infection. Their findings can help cancer clinicians better determine when biopsy surgeries are necessary in diagnosing lung cancer.

“If you have histoplasmosis antibodies — IgG and IgM — in your blood that are both strongly positive tests, based on the work we’re doing, I’m not going to take you to the operating room,” said Eric Grogan, MD, MPH, associate professor of Thoracic Surgery. “I am going to say, ‘You need to be watched, and let’s see how this does before we end up doing invasive procedures.’”

Grogan and Stephen Deppen, PhD, an epidemiologist and assistant professor of Thoracic Surgery, presented an update of their research in March to the National Institute of Allergy and Infectious Diseases. They are looking to form a benign lung nodule consortium with other medical research institutions across the country to validate and extend their work into clinical practice.

Histoplasmosis is caused by inhalation of a fungus that thrives in dark damp soil, but it is also spread by birds. Exposure to the soil-based fungus is common throughout Middle Tennessee, and most infections have no symptoms or are flu-like when symptoms do occur. In the vast majority of cases, individuals recover from the infections without ever being diagnosed.

Medicare and private insurers began in 2015 covering CT scans for people who are at high risk for lung cancer, specifically people between the ages of 55 and 80 with a history of heavy smoking and who currently smoke or have quit within the past 15 years. Although the lung scans can save lives by detecting cancer early, the screenings also set up the scenario for possibly unnecessary diagnostic surgeries to evaluate discovered lung abnormalities.

“The tools that we have are good for finding cancer,” Deppen said. “They are not good for ruling out benign disease.”

Even though the new test for histoplasmosis antibodies is more sensitive, it has limitations, he noted, because people can still have nodules from a prior fungal infection for which their immune systems are no longer responding.

“If the test says you don’t have a histoplasmosis exposure, that doesn’t tell you that you have cancer,” Deppen said. “It just says we can’t measure if you had antibodies from exposure to a fungus that may have caused what we see on chest imaging. So, a negative test really does not help you. On the other hand, a positive test does.”

The researchers did serum tests on 162 patients, and 13% of those without cancer tested positive for both IgM and IgG antibodies. All those cases turned out to be benign. Seventy-two percent of patients who tested positive for only the IgG antibody had benign nodules, suggesting that clinicians may want to monitor those patients with subsequent CT scans at three- or six-month intervals instead of pursuing a tissue diagnosis.

However, active surveillance may not be clinically defensible, the researchers cautioned, because 11 patients who tested positive for only the IgG antibody also had cancer. Follow-up studies with larger numbers of patients are necessary to provide clarity, they concluded, as well as research to develop more sensitive biomarker tests for benign lung disease.

Pierre Massion, MD, Cornelius Vanderbilt Professor of Medicine and director of the Cancer Early Detection and Prevention Initiative at VICC, is the principal investigator of a National Cancer Institute initiative to distinguish between benign and malignant nodules. He is also a co-author on the histoplasmosis study.

“As we implement lung cancer screening, we need to develop strategies to further reduce the number of invasive procedures we perform in patients presenting with lung nodules that are not cancer,” Massion said.

“In this part of the country, i.e. the Mississippi and Ohio river basins, histoplasmosis is the most prevalent cause for false positives. This research may dramatically improve our ability to better personalize the management of indeterminate pulmonary nodules.”

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