Emerging Yeasts

Labs are on the frontline of identifying life-threatening, invasive fungal infections

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In Season 3 of "The Sopranos," Burt Young made a guest appearance as a former hit man who was struggling with lung cancer. He is being grilled by Corrado "Uncle Junior" Soprano about treatment. Young's character, while gasping and viciously coughing up blood, wagged his finger at Junior, half in admonishment and half as a warning.

"The cure is worse than the illness," he finally said

As many patients with cancer and other diseases that weaken immune systems know, this was not as much an exaggeration born of artistic license as it was an accurate portrayal of desperation in patients who face obstacles in their battles to get well.

Increased usage of advanced medical advances prior generations could only dream about -- from aggressive chemotherapy for cancer patients to organ and stem cell transplants -- has come with inherent risks beyond the known side effects of treatment.

An example of the steep price paid for increased use of advanced approaches to diagnoses once seen as death sentences is the increased risk of invasive fungal infections (IFIs), many caused by unusual yeasts, that can prove just as fatal as the initial malady.

IFIs on the Rise
As the numbers of patients at risk has risen in the past two decades, so has the incidence of IFIs with patients with severely compromised immune systems.

"Emerging yeast can be a significant problem if they are not recognized or if they are misidentified," said Mary E. Brandt, PhD, chief of the CDC's Mycotic Diseases Branch. "The wrong treatment or an ineffective treatment can be administered to a patient if the organism is not properly detected and identified. Wrong or ineffective treatment can result in death of the patient, or can result in significant medical costs and extended hospitalization time for that patient."

Pointing out that recognition is an increasingly difficult nut to crack, she added, that there are "a number of yeast that have not historically been common in the hospitalized patient. More and more institutions are beginning to describe cases and clusters of infection caused by these yeasts."

As an example, she pointed to the yeast Trichosporon, prompting the CDC to investigate an outbreak in Jamaica, that was proven to have been caused by contaminated bedpans and cleaning brushes.

Other examples of these yeasts are Malassezia (skin infections), Saccharomyces (food) and Rhodotorula (in soil, water and air), she added.

Explaining that many of these yeasts "are not especially virulent," in the sense that they "do not have a high innate ability to cause disease," Brandt warns that they "can cause serious disease in patients who are very sick and lack the immune system needed to fight infection."

The Problem of Resistance
Another problem, Brandt adds, is that many of these yeasts are resistant to the commonly used antifungal drugs and these drugs are therefore not useful. We only have a few types of antifungal drugs so this can cause a problem in trying to find a way to treat these patients."

As such, this is a crisis than can be considered nothing short of a war against an unseen enemy, and the soldiers on the front lines are not dressed in camouflage and toting machine guns.

They are wearing laboratory jackets and looking through microscopes, and are trying to avoid going into retreat mode.

"DNA-based testing is always important," said Brandt. "The bigger clinical microbiology laboratories use DNA sequencing to identify these organisms. Smaller laboratories may have more difficulty identifying these organisms because they still rely on sugar utilization tests, which are not as reliable."

Brandt pointed to a cutting edge method to identify organisms called MALDI-TOF (matrix-assisted laser desorption ionization-time of flight) as the cutting-edge method to identifying organisms. The two-step process allows the analysis of DNA (as well as other biomolecules such as proteins and sugars), as well as larger more fragile organic molecules that did not always hold up under more conventional approaches.

 "This method uses mass spectroscopy to analyze a small amount of the organism that is smeared on a special slide," said Brandt. "The instrument breaks down the components in the organism into a series of peaks and displays those peaks on the computer screen. Then the instrument compares the number and placement of peaks to the patterns of known organisms in its library and determines the identification of the unknown organism based on the closest peak matches.

"MALDI has shown great promise to identify yeast very rapidly. Of course these methods need to be approved by the FDA before they can be used in US clinical laboratories. There are also a number of research methods that have not yet been widely tested or validated."

Vigilance in Labs
Meanwhile, vigilance throughout the medical community remains on high alert while laboratories work to keep pace with the number of patients with compromised immune systems.

The CDC, in 2010, estimated that there are 50,000 new cases of HIV in the U.S. each year. Around the world, as of 2011, the estimate of new cases was in the range of 2.45 million. And the World Health Organization predicted an imminent "human disaster" with a projected surge of cancer cases from 14 million to 22 million (57 %) worldwide in the next two decades. With those dire predictions comes the increased risk of IFIs, but the CDC is not interested in waving the white flag on combating the growing scourge.

In a 2011 fact sheet, the CDC broke IFIs into three sub-types -- opportunistic, hospital-associated and community-acquired.

The list of challenges included:

  • Defining the public health burden of emerging fungal diseases
  • Developing improved methods for earlier diagnosis of disease
  • Understanding the reasons for the rising number of endemic fungal infections
  • Determining the effects of climate change on fungi
  • Identifying groups of people at risk to help focus on prevention.

Key in the strategy to combat IFIs -- along with responding to outbreaks and being set up to monitor long-term trends - was working with laboratories, here and abroad, to investigate and study outbreaks.

As part of its proactive approach, the CDC looked at Candida, which is the third most common cause of hospital-associated bloodstream infections in the U.S.

"Most people think about Candida when they think about yeast that cause disease," said Brandt. "Candida albicans, Candida parapsilosis, and Candida glabrata are the most common yeasts causing disease in hospitalized and immunosuppressed patients in the US. Some species of Candida are more unusual and are not as common; these include Candida famata, Candida lusitaniae, Candida guilliermondii, and others."

Laboratory Surveillance
This brings us back to the frontlines, to the laboratory personnel empowering doctors and hospitals to win the war, specifically when the attempts to cure become perceived as costly examples of being worse than the illnesses.

Particular focus, dating back to 2008, has been on "active laboratory" surveillance around the U.S. to "monitor to epidemiology of candidemia." This includes identifying drug resistance to various types of Candida.

According to the CDC, this work reveals that candidemia has been on the rise among some age groups, and that there is a troubling growing resistance to some medications.

As of its 2010 report, according to the Oncology Nursing Society the price tag -- beyond the suffering -- was staggering. The average cost for a patient with aspergillious (an airborne fungus found in dirty air conditioning units and most aggressive for at-risk patients) was $82,425 per case, with a hospital stay of 17.5 days. For patients with invasive candidiasis (yeast infections) the tab was between $34,000 and $44,500.

According to an 2103 article authored by UpToDate.com's section editor on fungal infections, Carol A. Kauffman, MD, professor of Internal Medicine, University of Michigan  Medical School, the mortality rate for untreated candidemia is 60 %. It is between 30 to 40 %, even with treatment. Additionally, mortality rates increase for each day -- 24% (first days) to 37% (second day) to 41 % (third day) -- that passes with a delay in treatment. For patients with septic shock, the mortality rate was 64%.

 "Medical personnel need to know that unusual yeast may cause infection in their patients, especially the patients who are immunocompromised," said Brandt. "They need to understand the capabilities of the tests they use to detect and identify agents of disease, and understand that organisms can be undetected or misidentified with these tests. They should reevaluate the identification and antifungal susceptibility profile of the organism if the patient is not getting better after an appropriate course of antifungal therapy."

Precaution for Home Care
With the projected increase in cancer patients and streamlined treatment for those other maladies that compromise immune systems, a growing concern is care at home.

As such, according to Brandt, patients should be counseled on preventive measures when not in the hospital. This counseling should include stern advice on exposure to molds (gardening, exploring caves, diet, etc.) while seeking protective home environments with strong (at least 90 percent) air filtration.

"Many individuals are taking immunosuppressive medications but continue to live normal lives at home," said Brandt. "These include people who have received organ transplants, and people who are taking tumor necrosis factor inhibitors for treatment of various autoimmune diseases such as rheumatoid arthritis. Some of these individuals may be at risk for infection with yeast such as Cryptococcus gattii, which is found in the Pacific Northwest and in the Southeast US.

 "Public health is concerned because of the danger of antifungal resistance," said Brandt. She added that the CDC is recognized and relied upon nationally and internationally for its ability to control infectious threats, and "we want to continue our expertise in being able to recognize and detect these organisms rapidly."

Brandt pointed to the CDC's Advanced Molecular Detection initiative, recently funded by Congress, as a proactive approach that won't make patients feel like the cure is worse than the illness.

A 2011 article in the Catholic University of Rome's Mediterranean Journal of Hematology and Infectious Diseases was on the same path, stating: "Molecular detection methods, combined with additional microbiological and clinical information, has the potential not only to accurately and rapidly identify fungal pathogens, but also to indicate whether the pathogen is likely to respond to conventional antifungal treatment. Inclusion of these methods in a diagnostic surveillance strategy to exclude IFI in high-risk patients with hematological malignancy should result in improved clinical management, thus allowing more rational use of antifungal drugs."

Gordon Glantz is a frequent contributor to ADVANCE.

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