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Negative Research Leads to new Plan to Battle Infections

RIchard Chole, MD, PhD, discussed research into the cause of cholesteatomas when he presented the the Michael M. Paparella, MD Endowed Lecture Monday.

RIchard Chole, MD, PhD, discussed research into the cause of cholesteatomas when he presented the the Michael M. Paparella, MD Endowed Lecture Monday.

Cholesteatoma threatens the middle ear with its continuous growth putting pressure on the bones in the area, and its pathophysiology has been a great mystery for centuries. However, research is providing insights into infections related to the condition, which eventually may help in controlling infections of cochlear implants.

Richard Chole, MD, PhD, shared this greater understanding Monday when he delivered AAO-HNSF/International Hearing Foundation/Michael M. Paparella, MD Endowed Lecture for Distinguished Contributions in Clinical Otology, “Cholesteatoma—What Have We Learned in 3,000 Years.”

“Bone destruction is the hallmark of cholesteatoma,” Dr. Chole said as he traced his career-long cholesteatoma research. He is the Lindburg Professor and chairman of the Department of Otolaryngology-Head and Neck Surgery at Washington University School of Medicine, St. Louis.

There are four theories about the pathogenesis of cholesteatoma. The metaplasia theory is based on vitamin A deficiency, but that theory has been discarded. The retraction pocket theory is that a blockage of the Eustachian tube causes the middle ear to fill with fluid, starting the development of keratin and keratin debris. It is observable clinically and experimentally provable, he said. The basal cell invasion theory is that the basal lamina breaks and is invaded by keratinocytes, and that has been confirmed. The fourth theory is the epidermal ingrowth theory that keratin overgrowth leads to the development of cholesteatoma.

The development of those theories led to four ideas about the pathophysiology of the bone resorption resulting from cholesteatoma, but only one, osteoclastic osteolysis, is accepted, Dr. Chole said. Researchers have found that osteoclasts are large transient cells with rough borders that erode the bone.

Switching gears, Dr. Chole explained how other research has shown that bacterial biofilms complicate efforts to control cholesteatoma. Biofilms form when bacteria adhere to a wet surface—like a wet middle ear—and grow to become a “large, slimy area.” A common example of a biofilm is a wet, slippery rock in a stream.

“The biofilms cause most of human disease,” Dr. Chole said. “The CDC estimates that 60 percent of human disease is caused by bacteria in biofilms. What’s the big deal about that? The big deal is they are highly resistant to antibiotics. This has all kinds of clinical consequences.”

Armed with this knowledge, researchers worked to alter the phenotype of biofilms to block infections, but they found that those efforts did not change the virulence in cholesteatomas, he said.

But this negative research led to the concept of the bacteria forming persister cells, which are tolerant to antibiotics and host defenses, Dr. Chole said.

“If you take one of the persisters and culture it in media that is favorable, it will go back to being its parent bacteria,” he said. “So, if we could interrupt this pattern of persister cell formation, then we would have a great tool to fight bacterial infections.

“It is not the bigger, badder antibiotic that can kill these organisms, but it is how to interrupt the process of persister cell formation. This is a much more important question if we are talking about implants than if we are talking about cholesteatomas. Everyone here knows how difficult it is to get rid of an infection in a cochlear implant.”

The next step for researchers is to study the RNA of persister cells to help identify genes involved in their development process and then target those genes for eradication, Dr. Chole said.