Andrew Goldberg, MD, never tires of telling people about how he was outsmarted by a patient while working as a second-year otolaryngology resident at the University of Pittsburgh. Now the director of rhinology and sinus surgery at the University of California San Francisco Medical Center, Dr. Goldberg recalled how he assisted in the examination of a patient with a history of chronic otitis externa in one ear. Despite repeated trips to doctors for antibiotics, vinegar washes and drops, the patient’s ear trouble always came back.
Not this time. The doctors assumed that their treatments had finally done the trick, only to be told by the patient that he had likely cured himself by taking earwax from his good ear and sticking it in his bad ear. “I had no idea what that meant. I’m sure that we assumed, at the time, that what he was telling us was nonsense, that he was a little nutty,” Dr. Goldberg said. “We never thought anything more about it.”
The home remedy, however, now seems prescient in light of accumulating research suggesting that microbiomes, or distinct bacterial communities that coexist with us throughout our bodies, may play key roles in maintaining human health. When he began conducting his own microbiome research about five years ago, Dr. Goldberg realized that his former patient may have taken an intact, healthy microbiome and used it to re-inoculate the disrupted bacterial community in his bad ear.
The Microbial Ecosystem
A new study by Dr. Goldberg and colleagues likewise concludes that the health of our sinus cavities, once thought to be largely sterile, may be highly dependent on the composition of their microbial residents (Sci Transl Med. 2012;4(151):151ra124).
The study, published September 2012 in Science Translational Medicine, found an intriguing shift in the types of microbes inhabiting the sinuses of seven patients with chronic rhinosinusitis (CRS) when compared with healthy counterparts. Beyond a significant decrease in the diversity of microorganisms among the patients, the researchers found a noticeable drop in a group of bacteria known as Lactobacilli, long associated with maintaining health in the gut. Concurrently, the researchers saw an increase in a little-known potential pathogen called Corynebacterium tuberculostearicum.
“Central to the concept that we’re putting forward is that there is a protective mechanism in a normal sinus that comes about as a result of the microbiome,” Dr. Goldberg said. Exactly how microbes such as Lactobacilli may keep pathogens at bay isn’t known. But study co-author Susan Lynch, PhD, associate professor of medicine and director of the Colitis and Crohn’s Disease Microbiome Research Core at the University of California San Francisco, noted that Lactobacilli could lower the surrounding pH through their production of lactic acid. The ensuing environmental change may influence which microbes can coexist in the sinuses and perhaps exclude some troublemakers.
“This is a great study, but it is a preliminary study,” said Jay Pinto, MD, associate professor of otolaryngology-head and neck surgery at the University of Chicago. Dr. Pinto, who wasn’t involved with the research, cautioned that the results will need to be confirmed in a larger group of patients. To zero in on future treatments, clinicians will also need to identify other bacteria that might be key players, along with which mechanisms they use and how their roles may vary in different types of sinusitis.
Despite the remaining holes, Dr. Pinto and other experts said the study could help prompt a broad reconsideration of how microbial communities influence chronic sinus conditions. Robert Kern, MD, professor and chair of the department of otolaryngology-head and neck surgery at Northwestern University Feinberg School of Medicine in Chicago, said the study’s individual findings may be less important than its overall concept. “What this study, in my mind, highlights is that it’s not the specific pathogen but the [bacterial] community that’s reoriented and triggering chronic inflammation within the patient that causes the symptoms,” he said. “It changes how we think of the disease, per se. It’s an excellent effort.”
Bacteria in Balance
The true cause of CRS has long been the subject of fierce debates. Some researchers view the chronic condition, which affects an estimated 30 million Americans and accounts for annual health care costs of more than $2.4 billion, primarily as an immune response that should be treated with anti-inflammatory medications. Others view it as an infectious disease that should be treated with antibiotics.
The latter approach, Dr. Goldberg said, has often employed a “scorched-earth policy,” with the goal of eradicating everything in the sinuses. Clinicians, however, have had to reconsider the “kill everything” strategy in light of recent studies suggesting that the overuse or misuse of antibiotics may have unintended consequences. In 2011, for example, Stanford University researchers demonstrated that giving people the potent antibiotic ciproflaxin twice over a 10-month period led to rapid and profound changes in the gut microbiome, including a loss of bacterial diversity that only partially reverted back to normal (Proc Natl Acad Sci U S A. 2011;108(Supp1):4554-4561).
Dangerous intestinal bacteria such as Clostridium difficile have taught doctors that the failure to reconstitute a normal microbial community can increase the risk that pathogens will fill the vacuum, a concept that Dr. Goldberg said is likely also at work in the sinuses. “The real take-home message of this paper is that you can’t just get rid of what’s there,” he said. “What you’re really working toward is putting back what used to be there.”
Dr. Lynch called that concept “restoration ecology,” which she believes could be aided by new technology that provides a more complete view of what should or shouldn’t be present in a healthy microbiome. “For us, we think it’s the bright horizon,” she said.
Traditional nasal swabs and bacterial cultures grown in agar, for example, provide only a partial census of the microbial inhabitants—both pathogenic and benign—within a sinus. “It’s a completely different environment,” Dr. Goldberg said. He, Dr. Lynch and co-author Steven Pletcher, MD, associate professor of otolaryngology-head and neck surgery at the UCSF Medical Center, instead used a microarray chip spotted with the DNA of 8,500 bacterial species to survey the presence and abundance of the microbes in diseased and healthy sinuses. In CRS patients, the collaborators detected an increased abundance in Corynebacterium tuberculostearicum, which is linked to opportunistic infections in other parts of the body but wouldn’t have been apparent in an agar culture.
To get a better idea of the pathogen’s potential role, the researchers studied it in a mouse model of sinusitis. After first perturbing the sinus microbiome with antibiotics—likely disrupting the normal flora—they added the Corynebacterium microbe, generating a sinusitis-like infection. When the researchers added Lactobacillus sakei, a bacterium better known for its role in the production of Japanese sake, they prevented the infection. “So it was kind of proof of concept that the Lactobacilli were beneficial in maintaining sinus health,” Dr. Goldberg said.
Andrew Lane, MD, professor of otolaryngology-head and neck surgery and director of the Johns Hopkins Sinus Center in Baltimore, accepts the idea that the sinus ecosystem can get out of whack and that antibiotics can create unintended consequences by leading to an imbalance. But Dr. Lane said the new study hasn’t resolved whether the observed bacterial shift is the cause or the effect of CRS. He also objects to the implied simplicity that the addition of one bacterial species can worsen the condition, while the addition of another can improve it. “As more studies are done, I think this is going to be refined,” he said. “I think the general concept—that there are shifts in bacteria—is true and needs to be put in this context of inflammation and host factors and different types of disease.”
—Andrew Goldberg, MD, UCSF
How might the inflammation versus infection debate be resolved? “Boy, that’s the million-dollar question,” Dr. Lane said. Studying patients longitudinally to examine potential microbiome shifts might provide better insights, though he cautioned that clinicians might need to keep those patients off antibiotics or steroid sprays to avoid skewing comparisons between a normal and abnormal bacterial profile. Narrowing the focus to patients with chronic, recalcitrant sinusitis that isn’t due to a blockage may also help. Dr. Lane’s lab is now collecting microbiome data on patients whose sinus problems continue even after a surgical intervention. Other groups are examining the sinus microbiome of patients at the time of surgery.
In their own unpublished research, Dr. Pinto and his collaborators have produced data suggesting that sinusitis patients with polyps, those without polyps and healthy controls all differ in their microbiome patterns. “We’re also seeing that other forms of upper airway disease may have environmental differences in their microbiome depending on what exposures people have, particularly what they breathe in,” he said.
As independent labs seek to verify and expand on the newest findings, Dr. Kern expects more pathogens to join Corynebacterium as potential instigators in patient subgroups. In fact, he suspects the observed decrease in potentially protective bacteria among CRS patients could prove more relevant, both therapeutically and etiologically. “It may be that the Corynebacterium is really a bystander, and it’s really the loss of the other bugs, the protective organisms, that are more important,” he said. “That’s more likely to me, intuitively.”
Multiple clinicians are already experimenting with therapies intended to return patients’ microbiomes to more protective states. In one early but promising study cited by Dr. Pinto, doctors administered probiotics to ward off necrotizing colitis in the guts of neonates; in another, clinicians gave probiotics to intubated patients with ventilator-associated pneumonia to prevent lower airway pathogens. And, of course, there’s the anecdotal success of the self-administered earwax transplant for chronic otitis.
“There are no current applications of that in the nose,” Dr. Pinto said, “but this study provides a nice justification for trying to develop such therapies, to either prevent or cure chronic sinusitis, which is pretty exciting.”