Are All Cases of Sinusitis the Same?

Ongoing and emerging research is providing a fuller picture of chronic rhinosinusitis (CRS) as a spectrum of diseases that goes beyond the current clinical phenotyping, based largely on the presence or absence of nasal polyps, to a deeper recognition of distinct subtypes of the disease based on pathogenic mechanisms.

It is hoped that research into these subtypes will lead to the ability to use them as biomarkers to better predict how best to treat patients with CRS, particularly given the rapid development and availability of biologic agents aimed at targeting specific pathologic mechanisms of disease.

The need for improved tailored treatments for people with CRS is highlighted by the sheer number of people with sinusitis symptoms, a limited ability to adequately treat these patients based on symptoms, and the current reliance on the presence or absence of polyps. “The epidemiology of CRS is still a work in progress, but studies suggest that a huge number of people, probably 39 million in this country, have the symptoms of chronic rhinosinusitis,” said Robert Kern, MD, chair of the department of otolaryngology–head and neck surgery at Northwestern Feinberg School of Medicine in Chicago, “Of those, I would estimate that perhaps 26 million or so really have sinusitis, confirmed by computed tomography, of which only approximately six million have polyps.”

Although targeting patients with polyps for treatment with intranasal and oral corticosteroids is the standard treatment approach, its impact on outcomes is less than satisfactory, he said. “Phenotyping or clinical evaluation alone has made only a limited impact on clinical care, or even the ability to tell a patient if they will do well or not on a given treatment,” he said.

To improve clinical outcomes, researchers like Dr. Kern are looking beyond clinical patterns of sinusitis into the patterns of tissue inflammation as a guide to better improve their ability to identify the patient subsets who will benefit from specific treatments. Called endotyping, the research looks at the underlying pathogenic mechanisms of disease, an approach that is similar to research that has already been conducted in the study of asthma and other atopic diseases.

For clinicians, this research, combined with ongoing studies into more advanced phenotyping based on attributes such as age and geography, highlights the need to look at CRS not as a singular disease, but as one with distinct clinical presentations and disparate—probably related—pathogenic mechanisms. “It is important to understand that all CRS patients are different,” said Justin H. Turner, MD, PhD, associate professor of otolaryngology–head and neck surgery at Vanderbilt University in Nashville. “CRS is a clinical syndrome, and patients may present very differently and have variable responses to medical and surgical interventions.”

Robert Kern, MDIn the future, we will be able to subdivide patient groups more precisely, and that will lead to rolling out precision, personalized medicine in which we can really predict from mucus or a blood sample how to treat patients. —Robert Kern, MD

Clinical Patterns and Subtypes

Although the presence or absence of nasal polyps is the cornerstone on which the current treatment of CRS is based, additional information on the clinical patterns of CRS is emerging that provides more direction for clinicians. These data point toward clinical indicators such as age, geography, ethnicity, and others associated with different underlying pathogenic mechanisms of CRS and, therefore, support the use of endotyping.

One area of research suggests the importance of age in distinguishing the type of inflammation and its potential impact on treatment outcomes. Dr. Turner and his colleagues recently published a study in which they found that older people with CRS had elevated tissue and mucus levels of pro-inflammatory cytokines associated with innate immune system dysfunction, were more likely to harbor colonizing bacteria in the sinonasal tract, and had more neutrophilic inflammation regardless of polyp status or other clinical variables when compared with younger patients (J Allergy Clin Immunol. 2019;143:990–1002). “Older CRS patients may appear similar to younger patients on physical exam but differ in many other ways,” said Dr. Turner. “Given the unique inflammatory signature that we have identified in older patients, we feel that it is essential that age be taken into account when planning treatment approaches.”

Specifically, when examining tissue and mucus specimens of 147 patients ranging in age from 18 to 78 years who underwent sinus surgery for CRS, the investigators found that the inflammatory signature of a subgroup of patients older than age 60 was very different from that found in patients younger than 60. Whereas the inflammatory signature in the younger patients was characterized by a group of cytokines (Th2-associated) found in most CRS in North America, these cytokines were not significantly elevated in older patients. Rather, the inflammatory signature in the older patients was associated with a neutrophilic proinflammatory response characterized by an elevation in cytokines linked to the body’s innate immune function and acute and chronic inflammatory response. “You don’t see an elevation in those cytokines until around age 60, and then from that age on, there’s a progressive increase in the levels of those cytokines seen in the mucus and tissue of those patients,” said Dr. Turner.

One important implication of this finding is that current treatment approaches for CRS may be less effective in older patients. “Neutrophilic inflammation is typically less responsive to topical and systematic corticosteroids,” said Dr. Turner. “This would suggest that great care should be taken when prescribing repeated courses of oral steroids in older patients, and strongly suggests the need for alternative therapies to more effectively target this vulnerable population.”

Another area of research shows that people with CRS living in Asian countries are likely to have more neutrophilic inflammation than people living in Europe/North American countries. For example, a 2017 study found that most people with CRS in Europe/North America (80%) have nasal polyps characterized by increases in eosinophilic cytokines (type 2 inflammation), compared to 20% in China and 60% in Korea or Thailand (J Allergy Clin Immunol. 2017;140:1230–1239).

According to Amber Luong, MD, PhD, associate professor in the department of otorhinolaryngology–head and neck surgery at McGovern Medical School of The University of Texas Health Science Center at Houston, the differences in the types of inflammation found in nasal polyps in these geographical populations highlights the fact that while people with CRS can look clinically similar (i.e., have the presence of nasal polyps), they are very different molecularly.

Justin H. Turner, MDAll CRS patients are different. CRS is a clinical syndrome and patients may present very differently and have variable responses to medical and surgical interventions. —Justin H. Turner, MD

She emphasized, however, that this is not an ethnic difference per se, adding that nasal polyps in second generation Asians with CRS living in Northern America or Europe are starting to look molecularly similar to nasal polyps in the populations of these countries. “This observation suggests that environmental exposure plays a critical role in driving the type of immune response contributing to rhinosinusitis,” she said. On the other hand, she cited a 2018 study that found that variations in cut-off levels of eosinophil numbers used to diagnose eosinophilic versus neutrophilic chronic rhinosinusitis may contribute to some of the differences in the percent of eosinophilic versus neutrophilic CRS between eastern and western countries (Curr Allergy Asthma Rep. 2018;18:46). Nonetheless, she added, the 2017 study highlights the fact that not all polyps are the same at a molecular level.

To that end, she said the research is pointing toward the future. “Maybe down the road you can take a biopsy sample that helps us to endotype our patients with chronic sinusitis,” she said.

For Noam A. Cohen, MD, PhD, director of rhinology research in the department of otorhinolaryngology–head and neck surgery at Perelman School of Medicine at the University of Pennsylvania in Philadelphia, another important component of what he sees as a multifactorial approach to explaining CRS is looking at taste receptors and the role they play in the development of the disease.

In studies published in 2012 and 2014, he and his colleagues showed that people with sensitive bitter taste receptors are less likely to develop a subtype of CRS based on the genetically determined function of these taste receptors (J Clin Invest. 2012;122:4145–4159; J Clin Invest. 2014;124:1393–1405). The research showed that one bitter taste receptor detects the molecule secreted by gram-negative bacteria that subsequently stimulate an immediate defense (nitric oxide production) in the cells lining the sinuses, which kills and clears out bacteria that play a common role in sinusitis. “What the receptor triggers is like a switch turned on in response to the bacteria, which not only kills the bacteria but sweeps the dead bugs away,” said Dr. Cohen.

Where this gets interesting, he said, is that there are a lot of genetic differences in the ability of people to taste bitter molecules. “Over the past five to six years, we’ve been able to show that patients in whom this bitter taste receptor doesn’t work are at much higher risk for developing gram-negative sinusitis,” he said.

With this finding, Dr. Cohen and his colleagues then looked at whether you could use the presence or absence of functioning bitter taste receptors to predict surgical outcomes, and they found that a subset of CRS patients without the functioning receptor were at higher risk for sub-optimal surgical outcomes.

Currently, Dr. Cohen and his colleagues are gearing up to launch a clinical trial to see whether it is possible for patients with CRS to forego conventional antibiotics after activation of their multiple bitter taste receptors and natural defense mechanism against the bacteria that cause rhinosinusitis.

Patterns of Inflammation

The potential to identify specific molecular biomarkers of CRS to individualize treatment is being advanced through research on CRS endotyping, through which investigators are looking at the patterns of inflammation in the tissue of nasal polyps in people with CRS. “We still rely on phenotypes in the clinic,” said Dr. Kern, “but we can gaze at the future in terms of endotyping.”

A recent study by Dr. Kern and colleagues that looked at the presence of subsets of innate lymphoid cells (ILCs) found that the subset ILC2 may play an important role in the development of type 2 inflammation found in patients with CRS and nasal polyps (Immun Inflammation Dis. 2017;5:233–243). In the study, the investigators used multiple techniques to look at the presence of subsets of ILCs in patients with CRS, both with and without nasal polyps. ILCs, along with T-helper lymphocytes, produce high levels of cytokines that are present in distinct patterns in the tissue. These patterns will likely define the clinically relevant endotypes, each of which will respond differently to current treatment options. Type 2 inflammation, defined by the presence of elevated type 2 cytokines (IL-4, 5 and 13), is present in the vast majority of patients with CRS with nasal polyps. This Type 2 endotype—or, more likely, a group of related type 2 endotypes—has been particularly difficult to treat, with a high recurrence rate after both medical and surgical therapy. Type 1 and Type 3 inflammations are less common and likely more responsive to treatment. In CRS patients without polyps, the inflammation is more heterogeneous, but a large percentage still exhibit Type 2 inflammation.

Figure 1. Unique Inflammatory Signatures in Aged CRS Patients. Reprinted from J Allergy Clin Immunol. 2019;143:990–1002, Copyright 2019, with permission from Elsevier.

Figure 1. Unique Inflammatory Signatures in Aged CRS Patients.
Reprinted from J Allergy Clin Immunol. 2019;143:990–1002, Copyright 2019, with permission from Elsevier.

According to Dr. Kern, each pattern of inflammation will likely respond differently to various treatment options in ways that should be predictable. “We are still working this out,” he said, emphasizing that the research is only relevant if it has clinical application—that is, if it can shed light on the natural history of the disease, help predict who will respond to what treatment, and determine which patients will do well on a given treatment.

For Dr. Kern and others, this is the direction in which CRS treatments are heading. “In the future, we will be able to subdivide patient groups more precisely, and that will lead to rolling out precision, personalized medicine in which we can really predict from mucus or a blood sample how to treat patients,” he said.

Underscoring the need for further research is the emergence of biologic agents that can target specific mechanisms of disease, a treatment already used for patients with asthma. This advance is on the doorstep for patients with CRS. Dr. Kern pointed to results of a study recently presented at the American Academy of Allergy, Asthma and Immunology (AAAI) meeting in February 2019 that showed the safety and efficacy of the biologic agent dupilumab for nasal polyps (“Efficacy and safety of dupilumab in patients with chronic rhinosinusitis with nasal polyps: results from the randomized phase 3 SINUS-24 study”).

According to Dr. Kern, the biologic agent will hopefully gain approval from the Food and Drug Administration for treatment of nasal polyps sometime later this year, representing a major advance in the ability to manage patients with severe CRS with nasal polyps. 

Mary Beth Nierengarten is a freelance medical writer based in Minnesota.

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New Research and Education at COSM 2019

AUSTIN, Texas—In May, Triological Society members and other attendees came together for the society’s 122nd Annual Meeting to share research and foster new ideas within the field of otolaryngology. The 2019 Triological Society Annual Meeting, held in conjunction with the Combined Otolaryngology Spring Meetings (COSM), welcomed 470 attendees plus residents and medical students, who joined discussions, heard panelists debate, and viewed an extensive array of scientific posters.

Nearly 900 residents and medical students attended COSM, many of whom were offered the opportunity to present clinical and research papers and posters during the society meetings. “I attended the conference to learn about the newest developments in otology and to support the excellent work of some of the medical students and residents with whom I work,” said Aaron Moberly, MD, an assistant professor in the division of otology, neurotology, and cranial base surgery in the department of otolaryngology–head and neck surgery at  The Ohio State University Wexner Medical Center in Columbus.

During the Triological Society’s scientific sessions, 65 podium presentations and seven panels were given. More than 160 posters were presented as a part of a combined poster session. The Triological Society again funded travel grants to fellows, residents, and medical students selected to present oral and poster presentations during the Society’s scientific sessions.

Presidential Address: A Patient’s Perspective on HNC

Sigsbee Duck, RPh, MD, said that he has had an incredible year as the president of the Triological Society. His presidential speech was made “to simply remind all otolaryngologists how important empathy and caring are for our cancer patients. I am just laying out the stark and personal reality of being a head and neck cancer patient first hand and the feelings associated with the treatment process.” He went on to thank all of his head and neck surgery colleagues who selflessly care for patients like him on a daily basis.

Dr. Duck definitely understands the importance of empathy and caring for cancer patients, as he himself is a head and neck cancer survivor. “On the morning of March 9, 2015, I was getting ready for work, shaving actually, when I felt a mass in my right upper neck. Denial set in and I convinced myself that it was an infection.” He put himself on antibiotics and after a few doses he realized it was not going down and seemed to be larger. Becoming quite concerned, he called the Huntsman Cancer in Salt Lake City and drove three hours from Wyoming the same Thursday for a biopsy. The physician told him the ultrasound characteristics appeared benign and to come back in one month if the mass was still present for a FNA. He responded, “I’m here now, so please proceed.” He did and the next Monday the endocrinologist called to inform him “you have metastatic epidermoid carcinoma.” Reality quickly set in.

“This couldn’t be happening to me,” Dr. Duck thought. He was asked to be back at the Huntsman on Wednesday for a PET scan, but as he had NCAA basketball tournament tickets in Kentucky the following weekend, he opted to wait a week and meet his family to let the reality of a totally surrealistic situation settle in. The next week the PET scan was completed. With his surgeon, Dr. Jason Hunt’s hand on his shoulder, he was informed he had a “large tonsillar carcinoma with neck metastasis.”

Dr. Duck underwent a radical tonsillectomy and a modified RND the next day. “I was still in denial,” he said. “Five hours later reality took hold when I awakened to find an NG tube, a Foley, a JP drain, an IV between the toes on my right foot, an inability to swallow and complete anesthesia from my mid cheek to my clavicle. When I finally woke up, reality once again hit and I sat up with a very kind nurse and cried for about three hours. Then came swallowing therapy and ultimately tubes were removed one at a time as my wife and I waited for the pathology reports to assure clear margins and positive testing for HPV and P-16.” He was blessed to have these findings. The day he left the hospital, a Basset Hound therapy dog came by to visit and he realized that “it’s the small things that really mean the most to patients.”

Sigsbee W. Duck, MDAs physicians, we must take extra time with our cancer patients. We must show genuine empathy. —Sigsbee W. Duck, MD

“Emotions run amuck while going through cancer treatment and they are very difficult to control,” Dr. Duck found out. “When I finally returned to work in Wyoming prior to radiation therapy, I was not successful—or nice. I was curt and downright rude. I had not realized the emotional toll cancer takes on patients.”

Radiation therapy was next. “Despite having sent hundreds of patients for these treatments, it was at this point that I realized that I really didn’t know anything about it. Now, more than ever, I genuinely admire my cancer patients, particularly the ones without the financial means or family support like I was blessed to have who must complete this therapy.” Dr. Duck recalled an older man who sat next to him before his first radiation treatment. “He had been told his radiation was palliative and to get his affairs in order. He asked why I was there and I told him and he said good luck. The next day, he was not there and I never saw him again. It is sad and disconcerting to see all these patients every day, and suddenly they are not there anymore.”

On his last day of radiation, the waiting room was full and he was informed that the machine was down. “I figured my options were to get mad, sulk, or cry. Well, I’m a crier,” he said. The other patients with whom he had bonded huddled around him for support, the machine was ultimately repaired and with radiation therapy completed, he finally left the Huntsman.

Dr. Duck’s long and emotionally difficult experience with surgery and radiation were not only grueling, but also educational. “The post-traumatic effects of surgery and radiation therapy, especially as radiation is over-utilized to treat this disease, particularly when used in conjunction with chemotherapy, are very real,” Dr. Duck stated. “And radiation is definitely the gift that keeps on giving—for the rest of your life. Your taste is permanently altered, you have pain and cramping with exercise, and you can never taste or swallow effectively.”

“And there is a stigma associated with HPV H&N cancer. Even my colleagues make jokes about sexual transmission. I had been married for 33 years, and I found no humor in their jokes,” he said. “Frankly, who knows what  bacteria any of us are harboring as otolaryngologists? My entire family has been tested and cleared and we have received the HPV vaccine including the P-16 and P-18 strains.

“No matter how many H&N cancer patients  you have cared for, always remember the absolute feelings of fear and helplessness that your patients experience. As physicians, we must take extra time with our cancer patients. We must show genuine empathy. Sit down by the bed as if you are not busy. These days, I share my experience with my patients and it reassures them in a positive way.” Dr. Duck added. “Most importantly, an opportunity to convey information to a patient’s family and exude a feeling of optimism and trust as to the care we are taking of their loved ones, is one of the greatest opportunities we have as physicians—to demonstrate compassion and caring through simple communication and basic kindness.”

Dr. Duck’s hard-earned message is this: “As cancer patients we are always looking over our shoulders; fear, anxiety, and reality are always lurking. More than ever [these patients] need a physician who is sensitive to that reality and who can show genuine empathy and caring.” 

Elizabeth Hofheinz is a freelance medical writer based in Louisiana.

Upcoming Triological Society Meetings

Combined Sections Meeting
January 23-25, 2020
Coronado, Calif.

123rd Annual Meeting at COSM
April 24-25, 2020
Atlanta, Ga.

Visit for more information.

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